Pleural effusion

From Wikipedia, the free encyclopedia

c
 



6



 
 Y

Y

Y 

Y
YYYY
Y
Y Y

YY
 Y

YYYYYYYY

Y
is excess fluid that accumulates in the fluid-filled space that
surrounds the lungs. Excessive amounts of such fluid can impair breathing by limiting
the expansion of the lungs during inspiration.

6



Y
Y

½YYY
Y
ëY
Y
m ë½Y
Y
m ëëY
Y
m ëY


YY

 Y!"Y  
Y
Y#
Y
m ½Y


Y
m ëY$

Y
m Y% & 
Y
]Y 
Y
VY'Y
Y
Y$ 
Y(Y
6Y) Y

1«.Types of fluids
Four types of fluids can accumulate in the pleural space:

§ Serous fluid (hydrothorax)

§ Blood (haemothorax)
§ Chyle (chylothorax)
§ Pus (pyothorax or empyema)
[edit]Diagnosis

CT scan of chest showing left sided pleural effusion. Effusion fluid often settles at the
lowest space due to gravity; here at the back as the patient is lying under scanner.

Pleural effusion is usually diagnosed on the basis of medical history and physical exam,
and confirmed by chest x-ray. Once accumulated fluid is more than 500 ml, there are
usually detectable clinical signs in the patient, such as decreased movement of the
chest on the affected side, dullness to percussion over the fluid, diminished breath
sounds on the affected side, decreased vocal resonance and fremitus (though this is an
inconsistent and unreliable sign), and pleural friction rub. Above the effusion, where the
lung is compressed, there may be bronchial breathing and egophony. In large effusion
there may be tracheal deviation away from the effusion. A systematic review (2009)
published as part of the Rational Clinical Examination Series in the Journal of the
American Medical Association showed that dullness to conventional percussion was
most accurate for diagnosing pleural effusion (summary positive likelihood ratio, 8.7;
95% confidence interval, 2.2-33.8), while the absence of reduced tactile vocal fremitus
made pleural effusion less likely (negative likelihood ratio, 0.21; 95% confidence
interval, 0.12-0.37).[1]
[edit]0 
Y
Normally the space between the two layers of the lung: visceral pleura and parietal
pleura, cannot be seen. A pleural effusion infiltrates the space between these layers.
Because the pleural effusion has a density similar to body fluid or water, it can be seen
on radiographs. Since the effusion has greater density than the rest of the lung, it will
gravitate towards the lower portions of the pleural cavity. The pleural effusion behaves
according to basic fluid dynamics, conforming to the shape of the lung and chest cavity.
If the pleural cavity contains both air and fluid, then the fluid will have a "fluid level" that
is horizontal instead of conforming to the lung space.[2] Chest radiographs acquired in
the lateral decubitus position (with the patient lying on his side) are more sensitive, and
can pick up as little as 50 ml of fluid. At least 300 ml of fluid must be present before
upright chest films can pick up signs of pleural effusion (e.g., blunted costophrenic
angles).

Micrograph of a pleural fluidcytopathology specimen showing malignant mesothelioma,

one cause of a pleural effusion.

[edit] 
Y
Once a pleural effusion is diagnosed, the cause must be determined. Pleural fluid is
drawn out of the pleural space in a process calledthoracentesis. A needle is inserted
through the back of the chest wall in the sixth, seventh or eighth intercostal space on
the midaxillary line, into the pleural space. The fluid may then be evaluated for the
following:

1. Chemical composition including protein, lactate

dehydrogenase (LDH), albumin, amylase, pH and glucose
 2. Gram stain and culture to identify possible bacterial infections
3. Cell count and differential
4. Cytopathology to identify cancer cells, but may also identify some infective
organisms
5. Other tests as suggested by the clinical situation - lipids, fungal culture, viral
culture, specific immunoglobulins
[edit]
YYY
 YY Ô

 


Y*Y
(Y*Y
Y
Ô



Y
Y Y

 

Y

Y
  +Y

Y
Y 


 

Y
Y
Y

Y  Y
,

Y #
Y #
Y
'Y
 Y -Y½.½ëY /Y½.ë.Y
0 YY -YëY&
!Y /Yë1Y&
!Y]Y
YY
Y YYY
-Y.VY /Y.VVY
 Y Y
 YY

2YY /Y½ëY&
!Y -Y½ëY&
!Y
Y2
Y
2Y
YYYYYYYY
Y!3YYYYYYYYY
-Y.Y Y-Y4Y /Y.]Y Y/Y4VY
 YY Y Y
YY
YYYY
-Y.5Y /Y.5Y
 YY
# YY -Y]VY&
!Y /Y]VY&
!]Y
'Y
 Y)

YY
Instruments for needle biopsy
of the pleura

The definitions of the terms "transudate" and "exudate" are the source of much
confusion.

Transudative pleural effusions are defined as effusions that are caused

by ? ?
 factors that alter the pleural equilibrium, or Starling forces. The components
of the Starling forces: hydrostatic pressure, permeability, oncotic pressure (effective
pressure due to the composition of the pleural fluid and blood), are altered in many
diseases e.g., left ventricular failure, renal failure, hepatic failure, and cirrhosis.
Exudative pleural effusions, by contrast, are caused by alterations in‘ ‘ factors that
influence the formation and absorption of pleural fluid (e.g., bacterial
pneumonia, cancer, pulmonary embolism, and viral infection).[7]

An accurate diagnosis of the cause of the effusion, transudate versus exudate, relies on
a comparison of the chemistries in the pleural fluid to those in the blood, using Light's
criteria. According to Light's criteria (Light, et al. 1972), a pleural effusion is likely
exudative if at least one of the following exists:[5]

1. The ratio of pleural fluid protein to serum protein is greater than 0.5
2. The ratio of pleural fluid LDH and serum LDH is greater than 0.6
3. Pleural fluid LDH is greater than 0.7 times the normal upper limit for serum
Although Light's criteria are relatively accurate, twenty-five percent of patients with
transudative pleural effusions are mistakenly identified by Light's criteria as having
exudative pleural effusions. Therefore, if a patient identified by Light's criteria as having
an exudative pleural effusion appears clinically to have a condition that usually
produces transudative effusions, additional testing is needed. In such
cases albumin levels in blood and pleural fluid are measured. If the difference between
the albumin levels in the blood and the pleural fluid is greater than 1.2 g/dL (12 g/L), this
suggests that the patient has a transudative pleural effusion[6]. However, pleural fluid
testing is not perfect, and the final decision about whether a fluid is a transudate or an
exudate is based not on chemical analysis of the fluid, but on accurate diagnosis of the
disease that produces the fluid.

The traditional definitions of transudate as a pleural effusion due to systemic factors and
an exudate as a pleural effusion due to local factors have been used since 1940 or
earlier (Light et al, 1972). Previous to Light's landmark study, which was basd on work
by Chandrasekhar, investigators unsuccessfully attempted to use other criteria, such as
specific gravity, pH, and protein content of the fluid, to differentiate between transudates
and exudates. Light's criteria are highly statistically sensitive for exudates (although not
very statistically specific). More recent studies have examined other characteristics of
pleural fluid that may help to determine whether the process producing the effusion is
local (exudate) or systemic (transudate). The chart at right illustrates some of the results
of these more recent studies. However, it should be borne in mind that Light's criteria
are still the most widely used criteria.
The Rational Clinical Examination Series review found that bilateral effusions,
symmetric and asymmetric, are the most common distribution in heart failure (60% of
effusions in heart failure will be bilateral). When there is asymmetry in heart failure-
associated pleural effusions (either unilateral or one side larger than the other), the right
side is usually more involved than the left.[8]

[edit]Causes

[edit]
Y
The most common causes of 
 pleural effusions in the United States are left
ventricular failure, and cirrhosis (causing hepatic hydrothorax). Pulmonary embolisms
were once thought to be transudative but have been recently shown to be exudative[9]
[edit]Y


Y
Chest x-ray of a pleural effusion. The arrow A shows fluid layering in
the right pleural cavity. The B arrow shows the normal width of the lung in the cavity

Once identified as exudative, additional evaluation is needed to determine the cause of

the excess fluid, and pleural fluid amylase, glucose, pH and cell counts are obtained.

§ Pleural fluid amylase is elevated in cases of esophageal rupture, pancreatic pleural

effusion, or cancer.
§ Glucose is decreased with cancer, bacterial infections, or rheumatoid pleuritis.
§ Pleural fluid pH is low in empyema (<7.2) and may be low in cancer.
§ If cancer is suspected, the pleural fluid is sent for cytology. If cytology is negative,
and cancer is still suspected, either a thoracoscopy, or needle biopsy[10] of the pleura
may be performed.
§ The fluid is also sent for Gram staining and culture, and, if suspicious for
tuberculosis, examination for TB markers (adenosine deaminase > 45
 IU/L, interferon gamma > 140 pg/mL, or positive polymerase chain reaction (PCR)
for tuberculous DNA).
The most common causes of  pleural effusions are bacterial pneumonia,
cancer (with lung cancer, breast cancer, and lymphomacausing approximately 75% of
all malignant pleural effusions), viral infection, and pulmonary embolism.
[edit] 
 Y
Other causes of pleural effusion include tuberculosis (though pleural fluid smears are
rarely positive for AFB, this is the most common cause of pleural effusion in some
developing countries), autoimmune disease such as systemic lupus erythematosus,
bleeding (often due to chest trauma), chylothorax (most commonly caused by trauma),
and accidental infusion of fluids.

Less common causes include esophageal rupture or pancreatic disease, intraabdominal

abscess, rheumatoid arthritis, asbestos pleural effusion, Meigs syndrome (ascites and
pleural effusion due to a benign ovarian tumor), and ovarian hyperstimulation syndrome.

Pleural effusions may also occur through medical/surgical interventions, including the
use of medications (pleural fluid is usually eosinophilic),coronary artery bypass surgery,
abdominal surgery, endoscopic variceal sclerotherapy, radiation therapy, liver or lung
transplantation, and intra- or extravascular insertion of central lines.

[edit]Treatment
The free end of the Chest Drainage Device is usually attached to an underwater seal,
below the level of the chest. This allows the air or fluid to escape from the pleural space,
and prevents anything returning to the chest.

Treatment depends on the underlying cause of the pleural effusion.

Therapeutic aspiration may be sufficient; larger effusions may require insertion of

an intercostal drain (either pigtail or surgical). When managing these chest tubes it is
important to make sure the chest tubes do not become occluded or clogged. A clogged
chest tube in the setting of continued production of fluid will result in residual fluid left
behind when the chest tube is removed. This fluid can lead to complications such as
hypoxia due to lung collapse from the fluid, or fibrothorax, late, when the space scars
down. Repeated effusions may require chemical
(talc, bleomycin, tetracycline/doxycycline) or surgical pleurodesis, in which the two
pleural surfaces are scarred to each other so that no fluid can accumulate between
them. This is a surgical procedure that involves inserting a chest tube, then either
mechanically abrading the pleura, or inserting the chemicals to induce a scar. This
requires the chest tube to stay in until the fluid drainage stops. This can be days to
weeks and can require prolonged hospitilizations. If the chest tube becomes clogged
fluid will be left behind and the pleurodesis will fail.

Pleurodesis fails in as many as 30% of cases. An alternative is to place a Pleurex or

Aspira Drainage Catheter. This is a 15Fr chest tube with a one way valve. Each day the
patient or care givers connect it to a simple vacuum tube and remove from 600 cc to
1000 cc. This can be repeated daily. When not in use, the tube is capped. This allows
patients to be outside the hospital. For patients with malignant pleural effusions, it
allows them to continue chemotherapy, if indicated. Generally the tube is in about 30
days and then it is removed when the space undergoes a spontaneous pleurodesis.
Y

Papilloma
From Wikipedia, the free encyclopedia

c 

6



 
 Y

Y



Y

YY2 
+Y36$+Y½.Y

06
 
5.V.&.Y


 .½.ë½ë Y
 

 refers to a benign epithelial tumor[1] growing exophytically (outwardly
projecting) in finger-like fronds. In this context papilla refers to the projection created by
the tumor, not a tumor on an already existing papilla (such as the nipple). When used
without context, it frequently refers to infections caused by human papillomavirus (HPV),
such as warts. There are, however, a number of other conditions that cause papilloma,
such as choroid plexus papilloma (CPP) and pearly penile papules of the penis.

Human Papilloma Virus infection is a major cause of cervical cancer, although most
HPV infections do not cause cancer.
Hemangioma
From Wikipedia, the free encyclopedia



  0



6



 
 Y

Y
,Y
Y

YY
Y

06
 ½5.Y!'Y½5.½.Y

06
 ëë5.Y

06
 
1½ë.&. Y



   .. Y


 

c  
..½]V1 Y





 &ë.½ Y


  ..1½ Y

A  
 Y Y

 (or  
 Y Y

) is a benign self-
involuting tumor of endothelial cells (the cells that line blood vessels). In most cases it
appears during the first days or weeks of life and will have resolved at the latest by age
10. In infancy, it is the most common tumor.[1]

The word "hemangioma" comes from the Greek word O (Greek: ĮȓȝĮ) meaning
"blood",   (Greek: ĮȖȖİȓȠ) meaning "vessel" and the suffix   (Greek: -ȦȝĮ)
meaning "tumor".

6



Y
Y

½Y Y
ëY0 
Y
Y#
Y
]Y#
Y
VY 
Y
Y0 Y
6Y7Y
5Y$ 
Y(Y

[edit]Terminology
Hemangioma on forehead showing signs of early regression

Before considering the hemangioma, it is important to understand that there have been
changes in the terminology used to define, describe and categorize vascular anomalies
(abnormal lumps made up of blood vessels). The term O   was originally used
to describe any vascular tumor-like structure, whether it was present at or around birth
or appeared later in life. Mulliken et al. categorized these conditions into two families: a
family of self-involuting tumors (growing lesions that eventually disappear) and another
family of malformations (enlarged or abnormal vessels present at birth and essentially
permanent). The importance of this distinction is that it makes it possible for early-in-life
differentiation between lesions that will resolve versus those that are permanent.
Examples of permanent malformations include Port-wine stains(capillary vascular
malformation) and masses of abnormal swollen veins (venous
malformations).[2] Unfortunately many textbooks and dictionaries are not up to date on
this point, creating great confusion.

[edit]Presentation

Hemangiomas are connected to the circulatory system and filled with blood. The
appearance depends on location. If they are on the surface of the skin, they are
reminiscent of a ripe strawberry (hence, they are sometimes referred to as "strawberry
hemangiomas"); however, if they are just under the skin they present as a bluish
swelling. Sometimes they grow in internal organs such as the liver or larynx. In most
cases, hemangiomas will disappear over time. Some are formed during gestation;
others (the most common) are not present at birth but appear during the first few weeks
of life. They are often misdiagnosed, initially, as a scratch or bruise; but the correct
diagnosis becomes obvious with further growth. Typically, at the earliest phase in a
superficial lesion, one will see a bluish red area with obvious blood vessels and
surrounding pallor. Sometimes they present as a flat red or pink area. Hemangiomas
are the most common childhood tumor, occurring in approximately ten percent of
Caucasians, and are less prevalent in other races. Females are three to five times as
likely to have hemangiomas as males. Hemangiomas are also more common in twin
pregnancies. Approximately 80% are located on the face and neck, with the next most
prevalent location being the liver.

[edit]Causes

The cause of hemangioma is currently unknown; however, several studies have

suggested the importance of estrogen signaling in hemangioma proliferation. In 2007, a
paper from the Stanford Children's Surgical Laboratory revealed that localized soft
tissue hypoxia coupled with increased circulating estrogen after birth may be the
stimulus.[3] There is also a hypothesis presented by researchers at Harvard and the
University of Arkansas that maternal placenta embolizes to the fetal dermis during
gestation resulting in hemangiomagenesis,[4][5]. However, researchers at Duke
University conducted genetic analyses of small nucleotide polymorphisms in
hemangioma tissue compared to the mother's DNA that contradicted this
hypothesis.[6] More research is required in order to fully understand the explosive nature
of hemangioma growth, which will hopefully yield targeted therapeutics to treat its most
complicated presentations.

[edit]Complications

The vast majority of hemangiomas are not associated with complications.

Hemangiomas may break down on the surface (ulcerate). If the ulceration is deep,
significant bleeding may occur in rare occasions. Ulceration on the diaper area can be
painful and problematic.

If a hemangioma develops in the larynx, breathing can be compromised. A hemangioma

can grow and block one of the eyes, causing an occlusion amblyopia. Very rarely,
extremely large hemangiomas can cause high-output heart failure due to the amount of
blood that must be pumped to excess blood vessels. Lesions adjacent to bone can also
cause erosion of the bone.

The most frequent complaints about hemangiomas, however, stem from psychosocial
complications: the condition can affect a person's appearance and can provoke
attention and malicious reactions from others. Particular problems occur if the lip or
nose is involved, as distortion can be difficult to treat surgically. The potential for
psychological injury develops from school age onward. It is therefore important to
consider treatment prior to school if adequate spontaneous improvement has not
occurred

Children with large Segmental Hemangiomas of the head and neck can be associated
with a disorder called PHACES Syndrome.[7][8]

[edit]Treatment

Most hemangiomas disappear without treatment, leaving minimal or no visible marks.

Large hemangiomas can leave visible skin changes secondary to severe stretching of
the skin or damage to surface texture. When hemangiomas interfere with vision,
breathing, or threaten significant cosmetic injury, they are usually treated.

Up until recently, the mainstay of treatment was oral corticosteroid therapy. Beta-
blocker treatment using agents such as propranolol is revolutionising therapy, producing
impressive responses. A publication in the international literature in June 2008 first
suggested that propranolol (a Beta Blocker) could be used to treat severe
hemangiomas[9]. This treatment is proving superior to corticosteroids, in terms of both
effectiveness and safety. The topically applied Beta Blocker gel Timolol, is also being
trialled for small facial hemangiomas that do not justify systemic treatment. Early results
are showing a modest benefit; however more study is needed[10].

Other treatments that have been used include interferon[11] or vincristine. They may be
considered if first-line therapy fails. Surgical removal is sometimes indicated, particularly
if there has been delay in commencing treatment and structural changes have become
irreversible. Surgery may also be necessary to correct distortion of facial features, again
in the case of inadequate or failed early medical intervention.

Blockage of the airway will often require a tracheostomy to be performed (insertion of an

external airway through the front of the neck into the trachea below the level of the
obstruction). Smaller raised lesions are sometimes treated with injection
of corticosteroid directly into the lesion. Pulsed dye laser can be useful for very early flat
superficial lesions if they appear in cosmetically significant areas or for those lesions
that leave residual surface blood vessels in the case of incomplete resolution.
Unfortunately raised lesions or lesions under the skin do not respond to laser.
Ulceration will usually heal with topical medication and special dressings under medical
supervision. Sometimes pulsed dye laser can be used to accelerate healing.

[edit]Prognosis

Hemangiomas go through three stages of development and decay:

1. In the 

stage, a hemangioma grows very quickly. This stage can last
up to twelve months.
2. In the  stage, there is very little change in a hemangioma's appearance. This
usually lasts until the infant is one to two years old.
3. In the 


phase, a hemangioma finally begins to diminish in size. 50% of
lesions will have disappeared by 5 years of age, and the vast majority will have
gone by 10 years of age.
 
Y Y

Y
CIMS Class : ( Cephalosporins ) Y
See available brands of cefadroxilY
Y

- Caution when used during pregnancyY

 - Caution when used during lactationY
Y - Lab interferenceY

See related cefadroxil information Y

IndicationY Susceptible infections.

DosageY Ñ
 c 1-2 g/day as a single dose or in 2 divided doses.
Click to view Dosage by Indications
AdministrationY May be taken with or without food. (May be taken w/ meals to
reduce GI discomfort.)
ContraindicationsY Hypersensitivity to cephalosporins.
Special
Impaired renal function; pregnancy and lactation.
PrecautionsY
Adverse Drug Nausea, vomiting, diarrhoea, abdominal discomfort; skin rash,
ReactionsY angioedema; elevated liver enzyme values; superinfection with
resistant organisms especially candida.



Y
YAnaphylactic reaction; pseudomembranous
colitis.
 Drug InteractionsY Prothrombin time prolonged; bleeding may occur when taken with
anticoagulants. Decreased elimination with probenecid.
Click to view more Drug Interactions
Lab InterferenceY For caution against possible drug interference in lab test results
... click to view
Pregnancy
Category (US
Y Y Y Y

Y
Y

Y6 Y:Y EitherY animal-reproduction

Y Y
Y

FDA) Y
studies have not
demonstrated a foetal risk but there are no controlled studies in
pregnant women or animal-reproduction studies have shown an Y
adverse effect (other than a decrease in fertility) that was not
confirmed in controlled studies in women in the 1st trimester (and
there is no evidence of a risk in later trimesters).Y
Storage Y
For special storage condition to ensure optimal shelf-life of
medicine... click to view
Mechanism of For details of the mechanism of action, pharmacology and
Action Y pharmacokinetics and toxicology ... click to view
CIMS Class Y Cephalosporins
ATC
J01DB05 - cefadroxil;
Classification Y

Y
Y

Ascites
From Wikipedia, the free encyclopedia

Ñ
 

6



 
 Y
 Y

YY
YY YY
Y Y
 YYYY

0
  Y

0
  Y

  
   Y


   !""Y! Y


  #$$"$ Y

Ñ ( /ԥ'sa ti'z/, 


 , from Greek ?
?, "baglike")[1] is
a gastroenterological term for an accumulation of fluid in the peritoneal cavity.
The medical condition is also known as 

YY
, 

Y
Y
,  
 or more archaically as 

Y . Although most
commonly due to cirrhosis and severe liver disease, its presence can portend other
significant medical problems. Diagnosis of the cause is usually with blood tests,
an ultrasound scan of the abdomen, and direct removal of the fluid by needle
orparacentesis (which may also be therapeutic). Treatment may be with medication
(diuretics), paracentesis, or other treatments directed at the cause.

6



Y%
&Y

Y'
YY Y
"Y(   Y
Y# 
 Y
Y(Y
Y)

 
Y
Y Y
m Y*

Y'+Y
§ Y'Y  Y
§ "Y#  Y
§  Y,Y  Y
§ Y) Y
§ Y- .Y Y
§ Y'
 
Y
m "Y-/Y'+Y
Y(  Y
m Y'Y Y   Y
Y'  YYY
YY

[edit]Signs and symptoms

Mild ascites is hard to notice, but severe ascites leads to abdominal distension. Patients
with ascites generally will complain of progressive abdominal heaviness and pressure
as well asshortness of breath due to mechanical impingement on the diaphragm.

Ascites is detected on physical examination of the abdomen by visible bulging of the

flanks in the reclining patient ("flank bulging"), "shifting dullness" (difference in
percussion note in the flanks that shifts when the patient is turned on the side) or in
massive ascites with a "fluid thrill" or "fluid wave" (tapping or pushing on one side will
generate a wave-like effect through the fluid that can be felt in the opposite side of the
abdomen).

Other signs of ascites may be present due to its underlying etiology. For instance,
in portal hypertension (perhaps due to cirrhosis or fibrosis of the liver) patients may also
complain of leg swelling, bruising, gynecomastia, hematemesis, or mental changes due
to encephalopathy. Those with ascites due to cancer (peritoneal carcinomatosis) may
complain of chronic fatigue or weight loss. Those with ascites due to heart failure may
also complain of shortness of breath as well as wheezing and exercise intolerance.

[edit]Classification

Ascites exists in three grades:[2]

§ Grade 1: mild, only visible on ultrasound

§ Grade 2: detectable with flank bulging and shifting dullness
§ Grade 3: directly visible, confirmed with fluid thrill
[edit]Diagnosis

Routine complete blood count (CBC), basic metabolic profile, liver enzymes,
and coagulation should be performed. Most experts recommend a
diagnostic paracentesis be performed if the ascites is new or if the patient with ascites is
being admitted to the hospital. The fluid is then reviewed for its gross appearance,
protein level, albumin, and cell counts (red and white). Additional tests will be performed
if indicated such as Gram stain and cytopathology.[3]

The
?
?‘
 
(SAAG) is probably a better discriminant than older
measures (transudate versus exudate) for the causes of ascites.[4] A high gradient (>
1.1 g/dL) indicates the ascites is due to portal hypertension. A low gradient (< 1.1 g/dL)
indicates ascites of non-portal hypertensive etiology.
Ultrasound investigation is often performed prior to attempts to remove fluid from the
abdomen. This may reveal the size and shape of the abdominal organs, and Doppler
studies may show the direction of flow in the portal vein, as well as detecting Budd-
Chiari syndrome and portal vein thrombosis. Additionally, the sonographer can make an
estimation of the amount of ascitic fluid, and difficult-to-drain ascites may be drained
under ultrasound guidance. Abdominal CT scan is a more accurate alternate to reveal
abdominal organ structure and morphology.

[edit]Causes

Causes of high SAAG ("transudate") are:[3]

§ Cirrhosis - 81% (alcoholic in 65%, viral in 10%, cryptogenic in 6%)

§ Heart failure - 3%
§ Hepatic Venous occlusion: Budd-Chiari syndrome or veno-occlusive disease
§ Constrictive pericarditis
§ Kwashiorkor
Causes of low SAAG ("exudate") are:

§ Cancer (primary peritoneal carcinomatosis and metastasis) - 10%

§ Infection: Tuberculosis - 2% or Spontaneous bacterial peritonitis
§ Pancreatitis - 1%
§ Serositis
§ Nephrotic syndrome or Protein losing enteropathy
§ Hereditary angioedema[5]
Other Rare causes:

§ Meigs syndrome
§ Vasculitis
§ Hypothyroidism
§ Renal Dialysis
§ Peritoneum Mesothelioma
[edit]Pathophysiology
Ascitic fluid can accumulate as a transudate or an exudate. Amounts of up to 25 liters
are possible.

Roughly, transudates are a result of increased pressure in the portal vein (>8 mmHg,
usually around 20 mmHg[6]),   due to cirrhosis, while exudates are actively secreted
fluid due toinflammation or malignancy. As a result, exudates are high in protein, high
in lactate dehydrogenase, have a low pH (<7.30), a low glucose level, and more white
blood cells. Transudates have low protein (<30g/L), low LDH, high pH, normal glucose,
and fewer than 1 white cell per 1000 mm³. Clinically, the most useful measure is the
difference between ascitic and serum albumin concentrations. A difference of less than
1 g/dl (10 g/L) implies an exudate.[3]

Portal hypertension plays an important role in the production of ascites by raising

capillary hydrostatic pressure within the splanchnic bed.

Regardless of the cause, sequestration of fluid within the abdomen leads to

additional fluid retention by the kidneys due to stimulatory effect on blood pressure
hormones, notablyaldosterone. The sympathetic nervous system is also activated,
and renin production is increased due to decreased perfusion of the kidney. Extreme
disruption of the renal blood flow can lead to the feared hepatorenal syndrome. Other
complications of ascites include spontaneous bacterial peritonitis (SBP), due to
decreased antibacterial factors in the ascitic fluid such ascomplement.

[edit]Treatment

Ascites is generally treated while an underlying etiology is sought, in order to prevent

complications, relieve symptoms, and prevent further progression. In patients with mild
ascites, therapy is usually as an outpatient. The goal is weight loss of no more than 1.0
kg/day for patients with both ascites and peripheral edema and no more than 0.5 kg/day
for patients with ascites alone.[7] In those with severe ascites causing a tense abdomen,
hospitalization is generally necessary for paracentesis.[8][9]
[edit]  Y ÑÑ Y
x
m 
 
Salt restriction is the initial treatment, which allows diuresis (production of urine) since
the patient now has more fluid than salt concentration. Salt restriction is effective in
about 15% of patients.[10]
x



Since salt restriction is the basic concept in treatment, and aldosterone is one of the
hormones that acts to increase salt retention, a medication that counteracts aldosterone
should be sought. Spironolactone (or other distal-tubule diuretics such
as triamterene or amiloride) is the drug of choice since they block the aldosterone
receptor in the collecting tubule. This choice has been confirmed in a randomized
controlled trial.[11] Diuretics for ascites should be dosed once per day.[12] Generally, the
starting dose is oral spironolactone 100 mg/day (max 400 mg/day). 40% of patients will
respond to spironolactone.[10] For nonresponders, a loop diuretic may also be added
and generally, furosemide is added at a dose of 40 mg/day (max 160 mg/day), or
alternatively (bumetanide or torasemide). The ratio of 100:40 reduces risks of potassium
imbalance.[12] Serum potassium level and renal function should be monitored closely
while on these medications.[13]
{
 
Y: Diuresis can be monitored by weighing the patient daily. The goal
is weight loss of no more than 1.0 kg/day for patients with both ascites and peripheral
edema and no more than 0.5 kg/day for patients with ascites alone.[7] If daily weights
cannot be obtained, diuretics can also be guided by the urinary sodium concentration.
Dosage is increased until a negative sodium balance occurs.[12] A random urine sodium-
to-potassium ratio of > 1 is 90% sensitivity in predicting negative balance (> 78-
mmol/day sodium excretion).[14]
!Y
: Diuretic resistance can be predicted by giving 80 mg intravenous
furosemide after 3 days without diuretics and on an 80 mEq sodium/day diet. The
urinary sodium excretion over 8 hours < 50 mEq/8 hours predicts resistance.[15]

If a patient exhibits a resistance to or poor response to diuretic

therapy, ultrafiltration [?
 
 ] or aquapheresis may be needed to achieve
adequate control of fluid retention and congestion. The use of such mechanical
methods of fluid removal can produce meaningful clinical benefits in patients with
diuretic resistance and may restore responsiveness to conventional doses of
diuretics.[16][17]

x
÷ 
 
Water restriction is needed if hyponatremia < 130 mmol per liter develops.[13]

x
c 
 

‘c
??
In those with severe (tense) ascites, therapeutic paracentesis may be needed in
addition to medical treatments listed above.[8][9] As this may deplete serum
albumin levels in the blood, albumin is generally administered intravenously in
proportion to the amount of ascites removed.

x
u     


‘‘
?‘

 

Ascites that is refractory to medical therapy is considered an indication for liver

transplantation. In the United States, the MELD score (online calculator)[18] is used to
prioritize patients for transplantation.

x
m

 
In a minority of patients with advanced cirrhosis that have recurrent ascites, shunts may
be used. Typical shunts used are portacaval shunt, peritoneovenous shunt, and
the transjugular intrahepatic portosystemic shunt (TIPS). However, none of these
shunts has been shown to extend life expectancy, and are considered to be bridges
to liver transplantation. A meta-analysis of randomized controlled trials by the
international Cochrane Collaboration concluded that "TIPS was more effective at
removing ascites as compared with paracentesis...however, TIPS patients develop
hepatic encephalopathy significantly more often.
 "Y ÑÑ Y
Exudative ascites generally does not respond to manipulation of the salt balance or
diuretic therapy. Repeated paracentesis and treatment of the underlying cause is the
mainstay of treatment.

Complications



 Y
Y
Y
Y

Cirrhosis
From Wikipedia, the free encyclopedia

   
 6



 
 Y

Y
0 

Y
/ 
Y
   Y  
Y Y

0
 1$ 2Y12Y1Y

0
  Y

  
  "" Y


   !  Y !Y


  #$$$ Y

6  (pronounced /s 'ro s s/) is a consequence of chronic liver disease

characterized by replacement of liver tissue by fibrosis, scartissue and
regenerative nodules (lumps that occur as a result of a process in which damaged
tissue is regenerated),[1][2][3] leading to loss of liver function. Cirrhosis is most commonly
caused by alcoholism, hepatitis B and C, and fatty liver disease but has many other
possible causes. Some cases are idiopathic, i.e., of unknown cause.

Ascites (fluid retention in the abdominal cavity) is the most common complication of
cirrhosis and is associated with a poor quality of life, increased risk of infection, and a
poor long-term outcome. Other potentially life-threatening complications are hepatic
encephalopathy(confusion and coma) and bleeding from esophageal varices. Cirrhosis
is generally irreversible, and treatment usually focuses on preventing progression and
complications. In advanced stages of cirrhosis the only option is a liver transplant.
The word "cirrhosis" derives from Greek țȓȡ'ȠȢ, meaning
 (the orange-yellow
colour of the diseased liver). While the clinical entity was known before, it was René
Laennec who gave it the name "cirrhosis" in his 1819 work in which he also describes
the stethoscope.[4]

6



Y%
&Y

Y'
YY Y
m Y(  Y
"Y(Y
Y)

 
Y
Y# 
 Y
m Y-Y  
Y
m "Y3

Y
m  Y4 Y
m Y)

Y
m Y+ 
Y
Y0
Y
m Y  
Y 
YY
m "Y). 
Y
Y .Y
Y
m  Y). 
Y  Y
§  Y Y
§  "Y4

Y. Y 
Y
§   Y* Y

Y
§  Y*Y Y
§  Y'Y Y   Y
m Y  Y
m Y#Y 
 Y
Y4  
Y
YY
Y45Y 6Y

[edit]Signs and symptoms

Some of the following signs and symptoms  occur in the presence of cirrhosis or as
a result of the complications of cirrhosis. Many are nonspecific and may occur in other
diseases and do not necessarily point to cirrhosis. Likewise, the absence of any does
not rule out the possibility of cirrhosis.

§
  
 or ?. Vascular lesions consisting of a central arteriole
surrounded by many smaller vessels due to an increase in estradiol. These occur in
about 1/3 of cases.[5]
§ c‘
O. Exaggerations of normal speckled mottling of the palm, due to
altered sex hormone metabolism.
§ D‘O ?.
§ O?‘? - paired horizontal bands separated by normal color due
to hypoalbuminemia (inadequate production of albumin).
§ Ô ?‘? - proximal two-thirds of the nail plate appears white with distal one-
third red, also due to hypoalbuminemia
§ 6‘

 - angle between the nail plate and proximal nail fold > 180 degrees
§   
 O ?
 
O 
O . Chronic proliferative periostitis of the long bones that
can cause considerable pain.
§ 
? 

. Thickening and shortening of palmar fascia that leads to
flexion deformities of the fingers. Thought to be due to fibroblastic proliferation and
disorderly collagen deposition. It is relatively common (33% of patients).
§ w  ?
. Benign proliferation of glandular tissue of male breasts presenting
with a rubbery or firm mass extending concentrically from the nipples. This is due to
increased estradiol and can occur in up to 66% of patients.
§    ?. Manifested as impotence, infertility, loss of sexual drive, and
testicular atrophy due to primary gonadal injury or suppression of hypothalamic or
pituitary function.
§ u? . Can be enlarged, normal, or shrunken.
§
‘  ‘ (increase in size of the spleen). Due to congestion of the red pulp as
a result of portal hypertension.
§ Ñ?
?. Accumulation of fluid in the peritoneal cavity giving rise to flank dullness
(needs about 1500 mL to detect flank dullness). It may be associated
with hydrocele and penile flomation (swelling of the penile shaft)[

 ] in men.
§ 6
?. In portal hypertension, the umbilical vein may open. Blood from the
portal venous system may be shunted through the periumbilical veins into the
 umbilical vein and ultimately to the abdominal wall veins, manifesting as caput
medusa.
§ 6‘O 
. Venous hum heard in epigastric region (on
examination by stethoscope) due to collateral connections between portal system
and the remnant of the umbilical vein in portal hypertension.
§ ›
O
?. Musty odor in breath due to increased dimethyl sulfide.
§ ÿ. Yellow discoloring of the skin, eye, and mucus membranes due to
increased bilirubin (at least 2±3 mg/dL or 30 mmol/L). Urine may also appear dark.
§ Ñ?
?. Bilateral asynchronous flapping of outstretched, dorsiflexed hands seen in
patients with hepatic encephalopathy.
§
O. Weakness, fatigue, anorexia, weight loss.
[edit]6 

Y
As the disease progresses, complications may develop. In some people, these may be
the first signs of the disease.

§ Bruising and bleeding due to decreased production of coagulation factors.

§ Jaundice due to decreased processing of bilirubin.
§ Itching (pruritus) due to bile salts products deposited in the skin.
§ Hepatic encephalopathy - the liver does not clear ammonia and related nitrogenous
substances from the blood, which are carried to the brain, affecting cerebral
functioning: neglect of personal appearance, unresponsiveness, forgetfulness,
trouble concentrating, or changes in sleep habits.
§ Sensitivity to medication due to decreased metabolism of the active compounds.
§ Hepatocellular carcinoma is primary liver cancer, a frequent complication of
cirrhosis. It has a high mortality rate.
§ Portal hypertension - blood normally carried from the intestines and spleen through
the hepatic portal vein flows more slowly and the pressure increases; this leads to
the following complications:
§ Ascites - fluid leaks through the vasculature into the abdominal cavity.
§ Esophageal varices - collateral portal blood flow through vessels in the stomach
and esophagus. These blood vessels may become enlarged and are more likely
to burst.
§ Problems in other organs.
 § Cirrhosis can cause immune system dysfunction, leading to infection. Signs and
symptoms of infection may be aspecific are more difficult to recognize (e.g.,
worsening encephalopathy but no fever).
§ Fluid in the abdomen (ascites) may become infected with bacteria normally
present in the intestines (spontaneous bacterial peritonitis).
§ Hepatorenal syndrome - insufficient blood supply to the kidneys, causing acute
renal failure. This complication has a very high mortality (over 50%).
§ Hepatopulmonary syndrome - blood bypassing the normal lung circulation
(shunting), leading to cyanosis and dyspnea (shortness of breath),
characteristically worse on sitting up.[6]
§ Portopulmonary hypertension - increased blood pressure over the lungs as a
consequence of portal hypertension.[6]
§ Portal hypertensive gastropathy which refers to changes in the mucosa of
the stomach in patients with portal hypertension, and is associated with cirrhosis
severity.[7]
[edit]Causes

Cirrhosis has many possible causes; sometimes more than one cause is present in the
same patient. In the Western World, chronic alcoholism and hepatitis C are the most
common causes.

§ ё O ‘‘?? (ALD). Alcoholic cirrhosis develops for between 10% and
20% of individuals who drink heavily for a decade or more.[8] There is great variability
in the amount of alcohol needed to cause cirrhosis (as little as 3-4 drinks a day in
some men and 2-3 in some women[

 ]). Alcohol seems to injure the liver by
blocking the normal metabolism of protein, fats, and carbohydrates. Patients may
also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and
anorexia. AST and ALT are both elevated but less than 300 IU/L with a AST:ALT
ratio > 2.0, a value rarely seen in other liver diseases. Liver biopsy may show
hepatocyte necrosis, Mallory bodies, neutrophilic infiltration with perivenular
inflammation.
§ 6O O

?6. Infection with the hepatitis C virus causes inflammation of the
liver and a variable grade of damage to the organ that over several decades can
lead to cirrhosis. Cirrhosis caused by hepatitis C is the most common reason for liver
transplant. Can be diagnosed with serologic assays that detect hepatitis C antibody
 or viral RNA. The enzyme immunoassay, EIA-2, is the most commonly used
screening test in the US.
§ 6O O

?. The hepatitis B virus causes liver inflammation and injury that
over several decades can lead to cirrhosis. Hepatitis D is dependent on the
presence of hepatitis B, but accelerates cirrhosis in co-infection. Chronic hepatitis B
can be diagnosed with detection of HBsAG > 6 months after initial infection. HBeAG
and HBV DNA are determined to assess whether patient will need antiviral therapy.
§ D ‘ O ‘?

O

? (NASH). In NASH, fat builds up in the liver and
eventually causes scar tissue. This type of hepatitis appears to be associated with
diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with
corticosteroid medications. This disorder is similar to that of alcoholic liver disease
but patient does not have an alcohol history. Biopsy is needed for diagnosis.
§ c 
‘ O ??. May be asymptomatic or complain of fatigue, pruritus, and
non-jaundice skin hyperpigmentation with hepatomegaly. There is prominent alkaline
phosphatase elevation as well as elevations in cholesterol and bilirubin. Gold
standard diagnosis is antimitochondrial antibodies with liver biopsy as confirmation if
showing florid bile duct lesions. It is more common in women.
§ c ?‘ ? O ‘ 
?. PSC is a progressive cholestatic disorder presenting
with pruritus, steatorrhea, fat soluble vitamin deficiencies, and metabolic bone
disease. There is a strong association with inflammatory bowel disease (IBD),
especially ulcerative colitis. Diagnosis is best with contrast cholangiography showing
diffuse, multifocal strictures and focal dilation of bile ducts, leading to a beaded
appearance. Non-specific serum immunoglobulins may also be elevated.
§ Ñ
O

?. This disease is caused by the immunologic damage to the
liver causing inflammation and eventually scarring and cirrhosis. Findings include
elevations in serum globulins, especially gamma globulins. Therapy with prednisone
+/- azathioprine is beneficial. Cirrhosis due to autoimmune hepatitis still has 10-year
survival of 90%+. There is no specific tool to diagnose autoimmune but it can be
beneficial to initiate a trial of corticosteroids.
§  
 O O 
??. Usually presents with family history of cirrhosis, skin
hyperpigmentation, diabetes mellitus, pseudogout, and/or cardiomyopathy, all due to
signs of iron overload. Labs will show fasting transferrin saturation of > 60% and
ferritin > 300 ng/mL. Genetic testing may be used to identify  › mutations. If these
are present, biopsy may not need to be performed. Treatment is with phlebotomy to
lower total body iron levels.
§ ÷‘? ???. Autosomal recessive disorder characterized by low
serum ceruloplasmin and increased hepatic copper content on liver biopsy. May also
have Kayser-Fleischer rings in the cornea and altered mental status.
§ ёO

 ? (AAT). Autosomal recessive disorder. Patients may
also have COPD, especially if they have a history of tobacco smoking. Serum AAT
levels are low. Recombinant AAT is used to prevent lung disease due to AAT
deficiency.
§ 6O ??. Due to chronic right sided heart failure which leads to liver
congestion.
§ Galactosemia
§ Glycogen storage disease type IV
§ Cystic fibrosis
§ Hepatotoxic drugs or toxins
§ Certain parasitic infections (such as schistosomiasis)
[edit]Pathophysiology

The liver plays a vital role in synthesis of proteins (e.g., albumin, clotting
factors and complement), detoxification and storage (e.g., vitamin A). In addition, it
participates in the metabolism of lipids and carbohydrates.

Cirrhosis is often preceded by hepatitis and fatty liver (steatosis), independent of the
cause. If the cause is removed at this stage, the changes are still fully reversible.

The pathological hallmark of cirrhosis is the development of scar tissue that replaces
normal parenchyma, blocking the portal flow of blood through the organ and disturbing
normal function. Recent research shows the pivotal role of the stellate cell, a cell type
that normally stores vitamin A, in the development of cirrhosis. Damage to the hepatic
parenchyma leads to activation of the stellate cell, which becomes contractile
(called myofibroblast) and obstructs blood flow in the circulation. In addition, it
secretes TGF-ȕ1, which leads to a fibrotic response and proliferation of connective
tissue. Furthermore, it disturbs the balance between matrix metalloproteinases and the
naturally occurring inhibitors (TIMP 1 and 2), leading tomatrix breakdown and
replacement by connective tissue-secreted matrix.[9]

The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace
the entire liver architecture, leading to decreased blood flow throughout.
The spleen becomes congested, which leads to hypersplenism and increased
sequestration of platelets. Portal hypertension is responsible for most severe
complications of cirrhosis.

[edit]Diagnosis

The gold standard for diagnosis of cirrhosis is a liver biopsy, through

a percutaneous, transjugular, laparoscopic, or fine-needle approach. Histologically
cirrhosis can be classified as micronodular, macronodular, or mixed, but this
classification has been abandoned since it is non-specific to the aetiology, it may
change as the disease progresses, and serological markers are much more
specific.[

 ]. However, a biopsy is not necessary if the clinical, laboratory, and
radiologic data suggests cirrhosis. Furthermore, there is a small but significant risk to
liver biopsy, and cirrhosis itself predisposes for complications due to liver biopsy.[10]
[edit]Y

Y
The following findings are typical in cirrhosis:

§ Ñ
??? - AST and ALT are moderately elevated, with AST > ALT.
However, normal aminotransferases do not preclude cirrhosis.
§ ё‘O ?O
? - usually slightly elevated.
§ w ‘
 ‘
?? ± correlates with AP levels. Typically much higher in
chronic liver disease from alcohol.
§ ‘
 - may elevate as cirrhosis progresses.
§ ё
 - levels fall as the synthetic function of the liver declines with worsening
cirrhosis since albumin is exclusively synthesized in the liver
§ c
O 

 - increases since the liver synthesizes clotting factors.
§ w‘
‘? - increased due to shunting of bacterial antigens away from the liver to
lymphoid tissue.
§
?  - hyponatremia due to inability to excrete free water resulting from
high levels of ADH and aldosterone.
§ ÔO 

 - due to both congestive splenomegaly as well as
decreased thrombopoietin from the liver. However, this rarely results in platelet
count < 50,000/mL.
§ u 
  - due to splenomegaly with splenic margination.
§ 6  ‘
 
? - the liver produces most of the coagulation factors and thus
coagulopathy correlates with worsening liver disease.
There is now a validated and patented combination of 6 of these markers as non-
invasive biomarker of fibrosis (and so of cirrhosis) : FibroTest [11].

Other laboratory studies performed in newly diagnosed cirrhosis may include:

§ Serology for hepatitis viruses, autoantibodies (ANA, anti-smooth muscle, anti-

mitochondria, anti-LKM)
§ Ferritin and transferrin saturation (markers of iron
overload), copper and ceruloplasmin (markers of copper overload)
§ Immunoglobulin levels (IgG, IgM, IgA) - these are non-specific but may assist in
distinguishing various causes
§ Cholesterol and glucose
§ Alpha 1-antitrypsin
[edit]0 
Y

Liver cirrhosis as seen on an axial CT of the abdomen.

å‘
?  is routinely used in the evaluation of cirrhosis, where it may show a small
and nodular liver in advanced cirrhosis along with increased echogenicity with irregular
appearing areas. Ultrasound may also screen for hepatocellular carcinoma, portal
hypertension and Budd-Chiari syndrome (by assessing flow in the hepatic vein).

A new type of device, the FibroScan (transient elastography), uses elastic waves to
determine liver stiffness which theoretically can be converted into a liver score based on
the METAVIR scale. The FibroScan produces an ultrasound image of the liver (from
20±80 mm) along with a pressure reading (in kPa.) The test is much faster than a
biopsy (usually last 2.5±5 minutes) and is completely painless. It shows reasonable
correlation with the severity of cirrhosis.[12]

Other tests performed in particular circumstances include abdominal CT and liver/bile

duct MRI (MRCP).
[edit]
  Y
Gastroscopy (endoscopic examination of the esophagus, stomach and duodenum) is
performed in patients with established cirrhosis to exclude the possibility of esophageal
varices. If these are found, prophylactic local therapy may be applied (sclerotherapy or
banding) and beta blocker treatment may be commenced.
Rarely diseases of the bile ducts, such as primary sclerosing cholangitis, can be causes
of cirrhosis. Imaging of the bile ducts, such as ERCPor MRCP (MRI of biliary tract and
pancreas) can show abnormalities in these patients, and may aid in the diagnosis.
[edit] 
Y

Cirrhosis leading to hepatocellular carcinoma (autopsy specimen).

Macroscopically, the liver is initially enlarged, but with progression of the disease, it
becomes smaller. Its surface is irregular, the consistency is firm and the color is often
yellow (if associates steatosis). Depending on the size of the nodules there are three
macroscopic types: micronodular, macronodular and mixed cirrhosis. In micronodular
form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm. In
macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm. The
mixed cirrhosis consists in a variety of nodules with different sizes.

However, cirrhosis is defined by its pathological features on microscopy: (1) the

presence of regenerating nodules of hepatocytes and (2) the presence of fibrosis, or the
deposition of connective tissue between these nodules. The pattern of fibrosis seen can
depend upon the underlying insult that led to cirrhosis; fibrosis can also proliferate even
if the underlying process that caused it has resolved or ceased. The fibrosis in cirrhosis
can lead to destruction of other normal tissues in the liver: including the sinusoids,
the space of Disse, and other vascular structures, which leads to altered resistance to
blood flow in the liver and portal hypertension.[13]

As cirrhosis can be caused by many different entities which injure the liver in different
ways, different cause-specific patterns of cirrhosis, and other cause-specific
abnormalities can be seen in cirrhosis. For example, in chronic hepatitis B, there is
infiltration of the liver parenchyma with lymphocytes;[13] in cardiac cirrhosis there
are erythrocytes and a greater amount of fibrosis in the tissue surrounding the hepatic
veins;[14] in primary biliary cirrhosis, there is fibrosis around the bile duct, the presence
ofgranulomas and pooling of bile;[15] and in alcoholic cirrhosis, there is infiltration of the
liver with neutrophils.[13]
[edit] 
Y
The severity of cirrhosis is commonly classified with the Child-Pugh score. This score
uses bilirubin, albumin, INR, presence and severity of ascites and encephalopathy to
classify patients in class A, B or C; class A has a favourable prognosis, while class C is
at high risk of death. It was devised in 1964 by Child and Turcotte and modified in 1973
by Pugh 
‘.[16]

More modern scores, used in the allocation of liver transplants but also in other
contexts, are the Model for End-Stage Liver Disease (MELD) score and its pediatric
counterpart, thePediatric End-Stage Liver Disease (PELD) score.

The hepatic venous pressure gradient, i.e., the difference in venous pressure between
afferent and efferent blood to the liver, also determines severity of cirrhosis, although
hard to measure. A value of 16 mm or more means a greatly increased risk of dying.[17]

[edit]Management

Generally, liver damage from cirrhosis cannot be reversed, but treatment could stop or
delay further progression and reduce complications. A healthy diet is encouraged, as
cirrhosis may be an energy-consuming process. Close follow-up is often necessary.
Antibiotics will be prescribed for infections, and various medications can help with
itching. Laxatives, such aslactulose, decrease risk of constipation; their role in
preventing encephalopathy is limited.
[edit]
Y


YY
Alcoholic cirrhosis caused by alcohol abuse is treated by abstaining from alcohol.
Treatment for hepatitis-related cirrhosis involves medications used to treat the different
types of hepatitis, such as interferon for viral hepatitis and corticosteroids for
autoimmune hepatitis. Cirrhosis caused by Wilson's disease, in which copper builds up
in organs, is treated withchelation therapy (e.g., penicillamine) to remove the copper.
[edit] 

Y Y
Y Y
Regardless of underlying cause of cirrhosis, alcohol and paracetamol, as well as other
potentially damaging substances, are discouraged. Vaccination of susceptible patients
should be considered for Hepatitis A and Hepatitis B.
[edit] 

Y 

Y
x
Ñ


‘Ñ?
?

Salt restriction is often necessary, as cirrhosis leads to accumulation of salt (sodium

retention). Diuretics may be necessary to suppress ascites.

x
J
  
  

‘? O ‘?

For portal hypertension, propranolol is a commonly used agent to lower blood pressure
over the portal system. In severe complications from portal hypertension, transjugular
intrahepatic portosystemic shunting is occasionally indicated to relieve pressure on the
portal vein. As this can worsen encephalopathy, it is reserved for those at low risk of
encephalopathy, and is generally regarded only as a bridge to liver transplantation or as
a palliative measure.

x
  


 


‘ 
O‘ 
O 

High-protein food increases the nitrogen balance, and would theoretically

increase encephalopathy; in the past, this was therefore eliminated as much as possible
from the diet. Recent studies show that this assumption was incorrect, and high-protein
foods are even    to maintain adequate nutrition.[18]

x
    


‘ 
‘?  
The hepatorenal syndrome is defined as a urine sodium less than 10 mmol/L and
a serum creatinine > 1.5 mg/dl (or 24 hour creatinine clearance less than 40 ml/min)
after a trial of volume expansion without diuretics.[19]

x
m 

    

‘
 
 ?

‘

?

Cirrhotic patients with ascites are at risk of spontaneous bacterial peritonitis.

[edit]



Y

‘u
?‘

 

If complications cannot be controlled or when the liver ceases functioning, liver

transplantation is necessary. Survival from liver transplantation has been improving over
the 1990s, and the five-year survival rate is now around 80%, depending largely on the
severity of disease and other medical problems in the recipient.[20] In the United States,
the MELD score is used to prioritize patients for transplantation.[21] Transplantation
necessitates the use of immune suppressants (cyclosporine or tacrolimus).
[edit]! 
Y Y
In patients with previously stable cirrhosis, decompensation may occur due to various
causes, such as constipation, infection (of any source), increased alcohol
intake, medication, bleeding from esophageal varices or dehydration. It may take the
form of any of the complications of cirrhosis listed above.

Patients with decompensated cirrhosis generally require admission to hospital, with

close monitoring of the fluid balance, mental status, and emphasis on adequate nutrition
and medical treatment - often
with diuretics, antibiotics, laxatives and/or enemas, thiamine and
occasionally steroids, acetylcysteine and pentoxifylline. Administration of saline is
generally avoided as it would add to the already high total body sodium content that
typically occurs in cirrhosis.

[edit]Epidemiology
Disability-adjusted life year for cirrhosis of the liver per 100,000 inhabitants in 2004.[22]

no data less than 50 50-100 100-200 200-300 300-400 400-

500 500-600 600-700 700-800 800-900 900-1000 more than 1000

Cirrhosis and chronic liver disease were the 10th leading cause of death for men and
the 12th for women in the United States in 2001, killing about 27,000 people each
year.[23] Also, the cost of cirrhosis in terms of human suffering, hospital costs, and lost
productivity is high.

Established cirrhosis has a 10-year mortality of 34-66%, largely dependent on the cause
of the cirrhosis; alcoholic cirrhosis has a worse prognosis than primary biliary cirrhosis
and cirrhosis due to hepatitis. The risk of death due to all causes is increased
twelvefold; if one excludes the direct consequences of the liver disease, there is still a
fivefold increased risk of death in all disease categories.[24]
Little is known on modulators of cirrhosis risk, apart from other diseases that cause liver
injury (such as the combination of alcoholic liver disease and chronic viral hepatitis,
which may act synergistically in leading to cirrhosis). Studies have recently suggested
that coffee consumption may protect against cirrhosis, especially alcoholic cirrhosis.[25]
÷ YY
 
#Y
Polyarthralgia is defined as aches in the joints, joint pains, arthralgia of multiple joints,
and multiple joint pain. Polyarthritis is the word usually used to describe pain affecting
five or more joints, while a patient with 2 to 4 joints involved would be said to have
oligoarticular disease.
Polyarthralgia is more common in women and even more so with increasing age.

 
Y 
Y
Y   Y
The initial symptoms, which usually appear in the third to fifth decade of life, include
painless swelling or thickening of the skin of the hands and fingers, pain and stiffness of
the joints (polyarthralgia), often mistaken for rheumatoid arthritis, and paroxysmal
blanching and cyanosis (becoming blue) of the fingers induced by exposure to cold
(Raynaud syndrome).
 
Y 
 - Literally means joint pain, it is a symptom of injury, infection,
illnesses (in particular arthritis) or an allergic reaction to medication. Main symptom is
pain; no clinical features of inflammation in the joints or morning stiffness; history of
intercurrent illness or viral infection.
$   Y  - At least four of these signs or symptoms for six weeks: pain and
swelling in at least three joint areas; symmetrical presentation; early morning joint
stiffness for more than one hour; involvement of metacarpophalangeal joints, proximal
interphalangeal joints, and wrists; subcutaneous nodules; positive rheumatoid factor;
radiological evidence of erosions.
 
 - People with Fibromyalgia experience pain in their tendons and
ligaments, along with tender points throughout their body along with fatigue. Even slight
pressure on tender points can cause pain. More women than men have Fibromyalgia,
which has been known as, 'chronic muscle pain,' psychogenic rheumatism,' 'tension
myalgias,' and, 'fibrositis,' in the past.

Y%

&   'Y  - Linked with psoriasis, bowel disease
(ulcerative colitis, Crohn's disease), bladder symptoms, and anterior uveitis. May occur
after infections (streptococcal throat infection, chlamydial urethritis, or bowel infection
with yersinia, salmonella, shigella). Mainly asymmetrical, large joint oligoarticular
involvement; possible spinal involvement (sacroiliitis)
   - Pain is usually in large, weight bearing joints, carpometacarpal joint of
thumb, or distal interphalangeal joints of the fingers; presence of Heberden's nodes,
crepitus; lifestyle factors such as overweight, sedentary occupation, repetitive use of
joints, and history of trauma to affected joints may be relevant.

Hepatic encephalopathy
From Wikipedia, the free encyclopedia



  

6



 
 Y

Y
0 

YY7
 Y Y33Y 2YY Y
YY Y
 Y

Y

0
 1" Y

0
 "" Y
    $$$ $" Y


   ! Y !""$Y


  #$$$ Y

 Y
 
  (also known as    Y
 
 ) is the
occurrence of confusion, altered level of consciousnessand coma as a result of liver
failure. In the advanced stages it is called Y  or  Y  . It may
ultimately lead to death.[1]
It is caused by accumulation in the bloodstream of toxic substances that are normally
removed by the liver. The diagnosis of hepatic encephalopathy requires the presence of
impaired liver function, and the exclusion of an alternative explanation for the
symptoms. Blood tests (ammonia levels) may assist in the diagnosis. Attacks are often
precipitated by an intercurrent problem, such as infection orconstipation.[1][2]

Hepatic encephalopathy is reversible with treatment. This relies on suppressing the

production of the toxic substances in the intestine. This is most commonly done with the
laxative lactulose or with non-absorbable antibiotics. In addition, the treatment of any
underlying condition may improve the symptoms. In particular settings, such as acute
liver failure, the onset of encephalopathy may indicate the need for a liver transplant.[1][3]

6



Y%
&Y

Y'
YY Y
"Y(Y
Y(   YY
 
Y
m Y,Y*.Y(  Y
m "Y Y
Y)

 Y
Y# 
 Y
m Y3.
 Y
m "Y0  Y*4Y
Y Y
m Y# Y
m "Y-! Y
m  Y   Y
m Y-8-Y
Y4  
YY
 Y
Y*  Y
YY

Signs and symptoms

The mildest form of hepatic encephalopathy is difficult to detect clinically, but may be
demonstrated on neuropsychological testing. It is experienced as forgetfulness, mild
confusion and irritability. More severe encephalopathy is characterised by an inverted
sleep-wake pattern (sleeping by day, being awake at night), marked irritability, tremor,
difficulties with coordination and trouble writing.[1]

More severe forms of hepatic encephalopathy lead to a worsening level of

consciousness, from lethargy to somnolence and eventually coma. In the intermediate
stages, a characteristic jerking movement of the limbs is observed (asterixis, "liver flap"
due to its flapping character); this disappears as the somnolence worsens. There is
disorientation and amnesia, and uninhibited behaviour may occur. Coma
and seizures represent the most advanced stage; cerebral oedema (swelling of the
brain tissue) leads to death.[1]

Encephalopathy often occurs together with other symptoms and signs of liver failure.
These may include jaundice (yellow discolouration of the skin and the whites of the
eyes), ascites(fluid accumulation in the abdominal cavity), and peripheral
oedema (swelling of the legs due to fluid build-up in the skin). The tendon reflexes may
be exaggerated, and the plantar reflexmay be abnormal, namely extending rather than
flexing (Babinski's sign) in severe encephalopathy. A particular smell ( 
O
?)
may be detected.[2]

Causes

In a small proportion of cases, the encephalopathy is caused directly by liver failure; this
is more likely in acute liver failure. More commonly, especially in chronic liver disease,
hepatic encephalopathy is caused or aggravated by an additional cause, and identifying
these causes can be important to treat the episode effectively.[1]

%&%"&%&
Ô   

( YY
YYY 2Y
  Y 
Y
YY


 
. YY Y


Y Y 2Y/

Y YYY
Y/2YY Y
 
5Y 
9  
Y/YY
YY2Y  Y

*  Y/Y Y.Y Y
YYY
6 Y/Y Y



Y
YY Y
Y6 
Y  2YYYY
YYY ;Y

 
 


Y6 YY Y.2Y
5 Y   Y5

Y.2Y

' .Y
YY7 7 YYYYY
Y/ 
/YY

  
 2Y YY 6 YY
YYYY .Y  
 

 
5  Y

0 
  ) 2Y  YY  2YY Y   2Y
Y  

'
 2Y
 YY
Y .Y 2Y  YYY .Y
Y
Y
  

  2Y
  YY

    3Y"$< $=YY2YYYYYY6YYYY

Hepatic encephalopathy may also occur after the creation of a transjugular intrahepatic
portosystemic shunt (TIPSS). This is used in the treatment of refractory ascites,
bleeding fromoesophageal varices and hepatorenal syndrome.[5][6] TIPSS-related
encephalopathy occurs in about 30% of cases, with the risk being higher in those with
previous episodes of encephalopathy, higher age, female sex and liver disease due to
causes other than alcohol.[4]

Classification and grading

÷Y 
Y6Y
The severity of hepatic encephalopathy is graded with the West Haven Criteria; this is
based on the level of impairment of autonomy, changes in consciousness, intellectual
function, behavior, and the dependence on therapy.[1][7][8].

§ Grade 1 - Trivial lack of awareness; Euphoria or anxiety; Shortened attention span;

Impaired performance of addition or subtraction
§ Grade 2 - Lethargy or apathy; Minimal disorientation for time or place; Subtle
personality change; Inappropriate behaviour
§ Grade 3 - Somnolence to semistupor, but responsive to verbal stimuli; Confusion;
Gross disorientation
§ Grade 4 - Coma (unresponsive to verbal or noxious stimuli)
Y

Micrograph showing liver cirrhosis, a condition that often precedes hepatic

encephalopathy. Trichrome stain.

A classification of hepatic encephalopathy was introduced at the World Congress

of Gastroenterology 1998 in Vienna. According to this classification, hepatic
encephalopathy is subdivided in type A, B and C depending on the underlying cause.[7]

§ Ô Ñ 
! describes hepatic encephalopathy associated with acute liver failure
§ Ô 
??! is caused by portal-systemic shunting without associated intrinsic
liver disease
§ Ô 6 O ??) occurs in patients with cirrhosis - this type is subdivided
in ? , ??

and ‘ encephalopathy
The term ‘O‘ 
O (MHE) is defined as encephalopathy that does not
lead to clinically-overt cognitive dysfunction, but can be demonstrated with
neuropsychological studies.[7][9] This is still an important finding, as minimal
encephalopathy has been demonstrated to impair quality of life and increase the risk of
involvement in road traffic accidents.[10]

[edit]Pathogenesis

Image of ball and stick model of ammonia; one nitrogen atom with three hydrogen
atoms. Accumulation of ammonia in the bloodstream is associated with hepatic
encephalopathy.

There are various explanations why liver dysfunction or portosystemic shunting might
lead to encephalopathy. In healthy subjects, nitrogen-containing compounds from
the intestine, generated by gut bacteria from food, are transported by the portal vein to
the liver, where 80±90% ismetabolised and/or excreted immediately. This process is
impaired in all subtypes of hepatic encephalopathy, either because
the hepatocytes(liver cells) are incapable of metabolising the waste products or
because portal venous blood bypasses the liver through collateral circulation or a
medically constructed shunt. Nitrogenous waste products accumulate in the systemic
circulation (hence the older term "portosystemic encephalopathy"). The most important
waste product is ammonia (NH3). This small molecule crosses the blood-brain
barrier and is absorbed and metabolised by the astrocytes, a population of cells in the
brain that constitutes 30% of the cerebral cortex. Astrocytes become swollen, there is
increased activity of the inhibitory Ȗ-aminobutyric acid (GABA) system, and the energy
supply to other brain cells is decreased. Despite numerous studies demonstrating the
central role of ammonia, ammonia levels don't always correlate with the severity of the
encephalopathy; it is suspected that this means that more ammonia has already been
absorbed into the brain in those with severe symptoms whose serum levels are
relatively low.[1][2] Other waste products implicated in hepatic encephalopathy
include mercaptans (substances containing a thiol group), short-chain fatty
acids and phenol.[2]

Numerous other abnormalities have been described in hepatic encephalopathy,

although their relative contribution to the disease state is uncertain. Benzodiazepine-like
compounds have been detected at increased levels as well as abnormalities in the
GABA neurotransmission system. An imbalance between aromatic amino
acids (phenylalanine, tryptophan and tyrosine) and branched-chain amino
acids (leucine, isoleucine and valine) has been described; this would lead to the
generation of false neurotransmitters (such octopamine and 2-hydroxyphenethylamine).
Dysregulation of the serotoninsystem, too, has been reported. Depletion of zinc and
accumulation of manganese may play a role.[1][2] Inflammation elsewhere in the body
may precipitate encephalopathy through the action of cytokines and
bacterial lipopolysaccharide on astrocytes.[4]

[edit]Diagnosis

Micrograph of Alzheimer type II astrocytes, as may be seen in hepatic encephalopathy.

[edit]0

Y
Alt=Two-dimensional graph of slow brain activity on an electroencephalogram

The diagnosis of hepatic encephalopathy can only be made in the presence of

confirmed liver disease (types A and C) or a portosystemic shunt (type B), as it leads to
similar symptoms to other encephalopathies. To make the distinction, abnormal liver
function tests and/orultrasound suggesting liver disease are required, and ideally liver
biopsy.[1][2] The symptoms of hepatic encephalopathy may also arise from other
conditions, such as cerebral haemorrhage and seizures (both of which are more
common in chronic liver disease). A CT scan of the brain may be required to exclude
haemorrhage, and if seizure activity is suspected an electroencephalograph (EEG)
study may be performed.[1]Rarer mimics of encephalopathy
are meningitis, encephalitis, Wernicke's encephalopathy and Wilson's disease; these
may be suspected on clinical grounds and confirmed with investigations.[2][7]

The diagnosis of hepatic encephalopathy is a clinical one, once other causes for
confusion or coma have been excluded; no test fully diagnoses or excludes it. Serum
ammonia levels are elevated in 90% of patients, but not all hyperammoninaemia (high
ammonia levels) is associated with encephalopathy.[1][2] A CT scan of the brain usually
shows no abnormality except in stage IV encephalopathy, when cerebral oedema may
be visible.[2] Other neuroimaging modalities, such as magnetic resonance
imaging (MRI), are not currently regarded as useful, although they may show
abnormalities.[7] Electroencephalography shows no clear abnormalities in stage 0, even
if minimal HE is present; in stages I, II and III there are triphasic waves over the frontal
lobes that oscillate at 5 Hz, and in stage IV there is slow delta wave activity.[1]However,
the changes in EEG are not typical enough to be useful in distinguishing hepatic
encephalopathy from other conditions.[7]

Once the diagnosis of encephalopathy has been made, efforts are made to exclude
underlying causes (such as listed above in "causes"). This requires blood tests (urea
and electrolytes, full blood count, liver function tests), usually a chest X-ray,
and urinalysis. If there is ascites, diagnostic paracentesis (removal of a fluid sample with
a needle) may be required to identify spontaneous bacterial peritonitis (SBP).[1]
[edit]{
 
Y Y
The diagnosis of minimal hepatic encephalopathy requires neuropsychological testing
by definition. Older tests include the "numbers connecting test" A and B (measuring the
speed at which one could connect randomly dispersed numbers 1±20), the "block
design test" and the "digit-symbol test".[7] In 2009 an expert panel concluded that
neuropsychological test batteries aimed at measuring multiple domains of cognitive
function are generally more reliable than single tests, and tend to be more strongly
correlated with functional status. Both the Repeatable Battery for the Assessment of
Neuropsychological Status (RBANS)[11] and PSE-Syndrom-Test[12] may be used for this
purpose.[9] The PSE-Syndrom-Test, developed in Germany and validated in several
other European countries, incorporates older assessment tools such as the number
connection test.[7][9][10][12]
[edit]Treatment

Those with severe encephalopathy (stages 3 and 4) are at risk of obstructing

their airway due to decreased protective reflexes such as the gag reflex. This can lead
to respiratory arrest. Nursing in an appropriate area, such as the intensive care unit, is
advocated in such situations, with intubation of the airway if necessary.[2][3] If the level of
consciousness is low there is a significant risk of aspiration pneumonia, and
a nasogastric tube is often inserted to allow the safe administration of nutrients and
medication.[1]

The treatment of hepatic encephalopathy depends on the suspected underlying cause

(types A, B or C) and the presence or absence of underlying causes. If encephalopathy
develops in acute liver failure (type A), even in a mild form (grade 1±2), it indicates that
a liver transplant may be required, and transfer to a specialist centre is
advised.[3] Hepatic encephalopathy type B may arise in those who have undergone a
TIPSS procedure; in most cases this resolves spontaneously or with the medical
treatments discussed below, but in a small proportion of about 5%, occlusion of the
shunt is required to address the symptoms.[4]

In hepatic encephalopathy type C, the identification and treatment of alternative or

underlying causes is central to the initial management.[1][2][4][10] Given the frequency of
infection as the underlying cause, antibiotics are often administered empirically (without
knowledge of the exact source and nature of the infection).[1][4] Once an episode of
encephalopathy has been effectively treated, a decision may need to be made on
whether to prepare for a liver transplant.[10]
[edit]!Y
In the past, it was thought that consumption of protein even at normal levels increased
the risk of hepatic encephalopathy. This has been shown to be incorrect. Furthermore,
many people with chronic liver disease are malnourished and require adequate protein
to maintain a stable body weight. A diet with adequate protein and energy is therefore
recommended.[1][4]
Dietary supplementation with branched-chain amino acids has shown improvement of
encephalopathy and other complications of cirrhosis.[1][4] Some studies have shown
benefit of administration of probiotics ("healthy bacteria").[4]
[edit]


Y
Lactulose and lactitol are disaccharides that are not absorbed from the digestive tract.
They are thought to improve the generation of ammonia by bacteria, render the
ammonia inabsorbable by converting it to ammonium (NH4), and increase transit of
bowel content through the gut. Doses of 15-30 ml are administered three times a day;
the result is aimed to be 3±5 soft stools a day, or (in some settings) a stool pH of
<6.0.[1][2][4][10] Lactulose may also be given by enema, especially if encephalopathy is
severe.[10] More commonly, phosphateenemas are used. This may relieve constipation,
one of the causes of encephalopathy, and increase bowel transit.[1]

A 2004 review by the Cochrane Collaboration concluded that there was insufficient
evidence to determine whether lactulose and lactitol are of benefit of hepatic
encephalopathy,[13] but it remains the first-line treatment for type C hepatic
encephalopathy.[1] In acute liver failure, it is unclear whether lactulose is beneficial.
Furthermore, it may lead to bloating and as such interfere with a liver transplant
procedure if required.[3]
[edit]Ñ
 Y
The antibiotics neomycin and metronidazole were previously used as a treatment for
hepatic encephalopathy. Again, the rationale of their use was the fact that ammonia and
other waste products are generated and converted by intestinal bacteria, and killing of
these bacteria would reduce the generation of these waste products. Neomycin was
chosen because of its low intestinal absorption, as neomycin and
similar aminoglycoside antibiotics may cause hearing loss and renal failure if used
extensively. Later studies showed that neomycin was indeed absorbed enterally, with
resultant complications. Metronidazole, similarly, was abandoned because prolonged
use could cause a peripheral neuropathy (nerve damage), and many experience
gastrointestinal side effects.[1]

A safer and probably more effective antibiotic is rifaximin, a nonabsorbable antibiotic

from the rifamycin class. This is thought to work in a similar way, but without the
complications attached to neomycin and metronidazole. The use of rifaximin is
supported by better evidence than lactulose.[13] Due to more widespread experience, it
is only used as a second-line treatment if lactulose is not effective or poorly tolerated.
When added to lactulose two combination may be more effective than each component
separately.[1] Rifaximin is more expensive than lactulose, but the cost may be offset by
reduced hospital admissions for encephalopathy.[10]
[edit]ÑY
A preparation of u-ornithine and u-aspartate (LOLA) is used to increase the generation
of urea through the urea cycle, a metabolic pathway that removes ammonia by turning it
into the neutral substance urea. It may be combined with lactulose and/or rifaximin if
these alone are ineffective at controlling symptoms.[1]

[edit]Epidemiology and prognosis

In those with cirrhosis, the risk of developing hepatic encephalopathy is 20% per year,
and at any time about 30±45% of people with cirrhosis exhibit evidence of overt
encephalopathy. The prevalence of minimal hepatic encephalopathy detectable on
formal neuropsychological testing is 60±80%; this increases the likelihood of developing
overt encephalopathy in the future.[10] Once hepatic encephalopathy has developed,
the prognosis is determined largely by other markers of liver failure, such as the levels
of albumin (a protein produced by the liver), the prothrombin time (a test of coagulation,
which relies on proteins produced in the liver), the presence of ascites and the level
of bilirubin (a breakdown product of hemoglobin which is conjugated and excreted by
the liver). Together with the severity of encephalopathy, these markers have been
incorporated into the Child-Pugh score; this score determines the one- and two-year
survival and may assist in a decision to offer liver transplantation.[7]

In acute liver failure, the development of severe encephalopathy strongly predicts short-
term mortality, and is almost as important as the nature of the underlying cause of the
liver failure in determining the prognosis. Historically widely used criteria for offering
liver transplantation, such as King's College Criteria, are of limited use and recent
guidelines discourage excessive reliance on these criteria. The occurrence of hepatic
encephalopathy in patients with Wilson's disease (hereditary copper accumulation) and
mushroom poisoning indicates an urgent need for a liver transplant.[3]

[edit]History

The occurrence of disturbed behaviour in people with jaundice may have been
described in antiquity by Hippocrates of Cos (ca. 460±
370 BCE). Celsus and Galen (first and third century respectively) both recognised the
condition. Many modern descriptions of the link between liver disease and
neuropsychiatric symptoms were made in the eighteenth and nineteenth century; for
instance, Giovanni Battista Morgagni (1682±1771) reported in 1761 that it was a
progressive condition.[12][14]

In the 1950s, several reports enumerated the numerous abnormalities reported

previously, and confirmed the previously enunciated theory that metabolic impairment
and portosystemic shunting are the underlying mechanism behind hepatic
encephalopathy, and that the nitrogen-rich compounds originate from the
intestine.[12][15] Many of these studies were done by Professor Dame Sheila
Sherlock (1918±2001), then at the Royal Postgraduate Medical School in London and
subsequently at the Royal Free Hospital. The same group investigated protein
restriction[14] and neomycin.[16]

The West Haven classification was formulated by Prof Harold Conn and colleagues
at Yale University while investigating the therapeutic efficacy of lactulose.[7][8]

[edit]References

Ileus
From Wikipedia, the free encyclopedia

0 

6



 
 Y

0
 1 2Y1$2Y1 212Y)2Y)Y

0
  "2Y$2Y$ 22YY


  
 $
 Y


  #$" Y

0
 or  


Y
[1] is a disruption of the normal
propulsive gastrointestinal motor activity due to non-mechanical causes[2][3]. In contrast,
motility disorders that result from structural abnormalities are termed mechanical bowel
obstruction. Some mechanical obstructions are misnomers, such as gallstone ileus
and meconium ileus, and are not true examples of ileus by the classic definition [4].

6



Y%
&Y

Y Y
m Y) .Y3Y
m "Y)  Y3Y
m  YY Y Y
"Y)

 Y
m "Y3
  YY5Y
m ""Y3 Y
m " Y>
Y Y
Y' Y
Y 6Y?Y
Y Y Y
Y
Y45Y 6Y
Y'YY
YY

[edit]Types

[edit]  Y0
Y
It is a temporary paralysis of a portion of the intestines typically after an abdominal
surgery. Since the intestinal content of this portion is unable to move forward, food or
drink should be avoided until peristaltic sound is heard from auscultation of the area
where this portion lies.
[edit] 
Y0
Y
Paralysis of the intestine. To be termed "paralytic ileus," the intestinal paralysis need not
be complete, but it must be sufficient to prohibit the passage of food through the
intestine and lead to intestinal blockage.

Paralytic ileus is a common side effect of some types of surgery. It can also result from
certain drugs and from various injuries and illnesses. Paralytic ileus causes constipation
and bloating. On listening to the abdomen with a stethoscope, no bowel sounds are
heard because the bowel is inactive.
[edit]ÑY

Y 
Y
Also known as Ogilvie's syndrome.

[edit]Pathogenesis

Gangrenous ileum.

[edit]0
 Y

Y
Y
[edit]0

 
Y
Ileus may increase adhesion formation, because intestinal segments have more
prolonged contact, allowing fibrous adhesions to form, and intestinal distention causes
serosal injury and ischemia. Intestinal distention has been shown to cause adhesions in
foals [5]. Some respondents also mentioned the importance of walking horses
postoperatively to stimulate motility. Repeat celiotomy to decompress chronically
distended small intestine and remove fibrinous adhesions is also a useful method of
treating ileus and reducting adhesions, and it has been associated with a good
outcome [6][7]
[edit](  
YY
[edit]Symptoms

Symptoms of ileus include, but are not limited to:

§ moderate, diffuse abdominal discomfort

§ constipation
§ abdominal distension
§ nausea/vomiting, especially after meals
§ lack of bowel movement and/or flatulence
§ excessive belching
[edit]Risk Factors

§ gastrointestinal surgery or other GI procedures

§ electrolyte imbalance
§ diabetic ketoacidosis (DKA)[8], and other causes of metabolic acidosis
§ hypothyroidism
§ medications (e.g. opiates)
§ severe illness (Inflammation with peritonitis)
§ spinal cord injury (SCI), those with injury above thoracic vertebrae 5 (T5) will have
hypomotility problems within the bowel
[edit]Treatment in humans

Nil per os (NPO or "Nothing by Mouth") is mandatory in all cases. Nasogastric

suction and parenteral feeds may be required until passage is restored.
There are several options in the case of paralytic ileus. Most treatment is supportive. If
caused by medication, the offending agent is discontinued or reduced. Bowel
movements may be stimulated by prescribing lactulose, erythromycin or, in severe
cases (Ogilvie's syndrome), neostigmine.

If possible the underlying cause is corrected (e.g. replace electrolytes).

Y

Ganglion cyst
From Wikipedia, the free encyclopedia

w  
 

6



 
 Y

Y
( YY

Y/ 
 0
 0 Y

0
 " Y

  
  "" Y


   
! Y


  #$ Y

A 


Y, also known as a 
Y, is a swelling that often appears on or
around joints and tendons in the hand or foot. The size of the cyst can vary over time. It
is most frequently located around the dorsum of wrist and on the fingers. The term
"Bible bump" comes from a common urban legend that treatment in the past consisted
of hitting the cyst with a Bible or another large book.[1]

6



Y%
&Y

Y(Y
"Y Y
Y4  
Y
Y3
Y
 Y
Y'YY
YY
Y45Y 6Y

Cause

Ganglion cysts are idiopathic, but presumably reflect a variation in normal joint
or tendon sheath function. Cysts near joints are connected to the joint and the leading
theory is that a type of check valve forms that allows fluid out of the joint, but not back
in. The cyst contains clear fluid similar to, but thicker than, normal synovial fluid. They
are most often found around the wrist joint, especially at the scapho-lunate joint, which
accounts for 80% of all ganglion cysts.

Treatment

If a ganglion cyst is symptomatic, it can be managed by aspiration or excision.

Aspiration and injection of hyaluronidase into the cyst is the simpler of the two
procedures, but cysts recur in more than 50% of cases. With surgery, the recurrence
rate is reduced to only 5 to 10% if the check valve at the joint capsule is
removed. Arthroscopy of the wrist is becoming available as an alternative to open
excision of ganglion cysts. During arthroscopy, the origin of the cyst can be seen within
the joint.

An out-dated method of treating a ganglion cyst was supposedly to strike the lump with
a large heavy book, causing the cyst to rupture and drain into the surrounding tissues.
An urban legend states that since even the poorest households often possessed a
Bible, this was commonly used, which led to the nicknaming of ganglion cysts as
"Jillian's lump", "Bible bumps" or "Gideon's disease."[1] This type of treatment is not
recommended by some doctors as it can damage the area around the cyst and may
have a higher recurrence rate than aspiration or excision.[

 ]
Epidemiology

The epidemiology of ganglion cysts is not well studied, but some have stated that they
occur most often in the 20±40 age group and are three times more common in
women.[2]

[edit]Image gallery

Ganglion
From Wikipedia, the free encyclopedia

› 
O??"?w ‘ ?
 
 !

#w ‘#
?O› 
O??"?w ‘?
 
 !

Micrograph of a 


. H&E stain.

In anatomy, a 


(pronounced /' æŋ liԥn/, wÑDw ‘, plural  ‘) is
a biological tissue mass, most commonly a mass of nerve cell bodies.[1] Cells found in a
ganglion are called ganglion cells, though this term is also sometimes used to refer
specifically to retinal ganglion cells.

6



Y%
&Y

Y>
Y
m Y@Y

 Y
"Y  Y 
Y
Y'YY
YY

[edit]Neurology

In neurological contexts, ganglia are composed mainly of somata and dendritic

structures which are bundled or connected together. Ganglia often interconnect with
other ganglia to form a complex system of ganglia known as a plexus. Ganglia provide
relay points and intermediary connections between different neurological structures in
the body, such as the peripheral and central nervous systems.

There are two major groups of ganglia:

§ Dorsal root ganglia (also known as the spinal ganglia) contain the cell bodies
of sensory (afferent) nerves.
§ Autonomic ganglia contain the cell bodies of autonomic nerves.
In the autonomic nervous system, fibers from the central nervous system to the ganglia
are known as preganglionic fibers, while those from the ganglia to the effector organ are
calledpostganglionic fibers.
[edit]
Y

Y
The term "ganglion" usually refers to the peripheral nervous system.[2]

However, in the brain (part of the central nervous system), the "basal ganglia" is a group
of nuclei interconnected with the cerebral cortex, thalamus and brainstem, associated
with a variety of functions: motor control, cognition, emotions and learning.

Partly due to this ambiguity, the Ô ‘ Ñ
 recommends using the
term
?‘‘ instead of
?‘  ‘.

[edit]Additional image

Y
,Y
 
Y Y
Y)8Y Y
Y(Y2 Y

Y
YY

Y6Y
 Y2
Y
 YY789Y Y
Y

YY
  
Y
2
Y7YY
Y
 YYYY
Y

÷ Y
` YY

+Y
Y
YY
Y

YYYYYYYYY
Y:Y Y
Y

Y
+YYY(Y
Y2
Y
YY
Y(Y;
YY
Y2YY Y

+Y
Y Y
 
YY2Y
+Y

Y
YY2 Y Y
 YYYYY
Y
Y2Y  
YY

Y
YY+Y
YYY Y
Y
YY

÷ 
Y
` 7 
+Y:Y

Y
Y
Y2 

Y2Y
Y
Y;
YYY

YY
Y
Y

Y'+Y2
YY
 +Y
Y: +Y Y:Y YY
Y 
+Y
Y

(Y Y YY
Y7+YY;
YY(+Y(Y+Y

YYYYY

+YY
Y2Y(Y
Y
YYY
Y2YY
Y YYY;<YY2+Y
YYYYY
Y

YY
YY(+YYY
(YY Y

YYYY
+Y YYY
YY
YY2
(YYYYYY (Y
Y(Y
YY
Y
+Y


YYY
YY2
YYYY

YYY
(Y=YYY Y

Y Y 
Y

+Y Y:Y;<Y

Y 
Y
Y 
Y  YYY2 
Y

Y YY
YYY
Y2
Y
(YYYY  Y
YYY
Y

Y

Y
Y2Y
` Y2 
Y;
Y
Y
Y Y

YYYY
(YY(Y

Y
Y

(YY

Y YY2
YY
2 2YYYY
Y
(
YYY2
Y YY
2 2YY
;
+Y2Y
YY2Y
2YY

YYY
 +Y
(YYY Y(Y>
+Y
2YYYYYY2YYY+YY;
Y
YYY2Y
Y(Y
Y:Y

` #YY Y
Y
 Y
m Y Y YYY2
(Y?
 
Y Y
?+YYY Y?
Y Y

?+Y YYYY2Y
YYY YYYY Y
:+YY



Y2Y
Y Y
Y
m Y
Y
YY2
YYY Y? Y
Y
Y?YYY Y
Y2YY
YY Y
YY
+Y

Y
YY
YY
Y
 
Y Y
Y
m Y2
(YYY
Y:YYY Y?Y?+YYYY2
YYY
 
YY
Y
Y
Y YYY 
+Y Y
Y
Y2Y

Y

Y

YY
Y:YYY
Y
Y
YYY
 Y Y
2Y YYY:Y

÷ 
   
Y
` =
Y

Y
Y
` ?% YY ?Y  

Y
Y

 Y

Y7',+YY
Y
 +Y
2 +Y
 +Y Y( Y#(YY Y

Y 

Y2Y
Y
Y

Y
Y
Y
` 'Y+YY 

Y

+YY
YYYY
Y
Y2(+Y

Y
  YYY'YY (+Y2YY
"Y 
YYYY
YY
2
(YYYY
Y2YY 

YY
YY 2
Y
Y 

YY



YYY
Y@2Y
YY2(+Y

Y
YY2Y

Y?8

"Y


?YYY Y
` 'YY
YY

YYY2Y(YYY
Y
Y Y

YYY
YYYY
Y:YYY Y"Y YY
YAYY
Y

YY
Y Y
YYY:Y

÷ 

  
Y
` 0 
Y
Y
YY

YYY YY

YY

÷ 
    
Y
` # Y
YY

YYY 2YY
` 0  2Y
YY  YYY
` 
YYYY
Y
Y

Y2Y:YY

YY YY (YY
2 Y YYY YY
Y
YYY Y:Y
` 0  Y  YY YYY

Y
YYY

Y YYYY Y

 
 


Y
Y

YY
YY

` 
Y
YY
Y Y(YY2Y 
YY
Y YY
YYY
 Y:Y
` #YY Y:Y
YY(YYY2
(Y
 Y  YYY:YYY
?

Y?+Y2Y
YY:YY 
YY
Y
YY:YY2Y

YY
 Y  YY9 Y
+YYYY2
(YYY YY2
(Y

2YYYY YYYY:YYY

Y+Y2YY
2YYYY
YYYY:YY

YY
` #YYY YYY Y
Y Y
Y
Y Y(YYY2
(Y
 Y
  Y
YYYY2
(YYY Y
 
Y Y
Y

÷  

  




Y
Y

YY
Y(
YY 2Y" Y
+Y2YYY
Y
Y

YY
Y YY
(
YY2Y
Y
 Y

Y2Y
Y
YY
(Y Y
YY
YY Y
Y

Y
Y 2YY9 Y
+Y

` 0
YY
Y2Y
Y2
YY

 Y 2Y Y
Y
YYYY
,Y+Y
Y


YY
Y
Y
Y2Y
YY
 Y
 +Y
2Y +Y
Y: Y Y
 Y
` #Y
Y
YYY
 Y2Y

Y
Y YYY 2YY
` #YYY2
(YYY
Y:YYY YYY
Y


YY

Y

(YY Y(+Y
Y;
YY

YY2Y
Y
Y2
 
YY Y
Y:+YY
Y
Y YY

%YYYYY
Y2Y



Y2Y
Y
+YYYY YY Y

Y
YYY
Y Y
Y (+Y

Y
Y2YYY
Y
Y
YY


YY YY@Y 
Y

Y 
YY Y
Y
YY

Y
YY 
Y
Cholecystitis
From Wikipedia, the free encyclopedia


  

6



 
 Y

Y
0 

YYY
Y/ 
Y

  Y
 Y

0
 1 Y

0
 $2YY

  
  ""$ Y


   !  Y


  #$$" Y

6
 is inflammation of the gall bladder.

6



Y%
& Y

Y(YY

Y
"Y' Y

Y# 
 Y

m Y#  Y 

 Y

§ YY
   Y

§ "Y(
 Y
   Y

§  YA 6Y#  Y

Y3.
 Y

m Y@Y

m "Y 
Y

Y
 Y

Y(  YY
   Y

m Y(  YY
  Y

§ Y+YY Y

Y'YY

YY

[edit]Causes and pathology

Cholecystitis is often caused by cholelithiasis (the presence of choleliths, or gallstones, in the gallbladder), with
choleliths most commonly blocking the cystic duct directly. This leads toinspissation (thickening) of bile,
bile stasis, and secondary infection by gut organisms, predominantly  ‘ and 
 ? species.

The gallbladder's wall becomes inflamed. Extreme cases may result in necrosis and rupture. Inflammation
often spreads to its outer covering, thus irritating surrounding structures such as the diaphragm and bowel.

Less commonly, in debilitated and trauma patients, the gallbladder may become inflamed and infected in the
absence of cholelithiasis, and is known as acute acalculous cholecystitis.

Stones in the gallbladder may cause obstruction and the accompanying acute attack. The patient might
develop a chronic, low-level inflammation which leads to a chronic cholecystitis, where the gallbladder is fibrotic
and calcified.

[edit]Symptoms

Cholecystitis usually presents as a pain in the right upper quadrant. This is usually a constant, severe pain. The
pain may be felt to 'refer' to the right flank or right scapular region at first.

This may also present with the above mentioned pain after eating greasy or fatty foods such as pastries, pies
and fried foods.
This is usually accompanied by a low grade fever, vomiting and nausea.

More severe symptoms such as high fever, shock and jaundice indicate the development of complications such
as abscess formation, perforation or ascending cholangitis. Another complication, gallstone ileus, occurs if the
gallbladder perforates and forms a fistula with the nearby small bowel, leading to symptoms of intestinal
obstruction.

Chronic cholecystitis manifests with non-specific symptoms such as nausea, vague abdominal pain, belching,
and diarrhea.

[edit]Diagnosis

Cholecystitis is usually diagnosed by a history of the above symptoms, as well examination findings:

§ fever (usually low grade in uncomplicated cases)

§ tender right upper quadrant +/- Murphy's sign

§ Ortner's sign - tenderness when hand taps the edge of right costal arch.

§ Georgievskiy-Myussi's sign (phrenic nerve sign) - pain when press between edges of sternocleidomastoid
muscle. [1]

Subsequent laboratory and imaging tests are used to confirm the diagnosis and exclude other possible causes.

Ultrasound can assist in the differential.[2][3]

[edit]!

Y
Y

x
Ñ




  

§ This should be suspected whenever there is acute right upper quadrant or epigastric pain.
§ Other possible causes include:

§ Perforated peptic ulcer

§ Acute peptic ulcer exacerbation

§ Amoebic liver abscess

§ Acute amoebic liver colitis

§ Acute pancreatitis

§ Acute intestinal obstruction

§ Renal colic
§ Acute retrocolic appendicitis
x
6




  

The symptoms of chronic cholecystitis are non-specific, thus chronic cholecystitis may be mistaken for other
common disorders:

§ Peptic ulcer
§ Hiatus hernia

§ Colitis
§ Functional bowel syndrome

It is defined pathologically by the columnar epithelium has reached down the muscular layer.

x
f

  

§ Biliary colic - Caused by obstruction of the cystic duct. It is associated with sharp and
constant epigastric pain in the absence of fever and usually there is a negative Murphy's sign. Liver
function tests are within normal limits since the obstruction does not necessarily cause blockage in the
common hepatic duct, thereby allowing normal bile excretion from the liver. An ultrasound scan is used to
visualise the gallbladder and associated ducts, and also to determine the size and precise position of the
obstruction.

§ Cholecystitis - Caused by blockage of the cystic duct with surrounding inflammation, usually due to
infection. Typically, the pain is initially 'colicky' (intermittent), and becomes constant and severe, mostly in
the right upper quadrant. Infectious agents that cause cholecystitis include 
 ‘, ‘
?‘‘, ?  ?,  ‘? and 
  ?. Murphy's sign is positive, particularly because
of increased irritation of the gallbladder lining, and similarly this pain radiates (spreads) to the shoulder,
flank or in a band like pattern around the lower abdomen. Laboratory tests frequently show raised
hepatocellular liver enzymes (AST, ALT) with a high white cell count (WBC). Ultrasound is used to
visualise the gallbladder and ducts.

§ Choledocholithiasis - This refers to blockage of the common bile duct where a gallstone has left the
gallbladder  has formed in the common bile duct (primary cholelithiasis). As with other biliary tree
obstructions it is usually associated with 'colicky' pain, and because there is direct obstruction of biliary
output, obstructive jaundice. Liver function tests will therefore show increased serum bilirubin, with
high conjugated bilirubin. Liver enzymes will also be raised, predominately GGT and ALP, which are
associated with biliary epithelium. The diagnosis is made using endoscopic retrograde
cholangiopancreatography (ERCP), or the nuclear alternative (MRCP). One of the more serious
complications of choledocholithiasis isacute pancreatitis, which may result in significant permanent
pancreatic damage and brittle diabetes.
§ Cholangitis - An infection of entire biliary tract, and may also be known as 'ascending cholangitis', which
refers to the presence of pathogens that typically inhabit more distal regions of the bowel[4]

Cholangitis is a medical emergency as it may be life threatening and patients can rapidly succumb to acute
liver failure or bacterial sepsis. The classical sign of cholangitis is Charcot's triad, which is right upper quadrant
pain, fever and jaundice. Liver function tests will likely show increases across all enzymes (AST, ALT, ALP,
GGT) with raised bilirubin. As with choledocholithiasis, diagnosis is confirmed using cholangiopancreatography.

0
? 
O
 
O

‘?
‘  
‘  
O 

"
 ?
O??

‘ ‘  
 $
?

[edit]Investigations

[edit]
Y

Laboratory values may be notable for an elevated alkaline phosphatase, possibly an

elevated bilirubin (although this may indicate choledocholithiasis), and possibly an elevation of theWBC count.
CRP (C-reactive protein) is often elevated. The degree of elevation of these laboratory values may depend on
the degree of inflammation of the gallbladder. Patients with acute cholecystitis are much more likely to manifest
abnormal laboratory values, while in chronic cholecystitis the laboratory values are frequently normal.

[edit]$
Y

Sonography is a sensitive and specific modality for diagnosis of acute cholecystitis; adjusted sensitivity and
specificity for diagnosis of acute cholecystitis are 88% and 80%, respectively. The 2 major diagnostic criteria
are cholelithiasis and sonographic Murphy's sign. Minor criteria include gallbladder wall thickening greater than
3mm, pericholecystic fluid, and gallbladder dilatation.

The reported sensitivity and specificity of CT scan findings are in the range of 90-95%. CT is more sensitive
than ultrasonography in the depiction of pericholecystic inflammatory response and in localizing pericholecystic
abscesses, pericholecystic gas, and calculi outside the lumen of the gallbladder. CT cannot see noncalcified
gallbladder calculi, and cannot assess for a Murphy's sign.

Hepatobiliary scintigraphy with technetium-99m DISIDA (bilirubin) analog is also sensitive and accurate for
diagnosis of chronic and acute cholecystitis. It can also assess the ability of the gall bladder to expel bile (gall
bladder ejection fraction), and low gall bladder ejection fraction has been linked to chronic cholecystitis.
However, since most patients with right upper quadrant pain do not have cholecystitis, primary evaluation is
usually accomplished with a modality that can diagnose other causes, as well.

[edit]Therapy
X-Ray during laparoscopic cholecystectomy

For most patients, in most centres, the definitive treatment is surgical removal of the gallbladder. Supportive
measures are instituted in the meantime and to prepare the patient for surgery. These measures include fluid
resuscitation and antibiotics. Antibiotic regimens usually consist of a broad spectrum antibiotic such as
piperacillin-tazobactam (Zosyn), ampicillin-sulbactam (Unasyn), ticarcillin-clavulanate (Timentin), or a
cephalosporin (e.g.ceftriaxone) and an antibacterial with good coverage (fluoroquinolone such asciprofloxacin)
and anaerobic bacteria coverage, such as metronidazole. For penicillin allergic patients, aztreonam and
clindamycin may be used.cis

Gallbladder removal, cholecystectomy, can be accomplished via open surgery or a laparoscopic procedure.
Laparoscopic procedures can have less morbidity and a shorter recovery stay. Open procedures are usually
done if complications have developed or the patient has had prior surgery to the area, making laparoscopic
surgery technically difficult. A laparoscopic procedure may also be 'converted' to an open procedure during the
operation if the surgeon feels that further attempts at laparoscopic removal might harm the patient. Open
procedure may also be done if the surgeon does not know how to perform a laparoscopic cholecystectomy.

In cases of severe inflammation, shock, or if the patient has higher risk for general anesthesia (required
for cholecystectomy), the managing physician may elect to have an interventional radiologist insert
a percutaneous drainage catheter into the gallbladder ('percutaneous cholecystostomy tube') and treat the
patient with antibiotics until the acute inflammation resolves. The patient may later warrant cholecystectomy if
their condition improves.

[edit]Complications of cholecystitis

§ Perforation or rupture
§ Ascending cholangitis
§ Rokitansky-Aschoff sinuses
[edit]6 

Y Y
 Y

§ bile leak ("biloma")

§ bile duct injury (about 5-7 out of 1000 operations. Open and laparoscopic surgeries have essentially equal
rate of injuries, but the recent trend is towards fewer injuries with laparoscopy. It may be that the open
cases often result because the gallbladder is too difficult or risky to remove with laparoscopy)
§ abscess

§ wound infection
§ bleeding (liver surface and cystic artery are most common sites)

§ hernia

§ organ injury (intestine and liver are at highest risk, especially if the gallbladder has become
adherent/scarred to other organs due to inflammation (e.g. transverse colon)

§ deep vein thrombosis/pulmonary embolism (unusual- risk can be decreased through use of sequential
compression devices on legs during surgery)

§ fatty acid and fat-soluble vitamin malabsorption

x
w    
Gall bladder perforation (GBP) is a rare but life-threatening complication of acute cholecystitis. The early
diagnosis and treatment of GBP are crucial to decrease patient morbidity and mortality.

Approaches to this complication will vary based on the condition of an individual patient, the evaluation of the
treating surgeon or physician, and the facilities' capability. Perforation can happen at the neck from pressure
necrosis due to the impacted calculus, or at the fundus. It can result in a local abscess, or perforation into the
general peritoneal cavity. If the bile is infected, diffuse peritonitis may occur readily and rapidly and may result
in death.

A retrospective study looked at 332 patients who received medical and/or surgical treatment with the diagnosis
of acute cholecystitis. Patients were treated with analgesics and antibiotics within the first 36 hours after
admission (with a mean of 9 hours), and proceeded to surgery for a cholecystectomy. Two patients died and 6
patients had further complications. The morbidity and mortality rates were 37.5% and 12.5%, respectively in the
present study. The authors of this study suggests that early diagnosis and emergency surgical treatment of
gallbladder perforation are of crucial importance.[5]

Y
Cholecystitis
From Wikipedia, the free encyclopedia


  

6



 
 Y

Y
0 

YYY
Y/ 
Y

  Y
 Y

0
 1 Y

0
 $2YY

  
  ""$ Y


   !  Y


  #$$" Y

6
 is inflammation of the gall bladder.

6



Y%
& Y

Y(YY

Y

"Y' Y

Y# 
 Y
 m Y#  Y 
 Y

§ YY
   Y

§ "Y(
 Y
   Y

§  YA 6Y#  Y

Y3.
 Y

m Y@Y

m "Y 
Y

Y
 Y

Y(  YY
   Y

m Y(  YY
  Y

§ Y+YY Y

Y'YY

YY

[edit]Causes and pathology

Cholecystitis is often caused by cholelithiasis (the presence of choleliths, or gallstones, in the gallbladder), with
choleliths most commonly blocking the cystic duct directly. This leads toinspissation (thickening) of bile,
bile stasis, and secondary infection by gut organisms, predominantly  ‘ and 
 ? species.

The gallbladder's wall becomes inflamed. Extreme cases may result in necrosis and rupture. Inflammation
often spreads to its outer covering, thus irritating surrounding structures such as the diaphragm and bowel.

Less commonly, in debilitated and trauma patients, the gallbladder may become inflamed and infected in the
absence of cholelithiasis, and is known as acute acalculous cholecystitis.

Stones in the gallbladder may cause obstruction and the accompanying acute attack. The patient might
develop a chronic, low-level inflammation which leads to a chronic cholecystitis, where the gallbladder is fibrotic
and calcified.

[edit]Symptoms

Cholecystitis usually presents as a pain in the right upper quadrant. This is usually a constant, severe pain. The
pain may be felt to 'refer' to the right flank or right scapular region at first.

This may also present with the above mentioned pain after eating greasy or fatty foods such as pastries, pies
and fried foods.

This is usually accompanied by a low grade fever, vomiting and nausea.

More severe symptoms such as high fever, shock and jaundice indicate the development of complications such
as abscess formation, perforation or ascending cholangitis. Another complication, gallstone ileus, occurs if the
gallbladder perforates and forms a fistula with the nearby small bowel, leading to symptoms of intestinal
obstruction.

Chronic cholecystitis manifests with non-specific symptoms such as nausea, vague abdominal pain, belching,
and diarrhea.

[edit]Diagnosis

Cholecystitis is usually diagnosed by a history of the above symptoms, as well examination findings:

§ fever (usually low grade in uncomplicated cases)

§ tender right upper quadrant +/- Murphy's sign

§ Ortner's sign - tenderness when hand taps the edge of right costal arch.

§ Georgievskiy-Myussi's sign (phrenic nerve sign) - pain when press between edges of sternocleidomastoid
muscle. [1]

Subsequent laboratory and imaging tests are used to confirm the diagnosis and exclude other possible causes.

Ultrasound can assist in the differential.[2][3]

[edit]!

Y
Y

x
Ñ




  

§ This should be suspected whenever there is acute right upper quadrant or epigastric pain.
§ Other possible causes include:
§ Perforated peptic ulcer
§ Acute peptic ulcer exacerbation

§ Amoebic liver abscess

§ Acute amoebic liver colitis

§ Acute pancreatitis

§ Acute intestinal obstruction

§ Renal colic
§ Acute retrocolic appendicitis

x
6




  

The symptoms of chronic cholecystitis are non-specific, thus chronic cholecystitis may be mistaken for other
common disorders:
§ Peptic ulcer
§ Hiatus hernia

§ Colitis

§ Functional bowel syndrome

It is defined pathologically by the columnar epithelium has reached down the muscular layer.

x
f

  

§ Biliary colic - Caused by obstruction of the cystic duct. It is associated with sharp and
constant epigastric pain in the absence of fever and usually there is a negative Murphy's sign. Liver
function tests are within normal limits since the obstruction does not necessarily cause blockage in the
common hepatic duct, thereby allowing normal bile excretion from the liver. An ultrasound scan is used to
visualise the gallbladder and associated ducts, and also to determine the size and precise position of the
obstruction.

§ Cholecystitis - Caused by blockage of the cystic duct with surrounding inflammation, usually due to
infection. Typically, the pain is initially 'colicky' (intermittent), and becomes constant and severe, mostly in
the right upper quadrant. Infectious agents that cause cholecystitis include 
 ‘, ‘
?‘‘, ?  ?,  ‘? and 
  ?. Murphy's sign is positive, particularly because
of increased irritation of the gallbladder lining, and similarly this pain radiates (spreads) to the shoulder,
flank or in a band like pattern around the lower abdomen. Laboratory tests frequently show raised
hepatocellular liver enzymes (AST, ALT) with a high white cell count (WBC). Ultrasound is used to
visualise the gallbladder and ducts.

§ Choledocholithiasis - This refers to blockage of the common bile duct where a gallstone has left the
gallbladder  has formed in the common bile duct (primary cholelithiasis). As with other biliary tree
obstructions it is usually associated with 'colicky' pain, and because there is direct obstruction of biliary
output, obstructive jaundice. Liver function tests will therefore show increased serum bilirubin, with
high conjugated bilirubin. Liver enzymes will also be raised, predominately GGT and ALP, which are
associated with biliary epithelium. The diagnosis is made using endoscopic retrograde
cholangiopancreatography (ERCP), or the nuclear alternative (MRCP). One of the more serious
complications of choledocholithiasis isacute pancreatitis, which may result in significant permanent
pancreatic damage and brittle diabetes.

§ Cholangitis - An infection of entire biliary tract, and may also be known as 'ascending cholangitis', which
refers to the presence of pathogens that typically inhabit more distal regions of the bowel[4]

Cholangitis is a medical emergency as it may be life threatening and patients can rapidly succumb to acute
liver failure or bacterial sepsis. The classical sign of cholangitis is Charcot's triad, which is right upper quadrant
pain, fever and jaundice. Liver function tests will likely show increases across all enzymes (AST, ALT, ALP,
GGT) with raised bilirubin. As with choledocholithiasis, diagnosis is confirmed using cholangiopancreatography.

0
? 
O
 
O

‘?
‘  
‘  
O 

"
 ?
O??

‘ ‘  
 $
?

[edit]Investigations

[edit]
Y

Laboratory values may be notable for an elevated alkaline phosphatase, possibly an

elevated bilirubin (although this may indicate choledocholithiasis), and possibly an elevation of theWBC count.
CRP (C-reactive protein) is often elevated. The degree of elevation of these laboratory values may depend on
the degree of inflammation of the gallbladder. Patients with acute cholecystitis are much more likely to manifest
abnormal laboratory values, while in chronic cholecystitis the laboratory values are frequently normal.

[edit]$
Y

Sonography is a sensitive and specific modality for diagnosis of acute cholecystitis; adjusted sensitivity and
specificity for diagnosis of acute cholecystitis are 88% and 80%, respectively. The 2 major diagnostic criteria
are cholelithiasis and sonographic Murphy's sign. Minor criteria include gallbladder wall thickening greater than
3mm, pericholecystic fluid, and gallbladder dilatation.

The reported sensitivity and specificity of CT scan findings are in the range of 90-95%. CT is more sensitive
than ultrasonography in the depiction of pericholecystic inflammatory response and in localizing pericholecystic
abscesses, pericholecystic gas, and calculi outside the lumen of the gallbladder. CT cannot see noncalcified
gallbladder calculi, and cannot assess for a Murphy's sign.

Hepatobiliary scintigraphy with technetium-99m DISIDA (bilirubin) analog is also sensitive and accurate for
diagnosis of chronic and acute cholecystitis. It can also assess the ability of the gall bladder to expel bile (gall
bladder ejection fraction), and low gall bladder ejection fraction has been linked to chronic cholecystitis.
However, since most patients with right upper quadrant pain do not have cholecystitis, primary evaluation is
usually accomplished with a modality that can diagnose other causes, as well.

[edit]Therapy
X-Ray during laparoscopic cholecystectomy

For most patients, in most centres, the definitive treatment is surgical removal of the gallbladder. Supportive
measures are instituted in the meantime and to prepare the patient for surgery. These measures include fluid
resuscitation and antibiotics. Antibiotic regimens usually consist of a broad spectrum antibiotic such as
piperacillin-tazobactam (Zosyn), ampicillin-sulbactam (Unasyn), ticarcillin-clavulanate (Timentin), or a
cephalosporin (e.g.ceftriaxone) and an antibacterial with good coverage (fluoroquinolone such asciprofloxacin)
and anaerobic bacteria coverage, such as metronidazole. For penicillin allergic patients, aztreonam and
clindamycin may be used.cis

Gallbladder removal, cholecystectomy, can be accomplished via open surgery or a laparoscopic procedure.
Laparoscopic procedures can have less morbidity and a shorter recovery stay. Open procedures are usually
done if complications have developed or the patient has had prior surgery to the area, making laparoscopic
surgery technically difficult. A laparoscopic procedure may also be 'converted' to an open procedure during the
operation if the surgeon feels that further attempts at laparoscopic removal might harm the patient. Open
procedure may also be done if the surgeon does not know how to perform a laparoscopic cholecystectomy.

In cases of severe inflammation, shock, or if the patient has higher risk for general anesthesia (required
for cholecystectomy), the managing physician may elect to have an interventional radiologist insert
a percutaneous drainage catheter into the gallbladder ('percutaneous cholecystostomy tube') and treat the
patient with antibiotics until the acute inflammation resolves. The patient may later warrant cholecystectomy if
their condition improves.

[edit]Complications of cholecystitis

§ Perforation or rupture
§ Ascending cholangitis
§ Rokitansky-Aschoff sinuses
[edit]6 

Y Y
 Y

§ bile leak ("biloma")

§ bile duct injury (about 5-7 out of 1000 operations. Open and laparoscopic surgeries have essentially equal
rate of injuries, but the recent trend is towards fewer injuries with laparoscopy. It may be that the open
cases often result because the gallbladder is too difficult or risky to remove with laparoscopy)
§ abscess

§ wound infection
§ bleeding (liver surface and cystic artery are most common sites)

§ hernia

§ organ injury (intestine and liver are at highest risk, especially if the gallbladder has become
adherent/scarred to other organs due to inflammation (e.g. transverse colon)

§ deep vein thrombosis/pulmonary embolism (unusual- risk can be decreased through use of sequential
compression devices on legs during surgery)

§ fatty acid and fat-soluble vitamin malabsorption

x
w    
Gall bladder perforation (GBP) is a rare but life-threatening complication of acute cholecystitis. The early
diagnosis and treatment of GBP are crucial to decrease patient morbidity and mortality.

Approaches to this complication will vary based on the condition of an individual patient, the evaluation of the
treating surgeon or physician, and the facilities' capability. Perforation can happen at the neck from pressure
necrosis due to the impacted calculus, or at the fundus. It can result in a local abscess, or perforation into the
general peritoneal cavity. If the bile is infected, diffuse peritonitis may occur readily and rapidly and may result
in death.

A retrospective study looked at 332 patients who received medical and/or surgical treatment with the diagnosis
of acute cholecystitis. Patients were treated with analgesics and antibiotics within the first 36 hours after
admission (with a mean of 9 hours), and proceeded to surgery for a cholecystectomy. Two patients died and 6
patients had further complications. The morbidity and mortality rates were 37.5% and 12.5%, respectively in the
present study. The authors of this study suggests that early diagnosis and emergency surgical treatment of
gallbladder perforation are of crucial importance.[5]

Y
Y

Cholecystitis
From Wikipedia, the free encyclopedia


  

6



 
 Y

Y
0 

YYY
Y/ 
Y

  Y
 Y

0
 1 Y

0
 $2YY

  
  ""$ Y


   !  Y


  #$$" Y

6
 is inflammation of the gall bladder.

6



Y%
& Y
Y(YY

Y

"Y' Y

Y# 
 Y

m Y#  Y 

 Y

§ YY
   Y

§ "Y(
 Y
   Y

§  YA 6Y#  Y

Y3.
 Y

m Y@Y

m "Y 
Y

Y
 Y

Y(  YY
   Y

m Y(  YY
  Y

§ Y+YY Y

Y'YY

YY

[edit]Causes and pathology

Cholecystitis is often caused by cholelithiasis (the presence of choleliths, or gallstones, in the gallbladder), with
choleliths most commonly blocking the cystic duct directly. This leads toinspissation (thickening) of bile,
bile stasis, and secondary infection by gut organisms, predominantly  ‘ and 
 ? species.

The gallbladder's wall becomes inflamed. Extreme cases may result in necrosis and rupture. Inflammation
often spreads to its outer covering, thus irritating surrounding structures such as the diaphragm and bowel.

Less commonly, in debilitated and trauma patients, the gallbladder may become inflamed and infected in the
absence of cholelithiasis, and is known as acute acalculous cholecystitis.

Stones in the gallbladder may cause obstruction and the accompanying acute attack. The patient might
develop a chronic, low-level inflammation which leads to a chronic cholecystitis, where the gallbladder is fibrotic
and calcified.

[edit]Symptoms

Cholecystitis usually presents as a pain in the right upper quadrant. This is usually a constant, severe pain. The
pain may be felt to 'refer' to the right flank or right scapular region at first.
This may also present with the above mentioned pain after eating greasy or fatty foods such as pastries, pies
and fried foods.

This is usually accompanied by a low grade fever, vomiting and nausea.

More severe symptoms such as high fever, shock and jaundice indicate the development of complications such
as abscess formation, perforation or ascending cholangitis. Another complication, gallstone ileus, occurs if the
gallbladder perforates and forms a fistula with the nearby small bowel, leading to symptoms of intestinal
obstruction.

Chronic cholecystitis manifests with non-specific symptoms such as nausea, vague abdominal pain, belching,
and diarrhea.

[edit]Diagnosis

Cholecystitis is usually diagnosed by a history of the above symptoms, as well examination findings:

§ fever (usually low grade in uncomplicated cases)

§ tender right upper quadrant +/- Murphy's sign

§ Ortner's sign - tenderness when hand taps the edge of right costal arch.

§ Georgievskiy-Myussi's sign (phrenic nerve sign) - pain when press between edges of sternocleidomastoid
muscle. [1]

Subsequent laboratory and imaging tests are used to confirm the diagnosis and exclude other possible causes.

Ultrasound can assist in the differential.[2][3]

[edit]!

Y
Y

x
Ñ




  

§ This should be suspected whenever there is acute right upper quadrant or epigastric pain.
§ Other possible causes include:

§ Perforated peptic ulcer

§ Acute peptic ulcer exacerbation

§ Amoebic liver abscess

§ Acute amoebic liver colitis

§ Acute pancreatitis

§ Acute intestinal obstruction

§ Renal colic
§ Acute retrocolic appendicitis
x
6




  

The symptoms of chronic cholecystitis are non-specific, thus chronic cholecystitis may be mistaken for other
common disorders:

§ Peptic ulcer
§ Hiatus hernia

§ Colitis
§ Functional bowel syndrome

It is defined pathologically by the columnar epithelium has reached down the muscular layer.

x
f

  

§ Biliary colic - Caused by obstruction of the cystic duct. It is associated with sharp and
constant epigastric pain in the absence of fever and usually there is a negative Murphy's sign. Liver
function tests are within normal limits since the obstruction does not necessarily cause blockage in the
common hepatic duct, thereby allowing normal bile excretion from the liver. An ultrasound scan is used to
visualise the gallbladder and associated ducts, and also to determine the size and precise position of the
obstruction.

§ Cholecystitis - Caused by blockage of the cystic duct with surrounding inflammation, usually due to
infection. Typically, the pain is initially 'colicky' (intermittent), and becomes constant and severe, mostly in
the right upper quadrant. Infectious agents that cause cholecystitis include 
 ‘, ‘
?‘‘, ?  ?,  ‘? and 
  ?. Murphy's sign is positive, particularly because
of increased irritation of the gallbladder lining, and similarly this pain radiates (spreads) to the shoulder,
flank or in a band like pattern around the lower abdomen. Laboratory tests frequently show raised
hepatocellular liver enzymes (AST, ALT) with a high white cell count (WBC). Ultrasound is used to
visualise the gallbladder and ducts.

§ Choledocholithiasis - This refers to blockage of the common bile duct where a gallstone has left the
gallbladder  has formed in the common bile duct (primary cholelithiasis). As with other biliary tree
obstructions it is usually associated with 'colicky' pain, and because there is direct obstruction of biliary
output, obstructive jaundice. Liver function tests will therefore show increased serum bilirubin, with
high conjugated bilirubin. Liver enzymes will also be raised, predominately GGT and ALP, which are
associated with biliary epithelium. The diagnosis is made using endoscopic retrograde
cholangiopancreatography (ERCP), or the nuclear alternative (MRCP). One of the more serious
complications of choledocholithiasis isacute pancreatitis, which may result in significant permanent
pancreatic damage and brittle diabetes.
§ Cholangitis - An infection of entire biliary tract, and may also be known as 'ascending cholangitis', which
refers to the presence of pathogens that typically inhabit more distal regions of the bowel[4]

Cholangitis is a medical emergency as it may be life threatening and patients can rapidly succumb to acute
liver failure or bacterial sepsis. The classical sign of cholangitis is Charcot's triad, which is right upper quadrant
pain, fever and jaundice. Liver function tests will likely show increases across all enzymes (AST, ALT, ALP,
GGT) with raised bilirubin. As with choledocholithiasis, diagnosis is confirmed using cholangiopancreatography.

0
? 
O
 
O

‘?
‘  
‘  
O 

"
 ?
O??

‘ ‘  
 $
?

[edit]Investigations

[edit]
Y

Laboratory values may be notable for an elevated alkaline phosphatase, possibly an

elevated bilirubin (although this may indicate choledocholithiasis), and possibly an elevation of theWBC count.
CRP (C-reactive protein) is often elevated. The degree of elevation of these laboratory values may depend on
the degree of inflammation of the gallbladder. Patients with acute cholecystitis are much more likely to manifest
abnormal laboratory values, while in chronic cholecystitis the laboratory values are frequently normal.

[edit]$
Y

Sonography is a sensitive and specific modality for diagnosis of acute cholecystitis; adjusted sensitivity and
specificity for diagnosis of acute cholecystitis are 88% and 80%, respectively. The 2 major diagnostic criteria
are cholelithiasis and sonographic Murphy's sign. Minor criteria include gallbladder wall thickening greater than
3mm, pericholecystic fluid, and gallbladder dilatation.

The reported sensitivity and specificity of CT scan findings are in the range of 90-95%. CT is more sensitive
than ultrasonography in the depiction of pericholecystic inflammatory response and in localizing pericholecystic
abscesses, pericholecystic gas, and calculi outside the lumen of the gallbladder. CT cannot see noncalcified
gallbladder calculi, and cannot assess for a Murphy's sign.

Hepatobiliary scintigraphy with technetium-99m DISIDA (bilirubin) analog is also sensitive and accurate for
diagnosis of chronic and acute cholecystitis. It can also assess the ability of the gall bladder to expel bile (gall
bladder ejection fraction), and low gall bladder ejection fraction has been linked to chronic cholecystitis.
However, since most patients with right upper quadrant pain do not have cholecystitis, primary evaluation is
usually accomplished with a modality that can diagnose other causes, as well.

[edit]Therapy
X-Ray during laparoscopic cholecystectomy

For most patients, in most centres, the definitive treatment is surgical removal of the gallbladder. Supportive
measures are instituted in the meantime and to prepare the patient for surgery. These measures include fluid
resuscitation and antibiotics. Antibiotic regimens usually consist of a broad spectrum antibiotic such as
piperacillin-tazobactam (Zosyn), ampicillin-sulbactam (Unasyn), ticarcillin-clavulanate (Timentin), or a
cephalosporin (e.g.ceftriaxone) and an antibacterial with good coverage (fluoroquinolone such asciprofloxacin)
and anaerobic bacteria coverage, such as metronidazole. For penicillin allergic patients, aztreonam and
clindamycin may be used.cis

Gallbladder removal, cholecystectomy, can be accomplished via open surgery or a laparoscopic procedure.
Laparoscopic procedures can have less morbidity and a shorter recovery stay. Open procedures are usually
done if complications have developed or the patient has had prior surgery to the area, making laparoscopic
surgery technically difficult. A laparoscopic procedure may also be 'converted' to an open procedure during the
operation if the surgeon feels that further attempts at laparoscopic removal might harm the patient. Open
procedure may also be done if the surgeon does not know how to perform a laparoscopic cholecystectomy.

In cases of severe inflammation, shock, or if the patient has higher risk for general anesthesia (required
for cholecystectomy), the managing physician may elect to have an interventional radiologist insert
a percutaneous drainage catheter into the gallbladder ('percutaneous cholecystostomy tube') and treat the
patient with antibiotics until the acute inflammation resolves. The patient may later warrant cholecystectomy if
their condition improves.

[edit]Complications of cholecystitis

§ Perforation or rupture
§ Ascending cholangitis
§ Rokitansky-Aschoff sinuses
[edit]6 

Y Y
 Y

§ bile leak ("biloma")

§ bile duct injury (about 5-7 out of 1000 operations. Open and laparoscopic surgeries have essentially equal
rate of injuries, but the recent trend is towards fewer injuries with laparoscopy. It may be that the open
cases often result because the gallbladder is too difficult or risky to remove with laparoscopy)
§ abscess

§ wound infection
§ bleeding (liver surface and cystic artery are most common sites)

§ hernia

§ organ injury (intestine and liver are at highest risk, especially if the gallbladder has become
adherent/scarred to other organs due to inflammation (e.g. transverse colon)

§ deep vein thrombosis/pulmonary embolism (unusual- risk can be decreased through use of sequential
compression devices on legs during surgery)

§ fatty acid and fat-soluble vitamin malabsorption

x
w    
Gall bladder perforation (GBP) is a rare but life-threatening complication of acute cholecystitis. The early
diagnosis and treatment of GBP are crucial to decrease patient morbidity and mortality.

Approaches to this complication will vary based on the condition of an individual patient, the evaluation of the
treating surgeon or physician, and the facilities' capability. Perforation can happen at the neck from pressure
necrosis due to the impacted calculus, or at the fundus. It can result in a local abscess, or perforation into the
general peritoneal cavity. If the bile is infected, diffuse peritonitis may occur readily and rapidly and may result
in death.

A retrospective study looked at 332 patients who received medical and/or surgical treatment with the diagnosis
of acute cholecystitis. Patients were treated with analgesics and antibiotics within the first 36 hours after
admission (with a mean of 9 hours), and proceeded to surgery for a cholecystectomy. Two patients died and 6
patients had further complications. The morbidity and mortality rates were 37.5% and 12.5%, respectively in the
present study. The authors of this study suggests that early diagnosis and emergency surgical treatment of
gallbladder perforation are of crucial importance.[5]

Y
Ñ
  Y
An angiogram is an X-ray test that uses a special dye and camera (fluoroscopy) to take pictures of the
blood flow in an artery (such as the aorta) or a vein (such as the vena cava). An angiogram can be used
to look at the arteries or veins in the head, arms, legs, chest, back, or belly.
Common angiograms can look at the arteries near the heart (coronary angiogram),lungs (pulmonary
angiogram), brain (cerebral angiogram), head and neck (carotid angiogram), legs or arms (peripheral),
and the aorta (aortogram).
During an angiogram, a thin tube called a catheter is placed into a blood vessel in the groin (femoral
artery or vein) or just above the elbow (brachial artery or vein). See a picture of catheter placement in the
femoral vein . The catheter is guided to the area to be studied. Then an iodine dye (contrast material)
is injected into the vessel to make the area show clearly on the X-ray pictures. This method is known as
conventional or catheter angiogram. The angiogram pictures can be made into regular X-ray films or
stored as digital pictures in a computer.
An angiogram can find a bulge in a blood vessel (aneurysm). It can also show narrowing or a blockage in
a blood vessel that affects blood flow. An angiogram can show if coronary artery disease is present and
how bad it is.
A magnetic resonance angiogram (MRA) or computed tomography angiogram (CTA) may be an option
instead of an angiogram. Each of these tests is less invasive than a standard angiogram. Some MRA
tests and all CTA tests require an injection of dye. A CTA also involves radiation exposure.

Nephrotic syndrome
From Wikipedia, the free encyclopedia

D 
  

6



 
 Y

Y
* 

Y 
YY  Y
 Y/ 
Y
 Y

 Y*B4Y Y
0
 >$ Y

0
  Y

  
  $ Y


   !"Y!Y


  #$$$ Y

Y Y
  !    "Y)Y .Y


Y Y Y YYÀ
 Y
Y

D


 ?
OO
?  

(  Y
  is a nonspecific disorder in which the kidneys are damaged, causing them to leak
large amounts of protein[1](proteinuria at least 3.5 grams per day per 1.73m2 body surface area)[2] from
the blood into the urine.

Kidneys affected by nephrotic syndrome have small pores in the podocytes, large enough to
permit proteinuria (and subsequentlyhypoalbuminemia, because some of the protein albumin has gone
from the blood to the urine) but not large enough to allow cells through (hence no hematuria). By contrast,
in nephritic syndrome, RBCs pass through the pores, causing hematuria.

6



Y%
& Y

Y) Y

"Y3.
 Y

Y(   YYY

m Y4 
Y   Y

m "Y* 
Y   Y

m  Y)  YY

m Y' YY

Y#  Y 

 YY
YY

Y# 
 Y
Y Y

m Y+YY .Y

m "Y'  YYY 

YY

m  Y#  Y Y

Y(  Y

Y)
 Y

Y'YY

$YY

Y45Y 6Y

[edit]Presentation

It is characterized
by proteinuria (>3.5g/day), hypoalbuminemia, hyperlipidemia and edema. Lipiduria (lipids in urine) can
also occur, but is not essential for diagnosis of nephrotic syndrome.

Hyperlipidemia is caused by 2 factors:

§ Hypoproteinemia stimulates protein synthesis in the liver, resulting in the overproduction of

lipoproteins.

§ Lipid catabolism is decreased due to lower levels of lipoprotein lipase, the main enzyme involved in
lipoprotein breakdown.[3]

A few other characteristics seen in nephrotic syndrome are:

§ The most common sign is excess fluid in the body due to the serum hypoalbuminemia. Lower serum
oncotic pressure causes fluid to accumulate in the interstitial tissues. Sodium and water retention
aggravate the edema. This may take several forms:

§ Puffiness around the eyes, characteristically in the morning.

§ Edema over the legs which is 

 (i.e., leaves a little pit when the fluid is pressed out, which
resolves over a few seconds).

§ Fluid in the pleural cavity causing pleural effusion. More commonly associated with excess fluid
is pulmonary edema.

§ Fluid in the peritoneal cavity causing ascites.

§ A generalized edema throughout the body known as anasarca

§ Hypertension (rarely)
§ Some patients may notice foamy urine, due to a lowering of the surface tension by the
severe proteinuria. Actual urinary complaints such as hematuria or oliguria are uncommon, and are
seen commonly in nephritic syndrome.

§ May have features of the underlying cause, such as the rash associated with Systemic Lupus
Erythematosus, or the neuropathy associated with diabetes.

§ Examination should also exclude other causes of gross edema²especially

the cardiovascular and hepatic system.
[edit]Investigations

The following are baseline, essential investigations

§ Urine sample shows proteinuria (>3.5g per 1.73 m2 per 24 hour). It is also examined for urinary casts;
which is more a feature of active nephritis.

§ Comprehensive metabolic panel (CMP) shows Hypoalbuminemia: albumin level ”2.5g/dL (normal=3.5-
5g/dL).

§ High levels of cholesterol (hypercholesterolemia), specifically elevated LDL, usually with concomitantly
elevated VLDL
§ Electrolytes, urea and creatinine (EUCs): to evaluate renal function

Further investigations are indicated if the cause is not clear

§ Biopsy of kidney
§ Auto-immune markers (ANA, ASOT, C3, cryoglobulins, serum electrophoresis)
[edit]Classification and causes

Nephrotic syndrome has many causes and may either be the result of a disease limited to the kidney,
called  nephrotic syndrome, or a condition that affects the kidney and other parts of the body,
called ?  nephrotic syndrome.

[edit]
Y

Y

A broad classification of nephrotic syndrome based on etiology:

Y Y Y Y Y Y >
 Y Y Y Y Y Y YY
Y

 Y
Y YY Y Y Y Y Y Y
Y Y Y
Y Y Y Y Y Y Y Y Y

Y YY Y Y Y Y Y
Y Y

Y Y Y Y Y Y Y Y

Y
Y
Y
)  Y Y Y Y Y Y Y ' Y
Y
[edit] 
Y

Y
Nephrotic syndrome is often classified histologically:

Y Y Y YY Y Y Y >
 Y Y Y Y YY

YYY Y Y Y YYY Y Y Y Y Y Y YY

Y Y YY Y Y Y Y Y Y Y Y Y YY Y Y
YY YY
Y Y Y YYY Y Y Y Y Y Y Y Y Y Y YYY Y Y

Y Y YY Y Y Y Y Y Y Y Y Y Y YY Y Y
YYY Y Y Y

Y Y Y YYY Y Y Y Y Y Y Y Y Y Y Y YYY Y Y

Y 0(# Y ?'+'
YYY

Y
YYY

Y
Y Y Y Y Y Y 0> Y 0)+> Y
YYY

[edit]  YY
Primary causes of nephrotic syndrome are usually described by the histology, i.e., minimal change
disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN).

They are considered to be "diagnoses of exclusion", i.e., they are diagnosed only after secondary causes
have been excluded.

[edit] 
YY
Secondary causes of nephrotic syndrome have the same histologic patterns as the primary causes,
though may exhibit some differences suggesting a secondary cause, such asinclusion bodies.

They are usually described by the underlying cause.

Secondary causes by histologic pattern

§ Hepatitis B
§ Sjögren's syndrome
§ Systemic lupus erythematosus(SLE)
§ Diabetes mellitus
§ Sarcoidosis
§ Syphilis
§ Drugs (such as corticosteroids, gold, intravenous heroin)
§ Malignancy (cancer)

Focal segmental glomerulosclerosis (FSGS)[4]

§ Hypertensive Nephrosclerosis
§ Human immunodeficiency virus (HIV)
§ Diabetes mellitus
§ Obesity
§ Kidney loss
Minimal change disease (MCD)[4]

§ Drugs, especially NSAID's in the elderly

§ Malignancy, especially Hodgkin's lymphoma
[edit]Differential diagnosis of gross edema

When someone presents with generalized edema, the following causes should be excluded:

1. Heart failure: The patient is older, with a history of heart disease. Jugular venous pressure is
elevated on examination, might hear heart murmurs. An echocardiogram is the gold standard
investigation.

2. Liver failure: History suggestive of hepatitis/ cirrhosis: alcoholic, IV drug user, some hereditary
causes.
Stigmata of liver disease are seen: jaundice (yellow skin and eyes), dilated veins over umbilicus
(caput medusae), scratch marks (due to widespread itching, known as "pruritus"), enlarged
spleen, spider angiomata, encephalopathy, bruising, nodular liver

3. Acute fluid overload in someone with kidney failure: These people are known to have kidney
failure, and have either drunk too much or missed their dialysis.

4. Metastatic cancer: When cancer seeds the lungs or abdomen it causes effusions and fluid
accumulation due to obstruction of lymphatics and veins as well as serous exudation.
[edit]Diagnosis

The gold standard in diagnosis of nephrotic syndrome is 24-hour urine protein measurement. Aiding in
diagnosis are blood tests and sometimes imaging of the kidneys (for structure and presence of 2
kidneys), and/or a biopsy of the kidneys.

[edit]Treatment

Y Y  
 
  
 Y

)Y
Y .Y
Y Y Y 
Y  YY YYCY Y Y
Y
Y

YY.YÀ  Y

Treatment includes:

[edit] 

Y Y% 'Y

§ Monitoring and maintaining euvolemia (the correct amount of fluid in the body):
§ monitoring urine output, BP regularly
§ fluid restrict to 1L
 § diuretics (IV furosemide)

§ Monitoring kidney function:

§ do EUCs daily and calculating GFR

§ Treat hyperlipidemia to prevent further atherosclerosis.

§ Prevent and treat any complications [see below]

§ Albumin infusions are generally not used because their effect lasts only transiently.

Prophylactic anticoagulation may be appropriate in some circumstances.[5]

[edit] Y 
Y Y


YY

§ Immunosuppression for the glomerulonephritides (corticosteroids[6], cyclosporin).

§ Standard ISKDC regime for first episode: prednisolone -60 mg/m2/day in 3 divided doses for 4 weeks
followed by 40 mg/m2/day in a single dose on every alternate day for 4 weeks.

§ Relapses by prednisolone 2 mg/kg/day till urine becomes negative for protein. Then, 1.5 mg/kg/day for
4 weeks.

§ Frequent relapses treated by: cyclophosphamide or nitrogen mustard or ciclosporin or levamisole.

§ Achieving stricter blood glucose control if diabetic.

§ Blood pressure control. ACE inhibitors are the drug of choice. Independent of their blood pressure
lowering effect, they have been shown to decrease protein loss.
[edit]!Y 

Y

Y Y  
 
  
 Y
)Y
Y .Y
Y Y Y 
Y  YY YYCY Y Y
Y Y

YY.YÀ  Y

Reduce sodium intake to 1000-2000 milligrams daily. Foods high in sodium include salt used in cooking
and at the table, seasoning blends (garlic salt, Adobo, season salt, etc.) canned soups, canned
vegetables containing salt, luncheon meats including turkey, ham, bologna, and salami, prepared foods,
fast foods, soy sauce, ketchup, and salad dressings. On food labels, compare milligrams of sodium to
calories per serving. Sodium should be less than or equal to calories per serving.
Eat a moderate amount of high protein animal food: 3-5 oz per meal (preferably lean cuts of meat, fish,
and poultry)

Avoid saturated fats such as butter, cheese, fried foods, fatty cuts of red meat, egg yolks, and poultry
skin. Increase unsaturated fat intake, including olive oil, canola oil, peanut butter, avocadoes, fish and
nuts. Eat low-fat desserts.

Increase intake of fruits and vegetables. There is no potassium or phosphorus restriction necessary.

Monitor fluid intake, which includes all fluids and foods that are liquid at room temperature. Fluid
management in nephrotic syndrome is tenuous, especially during an acute flare.

[edit]Complications

§ Venous thrombosis: due to leak of anti-thrombin 3, which helps prevent thrombosis. This often occurs
in the renal veins. Treatment is with oral anticoagulants (not heparin as heparin acts via anti-thrombin
3 which is lost in the proteinuria so it will be ineffective.)

§ Infection: due to leakage of immunoglobulins, encapsulated bacteria such as   O‘?

‘  and


 ?  can cause infection.

§ Acute renal failure is due to hypovolemia. Despite the excess of fluid in the tissues, there is ‘?? fluid in
the vasculature. Decreased blood flow to the kidneys causes them to shutdown. Thus it is a tricky
task to get rid of excess fluid in the body while maintaining circulatory euvolemia.

§ Pulmonary edema: again due to fluid leak, sometimes it leaks into lungs
causing hypoxia and dyspnoea.

§ Growth retardation: does not occur in MCNS.It occurs in cases of relapses or resistance to therapy.
Causes of growth retardation are protein deficiency from the loss of protein in
urine, anorexia (reduced protein intake), and steroid therapy (catabolism).

§ Vitamin D deficiency can occur. Thyroxine is reduced due to decreased thyroid binding globulin.

§ Microcytic hypochromic anaemia is typical. It is iron-therapy resistant.

§ Hypocalcemia can occur as a result of Nephrotic Syndrome. It may be significant enough to

cause Tetany.
[edit]Prognosis
 The prognosis depends on the cause of nephrotic syndrome. It is usually good in children,
because minimal change disease responds very well to steroids and does not cause chronic renal failure.
However other causes such as focal segmental glomerulosclerosis frequently lead to end stage renal
disease. Factors associated with a poorer prognosis in these cases include level of proteinuria, blood
pressure control and kidney function (GFR).

Uterine fibroids
From Wikipedia, the free encyclopedia

  

6



 
 Y

Y
C Y?  Y

0
 #" Y

0
 " Y

0  $ Y

  
  $ Y


    ! Y


  #$$ Y
A 
Y  (also 
Y
  ,[1]  ,   ,
   , 
  ,
and  ) (‘‘ of   is  ? or  
) is a benign (non-cancerous) tumor that
originates from the smooth muscle layer (myometrium) and the accompanying connective tissue of the uterus.

Fibroids are the most common benign tumors in females and typically found during the middle and later
reproductive years. While most fibroids are asymptomatic, they can grow and cause heavy and painful
menstruation, painful sexual intercourse, and urinary frequency and urgency. Some fibroids may interfere with
pregnancy although this appears to be very rare.[2]

In the US, symptoms caused by uterine fibroids are a very frequent indication for hysterectomy.[3] Fibroids are
often multiple and if the uterus contains too many leiomyomatas to count, it is referred to as diffuse uterine
leiomyomatosis. The malignant version of a fibroid is uncommon and termed a leiomyosarcoma.

6



Y%
& Y

Y).Y

"Y)

YY

Y

m "Y- Y

Y 
YY

 Y

Y' Y

Y# 
 Y

Y(5  
Y Y

Y Y

m Y45Y
Y

m "Y'
 Y

m  YC Y Y 7 Y

m YC Y Y
 Y

m Y YD Y Y

m Y4 Y Y

m Y0  Y

m Y0
 Y9+ Y?YCY

m Y8
Y

Y0
 Y

Y0 Y

$Y8
 7 2Y
YY  YY
 m $Y?  Y
YY4 YYY"$$Y

Y?  Y Y Y

"Y'YY

 YY

[edit]Prevalence

A relatively large submucosal leiomyoma; it fills out the major part of the endometrial cavity

About 20±40% of women will be diagnosed with leiomyoma but only a fraction of those will cause problems or
require treatment.[3]

The condition is about twice as common in black women as white women.[4][5].

Leiomyoma are more common in overweight women (perhaps because of increased estrogen from
adipose aromatase activity).[6] Fibroids are dependent on estrogen and progesterone to grow and therefore
relevant only during the reproductive years, they are expected to shrink after menopause.

[edit]Pathology and histology

Leiomyomas grossly appear as round, well circumscribed (but not encapsulated), solid nodules that are white
or tan, and show whorled appearance on histological section. The size varies, from microscopic to lesions of
considerable size. Typically lesions the size of a grapefruit or bigger are felt by the patient herself through the
abdominal wall.
Micrograph of a

  , a type of leiomyoma. H&E stain.

Microscopically, tumor cells resemble normal cells (elongated, spindle-shaped, with a cigar-shaped nucleus)
and form bundles with different directions (whorled). These cells are uniform in size and shape, with scarce
mitoses. There are three benign variants: bizarre (atypical); cellular; and mitotically active.

[edit] 
Y

An enucleated uterine
   ± external surface on left, cut surface on right.

large subserosal fibroid

Growth and location are the main factors that determine if a fibroid leads to symptoms and problems.[3] A small
lesion can be symptomatic if located within the uterine cavity while a large lesion on the outside of the uterus
may go unnoticed. Different locations are classified as follows:

§ 0
 
Y  are located within the wall of the uterus and are the most common type; unless large,
they may be asymptomatic. Intramural fibroids begin as small nodules in the muscular wall of the uterus.
With time, intramural fibroids may expand inwards, causing distortion and elongation of the uterine cavity.

§  
Y  are located underneath the mucosal (peritoneal) surface of the uterus and can
become very large. They can also grow out in a papillary manner to become 

Y .
These pedunculated growths can actually detach from the uterus to become a parasitic leiomyoma.

§   
Y  are located in the muscle beneath the endometrium of the uterus and distort the
uterine cavity; even small lesion in this location may lead to bleeding and infertility. A pedunculated lesion
within the cavity is termed an 
Y  and can be passed through the cervix.

§ 6
Y  are located in the wall of the cervix (neck of the uterus). Rarely fibroids are found in the
supporting structures (round ligament, broad ligament, or uterosacral ligament) of the uterus that also
contain smooth muscle tissue.

Fibroids may be single or multiple. Most fibroids start in an intramural location, that is the layer of the muscle of
the uterus. With further growth, some lesions may develop towards the outside of the uterus or towards the
internal cavity. Secondary changes that may develop within fibroids are hemorrhage, necrosis, calcification,
and cystic changes.

[edit]Aetiology and pathogenesis

Fibroids are monoclonal tumors, approximately 40 to 50% show karyotypically detectable chromosomal
abnormalities.

Their growth is strongly dependent on estrogen and progesterone. Although both estrogen and progesterone
are usually regarded as growth promoting they will also cause growth restriction in some circumstances.
Paradoxically fibroids will rarely grow during pregnancy despite very high steroid hormone levels and
pregnancy appears to exert a certain protective effect. [2]

It is believed that estrogen and progesterone have both mitogenic effect on leiomyoma cells and also act by
influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as
other hormones. Furthermore the actions of estrogen and progesterone are modulated by the cross-talk
between estrogen, progesterone and prolactin signalling which controls the expression of the respective
nuclear receptors. It is believed that estrogen is growth promoting by up-regulating IGF-1, EGFR, TGF-beta1,
TGF-beta3 and PDGF, promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing
expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signalling. Progesterone is
thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and the
survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to
counteract growth by downregulating IGF-1.[7][8][9] Expression of transforming growth interacting factor (TGIF) is
increased in leiomyoma compared with myometrium.[10] TGIF is a potential repressor of TGF-ȕ pathways in
myometrial cells.[10]

Whereas in premenopausal fibroids the ER-beta, ER-alpha and progesterone receptors are found
overexpressed, in the rare postmenopausal fibroids only ER-beta was found significantly
overexpressed.[11] Most studies found that polymorphisms in ER and PR gene encodings are not correlated
with incidence of fibroids in Caucasian populations [12][13] however a special ER-alpha genotype was found
correlated with incidence and size of fibroids. The higher prevalence of this genotype in black women may also
explain the high incidence of fibroids in this group.[14]

Aromatase and 17beta-hydroxysteroid dehydrogenase are aberrantly expressed in fibroids, indicating that
fibroids can convert circulating androstenedione into estradiol. [15] Similar mechanism of action has been
elucidated in endometriosis and other endometrial diseases. [16] Aromatase inhibotors are currently considered
for treatment, at certain doses they would completely inhibit estrogen production in the fibroid while not largely
affecting ovarian production of estrogen (and thus systemic levels of it). Aromatase overexpression is
particularly pronounced in Afro-American women [17]

Genetic and hereditary causes are being considered and several epidemiologic findings indicate considerable
genetic influence especially for early onset cases. First degree relatives have a 2.5-fold risk, and nearly 6-fold
risk when considering early onset cases. Monozygotic twins have double concordance rate for hysterectomy
compared to dizygotic twins.[18]

Like keloids fibroids have disregulated production of extracellular matrix. Recent studies suggest that this
production may represent an abnormal response to ischemic and mechanical tissue stress.[19] Several factors
indicate significant involvement of extracellular signaling pathways such as ERK1 and ERK2, which in fibroids
are prominently influenced by hormones.[20] Paradoxically and unlike most other conditions involving significant
fibrosis the Cyr61 gene has been found downregulated in fibroids.[21]

Cyr61 is also known for its role as tumor suppressing factor and in angiogenesis. Hence fibroids are one of the
very few tumors with reduced vascular density. [21]

[edit]Symptoms

Generally, symptoms relate to the location of the lesion and its size (mass effect). Important symptoms include
abnormal gynecologic hemorrhage, heavy or painful periods, abdominal discomfort or bloating, painful
defecation, back ache, urinary frequency or retention, and in some cases, infertility.[22] There may also be pain
during intercourse, depending on the location of the fibroid. During pregnancy they may be the cause
of miscarriage, bleeding, premature labor, or interference with the position of the fetus.

Fibroids, particularly when small, may be entirely asymptomatic. The U.S. Department of Health & Human
Services states that "Fibroids are almost always benign (not cancerous). Rarely (less than one in 1,000) a
cancerous fibroid will occur. This is called leiomyosarcoma. Doctors think that these cancers do not arise from
an already-existing fibroid. Having fibroids does not increase the risk of developing a cancerous fibroid. Having
fibroids also does not increase a woman's chances of getting other forms of cancer in the uterus."[23]

While fibroids are common, they are not a typical cause for infertility accounting for about 3% of reasons why a
woman may not have a child.[24] Typically in such cases a fibroid is located in a submucosal position and it is
thought that this location may interfere with the function of the lining and the ability of the embryo
to implant.[24] Also larger fibroids may distort or block the fallopian tubes.

[edit]Diagnosis

While a bimanual examination typically can identify the presence of larger fibroids, gynecologic
ultrasonography (ultrasound) has evolved as the standard tool to evaluate the uterus for fibroids. Sonography
will depict the fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the
ultrasound beam. The location can be determined and dimensions of the lesion measured. Also magnetic
resonance imaging (MRI) can be used to define the depiction of the size and location of the fibroids within the
uterus.

Imaging modalities cannot clearly distinguish between the benign uterine leiomyoma and the malignant uterine
leiomyosarcoma, however, the latter is quite rare. However fast growth or unexpected growth such as
enlargement of a lesion after the menopause raise the level of suspicion that the lesion might be a sarcoma.
Also, with advanced malignant lesions there may be evidence of local invasion. A more recent study has
suggested that diagnostic capabilities using MRI have improved the ability to detect sarcomatous
lesions.[25] Biopsy is rarely performed and if performed, is rarely diagnostic. Should there be an uncertain
diagnosis after ultrasounds and MRI imaging, surgery is generally indicated.

Other imaging techniques that may be helpful specifically in the evaluation of lesions that affect the uterine
cavity are hysterosalpingography or sonohysterography.

[edit]Coexisting disorders

Fibroids that lead to heavy vaginal bleeding lead to anemia and iron deficiency. Due to pressure effects
gastrointestinal problems are possible such as constipation and bloatedness. Compression of the ureter may
lead to hydronephrosis. Fibroids may also present alongside endometriosis, which itself may cause
infertility. Adenomyosis may be mistaken for or coexist with fibroids.
In very rare cases, malignant (cancerous) growths, leiomyosarcoma, of the myometrium can develop.[26]

[edit]Treatment

submucosal fibroid in hysteroscopy

Treatment of an intramural fibroid bylaparoscopic surgery

After treatment of an intramural fibroid bylaparoscopic surgery

[edit]
Y 
 
Y
The presence of fibroids does not mean that they need to be treated; lesions can be managed expectantly
depending on the symptomatology and presence of related conditions. Thus most cases of fibroids are
managed by "watchful waiting" which includes periodic sonographic assessment. After menopause fibroids
shrink and it is unusual for fibroids to cause problems.

The presence of symptomatic uterine fibroids can be solved by:

[edit] Y
: Surgical removal of a uterine fibroid usually takes place via hysterectomy, in which the entire uterus is
removed, or myomectomy, in which only the fibroid is removed. It is possible to remove multiple fibroids during
a myomectomy. Although a myomectomy cannot prevent the recurrence of fibroids at a later date, such surgery
is increasingly recommended, especially in the case of women who have not completed bearing children or
who express an explicit desire to retain the uterus. There are three different types of myomectomy:

§ In a O ?
 ?  myomectomy, the fibroid is removed by the use of a resectoscope,

an endoscopic instrument that can use high-frequency electrical energy to cut tissue. Hysteroscopic
myomectomies can be done as an outpatient procedure, with either local or general anesthesia used.
Hysteroscopic myomectomy is most often recommended for submucosal fibroids. A French study collected
results from 235 patients suffering from submucous myomas who were treated with hysteroscopic
myomectomies; in none of these cases was the fibroid greater than 5 cm.[27]

§ A ‘ ?  myomectomy requires a small incision near the navel. The physician then inserts a
laparoscope into the uterus and uses surgical instruments to remove the fibroids. Studies have suggested
that laparoscopic myomectomy leads to lower morbidity rates and faster recovery than does laparotomic
myomectomy.[28] As with hysteroscopic myomectomy, laparoscopic myomectomy is not generally used on
very large fibroids. A study of laparoscopic myomectomies conducted between January 1990 and October
1998 examined 106 cases of laparoscopic myomectomy, in which the fibroids were intramural or
subserous and ranged in size from 3 to 10 cm.[29]

§ A ‘
 myomectomy (also known as an  or 
 ‘ myomectomy) is the most invasive
surgical procedure to remove fibroids. The physician makes an incision in the abdominal wall and removes
the fibroid from the uterus. A particularly extensive laparotomic procedure may necessitate that any future
births be conducted by Caesarean section.[24] Recovery time from a laparatomic procedure is generally
expected to be four to six weeks.
[edit]å
YY 
)
Y
å
YY 
)
(UAE): Using interventional radiology techniques, the interventional radiologist
occludes both uterine arteries, thus reducing blood supply to the fibroid[30] . A small catheter (1 mm in diameter)
is inserted into the femoral artery at the level of the groin under local anesthesia. Under imaging guidance, the
interventional radiologist will enter selectively into both uterine arteries and inject small (500 µm) particles that
will block the blood supply to the fibroids. A patient will usually recover from the procedure within a few days.
The UAE procedure should result in limited blood supply to the fibroids which should prevent them from further
growth, heavy bleeding and possibly shrink them.

A retrospective cohort study showed that UAE has much fewer serious adverse effects than hysterectomy
(odds ratio 0.25) and similar rates of satisfaction. In this study, 86% of women treated with UAE would
recommend the treatment to a friend compared to 70% of those treated by hysterectomy.[31]

[edit]å
YY

Y

å
YY

: a minimaly invasive surgery to limit blood supply of the uterus that can be performed
transvaginally or laparoscopically. The principal mechanism of action is same like in UAE. This is a relatively
new method which demonstrated similar efficiacy like UAE but is easier to perform and for this reason fewer
side effects are expected.[32][33][34]

[edit]$ Y*
Y

Y

$ *
Y

: One of the newest minimally invasive treatments for fibroids is radiofrequency
ablation [35]. In this technique the fibroid is shrunk by inserting a needle-like device into the fibroid through the
abdomen and heating it with radio-frequency (RF) electrical energy. The treatment is a potential option for
women who have fibroids, have completed child-bearing and want to avoid a hysterectomy.

[edit]
 
Y

Y

 
Y

can be used if the fibroids are only within the uterus and not intramural and relatively
small. High failure and recurrence rates are expected in the presence of larger or intramural fibroids.

[edit]{
Y

Gonadotropin-releasing hormone analogs cause regression of fibroids by decreasing estrogen levels. Because
of the limitations and side effects of this medication it is rarely recommended other than for preoperative use to
shrink the size of the fibroids and uterus before surgery. Its is typically used for a maximum of 6 months or
shorter because after longer use they could cause osteoporosis and other typically postmenopausal
complications. The main side effects are transient postmenopausal symptoms. In many cases the fibroids will
regrow after cessation of treatment, however significant benefits may persists for much longer time in some
cases. Several variations are possible, such as GnRH agonists with add-back regimens intended to decrease
the adverse effects of estrogen deficiency. Several add-back regimes are
possible, tibolone, raloxifene, progestogens alone, estrogen alone, and combined estrogens and
progestogens.[36]
Levonorgestrel intrauterine devices are highly effective in limiting menstrual blood flow. Side effects are
typically very moderate because the levonorgestrel (a progestin) is released in low concentration locally. While
most Levongestrel-IUD studies concentrated on treatment of women without fibroids a few reported very good
results specifically for women with fibroids.[37]One reported problem is that women with large fibroids had more
frequently spontaneous expulsion of the IUD, however many of those asked for reinsertion of the device
indicating a high rate of satisfaction despite the expulsion.[36][38]

Aromatase inhibitors have been used experimentally to reduce fibroids. The effect is believed to be due
partially by lowering systemic estrogen levels and partially by inhibiting locally overexpressed aromatase in
fibroids.[36] Experience from experimental aromatase inhibitor treatment of endometriosis indicates that
aromatase inhibitors might be particularly useful in combination with a progestogenic ovulation inhibitor.

Progesterone antagonists have been shown in small studies to decrease the size of uterine
fibroids. Mifepristone was effective in a placebo-controlled pilot study.[39] Selective progesterone receptor
modulators, such as Progenta, have been under investigation.

The selective progesterone receptor modulator Asoprisnil is currently tested with very promising results as a
possible use as a treatment for fibroids - the hope is that it will provide the advantages of progesterone
antangonitst without their adverse effects.[36]

The long term safety of progesterone antagonists as well as selective progesterone receptor modulators has
yet to be established.[40][41]

A number of secondary medications are in use to alleviate symptoms caused by fibroids. This allows an
otherwise expectant approach to bring the patient hopefully to menopause when symptoms naturally regress.
Thus oral contraceptive pills, either combination pills with low-dose estrogens or progestin-only, are prescribed
in an effort to reduce uterine bleeding and cramps. Such medications seem to have little or no effect on the size
of the lesions.[24] Anemia may have to be treated with iron supplementation. NSAIDs can be used to reduce
painful menses.

[edit]{
Y$

& Y Yå
 
Y
Magnetic Resonance guided Focused Ultrasound (MRgFUS), is a non-invasive intervention (requiring no
incision) that uses high intensity focused ultrasound ( 0å) waves to ablate (destroy) tissue in combination with
Magnetic Resonance Imaging (MRI), which guides and monitors the treatment. This technique was approved
by the FDA in 2004. Ultrasound is a form of energy that passes through skin, muscle, fat and other soft tissue.
High intensity focused ultrasound energy, focused on a small target volume (tumor), provides a therapeutic
effect by raising the tissue temperature of the target (tumor) high enough to destroy it. This is similar to the
manner in which sunlight focused by a magnifying glass can create sufficient heat to start a fire. The use of
heat to destroy tissue is called thermal ablation. Treatments consist of multiple exoposures of focused energy
or sonications. MRgFUS uses a Magnetic Resonance Imaging (MRI) scanner to identify tissues in the body and
plan the treatment. During the procedure, delivery of focused ultrasound energy is guided and controlled using
MR thermal imaging. ‡ MR imaging provides a three-dimensional view of the target tissue, allowing for precise
focusing of ultrasound energy within a desired volume. ‡ Additionally, the MR imaging provides quantitative,
real-time, thermal images of the treated area. This allows the physician to ensure that the temperature
generated during each cycle of ultrasound energy is sufficient to cause thermal ablation within the desired
tissue and if not, to adapt the parameters. The advantage and value of MR guidance ensures safe and
accurate treatment. [42]

[edit] Y

The use of vitex herbal medicine lacks supporting evidence.

[edit]Malignancy

About 1 out of 1000 lesions[24] are or become malignant, typically as a leiomyosarcoma on histology. A sign that
a lesion may be malignant is growth after menopause.[24] There is no consensus among pathologists regarding
the transformation of Leiomyoma into a sarcoma. Most pathologists believe that a Leiomyosarcoma is a 
  disease[

 ]
.

[edit]Metastasis

There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can
be dangerous depending on their location.[43]

§ In
  Y" Y
Y


, an ordinary-appearing fibroid invades into a vessel but there is no
risk of recurrence.

§ In 0

Y
   , leiomyomata grow in veins with uterine fibroids as their source. Cardiac
involvement can be fatal.

§ In 

Y )
Y
  , leiomyomata grow in more distant sites such as the lungs and
lymph nodes. The source is not entirely clear. Pulmonary involvement can be fatal.

§ In  
Y


Y
   , leiomyomata grow diffusely on the peritoneal and
omental surfaces, with uterine fibroids as their source. This can simulate a malignant tumor but behaves
benignly.
[edit]Organizations, research and political aspects

The Center for Uterine Fibroids which is associated with Brigham and Women¶s Hospital in Boston MA ([1]) is
currently recruiting volunteers for an investigation of all aspects of the aetiology, pathology of fibroids and
development of treatment options. This institution also has a lot of clinical trials focused on African American
women. The focus of one study is the search for a specific gene associated with the development of fibroids.
Since one risk factor for uterine fibroids is having a family history of fibroids, the results of this study will provide
some answers on the heredity of the illness. Some women may interact with the healthcare system by getting
an ultrasound to diagnosis symptoms if they¶ve had a mother, sister or grandmother who has previously
suffered with these benign tumors.

[edit] Y$ Y
Y
YÑY Y+,,-Y

The 2005 S.1289 bill was read twice and referred to the committee on Health, Labor and Pensions but never
passed for a Senate or House vote. The proposed Uterine Fibroid Research and Education Act of 2005
mentioned that $5 billion dollars is spent annually on hysterectomy surgeries each year, which affect 22% of
African Americans and 7% of Caucasian women. The bill also called for more funding for research and
educational purposes. It also states that of the $27 million dollars issued to NIH, only $5 million was allocated
for Uterine Fibroids in 2004.

[edit]Fibroids in animals

Uterine fibroids are rare in animals. They have been observed in certain dogs and Baltic Gray Seals.[44]

Fibroadenoma
From Wikipedia, the free encyclopedia

› 

6



 
 Y

Y
* 

Y 
YYY Y(YY  Y

*5  YBY Y Y

0
 #" Y
 0
 " Y

0
#  0$$!$90$"2Y0$"$2Y0$ $Y

  
   Y

   $$" Y


    !$ Y


  #$"" Y

 
 of the breast are small, solid, rubbery, noncancerous, harmless lumps composed of fibrous
and glandular tissue. Becausebreast cancer can also appear as a lump, doctors usually recommend a tissue
sample (biopsy) to rule out cancer. Unlike typical lumps from breast cancer, fibroadenomas are easy to move,
with clearly defined edges.[1][2]

6



Y%
& Y

Y'
YY Y

"Y# 
 Y

Y4 
YY  
Y

Y)

Y

m Y( 
Y

m "Y0 Y

m  Y0  Y

Y Y

m Y(  Y Y

Y? Y 

Y

YE YY? Y

YY

[edit]Signs and symptoms

The typical case is the presence of a painless, firm, solitary, mobile, slowly growing lump in the breast of a
woman of childbearing years.[2][3][4]

In the male breast, fibroepithelial tumors are very rare, and are mostly Phyllodes tumors. Exceptionally rare
case reports exist of fibroadenomas in the male breast, however these cases may be associated
with antiandrogen treatment.[5]

[edit]Diagnosis

A fibroadenoma is usually diagnosed through clinical examination, ultrasound or mammography, and often
a needle biopsy sample of the lump [3].

[edit]Etiology and epidemiology

Fibroadenomas arise in the terminal duct lobular unit of the breast. They are the most common breast tumor in
adolescent women. They also occur in a small number of post-menopausal women. Their incidence declines
with increasing age, and they generally appear before the age of thirty years, probably partly as a result of
normal estrogenic hormonal fluctuation. Although fibroadenoma is considered a neoplasm, some authors
believe fibroadenoma arises from hyperplasia of normal breast lobule components.[2][6].[4]

[edit]Pathology

[edit]6
Y

The diagnostic findings on needle biopsy consist of abundant stromal cells, which appear as bare bipolar
nuclei, throughout the aspirate; sheets of fairly uniform sized epithelial cells which are typically arranged in
either an antler-like pattern, or a honeycomb pattern. These epithelial sheets tend to show
typical metachromatic blue staining on DiffQuick staining. Foam cells and apocrine cells may also be seen,
although these are less diagnostic features.[3][6] The gallery images below demonstrate these features.

[edit]{  Y

Approximately ninety percent of fibroadenomas are less than three centimetres in diameter. The vast majority
of the remaining ten percent that are four centimetres or larger occur mostly in women under twenty years of
age. The tumor is round or ovoid, elastic, nodular, and has a smooth surface. The cut surface usually
appears homogenous and firm, and is grey-white or tan in colour.[6]

[edit]{  Y

The proliferation forms duct-like spaces. These are surrounded by fibroblastic stroma. The proliferating
epithelium is of normal appearance. Fibroadenomas may be sub-classified into two types, intracanalicular and
pericanalicular, depending on the relative amounts of epithelial and stromal tissue present. There is also a
mixed type, in which both forms coexist simultaneously. Intracanalicular fibroadenomas show predominant
stromal proliferation that compresses the ducts, which are irregular and reduced to slits. Pericanalicular
fibroadenomas show fibrous stromal proliferation around the ductal spaces that allows the duct spaces remain
round or oval.[7] The gallery image below demonstrates both morphological subtypes.

[edit]Treatment

Most fibroadenomas are left in situ and monitored by a doctor, or the patient in question. Some are treated by
surgical excision. They are removed with a small margin of normal breast tissue if the preoperative clinical
investigations are suggestive of the diagnosis. A small amount of normal tissue must be removed in case the
lesion turns out to be a phyllodes tumouron microscopic examination.[6][8]

Because needle biopsy is often a reliable diagnostic investigation, some doctors may decide not to operate to
remove the lesion, and instead opt for clinical follow-up to serially observe the lesion over time using clinical
examination and mammography to determine the rate of growth, if any, of the lesion. A growth rate of less than
sixteen percent per month in women under fifty years of age, and a growth rate of less than thirteen percent per
month in women over fifty years of age have been published as safe growth rates for continued non-operative
treatment and clinical observation.[9]

Fibroadenomas have not been shown to recur following complete excision or transform into phyllodes
tumours following partial or incomplete excision.[6]

There are also natural treatments being touted to diminish fibroadenomas, such as Fibrosolve, but no definite
studies have been made as to prove their effectiveness.

[edit]6 

Y 
Y
The FDA has approved cryoablation (the use of extreme cold to destroy tissue) of a fibroadenoma as a safe,
effective and minimally-invasive alternative to open surgical removal.[10] In the procedure, ultrasound imaging is
used to guide a probe into the mass of breast tissue. Extremely cold temperatures are then used to destroy the
abnormal cells[11] and over time the cells are reabsorbed into the body. The procedure can be performed in an
office setting with local anesthesia only and leaves substantially less scarring than open surgical procedures.[11]

The American Society of Breast Surgeons recommends the following criteria to establish a patient as a
candidate for cryoablation of a fibroadenoma:[10]

1. The lesion must be sonographically visible.

2. The diagnosis of fibroadenoma must be confirmed histologically.

3. Lesions should be less than 4 cm in diameter.

[edit]Fibroadenoma images
 Y Y Y Y

92 


Y3Y 92 


+Y9Y7
Y 92 


+Y9Y7
Y 3
Y
YY
36$YY
Y ,
Y@Y8
Y Y ,
Y@Y 2 
Y2 


Y# Y


Y



Y 

B( 
YY
Y 0

Y
YY 
Y2Y3
Y
 YY Y

Y Y
2

Y2
Y2
Y 
YY
YYY 6YY
Y
 


Y Y  
YY 
YY 
YYYY
Y
2YY 
 
Y
YY
 Y
 Y

Cerebral venous sinus thrombosis

From Wikipedia, the free encyclopedia

        

6



 
 Y

Y
#Y. Y
 0
 3 2Y3Y

0
 "2Y Y

  
  """ Y


   !"Y !$Y

6
Y
Y
Y    (6
) is a rare form of stroke that results from thrombosis (a blood clot)
of the dural venous sinuses, which drain blood from the brain. Symptoms may include headache, abnormal
vision, any of the symptoms of stroke such as weakness of the face and limbs on one side of the body,
and seizures. The diagnosis is usually by computed tomography (CT/CAT scan) or magnetic resonance
imaging (MRI) employing radiocontrast to demonstrate obstruction of the venous sinuses by thrombus.[1]

Treatment is with anticoagulants (medication that suppresses blood clotting), and

rarely thrombolysis (enzymatic destruction of the blood clot). Given that there is usually an underlying cause for
the disease, tests may be performed to look for these. The disease may be complicated by raised intracranial
pressure, which may warrant surgical intervention such as the placement of a shunt.[1] There are several other
terms for the condition, such as 
Y
Y  Y
Y   , % 'Y
Y
Y
   , 
Y
Y    and 


Y
Y    as well as the older
term 
Y   
.

6



Y%
& Y

Y'
YY Y

"Y(Y

m "Y 6YY

Y# 
 Y

m Y3.
 Y

m "Y?
YY

Y)

 Y

Y Y

Y)
 Y

Y4  
Y
Y*  Y

YY

$Y45Y 6Y

[edit]Signs and symptoms

Nine in ten people with sinus thrombosis have a headache; this tends to worsen over the period of several
days, but may also develop suddenly (thunderclap headache).[1] The headache may be the only symptom of
cerebral venous sinus thrombosis.[2] Many patients have symptoms of stroke: inability to move one or more
limbs, weakness on one side of the face ordifficulty speaking. This does not necessarily affect one side of the
body as in the more common "arterial" stroke.[1]

40% of all patients have seizures, although it is more common still in women who develop sinus thrombosis
peripartum (in the period before and after giving birth).[3] These are mostly seizures affecting only one part of
the body and unilateral (occurring on one side), but occasionally the seizures are generalised and rarely they
lead to status epilepticus (persistent or recurrent seizure activity for a long period of time).[1]

In the elderly, many of the aforementioned symptoms may not occur. Common symptoms in the elderly with
this condition are otherwise unexplained changes in mental status and a depressed level of consciousness.[4]

The intracranial pressure (pressure around the brain) may rise, causing papilledema (swelling of the optic disc)
which may be experienced as visual obscurations. In severely raised intracranial pressure, the level of
consciousness is decreased, the blood pressure rises, the heart rate falls and the patient assumes an
abnormal posture.[1]

[edit]Causes

[edit]$.Y Y

Cerebral venous sinus thrombosis is more common in particular situations. 85% of patients have at least one of
these risk factors:[1]

§ Thrombophilia, a tendency to develop blood clots due to abnormalities in coagulation, e.g. factor V Leiden,
deficiency of protein C, protein S or antithrombin, or related problems
§ Nephrotic syndrome, a kidney problem causing protein loss in the urine
§ Chronic inflammatory diseases, such as inflammatory bowel disease, lupus and Behçet's disease

§ Pregnancy and puerperium (the period after giving birth)

§ Particular blood disorders, especially polycythemia vera and paroxysmal nocturnal hemoglobinuria
§ Use of estrogen-containing forms of hormonal contraception

§ Meningitis and infections of the ear, nose and throat area such as mastoiditis and sinusitis
§ Direct injury to the venous sinuses

§ Medical procedures in the head and neck area

[edit]Diagnosis

[edit]0

Y

The diagnosis may be suspected on the basis of the symptoms, for example the combination of headache,
signs of raised intercranial pressure and focal neurological abnormalities, or when alternative causes of
headache and neurological abnormalities, such as a subarachnoid hemorrhage, have been excluded.[1]

6/Y{$0Y
Y
  Y

CT venogram showing a filling defect in the sagittal sinus (black arrow)

There are various neuroimaging investigations that may detect cerebral sinus thrombosis. Cerebral edema and
venous infarction may be apparent on any modality, but for the detection of the thrombus itself, the most
commonly used tests are computed tomography (CT) andmagnetic resonance imaging (MRI), both using
various types of radiocontrast to perform a venogram and visualise the veins around the brain.[1]

Computed tomography, with radiocontrast in the venous phase (6Ô O or CTV), has a detection rate
that in some regards exceeds that of MRI. The test involves injection into a vein (usually in the arm) of a
radioopaque substance, and time is allowed for the bloodstream to carry it to the cerebral veins - at which point
the scan is performed. It has a sensitivity of 75-100% (it detects 75-100% of all clots present), and
a specificity of 81-100% (it would be incorrectly positive in 0-19%). In the first two weeks, the "empty delta sign"
may be observed (in later stages, this sign may disappear).[5]
Magnetic resonance venography employs the same principles, but uses MRI as a scanning modality. MRI has
the advantage of being better at detecting damage to the brain itself as a result of the increased pressure on
the obstructed veins, but it is not readily available in many hospitals and the interpretation may be difficult.[5]

Cerebral angiography may demonstrate smaller clots than CT or MRI, and obstructed veins may give the
"corkscrew appearance".[1] This, however, requires puncture of the femoral artery with a sheath and advancing
a thin tube through the blood vessels to the brain where radiocontrast is injected before X-ray images are
obtained. It is therefore only performed if all other tests give unclear results or when other treatments may be
administered during the same procedure.

!& Y

A 2004 study suggested that the D-dimer blood test, already in use for the diagnosis of other forms of
thrombosis, was abnormal (above 500 ȝg/l) in 34 out of 35 patients with cerebral sinus thrombosis, giving it
a sensitivity of 97.1%, a negative predictive value of 99.6%, a specificity of 91.2%, and a positive predictive
value of 55.7%. Furthermore, the level of the D-dimer correlated with the extent of the thrombosis.[6] A
subsequent study, however, showed that 10% of patients with confirmed thrombosis had a normal D-dimer,
and in those who had presented with only a headache 26% had a normal D-dimer. The study concludes that D-
dimer is not useful in the situations where it would make the most difference, namely in lower probability
cases.[7]

[edit] YY

In most patients, the direct cause for the cerebral sinus thrombosis is not readily apparent. Identifying a source
of infection is crucial; it is common practice to screen for various forms ofthrombophilia (a propensity to form
blood clots).[1]

[edit]Pathogenesis

The veins of the brain, both the superficial veins and the deep venous system, empty into the dural venous
sinuses, which carry blood back to the jugular vein and thence to the heart. In cerebral venous sinus
thrombosis, blood clots usually form both in the veins of the brain and the venous sinuses. The thrombosis of
the veins themselves causes venous infarction±damage to brain tissue due to a congested and therefore
insufficient blood supply. This results in cerebral edema (both ?  and 

 edema), and leads to
small petechialhaemorrhages that may merge into large haematomas. Thrombosis of the sinuses is the main
mechanism behind the increase in intracranial pressure due to decreased resorption of cerebrospinal fluid
(CSF). The condition does not lead to hydrocephalus, however, because there is no difference in pressure
between various parts of the brain.[1]

Any blood clot forms due to an imbalance between coagulation (the formation of the insoluble blood
protein fibrin) and fibrinolysis. The three major mechanisms for such an imbalance are enumerated in Virchow's
triad: alterations in normal blood flow, injury to the blood vessel wall, and alterations in the constitution of blood
(hypercoagulability). Most cases of cerebral venous sinus thrombosis are due to hypercoagulability.[1]

It is possible for the clot to break off and migrate (embolise) to the lungs, causing a pulmonary embolism.[1][3] An
analysis of earlier case reports concludes that this occurs in about 10% of cases, but has a very poor
prognosis.[8]

[edit]Treatment

Various studies have investigated the use of anticoagulation to suppress blood clot formation in cerebral
venous sinus thrombosis. Before these trials had been conducted, there had been a concern that small areas
of hemorrhage in the brain would bleed further as a result of treatment; the studies showed that this concern
was unfounded.[9] Clinical practice guidelines now recommend heparin or low molecular weight heparin in the
initial treatment, followed by warfarin, provided there are no other bleeding risks that would make these
treatments unsuitable.[3][10][11] Some experts discourage the use of anticoagulation if there is extensive
hemorrhage; in that case, they recommend repeating the imaging after 7±10 days. If the hemorrhage has
decreased in size, anticoagants are commenced, while no anticoagulants are given if there is no reduction.[12]

The duration of warfarin treatment depends on the circumstances and underlying causes of the condition. If the
thrombosis developed under temporary circumstances (e.g. pregnancy), three months are regarded as
sufficient. If the condition was unprovoked but there are no clear causes or a "mild" form of thrombophilia, 6 to
12 months is advised. If there is a severe underlying thrombosis disorder, warfarin treatment may need to
continue indefinitely.[3]

Thrombolysis (removal of the blood clot with "clot buster" medication) has been described, either systemically
by injection into a vein or directly into the clot during angiography. The 2006European Federation of
Neurological Societies guideline recommends that thrombolysis is only used in patients who deteriorate despite
adequate treatment, and other causes of deterioration have been eliminated. It is unclear which drug and which
mode of administration is the most effective. Bleeding into the brain and in other sites of the body is a major
concern in the use of thrombolysis.[3] American guidelines make no recommendation with regards to
thrombolysis, stating that more research is needed.[11]

Raised intracranial pressure, if severe or threatening vision, may require therapeutic lumbar puncture (removal
of excessive cerebrospinal fluid), medication (acetazolamide), orneurosurgical treatment (optic nerve sheath
fenestration or shunting).[1] In certain situations, anticonvulsants may be used to prevent seizures; these are
focal neurological problems (e.g. inability to move a limb) and/or focal changes of the brain tissue on CT or MRI
scan.[3]

[edit]Prognosis
In 2004 the first adequately large scale study on the natural history and long-term prognosis of this condition
was reported; this showed that at 16 months follow-up 57.1% of patients had full recovery, 29.5%/2.9%/2.2%
had respectively minor/moderate/severe symptoms or impairments, and 8.3% had died. Severe impairment or
death were more likely in those aged over 37 years, male, affected by coma, mental status disorder,
intracerebral hemorrhage, thrombosis of the deep cerebral venous system, central nervous system infection
and cancer.[13] A subsequent systematic review of nineteen studies in 2006 showed that mortality is about 5.6%
during hospitalisation and 9.4% in total, while of the survivors 88% make a total or near-total recovery. After
several months, two thirds of the cases has resolution ("recanalisation") of the clot. The rate of recurrence was
low (2.8%).[14]

In children with CVST, the mortality averages 50%. Poor outcome is more likely if a child with CVST develops
seizures or has evidence of venous infarction on imaging.[15]

[edit]Epidemiology

Cerebral venous sinus thrombosis is rare, with an estimated 3-4 cases per million annual incidence in adults.
While it may occur in all age groups, it is most common in the third decade. 75% are female.[3] Given that older
studies show no difference in incidence between men and women, it has been suggested that the use of oral
contraceptives in women is behind the disparity between the sexes.[1] A 1995 report from Saudi Arabia found a
doubled incidence at 7 cases per 100,000; this was attributed to the fact that Behçet's disease, which increases
risk of CVST, is more common in the Middle East.[16]

A 1973 report found that CVST could be found on autopsy (examination of the body after death) in nine percent
of all people. Many of these were elderly and had neurological symptoms in the period leading up to their
death, and many suffered from concomitant heart failure.[17]

In children, a Canadian study reported in 2001 that CVST occurs in 6.7 per million annually. 43% occur in the
newborn (less than one month old), and a further 10% in the first year of life. Of the newborn, 84% were
already ill, mostly from complications after childbirth and dehydration.[15]

[edit]History

The first description of thrombosis of the cerebral veins and sinuses is attributed to the French physician Ribes,
who in 1825 observed thrombosis of the saggital sinus and cerebral veins in a man who had suffered from
seizures and delirium.[18] Until the second half of the 20th century it remained a diagnosis generally made after
death.[19] In the 1940s, reports by DrCharles Symonds and others allowed for the clinical diagnosis of cerebral
venous thrombosis, using characteristic signs and symptoms and results of lumbar puncture.[20][21]
Improvements on the diagnosis of cerebral venous sinus thrombosis in life were made with the introduction
of venography in 1951,[22] which also aided in the distinction from idiopathic intracranial hypertension,[23] which
has similar presenting signs and symptoms in many cases.[19]

The British gynecologist Stansfield is credited with the introduction, in 1942, of the just recently introduced
anticoagulant heparin in the treatment of CVST in 1942.[19][21] Clinical trials in the 1990s finally resolved the
concern about using anticoagulants in most cases of CVST.[3]

Cyanosis
From Wikipedia, the free encyclopedia

   

Y Y/ 
YY
Y  Y>YY Y

0
 " $ Y

0
 " Y

6
 is a blue coloration of the skin and mucous membranes due to the presence of greater than, or equal
to, 2.5 g/dL of deoxygenatedhemoglobin in blood vessels near the skin surface. [1]
Although human blood is always a shade of red (except in rare cases of hemoglobin-related disease), the
optical properties of skin distort the dark red color of deoxygenated blood to make it appear bluish.[2]

The elementary principle behind cyanosis is that deoxygenated hemoglobin is more prone to the optical bluish
discoloration, and also produces vasoconstriction that makes it more evident. The scattering of color that
produces the blue hue of veins and cyanosis is similar to the process that makes the sky appear blue: some
colors are refracted and absorbed more than others. During cyanosis, tissues are uncharacteristically low on
oxygen, and therefore tissues that would normally be filled with bright oxygenated blood are instead filled with
darker, deoxygenated blood. Darker blood is much more prone to the blue-shifting optical effects,[3] and thus
oxygen deficiency - hypoxia - leads to blue discoloration of the lips and other mucous membranes.

The name is derived from the color cyan, which comes from   ?, the Greek word for blue.

Cyanosis is an abnormal blue discoloration of the skin and mucous membranes and requires an absolute
concentration of deoxygenated haemoglobin of > 5 g/dL. It is actually easier to appreciate in those with high
hemoglobin than those with anemia. It can be difficult to detect in patients with deeply pigmented skin. When
signs of cyanosis first appear, intervention must be made within 3±5 minutes.

6



Y%
& Y

Y#   Y

"Y#  Y 

 Y

m "Y(Y  Y

§ "Y(Y

m ""Y) 
Y  Y

§ ""Y(Y

Y'YY

YY

Y45Y 6Y

[edit]Definition

Cyanosis is divided in to two main types: central (around the core and lips) and peripheral (only the extremities
are affected).

[edit]Differential diagnosis

Cyanosis can occur in the fingers, including underneath the fingernails, as well as other extremities (called
peripheral cyanosis), or in the lips and tongue (central cyanosis).
[edit]6

Y
Y

Central cyanosis is often due to a circulatory or ventilatory problem that leads to poor blood oxygenation in the
lungs or greater oxygen extraction due to slowing down of blood circulation in the skin's blood vessels.

Acute cyanosis can be a result of asphyxiation or choking, and is one of the surest signs that respiration is
being blocked.

x
6


1. Central Nervous System:

§ Intracranial hemorrhage
§ Cerebral anoxia

§ Drug overdose (e.g. Heroin)

2. Respiratory System:

§ Bronchiolitis
§ Bronchospasm (e.g. Asthma)
§ Lung disease
§ Pulmonary embolism
§ Hypoventilation
§ COPD (emphysema and chronic bronchitis)

3.Cardiac Disorders:

§ Congenital heart disease (e.g. Tetralogy of Fallot, Right to left shunts in heart or great vessels)
§ Heart failure
§ Heart valve disease
§ Myocardial infarction

4.Blood:

§ Methemoglobinemia
§ Polycythaemia

5.Others:

§ High altitude
§ Hypothermia
§ Congenital cyanosis (HbM Boston) arises from a mutation in the Į-codon which results in a change
of primary sequence, H --> Y. Tyrosine stabilises the Fe(III) form (oxyhaemoglobin) creating a permanent
T-state of Hb.
[edit]  
Y
Y
Peripheral cyanosis is the blue tint in fingers or extremities, due to inadequate circulation. The blood reaching
the extremities is not oxygen rich and when viewed through the skin a combination of factors can lead to the
appearance of a blue color. All factors contributing to central cyanosis can also cause peripheral symptoms to
appear, however peripheral cyanosis can be observed without there being heart or lung failures. Small blood
vessels may be restricted and can be treated by increasing the normal oxygenation level of the blood.

x
6


§ All common causes of central cyanosis

§ Arterial obstruction
§ Cold exposure (due to vasoconstriction)
§ Raynaud's phenomenon (vasoconstriction)
§ Reduced cardiac output (e.g. heart failure, hypovolaemia)
§ Vasoconstriction
§ Venous obstruction (e.g. deep vein thrombosis)
Y

Circulatory system
From Wikipedia, the free encyclopedia

ÔO?
‘?


O  ? ?
› 
O
"?6‘
 

?
› 
? 
‘
?"
?%?‘
??

6




 Y

Y
Y  Y YY  Y5

Y2YY

 Y5
Y

u  




Y

The 
 Y is an organ system that passes nutrients (such as amino acids and electrolytes),
gases, hormones, blood cells, etc. to and from cells in the body to help fight diseases and help stabilize body
temperature and pH to maintain homeostasis.

This system may be seen strictly as a blood distribution network, but some consider the circulatory system as
composed of the 
Y , which distributes blood,[1] and the
  Y ,[2] which
distributes lymph. While humans, as well as other vertebrates, have a closed cardiovascular system (meaning
that the blood never leaves the network of arteries, veins and capillaries), some invertebrate groups have an
open cardiovascular system. The most primitive animal phyla lack circulatory systems. The lymphatic system,
on the other hand, is an open system.

Two types of fluids move through the circulatory system: blood and lymph. The blood, heart, and blood vessels
form the cardiovascular system. The lymph, lymph nodes, and lymph vessels form the lymphatic system. The
cardiovascular system and the lymphatic system collectively make up the circulatory system.

6



 Y%
& Y

Y*Y .Y Y

m Y) Y  Y

m "Y'  Y  Y

m  Y( Y  Y

m Y*Y

m Y(Y .Y Y

m Y0Y
 DY

m Y*
YY Y

m Y85
Y Y

"Y>
Y

m "Y8
Y.Y

m ""Y8Y  Y Y

m " YYY  Y Y

Y*  YY . Y

Y8
Y 
Y

Y'YY

YY

Y45Y 6Y

Human cardiovascular system

The main components of the human cardiovascular system are the heart and the blood vessels.[3] It includes:
the pulmonary circulation, a "loop" through the lungs where blood is oxygenated; and the systemic circulation, a
"loop" through the rest of the body to provide oxygenated blood. An average adult contains five to six quarts
(roughly 4.7 to 5.7 liters) of blood, which consists of plasma, red blood cells, white blood cells, and platelets.
Also, the digestive system works with the circulatory system to provide the nutrients the system needs to keep
the heart pumping.



Y

Y

‘c‘  ‘
 

The Pulmonary circulation is the portion of the cardiovascular system which transports oxygen-
depleted blood away from the heart, to the lungs, and returns oxygenated blood back to the heart.
Oxygen deprived blood from the vena cava enters the right atrium of the heart and flows through the tricuspid
valve into the right ventricle, from which it is pumped through the pulmonary semilunar valve into the pulmonary
arteries which go to the lungs. Pulmonary veins return the now oxygen-rich blood to the heart, where it enters
the left atrium before flowing through themitral valve into the left ventricle. Then, oxygen-rich blood from the left
ventricle is pumped out via the aorta, and on to the rest of the body.

 Y

Y

‘
?
‘
 

Systemic circulation is the portion of the cardiovascular system which transports oxygenated blood away from
the heart, to the rest of the body, and returns oxygen-depleted blood back to the heart. Systemic circulation is,
distance-wise, much longer than pulmonary circulation, transporting blood to every part of the body.

6 
Y

Y

‘6   ‘
 

The coronary circulatory system provides a blood supply to the heart. As it provides oxygenated blood to the
heart, it is by definition a part of the systemic circulatory system.

 Y

View from the front, which means the right side of the heart is on the left of the diagram (and vice-versa)


‘O

The heart pumps oxygenated blood to the body and deoxygenated blood to the lungs. In the human heart there
is one atrium and one ventricle for each circulation, and with both a systemic and a pulmonary circulation there
are four chambers in total: left atrium, left ventricle, right atrium and right ventricle. The right atrium is the upper
chamber of the right side of the heart. The blood that is returned to the right atrium is deoxygenated (poor in
oxygen) and passed into the right ventricle to be pumped through the pulmonary artery to the lungs for re-
oxygenation and removal of carbon dioxide. The left atrium receives newly oxygenated blood from the lungs as
well as the pulmonary vein which is passed into the strong left ventricle to be pumped through the aorta to the
different organs of the body.

6
Y 
Y Y
The cardiovascular systems of humans are closed, meaning that the blood never leaves the network of blood
vessels. In contrast, oxygen and nutrients diffuse across the blood vessel layers and enters interstitial fluid,
which carries oxygen and nutrients to the target cells, and carbon dioxide and wastes in the opposite direction.
The other component of the circulatory system, thelymphatic system, is not closed. The heart is located in the
center of the body between the two lungs. The reason that the heart beat is felt on the left side is because the
left ventricle is pumping harder.

{ 
Y
*Y

§ Electrocardiogram²for cardiac electrophysiology

§ Sphygmomanometer and stethoscope²for blood pressure
§ Pulse meter²for cardiac function (heart rate, rhythm, dropped beats)
§ Pulse²commonly used to determine the heart rate in absence of certain cardiac pathologies
§ Heart rate variability -- used to measure variations of time intervals between heart beats
§ Nail bed blanching test²test for perfusion

§ Vessel cannula or catheter pressure measurement²pulmonary wedge pressure or in older animal

experiments.
 
 Y
YY

‘6 ?‘??


‘6  
‘O




Y
 
Y

‘‘ &  
? 


About 98.5% of the oxygen in a sample of arterial blood in a healthy human breathing air at sea-level pressure
is chemically combined with haemoglobin molecules. About 1.5% is physically dissolved in the other blood
liquids and not connected to Hgb. The haemoglobin molecule is the primary transporter of oxygen
in mammals and many other species.

Nonhuman
 YY
The circulatory systems of all vertebrates, as well as of annelids (for example, earthworms)
and cephalopods (squid and octopus) are ‘ ?, just as in humans. Still, the systems
of fish,amphibians, reptiles, and birds show various stages of the evolution of the circulatory system.

In fish, the system has only one circuit, with the blood being pumped through the capillaries of the gills and on
to the capillaries of the body tissues. This is known as ? ‘ ‘circulation. The heart of fish is therefore only
a single pump (consisting of two chambers).

In amphibians and most reptiles, a double circulatory system is used, but the heart is not always completely
separated into two pumps. Amphibians have a three-chambered heart.

In reptiles, the ventricular septum of the heart is incomplete and the pulmonary artery is equipped with
a sphincter muscle. This allows a second possible route of blood flow. Instead of blood flowing through the
pulmonary artery to the lungs, the sphincter may be contracted to divert this blood flow through the incomplete
ventricular septum into the left ventricle and out through the aorta. This means the blood flows from the
capillaries to the heart and back to the capillaries instead of to the lungs. This process is useful
to ectothermic (cold-blooded) animals in the regulation of their body temperature.

Birds and mammals show complete separation of the heart into two pumps, for a total of four heart chambers; it
is thought that the four-chambered heart of birds evolved independently from that of mammals.


Y
 Y Y
The Open Circulatory System is a system in which fluid (called hemolymph) in a cavity called
the hemocoel bathes the organs directly with oxygen and nutrients and there is no distinction
between blood and interstitial fluid; this combined fluid is called hemolymph or haemolymph. Muscular
movements by the animal during locomotion can facilitate hemolymph movement, but diverting flow from one
area to another is limited. When the heart relaxes, blood is drawn back toward the heart through open-ended
pores (ostia).

Hemolymph fills all of the interior hemocoel of the body and surrounds all cells. Hemolymph is composed
of water, inorganic salts (mostly Na+, Cl-, K+, Mg2+, and Ca2+), and organic
compounds (mostly carbohydrates, proteins, and lipids). The primary oxygen transporter molecule
is hemocyanin.
There are free-floating cells, the hemocytes, within the hemolymph. They play a role in the arthropod immune
system.

Ñ
Y Y
 Y Y
Circulatory systems are absent in some animals, including flatworms (phylum Platyhelminthes). Their body
cavity has no lining or enclosed fluid. Instead a muscular pharynx leads to an extensively branched digestive
system that facilitates direct diffusion of nutrients to all cells. The flatworm's dorso-ventrally flattened body
shape also restricts the distance of any cell from the digestive system or the exterior of the
organism. Oxygen can diffuse from the surrounding water into the cells, and carbon dioxide can diffuse out.
Consequently every cell is able to obtain nutrients, water and oxygen without the need of a transport system.

Some animals, such as jellies, have more extensive branching from their gastrovascular cavity (which functions
as both a place of digestion and a form of circulation), this branching allows for bodily fluids to reach the outer
layers, since the digestion begins in the inner layers.

History of discovery
The earliest known writings on the circulatory system are found in the Ebers Papyrus (16th century BCE),
an ancient Egyptian medical papyrus containing over 700 prescriptions and remedies, both physical and
spiritual. In the papyrus, it acknowledges the connection of the heart to the arteries. The Egyptians thought air
came in through the mouth and into the lungs and heart. From the heart, the air traveled to every member
through the arteries. Although this concept of the circulatory system is greatly flawed, it represents one of the
earliest accounts of scientific thought.

In the 6th century BCE, the knowledge of circulation of vital fluids through the body was known to
the Ayurvedic physician Sushruta in ancient India.[4] He also seems to have possessed knowledge of
the arteries, described as 'channels' by Dwivedi & Dwivedi (2007).[4] The valves of the heart were discovered by
a physician of the Hippocratean school around the 4th century BCE. However their function was not properly
understood then. Because blood pools in the veins after death, arteries look empty. Ancient anatomists
assumed they were filled with air and that they were for transport of air.

The Greek physician, Herophilus, distinguished veins from arteries but thought that the pulse was a property of
arteries themselves. Greek anatomist Erasistratus observed that arteries that were cut during life bleed. He
ascribed the fact to the phenomenon that air escaping from an artery is replaced with blood that entered by
very small vessels between veins and arteries. Thus he apparently postulated capillaries but with reversed flow
of blood.[5]

In 2nd century AD Rome, the Greek physician Galen knew that blood vessels carried blood and identified
venous (dark red) and arterial (brighter and thinner) blood, each with distinct and separate functions. Growth
and energy were derived from venous blood created in the liver from chyle, while arterial blood gave vitality by
containing pneuma (air) and originated in the heart. Blood flowed from both creating organs to all parts of the
body where it was consumed and there was no return of blood to the heart or liver. The heart did not pump
blood around, the heart's motion sucked blood in during diastole and the blood moved by the pulsation of the
arteries themselves.

Galen believed that the arterial blood was created by venous blood passing from the left ventricle to the right by
passing through 'pores' in the interventricular septum, air passed from the lungs via the pulmonary artery to the
left side of the heart. As the arterial blood was created 'sooty' vapors were created and passed to the lungs
also via the pulmonary artery to be exhaled.

In 1025, ÔO6   by the Persian physician, Avicenna, "erroneously accepted the Greek notion
regarding the existence of a hole in the ventricular septum by which the blood traveled between the ventricles."
Despite this, Avicenna "correctly wrote on the cardiac cycles and valvular function", and "had a vision of blood
circulation" in his Ô
? c‘?.[6] While also refining Galen's erroneous theory of the pulse, Avicenna
provided the first correct explanation of pulsation: "Every beat of the pulse comprises two movements and two
pauses. Thus, expansion : pause : contraction : pause. [...] The pulse is a movement in the heart and arteries
... which takes the form of alternate expansion and contraction."[7]

In 1242, the Arabian physician, Ibn al-Nafis, became the first person to accurately describe the process
of pulmonary circulation, for which he is sometimes considered the father ofcirculatory physiology.[8][


 

]
Ibn al-Nafis stated in his 6 
  Ñ
 Ñ?6 :

"...the blood from the right chamber of the heart must arrive at the left chamber but there is no direct pathway
between them. The thick septum of the heart is not perforated and does not have visible pores as some people
thought or invisible pores as Galen thought. The blood from the right chamber must flow through the vena
arteriosa (pulmonary artery) to the lungs, spread through its substances, be mingled there with air, pass
through the arteria venosa (pulmonary vein) to reach the left chamber of the heart and there form the vital
spirit..."

In addition, Ibn al-Nafis had an insight into what would become a larger theory of the capillary circulation. He
stated that "there must be small communications or pores (O in Arabic) between the pulmonary artery
and vein," a prediction that preceded the discovery of the capillary system by more than 400 years.[9] Ibn al-
Nafis' theory, however, was confined to blood transit in the lungs and did not extend to the entire body.

Finally William Harvey, a pupil of Hieronymus Fabricius (who had earlier described the valves of the veins
without recognizing their function), performed a sequence of experiments, and published 

 Ñ


6 ?

 ?Ñ‘
? in 1628, which "demonstrated that there had to be a direct
connection between the venous and arterial systems throughout the body, and not just the lungs. Most
importantly, he argued that the beat of the heart produced a continuous circulation of blood through minute
connections at the extremities of the body. This is a conceptual leap that was quite different from Ibn al-Nafis'
refinement of the anatomy and bloodflow in the heart and lungs."[10] This work, with its essentially correct
exposition, slowly convinced the medical world. However, Harvey was not able to identify the capillary system
connecting arteries and veins; these were later discovered by Marcello Malpighi in 1661.

Other images

Y
Y

 Y

Y

Y

Bubonic plague
From Wikipedia, the free encyclopedia

ÔO?
‘?


O?? ‘›  
 


O‘ ‘ "?‘


O

 


6



 
 Y

Y
 %&
0
 "$$Y Y

0
 $"Y$$Y%&Y

  
  "" Y


Y
 is the best known manifestation of the plague, caused by the Gram-
negative bacterium ??
? (formerly known asc?
‘‘?
?). It belongs to the
family Enterobacteriaceae. The term

‘  is derived from the Greek word bubo, meaning "swollen
gland". Swollen lymph nodes (buboes) especially occur in the armpit and groin in persons suffering from
bubonic plague. 
‘  was often used synonymously for plague, but it does in fact refer specifically to
an infection that enters through the skin and travels through the lymphatics, as is often seen in flea-borne
infections. The bubonic plague kills about two out of three of infected patients in 2±6 days without treatment. It
may have been the cause of the Black Death that swept through Europe in the 14th century and killed more
than 25 million people, one third of the European population.[2]

6



Y%
& Y

Y'
YY Y

"Y)

 
Y

Y Y

Y*  Y

Y@ 
Y/Y

Y'YY

Y?Y

YY

Y?
Y 
Y

[edit]Signs and symptoms

The most famous symptom of bubonic plague is painful, swollen lymph glands, called buboes. These are
commonly found in the armpits, groin or neck. Due to its bite-based form of infection, the bubonic plague is
often the first step of a progressive series of illness. Two other forms of the plague, pneumonic and septicemic,
often resulted after a patient with the bubonic plague developed pneumonia or blood poisoning.
However, pneumonic plague, unlike the bubonic or septicemic, induced coughing, was also very infectious and
allowed person-to-person spread.

Other symptoms include heavy breathing, continuous blood vomiting, urination of blood, aching limbs,
coughing, and extreme pain. The pain is usually caused by the decaying, or decomposing, of the skin while the
person is still alive. Additional symptoms include fever, headaches, chills, extreme tiredness, gastrointestinal
problems, lenticulae (black dots scattered throughout the body), delirium, coma and death.

[edit]Pathophysiology

The bubonic plague is an infection of the lymphatic system, usually resulting from the bite of an infected
flea, d ? ‘‘O ? (the rat flea). The fleas are often found on rodents, such as rats and mice, and seek
out other prey when their rodent hosts die. The bacteria form aggregates in the gut of infected fleas and this
results in the flea regurgitating ingested blood, which is now infected, into the bite site of a rodent or human
host. Once established, bacteria rapidly spread to the lymph nodes and multiply. ?
? bacilli can resist
phagocytosis and even reproduce inside phagocytes and kill them. As the disease progresses, the lymph
nodes can haemorrhage and become swollen and necrotic. Bubonic plague can progress to lethal septicemic
plague in some cases. The plague is also known to spread to the lungs and become the disease known as
the pneumonic plague. This form of the disease is highly infectious as the bacteria can be transmitted in
droplets emitted when coughing or sneezing, as well as physical contact with victims of the plague or flea-
bearing rodents that carry the plague.

[edit]Treatment

In modern times, several classes of antibiotics are effective in treating bubonic plague. These include
the aminoglycosides streptomycin and gentamicin, the tetracyclines anddoxycycline and
the fluoroquinolone ciprofloxacin. Mortality associated with treated cases of bubonic plague are about 1-15%,
compared to a mortality rate of 40-60% in untreated cases.[3]

[edit]History


‘?c‘  ÿ?
"‘
O"ÔOc

The deadly disease has claimed nearly 200 million lives (although there is some debate as to whether all of the
plagues attributed to it are in fact the same disease). The first recorded epidemic ravaged the Byzantine
Empire during the sixth century, and was named the Plague of Justinian after emperor Justinian I, who was
infected but survived through extensive treatment.[4][5]

The most infamous and devastating instance of the plague was the Black Death, which killed a quarter to half
of the population of Europe. In affected cities, proper burial rituals were abandoned and bodies were buried in
mass graves, or abandoned in the street. The Black Death is thought to have originated in the Gobi Desert.
Carried by the fleas on rats, it spread along trade routes and reached the Crimea in 1346. (It also spread
eastward to the Yangtse river valley, and the resulting epidemic, ignored by the government, brought down
the Yuan dynasty[

 ]
.) In 1347 it spread to Constantinople and then Alexandria, killing thousands every
day, and soon arrived in Western Europe. It is thought that the name Black Death comes from the fact that the
tissue turns a distinctive black color during necrosis, or from the general gloominess surrounding the plague.
However, this name was not applied until many years later.

Terrible conditions in medieval Europe were only part of the reason it reached such pandemic proportions. The
people of Europe believed cats were evil and so domestic house cats were killed. Without these cats, the rat
population was dramatically increased, there were more infectious fleas, and disease transmission was more
likely.[6] Also, poor harvests over the previous decades may have led to an undernourished European
population that was more susceptible to disease.[

 ]

The next few centuries were marked by several local outbreaks of lesser severity. The Great Plague of Seville,
1649, the Great Plague of London, 1665±1666, and the Great Plague of Vienna, 1679, were the last major
outbreaks of the bubonic plague in Europe.

The children's game of "Ring Around the Rosy" (or Ring a Ring o' Roses) may be derived from the appearance
of the bubonic plague. Proponents claim that "Ring around the rosy" refers to the rosy-red, rash-like ring that
appeared as a symptom of the plague. "Pocket full of posy" referred to carrying flower petals as at the time it
was believed the disease was spread through the ether of unhygene and scent stopped the spread. "Ashes,
ashes" referred to the burning of infected corpses (in the UK the words of the rhyme are "atishoo, atishoo"
mimicing sneezing), and "we all fall down" referred to the virulent deaths attributed to the plague.[7] Some
folklorists state the claim is baseless.[8][9]

Directions for searchers, Pune plague of 1897

The plague resurfaced in the mid-19th century; like the Black Death, the Third Pandemic began in Central Asia.
The disease killed millions in China and India - then a British colony - and then spread worldwide. The outbreak
continued into the early 20th century. In 1897, Pune in India, was severely affected by the outbreak. The
government responded to the plague with a committee system that used the military to perpetrate repression
and tyranny as it tackled the pandemic. Nationalistspublicly berated the government. On 22 June 1897, two
young brahmins, the Chapekar brothers, shot and killed two British officers, the Committee chairman and his
military escort. This act has been considered a landmark event in India's struggle for freedom as well as the
worst violence against political authority seen in the world during the third plague pandemic.[10] The award
winning Marathi film ëëÿ'() covers events prior to the assassination, the act and its aftermath.[11][12] In
1994 and 2010 there have been cases reported in Peru.[13]

Influenza
From Wikipedia, the free encyclopedia

#›‘#
?O› 
O??"?›‘?
 
 !

ÔO?
‘?


O??‘ › 
O‘  ??
O
?
O??"

? 
O   

0  $

6



 
 Y

Y
40YY
 . Y Y 7Y.  2Y
  Y5  Y

$$2$$$Y Y
0
 ÿ$2YÿY

0
  Y

  
   Y

   $$$$$ Y


   !$Y! $$Y


  #$$" Y

0  $%›&

Ô 

. Y!*>Y 'Y( Y

4D 'Y'/ Y!*>Y Y

(

  

"$$Y Y) 5Y

(09?-C9'Y?7'Y3.Y

- .YY?0 'Y8Y

 Ô  

 'Y 'Y-  . Y

8 . 'Y) . 'Y  Y

E  Y#'YF . Y

 


"$$'Y<Y*
Y1
'YY

 

"$$Y,Y@
Y

"$$Y@Y0
/Y*>Y

"$$Y YD Y

"$$Y*>Y3 'YY/ YY

 

?Y'Y37Y. Y

37Y
Y

379 6Y Y

.YGYY GYY

0


), commonly referred to as the 
, is an infectious disease caused by RNA viruses of
the family Orthomyxoviridae (the influenza viruses), that affects birds and mammals. The most common
symptoms of the disease are chills, fever, sore throat, muscle pains, severeheadache, coughing,
weakness/fatigue and general discomfort.[1] Sore throat, fever and coughs are the most frequent symptoms. In
more serious cases, influenza causes pneumonia, which can be fatal, particularly for the young and the elderly.
Although it is often confused with other influenza-like illnesses, especially the common cold, influenza is a more
severe disease than the common cold and is caused by a different type of virus.[2] Influenza may
produce nausea and vomiting, particularly in children,[1] but these symptoms are more common in the
unrelated gastroenteritis, which is sometimes called "stomach flu" or "24-hour flu".[3]

Typically, influenza is transmitted through the air by coughs or sneezes, creating aerosols containing the virus.
Influenza can also be transmitted by direct contact with bird droppings or nasal secretions, or through contact
with contaminated surfaces. Airborne aerosols have been thought to cause most infections, although which
means of transmission is most important is not absolutely clear.[4] Influenza viruses can be inactivated
by sunlight, disinfectants and detergents.[5][6] As the virus can be inactivated by soap, frequent hand washing
reduces the risk of infection.

Influenza spreads around the world in seasonal epidemics, resulting in the deaths of between 250,000
and 500,000 people every year,[7] up to millions in some pandemic years. On average 41,400 people died each
year in the United States between 1979 and 2001 from influenza.[8]Three influenza pandemics occurred in the
20th century and killed tens of millions of people, with each of these pandemics being caused by the
appearance of a new strain of the virus in humans. Often, these new strains appear when an existing flu virus
spreads to humans from other animal species, or when an existing human strain picks up new genes from a
virus that usually infects birds or pigs. An avian strain named H5N1 raised the concern of a new influenza
pandemic, after it emerged in Asia in the 1990s, but it has not evolved to a form that spreads easily between
people.[9] In April 2009 a novel flu strain evolved that combined genes from human, pig, and bird flu, initially
dubbed "swine flu" and also known as influenza A/H1N1, emerged in Mexico, the United States, and several
other nations. The World Health Organization officially declared the outbreak to be a pandemic on June 11,
2009 (see 2009 flu pandemic). The WHO's declaration of a pandemic level 6 was an indication of spread, not
severity, the strain actually having a lower mortality rate than common flu outbreaks.[10]

Vaccinations against influenza are usually given to people in developed countries[11] and to farmed
poultry.[12] The most common human vaccine is the trivalent influenza vaccine (TIV) that contains purified and
inactivated material from three viral strains. Typically, this vaccine includes material from two influenza A
virus subtypes and one influenza B virus strain.[13] The TIV carries no risk of transmitting the disease, and it has
very low reactivity. A vaccine formulated for one year may be ineffective in the following year, since the
influenza virus evolves rapidly, and new strains quickly replace the older ones. Antiviral drugs can be used to
treat influenza, with neuraminidase inhibitors being particularly effective.

6



Y%
& Y

Y(   Y

m Y YY 7Y. Y

§ Y37. YY

 § "Y37. Y@Y

§  Y37. Y(Y

m "Y'2Y 2YY YY

m  Y  Y

"Y'
YY Y

Y0
 Y

m Y   Y

m "Y)

 
Y

Y). Y

m YE  Y

m "Y3 YY

Y Y

m Y>  Y 
 Y

m "Y0"Y 
 YY

Y)
 Y

Y4  
Y

m Y'Y.  Y

m "Y4  YY YY

Y*  Y

m Y4 
Y

m "Y) Y

Y'  YYY

$Y
Y

Y3 Y Y
Y Y

m Y@ YY

m "Y'/ YY

"Y'YY

 YY

Y?
Y 
Y

Y45Y 6Y

[edit]Classification

[edit]Y Y



)YY
Structure of the influenza virion. Thehemagglutinin (HA) and neuraminidase (NA) proteins are shown on the surface of the
particle. The viral RNAs that make up thegenome are shown as red coils inside the particle and bound to Ribonuclear
Proteins (RNPs).

In virus classification influenza viruses are RNA viruses that make up three of the five genera of the
family Orthomyxoviridae:[14]

§ Influenzavirus A
§ Influenzavirus B
§ Influenzavirus C

These viruses are only distantly related to the human parainfluenza viruses, which are RNA viruses belonging
to the paramyxovirus family that are a common cause of respiratory infections in children such as croup,[15] but
can also cause a disease similar to influenza in adults.[16]

x
0
 
Ñ

This genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of
influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks
in domestic poultry or give rise to human influenza pandemics.[17]The type A viruses are the most virulent
human pathogens among the three influenza types and cause the most severe disease. The influenza A virus
can be subdivided into different serotypes based on the antibody response to these viruses.[18] The serotypes
that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

§ H1N1, which caused Spanish flu in 1918, and the 2009 flu pandemic
§ H2N2, which caused Asian Flu in 1957

§ H3N2, which caused Hong Kong Flu in 1968

§ H5N1, a current pandemic threat

§ H7N7, which has unusual zoonotic potential[19]

§ H1N2, endemic in humans and pigs

§ H9N2

§ H7N2

§ H7N3

§ H10N7

x
0
 


Influenza virus nomenclature (for a Fujian flu virus)

This genus has one species, influenza B virus. Influenza B almost exclusively infects humans[18] and is less
common than influenza A. The only other animals known to be susceptible to influenza B infection are
the seal[20] and the ferret.[21] This type of influenza mutates at a rate 2±3 times slower than type A[22] and
consequently is less genetically diverse, with only one influenza B serotype.[18] As a result of this lack
of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However,
influenza B mutates enough that lasting immunity is not possible.[23] This reduced rate of antigenic change,
combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of
influenza B do not occur.[24]

x
0
 
6

This genus has one species, influenza C virus, which infects humans, dogs and pigs, sometimes causing both
severe illness and local epidemics.[25][26] However, influenza C is less common than the other types and usually
only causes mild disease in children.[27][28]

[edit] /Y /Y

YY


Y
Influenzaviruses A, B and C are very similar in overall structure.[29] The virus particle is 80±120 nanometres in
diameter and usually roughly spherical, although filamentous forms can occur.[30][31] These filamentous forms
are more common in influenza C, which can form cordlike structures up to 500 micrometres long on the
surfaces of infected cells.[32] However, despite these varied shapes, the viral particles of all influenza viruses
are similar in composition.[32] These are made of a viral envelope containing two main types of glycoproteins,
wrapped around a central core. The central core contains the viral RNA genome and other viral proteins that
package and protect this RNA. RNA tends to be single stranded but in special cases it is double.[31] Unusually
for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of
segmented negative-sense RNA, each piece of RNA containing either one or two genes.[32] For example, the
influenza A genome contains 11 genes on eight pieces of RNA, encoding for
11 proteins: hemagglutinin (HA),neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2(NEP), PA, PB1,
PB1-F2 and PB2.[33]

Hemagglutinin (HA) and neuraminidase (NA) are the two large glycoproteins on the outside of the viral
particles. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the
target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind
the mature viral particles.[34] Thus, these proteins are targets for antiviral drugs.[35] Furthermore, they
are antigens to which antibodies can be raised. Influenza A viruses are classified into subtypes based on
antibody responses to HA and NA. These different types of HA and NA form the basis of
the   and D distinctions in, for example,   D.[36] There are 16 H and 9 N subtypes known, but only H 1, 2 and
3, and N 1 and 2 are commonly found in humans.[37]

[edit]$

Y

Host cell invasion and replication by the influenza virus. The steps in this process are discussed in the text.

Viruses can only replicate in living cells.[38] Influenza infection and replication is a multi-step process: firstly the
virus has to bind to and enter the cell, then deliver its genome to a site where it can produce new copies of viral
proteins and RNA, assemble these components into new viral particles and finally exit the host cell.[32]
Influenza viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells; typically
in the nose, throat and lungs of mammals and intestines of birds (Stage 1 in infection figure).[39] After the
hemagglutinin is cleaved by aprotease, the cell imports the virus by endocytosis.[40]

Once inside the cell, the acidic conditions in the endosome cause two events to happen: first part of the
hemagglutinin protein fuses the viral envelope with the vacuole's membrane, then the M2 ion
channel allows protons to move through the viral envelope and acidify the core of the virus, which causes the
core to dissemble and release the viral RNA and core proteins.[32] The viral RNA (vRNA) molecules, accessory
proteins and RNA-dependent RNA polymerase are then released into the cytoplasm (Stage 2).[41] The M2 ion
channel is blocked by amantadine drugs, preventing infection.[42]

These core proteins and vRNA form a complex that is transported into the cell nucleus, where the RNA-
dependent RNA polymerase begins transcribing complementary positive-sense vRNA (Steps 3a and b).[43] The
vRNA is either exported into the cytoplasm and translated (step 4), or remains in the nucleus. Newly
synthesised viral proteins are either secreted through theGolgi apparatus onto the cell surface (in the case of
neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to bind vRNA and form new
viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading
cellular mRNA and using the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell
mRNAs.[44]

Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA polymerase, and other
viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in
the cell membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion
(step 6). The mature virus buds off from the cell in a sphere of host phospholipid membrane, acquiring
hemagglutinin and neuraminidase with this membrane coat (step 7).[45] As before, the viruses adhere to the cell
through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues
from the host cell.[39] Drugs that inhibit neuraminidase, such as oseltamivir, therefore prevent the release of new
infectious viruses and halt viral replication.[35] After the release of new influenza viruses, the host cell dies.

Because of the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase that copies the
viral genome makes an error roughly every 10 thousand nucleotides, which is the approximate length of the
influenza vRNA. Hence, the majority of newly manufactured influenza viruses are mutants; this causes
"antigenic drift", which is a slow change in the antigens on the viral surface over time.[46] The separation of the
genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one type
of influenza virus infects a single cell. The resulting rapid change in viral genetics produces antigenic shifts,
which are sudden changes from one antigen to another. These sudden large changes allow the virus to infect
new host species and quickly overcome protective immunity.[36] This is important in the emergence of
pandemics, as discussed below in the section onEpidemiology.
[edit]Signs and symptoms
        
  $%&

#    

 

› <=Y "< =Y

  <=Y <"=Y

D 
<=Y <=Y

   

Symptoms of influenza,[48] with fever and cough the most common § Y
Y  
2Y  Y.2Y/YY  .Y

symptoms.[47] Y Y.Y$Y YY

 Y

Symptoms of influenza can start quite suddenly one to two days

after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the
infection, with body temperatures ranging from 38-39 °C (approximately 100-103 °F).[49] Many people are so ill
that they are confined to bed for several days, with aches and pains throughout their bodies, which are worse in
their backs and legs.[1]Symptoms of influenza may include:

§ Fever and extreme coldness (chills shivering, shaking (rigor))

§ Cough
§ Nasal congestion
§ Body aches, especially joints and throat
§ Fatigue

§ Headache
§ Irritated, watering eyes

§ Reddened eyes, skin (especially face), mouth, throat and nose

§ In children, gastrointestinal symptoms such as diarrhea and abdominal pain,[50][51] (may be severe in
children with influenza B)[52]

It can be difficult to distinguish between the common cold and influenza in the early stages of these
infections,[2] but a flu can be identified by a high fever with a sudden onset and extreme fatigue. Diarrhea is not
normally a symptom of influenza in adults,[47] although it has been seen in some human cases of
the H5N1 "bird flu"[53] and can be a symptom in children.[50] The symptoms most reliably seen in influenza are
shown in the table to the right.[47]
Since antiviral drugs are effective in treating influenza if given early (see treatment section, below), it can be
important to identify cases early. Of the symptoms listed above, the combinations of fever with cough, sore
throat and/or nasal congestion can improve diagnostic accuracy.[54]Two decision analysis studies[55][56] suggest
that  ‘ ‘ 

? of influenza, the prevalence will be over 70%,[56] and thus patients with any of these
combinations of symptoms may be treated with neuraminidase inhibitors without testing. Even in the absence
of a local outbreak, treatment may be justified in the elderly during the influenza season as long as the
prevalence is over 15%.[56]

The available laboratory tests for influenza continue to improve. The United States Centers for Disease Control
and Prevention (CDC) maintains an up-to-date summary of available laboratory tests.[57] According to the CDC,
rapid diagnostic tests have a sensitivity of 70±75% and specificity of 90±95% when compared with viral culture.
These tests may be especially useful during the influenza season (prevalence=25%) but in the absence of a
local outbreak, or peri-influenza season (prevalence=10%[56]).

[edit]Mechanism

[edit]
 
Y

Sneezing can transmit influenza.

Influenza virus shedding (the time during which a person might be infectious to another person) begins the day
before symptoms appear and virus is then released for between 5 to 7 days, although some people may shed
virus for longer periods. People who contract influenza are most infective between the second and third days
after infection.[58] The amount of virus shed appears to correlate with fever, with higher amounts of virus shed
when temperatures are highest.[59] Children are much more infectious than adults and shed virus from just
before they develop symptoms until two weeks after infection.[58][60] The transmission of influenza can
be modeled mathematically, which helps predict how the virus will spread in a population.[61]

Influenza can be spread in three main ways:[62][63] by direct transmission (when an infected person sneezes
mucus directly into the eyes, nose or mouth of another person); the airborne route (when someone inhales
the aerosols produced by an infected person coughing, sneezing or spitting) and through hand-to-eye, hand-to-
nose, or hand-to-mouth transmission, either from contaminated surfaces or from direct personal contact such
as a hand-shake. The relative importance of these three modes of transmission is unclear, and they may all
contribute to the spread of the virus.[4][64] In the airborne route, the droplets that are small enough for people to
inhale are 0.5 to 5 µm in diameter and inhaling just one droplet might be enough to cause an
infection.[62] Although a single sneeze releases up to 40,000 droplets,[65] most of these droplets are quite large
and will quickly settle out of the air.[62] How long influenza survives in airborne droplets seems to be influenced
by the levels of humidity and UV radiation: with low humidity and a lack of sunlight in winter aiding its
survival.[62]

As the influenza virus can persist outside of the body, it can also be transmitted by contaminated surfaces such
as banknotes,[66] doorknobs, light switches and other household items.[1] The length of time the virus will persist
on a surface varies, with the virus surviving for one to two days on hard, non-porous surfaces such as plastic or
metal, for about fifteen minutes from dry paper tissues, and only five minutes on skin.[67] However, if the virus is
present in mucus, this can protect it for longer periods (up to 17 days on banknotes).[62][66]Avian influenza
viruses can survive indefinitely when frozen.[68] They are inactivated by heating to 56 °C (133 °F) for a minimum
of 60 minutes, as well as by acids (at pH <2).[68]

[edit]   
Y

The different sites of infection (shown in red) of seasonal H1N1 versus avian H5N1. This influences their lethality and ability
to spread.

The mechanisms by which influenza infection causes symptoms in humans have been studied intensively. One
of the mechanisms is believed to be the inhibition of adrenocorticotropic hormone (ACTH) resulting in lowered
cortisol levels.[69] Knowing which genes are carried by a particular strain can help predict how well it will infect
humans and how severe this infection will be (that is, predict the strain's pathophysiology).[26][70]

For instance, part of the process that allows influenza viruses to invade cells is the cleavage of the
viral hemagglutinin protein by any one of several human proteases.[40] In mild and avirulent viruses, the
structure of the hemagglutinin means that it can only be cleaved by proteases found in the throat and lungs, so
these viruses cannot infect other tissues. However, in highly virulent strains, such as H5N1, the hemagglutinin
can be cleaved by a wide variety of proteases, allowing the virus to spread throughout the body.[70]

The viral hemagglutinin protein is responsible for determining both which species a strain can infect and where
in the human respiratory tract a strain of influenza will bind.[71] Strains that are easily transmitted between
people have hemagglutinin proteins that bind to receptors in the upper part of the respiratory tract, such as in
the nose, throat and mouth. In contrast, the highly lethal H5N1 strain binds to receptors that are mostly found
deep in the lungs.[72] This difference in the site of infection may be part of the reason why the H5N1 strain
causes severe viral pneumonia in the lungs, but is not easily transmitted by people coughing and
sneezing.[73][74]

Common symptoms of the flu such as fever, headaches, and fatigue are the result of the huge amounts of
proinflammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced from
influenza-infected cells.[2][75] In contrast to the rhinovirus that causes the common cold, influenza does cause
tissue damage, so symptoms are not entirely due to the inflammatory response.[76] This massive immune
response might produce a life-threatening cytokine storm. This effect has been proposed to be the cause of the
unusual lethality of both the H5N1 avian influenza,[77] and the 1918 pandemic strain.[78][79] However, another
possibility is that these large amounts of cytokines are just a result of the massive levels of viral replication
produced by these strains, and the immune response does not itself contribute to the disease.[80]

[edit]Prevention

[edit]


Y

›
O 
 0‘ 

Giving an influenza vaccination.

Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as
children and the elderly, or in people who have asthma, diabetes, heart disease, or are immuno-compromised.
Influenza vaccines can be produced in several ways; the most common method is to grow the virus in
fertilized hen eggs. After purification, the virus is inactivated (for example, by treatment with detergent) to
produce an inactivated-virus vaccine. Alternatively, the virus can be grown in eggs until it loses virulence and
the avirulent virus given as a live vaccine.[36] The effectiveness of these influenza vaccines are variable. Due to
the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a
few years. Every year, the World Health Organization predicts which strains of the virus are most likely to be
circulating in the next year, allowing pharmaceutical companies to develop vaccines that will provide the best
immunity against these strains.[81] Vaccines have also been developed to protect poultry from avian influenza.
These vaccines can be effective against multiple strains and are used either as part of a preventative strategy,
or combined with culling in attempts to eradicate outbreaks.[82]

It is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few
specific flu strains but cannot possibly include all the strains actively infecting people in the world for that
season. It takes about six months for the manufacturers to formulate and produce the millions of doses
required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent
during that time and infects people although they have been vaccinated (as by the H3N2 Fujian flu in the 2003±
2004 flu season).[83] It is also possible to get infected just before vaccination and get sick with the very strain
that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.[84]

The 2006±2007 season was the first in which the CDC had recommended that children younger than 59
months receive the annual influenza vaccine.[85] Vaccines can cause the immune system to react as if the body
were actually being infected, and general infection symptoms (many cold and flu symptoms are just general
infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza.
The most dangerous side effect is a severe allergic reaction to either the virus material itself or residues from
the hen eggs used to grow the influenza; however, these reactions are extremely rare.[86]

In addition to vaccination against seasonal influenza, researchers are working to develop a vaccine against a
possible influenza pandemic. The rapid development, production, and distribution of pandemic influenza
vaccines could potentially save millions of lives during an influenza pandemic. Due to the short time frame
between identification of a pandemic strain and need for vaccination, researchers are looking at non-egg-based
options for vaccine production. Live attenuated (egg-based or cell-based) technology and recombinant
technologies (proteins and virus-like particles) could provide better "real-time" access and be produced more
affordably, thereby increasing access for people living in low- and moderate-income countries, where an
influenza pandemic may likely originate. As of July 2009, more than 70 known clinical trials have been
completed or are ongoing for pandemic influenza vaccines.[87]In September 2009, the US Food and Drug
Administration approved four vaccines against the 2009 H1N1 influenza virus (the current pandemic strain),
and expect the initial vaccine lots to be available within the following month.[88]

[edit]0

Y

Y
›
O 
 0‘ 
 

Reasonably effective ways to reduce the transmission of influenza include good personal health and hygiene
habits such as: not touching your eyes, nose or mouth;[89] frequent hand washing (with soap and water, or with
alcohol-based hand rubs);[90] covering coughs and sneezes; avoiding close contact with sick people; and
staying home yourself if you are sick. Avoiding spitting is also recommended.[91]

Although face masks might help prevent transmission when caring for the sick,[92][93] there is mixed evidence on
beneficial effects in the community.[91][94] Smoking raises the risk of contracting influenza, as well as producing
more severe disease symptoms.[95][96] Thus, according to the laws of mathematical modelling of infectious
diseases, smokers raise theexponential growth rates of influenza epidemics and may indirectly be responsible
for a large percentage of influenza cases.

Since influenza spreads through both aerosols and contact with contaminated surfaces, surface sanitizing may
help prevent some infections.[97] Alcohol is an effective sanitizer against influenza viruses, while quaternary
ammonium compounds can be used with alcohol so that the sanitizing effect lasts for longer.[98] In hospitals,
quaternary ammonium compounds andbleach are used to sanitize rooms or equipment that have been
occupied by patients with influenza symptoms.[98] At home, this can be done effectively with a diluted chlorine
bleach.[99]

During past pandemics, closing schools, churches and theatres slowed the spread of the virus but did not have
a large effect on the overall death rate.[100][101] It is uncertain if reducing public gatherings, by for example
closing schools and workplaces, will reduce transmission since people with influenza may just be moved from
one area to another; such measures would also be difficult to enforce and might be unpopular.[91] When small
numbers of people are infected, isolating the sick might reduce the risk of transmission.[91]

[edit]Treatment

›
O 
 0‘ 




People with the flu are advised to get plenty of rest, drink plenty of liquids, avoid
using alcohol and tobacco and, if necessary, take medications such as acetaminophen (paracetamol) to relieve
the fever and muscle aches associated with the flu.[102] Children and teenagers with flu symptoms (particularly
fever) should avoid taking aspirin during an influenza infection (especially influenza type B), because doing so
can lead to Reye's syndrome, a rare but potentially fatal disease of the liver.[103] Since influenza is caused by a
virus, antibiotics have no effect on the infection; unless prescribed for secondary infections such as bacterial
pneumonia. Antiviral medication can be effective, but some strains of influenza can show resistance to the
standard antiviral drugs.[104]
The two classes of antiviral drugs used against influenza are neuraminidase inhibitors and M2 protein inhibitors
(adamantane derivatives). Neuraminidase inhibitors are currently preferred for flu virus infections since they are
less toxic and more effective.[80] The CDC recommended against using M2 inhibitors during the 2005±06
influenza season due to high levels of drug resistance.[105] As pregnant women seem to be more severely
affected than the general population by the 2009 H1N1 influenza virus, prompt treatment with anti-influenza
drugs has been recommended.[106]

[edit]( 
Y
 Y
Antiviral drugs such as oseltamivir (trade name Tamiflu) and zanamivir (trade name Relenza)
are neuraminidase inhibitors that are designed to halt the spread of the virus in the body.[107]These drugs are
often effective against both influenza A and B.[108] The Cochrane Collaboration reviewed these drugs and
concluded that they reduce symptoms and complications.[109]Different strains of influenza viruses have differing
degrees of resistance against these antivirals, and it is impossible to predict what degree of resistance a future
pandemic strain might have.[110]

[edit]{+Y
 Y% 

'Y
The antiviral drugs amantadine and rimantadine block a viral ion channel (M2 protein) and prevent the virus
from infecting cells.[42] These drugs are sometimes effective against influenza A if given early in the infection
but are always ineffective against influenza B because B viruses do not possess M2 molecules.[108] Measured
resistance to amantadine and rimantadine in American isolates of H3N2 has increased to 91% in 2005.[111] This
high level of resistance may be due to the easy availability of amantadines as part of over-the-counter cold
remedies in countries such as China and Russia,[112] and their use to prevent outbreaks of influenza in farmed
poultry.[113][114]

[edit]Prognosis

Influenza's effects are much more severe and last longer than those of the common cold. Most people will
recover completely in about one to two weeks, but others will develop life-threatening complications (such
as pneumonia). Influenza, thus, can be deadly, especially for the weak, young and old, or chronically
ill.[36] People with a weak immune system, such as people with advanced HIV infection or transplant patients
(whose immune systems are medically suppressed to prevent transplant organ rejection), suffer from
particularly severe disease.[115] Other high-risk groups include pregnant women and young children.[116]

The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may
experience shortness of breath while they have the flu, and influenza may cause worsening of coronary heart
disease or congestive heart failure.[117] Smoking is another risk factor associated with more serious disease and
increased mortality from influenza.[118]
According to the World Health Organization: "Every winter, tens of millions of people get the flu. Most are only
ill and out of work for a week, yet the elderly are at a higher risk of death from the illness. We know the
worldwide death toll exceeds a few hundred thousand people a year, but even in developed countries the
numbers are uncertain, because medical authorities don't usually verify who actually died of influenza and who
died of a flu-like illness."[119] Even healthy people can be affected, and serious problems from influenza can
happen at any age. People over 50 years old, very young children and people of any age with chronic medical
conditions are more likely to get complications from influenza, such as pneumonia,bronchitis, sinus, and ear
infections.[84]

In some cases, an autoimmune response to an influenza infection may contribute to the development
of Guillain-Barré syndrome.[120] However, as many other infections can increase the risk of this disease,
influenza may only be an important cause during epidemics.[120][121] This syndrome can also be a rare side
effect of influenza vaccines, with an incidence of about one case per million vaccinations.[122]

[edit]Epidemiology

[edit] 

Y
Y
›
O 
 ›‘?? 

Influenza reaches peak prevalence in winter, and because the Northern and Southern Hemispheres have
winter at different times of the year, there are actually two different flu seasons each year. This is why
the World Health Organization (assisted by the National Influenza Centers) makes recommendations for two
different vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere.[81]

A long-standing puzzle has been why outbreaks of the flu occur seasonally rather than uniformly throughout the
year. One possible explanation is that, because people are indoors more often during the winter, they are in
close contact more often, and this promotes transmission from person to person. Increased travel due to the
Northern Hemisphere winter holiday season may also play a role.[123] Another factor is that cold temperatures
lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The
virus also survives longer on surfaces at colder temperatures and aerosol transmission of the virus is highest in
cold environments (less than 5 °C) with low relative humidity.[124] Indeed, the lower air humidity in winter seems
to be the main cause of seasonal influenza transmission in temperate regions.[125][126]

However, seasonal changes in infection rates also occur in tropical regions, and in some countries these peaks
of infection are seen mainly during the rainy season.[127] Seasonal changes in contact rates from school terms,
which are a major factor in other childhood diseases such as measles and pertussis, may also play a role in the
flu. A combination of these small seasonal effects may be amplified by dynamical resonance with the
endogenous disease cycles.[128] H5N1 exhibits seasonality in both humans and birds.[129]
An alternative hypothesis to explain seasonality in influenza infections is an effect of vitamin D levels on
immunity to the virus.[130] This idea was first proposed by Robert Edgar Hope-Simpson in 1965.[131] He
proposed that the cause of influenza epidemics during winter may be connected to seasonal fluctuations of
vitamin D, which is produced in the skin under the influence of solar (or artificial) UV radiation. This could
explain why influenza occurs mostly in winter and during the tropical rainy season, when people stay indoors,
away from the sun, and their vitamin D levels fall.

[edit] Y
Y
 YY
›
O 
 ›‘

Antigenic drift creates influenza viruses with slightly modified antigens, whileantigenic shift generates viruses with entirely
novel antigens.

As influenza is caused by a variety of species and strains of viruses, in any given year some strains can die out
while others create epidemics, while yet another strain can cause a pandemic. Typically, in a year's normal
two flu seasons (one per hemisphere), there are between three and five million cases of severe illness and up
to 500,000 deaths worldwide, which by some definitions is a yearly influenza epidemic.[132]Although the
incidence of influenza can vary widely between years, approximately 36,000 deaths and more than 200,000
hospitalizations are directly associated with influenza every year in the United States.[133][134] Roughly three
times per century, a pandemic occurs, which infects a large proportion of the world's population and can kill
tens of millions of people (see history section). Indeed, one study estimated that if a strain with
similar virulence to the 1918 influenza emerged today, it could kill between 50 and 80 million people.[135]
Antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human influenza

New influenza viruses are constantly evolving by mutation or by reassortment.[18] Mutations can cause small
changes in the hemagglutinin and neuraminidase antigens on the surface of the virus. This is called antigenic
drift, which slowly creates an increasing variety of strains until one evolves that can infect people who are
immune to the pre-existing strains. This new variant then replaces the older strains as it rapidly sweeps through
the human population²often causing an epidemic.[136] However, since the strains produced by drift will still be
reasonably similar to the older strains, some people will still be immune to them. In contrast, when influenza
viruses reassort, they acquire completely new antigens²for example by reassortment between avian strains
and human strains; this is called antigenic shift. If a human influenza virus is produced that has entirely new
antigens, everybody will be susceptible, and the novel influenza will spread uncontrollably, causing a
pandemic.[137] In contrast to this model of pandemics based on antigenic drift and shift, an alternative approach
has been proposed where the periodic pandemics are produced by interactions of a fixed set of viral strains
with a human population with a constantly changing set of immunities to different viral strains.[138]

[edit]History

[edit]
Y
The word 0‘  comes from the Italian language meaning "influence" and refers to the cause of the
disease; initially, this ascribed illness to unfavorable astrological influences.[139] Changes in medical thought led
to its modification to ‘ ‘ , meaning "influence of the cold". The word ‘  was first used in
English in 1743 when it was adopted, with an anglicized pronunciation, during an outbreak of the disease in
Europe.[140] Archaic terms for influenza include 
O,  (from the French), ?
 ???,
and
?O(particularly for the 1918 flu pandemic strain).[141]

[edit] 
 Y
›
O 
 0‘ "
?O‘"   *  ‘

The difference between the influenza mortality age distributions of the 1918 epidemic and normal epidemics. Deaths per

100,000 persons in each age group, United States, for the interpandemic years 1911±1917 (dashed line) and the pandemic
year 1918 (solid line).[142]

The symptoms of human influenza were clearly described by Hippocrates roughly 2,400 years
ago.[143][144] Although the virus seems to have caused epidemics throughout human history, historical data on
influenza are difficult to interpret, because the symptoms can be similar to those of other respiratory
diseases.[145][146] The disease may have spread from Europe to the Americas as early as the European
colonization of the Americas; since almost the entire indigenous population of the Antilles was killed by an
epidemic resembling influenza that broke out in 1493, after the arrival of Christopher Columbus.[147][148]

The first convincing record of an influenza pandemic was of an outbreak in 1580, which began in Russia and
spread to Europe via Africa. In Rome, over 8,000 people were killed, and several Spanish cities were almost
wiped out. Pandemics continued sporadically throughout the 17th and 18th centuries, with the pandemic of
1830±1833 being particularly widespread; it infected approximately a quarter of the people exposed.[146]

The most famous and lethal outbreak was the 1918 flu pandemic (Spanish flu pandemic) (type A
influenza, H1N1 subtype), which lasted from 1918 to 1919. It is not known exactly how many it killed, but
estimates range from 20 to 100 million people.[149][150] This pandemic has been described as "the greatest
medical holocaust in history" and may have killed as many people as the Black Death.[146] This huge death toll
was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms,
suspected to be caused by cytokine storms.[150] Indeed, symptoms in 1918 were so unusual that initially
influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of
the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine.
Bleeding from the ears and petechial hemorrhages in the skin also occurred."[149] The majority of deaths were
from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly,
causing massivehemorrhages and edema in the lung.[142]

The 1918 flu pandemic (Spanish flu pandemic) was truly global, spreading even to the Arctic and
remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed
to the more usual flu epidemic mortality rate of 0.1%.[142][149] Another unusual feature of this pandemic was that
it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more
than half in young adults 20 to 40 years old.[151] This is unusual since influenza is normally most deadly to the
very young (under age 2) and the very old (over age 70). The total mortality of the 1918±1919 pandemic is not
known, but it is estimated that 2.5% to 5% of the world's population was killed. As many as 25 million may have
been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.[149]

The influenza viruses that causedHong Kong flu. (magnified approximately 100,000 times)

Later flu pandemics were not so devastating. They included the 1957 Asian Flu (type A, H2N2 strain) and the
1968 Hong Kong Flu (type A, H3N2strain), but even these smaller outbreaks killed millions of people. In later
pandemics antibiotics were available to control secondary infections and this may have helped reduce mortality
compared to the Spanish Flu of 1918.[142]

% &%&%"&
ö   


 
  


D 


 
   0  
 Ñ 
%)  &
% & <$Y Y  Y $=Y   Y* >Y >Y
› 

 
 "$YY$$Y

<"$Y "=Y *> Y
%
  &%&
Y

  Y

Ñ  ›  <Y YYY  Y $ =Y *">" Y "Y

$YYY
 ö ›  <Y H$=Y * >" Y "Y
  Y

"$$<
* 
%&  $2$$$YY#YY $$9$$ =Y *> Y >Y
)Y

The first influenza virus to be isolated was from poultry, when in 1901 the agent causing a disease called "fowl
plague" was passed throughChamberland filters, which have pores that are too small for bacteria to pass
through.[156] The etiological cause of influenza, the Orthomyxoviridae family of viruses, was first discovered
inpigs by Richard Shope in 1931.[157] This discovery was shortly followed by the isolation of the virus from
humans by a group headed by Patrick Laidlaw at the Medical Research Councilof the United Kingdom in
1933.[158] However, it was not until Wendell Stanley first crystallized tobacco mosaic virus in 1935 that the non-
cellular nature of viruses was appreciated.

The main types of influenza viruses in humans. Solid squares show the appearance of a new strain, causing recurring
influenza pandemics. Broken lines indicate uncertain strain identifications.[159]

The first significant step towards preventing influenza was the development in 1944 of a killed-virus vaccine for
influenza byThomas Francis, Jr.. This built on work by Australian Frank Macfarlane Burnet, who showed that
the virus lost virulence when it was cultured in fertilized hen's eggs.[160] Application of this observation by
Francis allowed his group of researchers at theUniversity of Michigan to develop the first influenza vaccine,
with support from the U.S. Army.[161] The Army was deeply involved in this research due to its experience of
influenza in World War I, when thousands of troops were killed by the virus in a matter of months.[149] In
comparison to vaccines, the development of anti-influenza drugs has been slower, with amantadine being
licensed in 1966 and, almost thirty years later, the next class of drugs (the neuraminidase inhibitors) being
developed.[37]

[edit]Society and culture

›
O 
 
‘
   D

Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect
costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion
per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct
and indirect costs.[162] However, the economic impacts of past pandemics have not been intensively studied,
and some authors have suggested that theSpanish influenza actually had a positive long-term effect on per-
capita income growth, despite a large reduction in the working population and severe short-
term depressive effects.[163]Other studies have attempted to predict the costs of a pandemic as serious as the
1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30%
sickness rate and a three-week length of illness would decrease the gross domestic product by 5%. Additional
costs would come from medical treatment of 18 million to 45 million people, and total economic costs would be
approximately $700 billion.[164]

Preventative costs are also high. Governments worldwide have spent billions of U.S. dollars preparing and
planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and
vaccines as well as developing disaster drills and strategies for improved border controls.[165] On 1 November
2005, United States President George W. Bushunveiled the National Strategy to Safeguard Against the Danger
of Pandemic Influenza[166] backed by a request to Congress for $7.1 billion to begin implementing the
plan.[167]Internationally, on 18 January 2006, donor nations pledged US$2 billion to combat bird flu at the two-
day International Pledging Conference on Avian and Human Influenza held in China.[168]

In an assessment of the 2009 H1N1 pandemic on selected countries in the Southern Hemisphere, data
suggest that all countries experienced some time-limited and/or geographically isolated socio/economic effects
and a temporary decrease in tourism most likely due to fear of 2009 H1N1 disease. It is still too early to
determine whether the H1N1 pandemic has caused any long-term economic impacts.[169]

[edit]Research

›
O 
 0‘ ?O

Dr. Terrence Tumpey examining a reconstructed 1918 Spanish flu virus in abiosafety level 3 environment.

Research on influenza includes studies on molecular virology, how the virus produces disease (pathogenesis),
host immune responses, viral genomics, and how the virus spreads (epidemiology). These studies help in
developing influenza countermeasures; for example, a better understanding of the body's immune system
response helps vaccine development, and a detailed picture of how influenza invades cells aids the
development of antiviral drugs. One important basic research program is the Influenza Genome Sequencing
Project, which is creating a library of influenza sequences; this library should help clarify which factors make
one strain more lethal than another, which genes most affectimmunogenicity, and how the virus evolves over
time.[170]

Research into new vaccines is particularly important, as current vaccines are very slow and expensive to
produce and must be reformulated every year. The sequencing of the influenza genome and recombinant
DNA technology may accelerate the generation of new vaccine strains by allowing scientists to substitute new
antigens into a previously developed vaccine strain.[171] New technologies are also being developed to grow
viruses in cell culture, which promises higher yields, less cost, better quality and surge capacity.[172] Research
on a universal influenza A vaccine, targeted against the external domain of the transmembrane viral M2
protein (M2e), is being done at the University of Ghent by Walter Fiers, Xavier Saelens and their
team[173][174][175] and has now successfully concluded Phase I clinical trials.

A number of biologics, therapeutic vaccines and immunobiologics are also being investigated for treatment of
infection caused by viruses. Therapeutic biologics are designed to activate the immune response to virus or
antigens. Typically, biologics do not target metabolic pathwayslike anti-viral drugs, but stimulate immune cells
such as lymphocytes, macrophages, and/or antigen presenting cells, in an effort to drive an immune response
towards a cytotoxic effect against the virus. Infuenza models, such as murine influenza, are convenient models
to test the effects of prophylactic and therapeutic biologics. For example, Lymphocyte T-Cell Immune
Modulator inhibits viral growth in the murine model of influenza.[176]

[edit]Infection in other animals

+D

§ 37YY. Y

§  Y*>Y

§ + YY

§ 3 Y

§ *Y  Y

§ +YY

§ Y"$$Y

§ Y"$$Y

§ Y"$$Y

§ Y"$$Y

§ ' Y Y

§ ) Y

.YGYY GYY

›
O 
 0‘ ?Ñ"  DÔ??? 
    D

Influenza infects many animal species, and transfer of viral strains between species can occur. Birds are
thought to be the main animal reservoirs of influenza viruses.[177] Sixteen forms of hemagglutinin and nine forms
of neuraminidase have been identified. All known subtypes (HxNy) are found in birds, but many subtypes are
endemic in humans, dogs, horses, and pigs; populations of camels, ferrets, cats, seals, mink, and whales also
show evidence of prior infection or exposure to influenza.[23] Variants of flu virus are sometimes named
according to the species the strain is endemic in or adapted to. The main variants named using this convention
are: Bird Flu, Human Flu, Swine Flu, Horse Flu and Dog Flu. (Cat flu generally refers to Feline viral
rhinotracheitis or Feline calicivirus and not infection from an influenza virus.) In pigs, horses and dogs,
influenza symptoms are similar to humans, with cough, fever and loss of appetite.[23] The frequency of animal
diseases are not as well-studied as human infection, but an outbreak of influenza in harbour seals caused
approximately 500 seal deaths off the New England coast in 1979±1980.[178] On the other hand, outbreaks in
pigs are common and do not cause severe mortality.[23]

[edit]Y
Y

Flu symptoms in birds are variable and can be unspecific.[179] The symptoms following infection with low-
pathogenicity avian influenza may be as mild as ruffled feathers, a small reduction in egg production, or weight
loss combined with minor respiratory disease.[180] Since these mild symptoms can make diagnosis in the field
difficult, tracking the spread of avian influenza requires laboratory testing of samples from infected birds. Some
strains such as AsianH9N2 are highly virulent to poultry and may cause more extreme symptoms and
significant mortality.[181] In its most highly pathogenic form, influenza inchickens and turkeys produces a sudden
appearance of severe symptoms and almost 100% mortality within two days.[182] As the virus spreads rapidly in
the crowded conditions seen in the intensive farming of chickens and turkeys, these outbreaks can cause large
economic losses to poultry farmers.

An avian-adapted, highly pathogenic strain of H5N1 (called HPAI A(H5N1), for "highly pathogenic avian
influenza virus of type A of subtype H5N1") causesH5N1 flu, commonly known as "avian influenza" or simply
"bird flu", and is endemic in many bird populations, especially in Southeast Asia. This Asian lineage strain of
HPAI A(H5N1) is spreading globally. It is epizootic (an epidemic in non-humans) and panzootic (a disease
affecting animals of many species, especially over a wide area), killing tens of millions of birds and spurring
the culling of hundreds of millions of other birds in an attempt to control its spread. Most references in the
media to "bird flu" and most references to H5N1 are about this specific strain.[183][184]

At present, HPAI A(H5N1) is an avian disease, and there is no evidence suggesting efficient human-to-human
transmission of HPAI A(H5N1). In almost all cases, those infected have had extensive physical contact with
infected birds.[185] In the future, H5N1 may mutate or reassort into a strain capable of efficient human-to-human
transmission. The exact changes that are required for this to happen are not well understood.[186] However, due
to the high lethality and virulence of H5N1, its endemic presence, and its large and increasing biological host
reservoir, the H5N1 virus was the world's pandemic threat in the 2006±07 flu season, and billions of dollars are
being raised and spent researching H5N1 and preparing for a potential influenza pandemic.[165]

[edit] "
Y
Y
Chinese inspectors on an airplane, checking passengers for fevers, a common symptom of swine flu

In pigs swine influenza produces fever, lethargy, sneezing, coughing, difficulty breathing and decreased
appetite.[187] In some cases the infection can cause abortion. Although mortality is usually low, the virus can
produce weight loss and poor growth, causing economic loss to farmers.[187] Infected pigs can lose up to 12
pounds of body weight over a 3 to 4 week period.[187] Direct transmission of an influenza virus from pigs to
humans is occasionally possible (this is called zoonotic swine flu). In all, 50 human cases are known to have
occurred since the virus was identified in the mid-20th century, which have resulted in six deaths.[188]

In 2009, a swine-origin H1N1 virus strain commonly referred to as "swine flu" caused the 2009 flu pandemic,
but there is no evidence that it is endemic to pigs (i.e. actually a swine flu) or of transmission from pigs to
people, instead the virus is spreading from person to person.[189][190]This strain is a reassortment of several
strains of H1N1 that are usually found separately, in humans, birds, and pigs.[191]

Rubella
From Wikipedia, the free encyclopedia

ÔO? ? 
O??› 
O?"?
‘‘?

)

6



 
 Y
 Y

0
 @$ Y

0
 $ Y

  
   Y

   $$ Y


   
! Y!"$"!"Y


  #$"$ Y

$

, commonly known as  

Y 
, is a disease caused by the rubella virus. The name "rubella"
is derived from the Latin, meaning ‘

‘. Rubella is also known as German measles because the disease
was first described by German physicians in the mid-eighteenth century. This disease is often mild and attacks
often pass unnoticed. The disease can last one to three days. Children recover more quickly than adults.
Infection of the mother by Rubella virus during pregnancy can be serious; if the mother is infected within the
first 20 weeks of pregnancy, the child may be born with congenital rubella syndrome (CRS), which entails a
range of serious incurable illnesses. Spontaneous abortion occurs in up to 20% of cases.[1]

Rubella is a common childhood infection usually with minimal systemic upset although
transient arthropathy may occur in adults. Serious complications are very rare. Apart from the effects of
transplacental infection on the developing fetus, rubella is a relatively trivial infection.

Acquired (i.e. not congenital) rubella is transmitted via airborne droplet emission from the upper respiratory
tract of active cases. The virus may also be present in the urine, feces and on the skin. There is no carrier
state: the reservoir exists entirely in active human cases. The disease has an incubation period of 2 to 3
weeks.[2]

In most people the virus is rapidly eliminated. However, it may persist for some months post partum in infants
surviving the CRS. These children are a significant source of infection to other infants and, more importantly, to
pregnant female contacts.

The name 
‘‘ is sometimes confused with 
 ‘, an alternative name for measles in English-speaking
countries; the diseases are unrelated.[3][4] In some other European languages, 
‘‘ and 
 ‘ are
synonyms, and 
 ‘ is not an alternative name for measles.[5]

6



Y%
& Y

Y'
YY Y

m Y(
 YY Y

"Y(Y

Y# 
 Y

Y). Y

Y Y

Y)
 Y

Y4  
Y

Y*  Y

Y'YY

$YY

Y45Y 6Y

[edit]Signs and symptoms

After an incubation period of 14±21 days, German measles causes symptoms that are similar to the flu. The
primary symptom of rubella virus infection is the appearance of a rash (exanthem) on the face which spreads to
the trunk and limbs and usually fades after three days (that is why it is often referred to as three-day measles).
The facial rash usually clears as it spreads to other parts of the body. Other symptoms include low grade fever,
swollen glands (sub occipital & posterior cervical lymphadenopathy), joint pains, headache and
conjunctivitis.[6] The swollen glands or lymph nodes can persist for up to a week and the fever rarely rises
above 38 oC (100.4 oF). The rash of German measles is typically pink or light red. The rash causes itching and
often lasts for about three days. The rash disappears after a few days with no staining or peeling of the skin.
When the rash clears up, the patient may notice that his skin sheds in very small flakes wherever the rash
covered it. Forchheimer's sign occurs in 20% of cases, and is characterized by small, red papules on the area
of the soft palate.

Rubella can affect anyone of any age and is generally a mild disease, rare in infants or those over the age of
40. The older the person is the more severe the symptoms are likely to be. Up to two-thirds of older girls or
women experience joint pain or arthritic type symptoms with rubella. The virus is contracted through the
respiratory tract and has an incubation period of 2 to 3 weeks. During this incubation period, the patient is
contagious typically for about one week before he develops a rash and for about one week thereafter.

x
6  
  


‘6  
‘
‘‘?  

Rubella can cause congenital rubella syndrome in the newly born. The syndrome (CRS) follows intrauterine
infection by Rubella virus and comprises cardiac, cerebral, ophthalmic and auditory defects.[7] It may also
cause prematurity, low birth weight, and neonatal thrombocytopenia, anaemia and hepatitis. The risk of major
defects or organogenesis is highest for infection in the first trimester. CRS is the main reason a vaccine for
rubella was developed. Many mothers who contract rubella within the first critical trimester either have a
miscarriage or a still born baby. If the baby survives the infection, it can be born with severe heart disorders
(PDA being the most common), blindness, deafness, or other life threatening organ disorders. The skin
manifestations are called "blueberry muffin lesions." [8]

[edit]Cause


‘+
‘‘?

The disease is caused by Rubella virus, a togavirus that is enveloped and has a single-stranded RNA
genome.[9] The virus is transmitted by the respiratory route and replicates in thenasopharynx and lymph nodes.
The virus is found in the blood 5 to 7 days after infection and spreads throughout the body. The virus
has teratogenic properties and is capable of crossing the placenta and infecting the fetus where it stops cells
from developing or destroys them.[6]
Increased susceptibility to infection might be inherited as there is some indication that HLA-A1 or factors
surrounding A1 on extended haplotypes are involved in virus infection or non-resolution of the disease.[10] [11]

[edit]Diagnosis

Rubella virus specific IgM antibodies are present in people recently infected by Rubella virus but these
antibodies can persist for over a year and a positive test result needs to be interpreted with caution.[12] The
presence of these antibodies along with, or a short time after, the characteristic rash confirms the diagnosis.[13]

[edit]Prevention


‘+

Rubella infections are prevented by active immunisation programs using live, disabled virus vaccines. Two live
attenuated virus vaccines, RA 27/3 and Cendehill strains, were effective in the prevention of adult disease.
However their use in prepubertile females did not produce a significant fall in the overall incidence rate of CRS
in the UK. Reductions were only achieved by immunisation of all children.

The vaccine is now given as part of the MMR vaccine. The WHO recommends the first dose is given at 12 to
18 months of age with a second dose at 36 months. Pregnant women are usually tested for immunity to rubella
early on. Women found to be susceptible are not vaccinated until after the baby is born because the vaccine
contains live virus.[14]

The immunisation program has been quite successful. Cuba declared the disease eliminated in the 1990s, and
in 2004 the Centers for Disease Control and Prevention announced that both the congenital and acquired
forms of rubella had been eliminated from the United States.[15][16]

[edit]Treatment

There is no specific treatment for Rubella; however, management is a matter of responding to symptoms to
diminish discomfort. Treatment of newly born babies is focused on management of the complications.
Congenital heart defects[

 ]
and cataracts can be corrected by direct surgery.[17] Management for ocular
CRS is similar to that for age-related macular degeneration, including counseling, regular monitoring, and the
provision of low vision devices, if required.[18]

[edit]Prognosis

Rubella infection of children and adults is usually mild, self-limiting and often asymptomatic. The prognosis in
children born with CRS is poor.[19]

[edit]Epidemiology
Rubella is a disease that occurs worldwide. The virus tends to peak during the spring in countries with
temperate climates. Before the vaccine to rubella was introduced in 1969, widespread outbreaks usually
occurred every 6±9 years in the United States and 3±5 years in Europe, mostly affecting children in the 5-9
year old age group.[20] Since the introduction of vaccine, occurrences have become rare in those countries with
high uptake rates.

Vaccination has interrupted the transmission of rubella in the Americas: no endemic case has been observed
since February 2009.[21] Since the virus can always be reintroduced from other continents, the population still
need to remain vaccinated to keep the western hemisphere free of rubella. During the epidemic in the US
between 1962-1965, Rubella virus infections during pregnancy were estimated to have caused 30,000 still
births and 20,000 children to be born impaired or disabled as a result of CRS.[22][23] Universal immunisation
producing a high level of herd immunity is important in the control of epidemics of rubella.[24]

In the UK, there remains a large population of men susceptible to rubella who have not been vaccinated.
Outbreaks of rubella occurred amongst many young men in the UK in 1993 and in 1996 the infection was
transmitted to pregnant women, many of whom were immigrants and were susceptible. Outbreaks still arise,
usually in developing countries where the vaccine is not as accessible.[25]

[edit]History

Rubella was first described in the mid-eighteenth century. Friedrich Hoffmann made the first clinical description
of rubella in 1740,[26] which was confirmed by de Bergen in 1752 and Orlow in 1758.[27]

In 1814, George de Maton first suggested that it be considered a disease distinct from both measles and
scarlet fever. All these physicians were German, and the disease was known as Rötheln (from the German
name +,
‘), hence the common name of "German measles".[28] Henry Veale, an English Royal Artillery
surgeon, described an outbreak in India. He coined the name "rubella" (from the Latin, meaning "little red") in
1866.[26][29][30][31]

It was formally recognised as an individual entity in 1881, at the International Congress of Medicine in
London.[32] In 1914, Alfred Fabian Hess theorised that rubella was caused by a virus, based on work with
monkeys.[33] In 1938, Hiro and Tosaka confirmed this by passing the disease to children using filtered nasal
washings from acute cases.[30]

In 1940, there was a widespread epidemic of rubella in Australia. Subsequently, ophthalmologist Norman
McAllister Gregg found 78 cases of congenital cataracts in infants and 68 of them were born to mothers who
had caught rubella in early pregnancy.[29][30] Gregg published an account, 6  
‘6

› ‘‘  
w?‘?
O
O, in 1941. He described a variety of problems now known as congenital rubella
syndrome (CRS) and noticed that the earlier the mother was infected, the worse the damage was. The virus
was isolated in tissue culture in 1962 by two separate groups led by physicians Parkman and Weller.[29][31]
There was a pandemic of rubella between 1962 and 1965, starting in Europe and spreading to the United
States.[31] In the years 1964-65, the United States had an estimated 12.5 million rubella cases. This led to
11,000 miscarriages or therapeutic abortions and 20,000 cases of congenital rubella syndrome. Of these, 2,100
died as neonates, 12,000 were deaf, 3,580 were blind and 1,800 were mentally retarded. In New York alone,
CRS affected 1% of all births [34]

In 1969 a live attenuated virus vaccine was licensed.[30] In the early 1970s, a triple vaccine containing
attenuated measles, mumps and rubella (MMR) viruses was introduced.[31]

Mumps
From Wikipedia, the free encyclopedia

› 
O?? 
O ? åc

"???
 
 !

 

6



 
 Y

Y
(
Y/ 
YY

0
 @" Y

0
 $" Y

  
   Y
    $$ Y


   
! "Y
! !$ Y


  #$$$ Y

{  and  Y  is a viral disease of the human species, caused by the mumps virus. Before
the development of vaccinationand the introduction of a vaccine, it was a common childhood
disease worldwide, and is still a significant threat to health in the third world.[1]

Painful swelling of the salivary glands (classically the parotid gland) is the most typical presentation.[2] Painful
testicular swelling (orchitis) and rash may also occur. The symptoms are generally not severe in children. In
teenage males and men, complications such as infertility orsubfertility are more common, although still rare in
absolute terms.[3][4][5] The disease is generally self-limited, running its course before receding, with no specific
treatment apart from controlling the symptoms with painkillers.

6



Y%
& Y

Y'
YY Y

m Y)Y

"Y(Y

Y# 
 Y

Y). Y

Y Y

Y)
 Y

Y4  
Y

YY

Y45Y 6Y

[edit]Signs and symptoms

Comparison of a person before and after contracting mumps

The more common symptoms of mumps are:

§ Parotid inflammation (or parotitis) in 60±70% of infections and 95% of patients with
symptoms.[2] Parotitis causes swelling and local pain, particularly when chewing. It can occur on one side
(unilateral) but is more common on both sides (bilateral) in about 90% of cases.[6]
§ Fever

§ Headache

§ Orchitis, referring to painful inflammation of the testicle.[7] Males past puberty who develop mumps have a
30 percent risk of orchitis.[8]

Other symptoms of mumps can include dry mouth, sore face and/or ears and occasionally in more serious
cases, loss of voice. In addition, up to 20% of persons infected with the mumps virus do not show symptoms,
so it is possible to be infected and spread the virus without knowing it.[9]

[edit]   Y
Fever and headache are prodromal symptoms of mumps, together with malaise and anorexia.

[edit]Cause

Mumps is a contagious disease that is spread from person-to-person through contact with respiratory
secretions such as saliva from an infected person. When an infected person coughs or sneezes, the droplets
aerosolize and can enter the eyes, nose, or mouth of another person. Mumps can also be spread by sharing
food, sharing drinks, and kissing. The virus can also survive on surfaces and then be spread after contact in a
similar manner. A person infected with mumps is contagious from approximately 6 days before the onset of
symptoms until about 9 days after symptoms start.[10][11] The incubation period (time until symptoms begin) can
be from 14±25 days but is more typically 16±18 days.[12]

[edit]Diagnosis

A physical examination confirms the presence of the swollen glands. Usually the disease is diagnosed on
clinical grounds and no confirmatory laboratory testing is needed. If there is uncertainty about the diagnosis, a
test of saliva, or blood may be carried out; a newer diagnostic confirmation, using real-time nested polymerase
chain reaction (PCR) technology, has also been developed.[13] An estimated 20%-30% of cases are
asymptomatic.[14] As with any inflammation of the salivary glands, serum amylase is often elevated.[15][16]

[edit]Prevention
The most common preventative measure against mumps is immunization with a mumps vaccine, invented
by Maurice Hilleman at Merck[17]. The vaccine may be given separately or as part of the MMR
immunization vaccine which also protects against measles and rubella. In the US, MMR is now being
supplanted by MMRV, which adds protection against chickenpox. The WHO (World Health Organization)
recommends the use of mumps vaccines in all countries with well-functioning childhood vaccination
programmes. In the United Kingdom it is routinely given to children at age 15 months. The American Academy
of Pediatrics recommends the routine administration of MMR vaccine at ages 12±15 months and at 4±6
years.[18] In some locations, the vaccine is given again between 4 to 6 years of age, or between 11 and 12
years of age if not previously given. The efficacy of the vaccine depends on the strain of the vaccine, but is
usually around 80%.[19],[20] The Jeryl Lynn strain is most commonly used in developed countries but has been
shown to have reduced efficacy in epidemic situations. The Leningrad-Zagreb strain commonly used in
developing countries appears to have superior efficacy in epidemic situations.[21]

Due to the outbreaks within college and university settings, many governments have established vaccination
programs to prevent large-scale outbreaks. In Canada, provincial governments and the Public Health Agency
of Canada have all participated in awareness campaigns to encourage students ranging from grade 1 to
college and university to get vaccinated.[22]

Some anti-vaccine activists protest against the administration of a vaccine against mumps, claiming that the
attenuated vaccine strain is harmful, and/or that the wild disease is beneficial. There is no evidence whatsoever
that the wild disease is beneficial, or that the MMR vaccine is harmful. Claims have been made that the MMR
vaccine is linked to autism andinflammatory bowel disease, including one study by Andrew Wakefield[

 

]
(paper retracted in 2010) that indicated a link between gastrointestinal disease, autism, and the MMR
vaccine. However, all further studies[

 ]
since that time have indicated no link between vaccination with
the MMR and autism or bowel disease. Furthermore, there is scant evidence to suggest that autism is linked to
bowel disease, though several poorly designed studies have indicated a weak link between the two disorders.
Since the dangers of the disease are well known, while the dangers of the vaccine are quite minimal, most
doctors recommend vaccination.

The WHO, the American Academy of Pediatrics, the Advisory Committee on Immunization Practices of
the Centers for Disease Control and Prevention, the American Academy of Family Physicians, the British
Medical Association and the Royal Pharmaceutical Society of Great Britain currently recommend routine
vaccination of children against mumps. The British Medical Association and Royal Pharmaceutical Society of
Great Britain had previously recommended against general mumps vaccination, changing that recommendation
in 1987. In 1988 it became United Kingdom government policy to introduce mass child mumps vaccination
programmes with the MMR vaccine, and MMR vaccine is now routinely administered in the UK.[

 ]
Before the introduction of the mumps vaccine, the mumps virus was the leading cause of viral
meningoencephalitis in the United States. However, encephalitis occurs rarely (less than 2 per 100,000). [23] In
one of the largest studies in the literature, the most common symptoms of mumps meningoencephalitis were
found to be fever (97%), vomiting (94%) and headache (88.8%).[24] The mumps vaccine was introduced into the
United States in December 1967: since its introduction there has been a steady decrease in the incidence of
mumps and mumps virus infection. There were 151,209 cases of mumps reported in 1968. Since 2001, the
case average was only 265 per year, excluding an outbreak of >6000 cases in 2006 attributed largely to
university contagion in young adults.[25][26]

[edit]Treatment

There is no specific treatment for mumps. Symptoms may be relieved by the application of intermittent ice or
heat to the affected neck/testicular area and by acetaminophen/paracetamol (Tylenol) for pain relief. Aspirin is
not used due to a hypothetical link with Reye's syndrome. Warm salt water gargles, soft foods, and extra fluids
may also help relieve symptoms.

Patients are advised to avoid fruit juice or any acidic foods, since these stimulate the salivary glands, which can
be painful.

[edit]Prognosis

Death is very unusual. The disease is self-limiting, and general outcome is good, even if other organs are
involved.

Known complications of mumps include:

§ Infection of other organ systems

§ Mumps viral infections in adolescent and adult males carry an up to 30% risk that the testes may become
infected (orchitis or epididymitis), which can be quite painful; about half of these infections result
in testicular atrophy, and in rare cases sterility can follow.[27]

§ Spontaneous abortion in about 27% of cases during the first trimester of pregnancy.[27]

§ Mild forms of meningitis in up to 10% of cases[27] (40% of cases occur without parotid swelling)

§ Oophoritis (inflammation of ovaries) in about 5% of adolescent and adult females,[27] but fertility is rarely
affected.
§ Pancreatitis in about 4% of cases, manifesting as abdominal pain and vomiting
§ Encephalitis (very rare, and fatal in about 1% of the cases when it occurs)[27]

§ Profound (91 dB or more) but rare sensorineural hearing loss, uni- or bilateral. Acute unilateral deafness
occurs in about 0.005% of cases.[27]
After the illness, life-long immunity to mumps generally occurs; reinfection is possible but tends to be mild and
atypical.[27]

Measles
From Wikipedia, the free encyclopedia

  

6



 
 Y

0
 @$ Y

0
 $ Y

  
  $ Y

   $$ Y


   !"Y
! ! Y


  #$$ Y

{




 Y

{
   Y

( 
 
 

+IY +YEY9>Y

8IY {

 Y

?  IY 

 

 Y

+IY {    Y

Ô 
 

{



Y

{
 is an infection of the respiratory system caused by a virus, specifically a paramyxovirus of the
genus  
‘‘?. Morbilliviruses, like other paramyxoviruses, are enveloped, single-stranded, negative-sense
RNA viruses. Symptoms include fever, cough, runny nose, red eyes and a
generalized, maculopapular, erythematous rash.

Measles (sometimes known as English Measles) is spread through respiration (contact with fluids from
an infected person's nose and mouth, either directly or through aerosol transmission), and is highly
contagious²90% of people without immunity sharing a house with an infected person will catch it. The
infection has an average incubation period of 14 days (range 6±19 days) and infectivity lasts from 2±4 days
prior, until 2±5 days following the onset of the rash (i.e. 4±9 days infectivity in total).[1]

An alternative name for measles in English-speaking countries is 
 ‘, which is sometimes confused
with 
‘‘ (German measles); the diseases are unrelated.[2][3]
 6



Y%
& Y

Y'
YY Y

m Y(  Y

"Y(Y

Y# 
 Y

Y). Y

Y Y

Y)
 Y

Y4  
Y

Y*  YYY

m Y*  Y

m "YY6Y

m  Y
Y Y

Y  Y 
Y

$Y'YY

YY

"Y45Y 6Y

[edit]Signs and symptoms

This patient presented on the third pre-eruptive day with ³Koplik spots´ indicative of the beginning onset of measles.

The classical symptoms of measles include four day fevers, the three 6s²cough, coryza (runny nose)
and conjunctivitis (red eyes). The fever may reach up to 40 °C (104 °F). * ‘??
? seen inside the mouth
are pathognomonic (diagnostic) for measles but are not often seen, even in real cases of measles, because
they are transient and may disappear within a day of arising.
The characteristic measles rash is classically described as a generalized, maculopapular, erythematousrash
that begins several days after the fever starts. It starts on the head before spreading to cover most of the body,
often causing itching. The rash is said to "stain", changing colour from red to dark brown, before
disappearing.[

 ]

[edit]6 

Y
Complications with measles are relatively common, ranging from relatively mild and less serious diarrhea,
to pneumonia and encephalitis (subacute sclerosing panencephalitis), corneal ulceration leading to corneal
scarring.[4] Complications are usually more severe amongst adults who catch the virus.

The fatality rate from measles for otherwise healthy people in developed countries is 3 deaths per thousand
cases, or 0.3%.[5] In underdeveloped nations with high rates of malnutritionand poor healthcare, fatality rates
have been as high as 28%.[5] In immunocompromised patients (  people with AIDS) the fatality rate is
approximately 30%.[6]

[edit]Cause

Patients with the measles should be placed on ?
 
 ?[7]

Humans are the only known natural host of measles, although the virus can infect some non-human primate
species.

[edit]Diagnosis

Clinical diagnosis of measles requires a history of fever of at least three days together with at least one of the
three 6s (cough, coryza, conjunctivitis). Observation of Koplik's spots is also diagnostic of measles.

Alternatively, laboratory diagnosis of measles can be done with confirmation of positive measles IgM antibodies
or isolation of measles virus RNA from respiratory specimens. In children, where phlebotomy is inappropriate,
saliva can be collected for salivary measles specific IgA test. Positive contact with other patients known to have
measles adds strong epidemiologicalevidence to the diagnosis. The contact with any infected person in any
way, including semen through sex, saliva, or mucus can cause infection.

[edit]Prevention
Rates of measles vaccination worldwide

Measles cases reported in the United States before and after introduction of the vaccine.

Measles cases reported in England andWales before and after the introduction of the vaccine. Coverage was not
widespread enough for herd immunity to interrupt episodic outbreaks until after the MMR vaccine was introduced in 1988.

In developed countries, most children are immunized against measles by the age of 18 months, generally as
part of a three-part MMR vaccine(measles, mumps, and rubella). The vaccination is generally not given earlier
than this because children younger than 18 months usually retain anti-measles immunoglobulins (antibodies)
transmitted from the mother during pregnancy. A second dose is usually given to children between the ages of
four and five, in order to increase rates of immunity. Vaccination rates have been high enough to make
measles relatively uncommon. Even a single case in a college dormitory or similar setting is often met with a
local vaccination program, in case any of the people exposed are not already immune.

In developing countries where measles is highly endemic, the WHO recommend that two doses of vaccine be
given at six months and at nine months of age. The vaccine should be given whether the child is HIV-infected
or not.[8] The vaccine is less effective in HIV-infected infants, but the risk of adverse reactions is low.

Unvaccinated populations are at risk for the disease. After vaccination rates dropped in northern Nigeria in the
early 2000s due to religious and political objections, the number of cases rose significantly, and hundreds of
children died.[9]
In 1998 the MMR vaccine controversy in the United Kingdom regarding a potential link between the combined
MMR vaccine (vaccinating children from mumps, measles and rubella) and autism prompted a reemergence of
the "measles party", where parents deliberately expose their child to measles in the hope of building up the
child's immunity without an injection. This practice poses many health risks to the child, and has been
discouraged by the public health authorities.[10] Scientific evidence provides no support for the hypothesis that
MMR plays a role in causing autism.[11] In 2009, ÔO
 Ô? reported that Wakefield had manipulated
patient data and misreported results in his 1998 paper, creating the appearance of a link with autism.[12] ÔO
u
fully retracted the 1998 paper on 2 February 2010.[13] In January 2010, another study of Polish children
found that vaccination with the measles,mumps,and rubella vaccine was not a risk factor for development of
autistic disorder, in fact the vaccinated patients had a slightly reduced risk of autistic disorder, although the
mechanism of action behind that is unknown,and this result may have been coincidental.[14][
?  O
 ]

The autism related MMR study in Britain caused use of the vaccine to plunge, and measles cases came back:
2007 saw 971 cases in England and Wales, the biggest rise in occurrence in measles cases since records
began in 1995.[15] A 2005 measles outbreak in Indianawas attributed to children whose parents refused
vaccination.[16]

The joint press release by members of the Measles Initiative brings to light another benefit of the fight against
measles: "Measles vaccination campaigns are contributing to the reduction of child deaths from other causes.
They have become a channel for the delivery of other life-saving interventions, such as bed nets to protect
against malaria, de-worming medicine and vitamin A supplements. Combining measles immunization with other
health interventions is a contribution to the achievement of Millennium Development Goal Number 4: a two-
thirds reduction in child deaths between 1990 and 2015."[17]

[edit]Treatment

There is no specific treatment for measles. Most patients with uncomplicated measles will recover with rest and
supportive treatment. It is, however, important to seek medical advice if the patient becomes more unwell as
they may be developing complications.

Some patients will develop pneumonia as a sequel to the measles. Other complications include ear
infections, bronchitis, and encephalitis. Acute measles encephalitis has a mortality rate of 15%. While there is
no specific treatment for measles encephalitis, antibiotics are required for bacterial pneumonia, sinusitis,
and bronchitis that can follow measles.

All other treatment is symptomatic, with ibuprofen, or acetaminophen (also called paracetamol) to reduce fever
and pain and, if required, a fast-acting bronchodilator for cough. Note that young children should never be
given aspirin without medical advice due to the risk of inducing a disease known as Reye's syndrome.[

 

]
The use of Vitamin A in treatment has been investigated. A systematic review of trials into its use found no
significant reduction in overall mortality, but that it did reduce mortality in children aged under 2 years.[18][19][20]

[edit]Prognosis

While the vast majority of patients survive measles, complications occur fairly frequently and may
include bronchitis, pneumonia, otitis media, hemorrhagic complications, acute disseminated encephalomyelitis,
acute measles encephalitis, subacute sclerosing panencephalitis (sspe), blindness, deafness, and death.
Statistically out of 1000 measles cases, 2-3 patients die, and 5-105 suffer complications. In patients who do not
develop complications, the prognosis is generally excellent. However, although most patients survive, it is still
important to get vaccinated, as up to 15 percent of measles patients experience complications, some fairly
mild, others (such as subacute sclerosing panencephalitis) typically fatal. Also, even if the patient is not
concerned about death or sequela from the measles, the person may spread the disease to an
immunocompromised patient, for whom the risk of death is much higher, due to complications such as giant
cell pneumonia. Acute measles encephalitis is another serious risk of measles virus infection. It typically occurs
2 days to one week after the breakout of the measles exanthem, and begins with very high fever, severe
headache, convulsions, and altered mentation. Patient may become comatose, and death or brain injury may
occur.[21]

[edit]Epidemiology

Disability-adjusted life year for measles per 100,000 inhabitants in 2002.

no data ” 10 10-25 25-50 50-75 75-100 100-250 250-500 500-750 750-1000 1000-1500 1500-2000 • 2000

According to the World Health Organization (WHO), measles is a leading cause of vaccine-preventable
childhood mortality. Worldwide, the fatality rate has been significantly reduced by a vaccination campaign led
by partners in the Measles Initiative: the American Red Cross, the United States Centers for Disease Control
and Prevention (CDC), the United Nations Foundation, UNICEF and the World Health Organization (WHO).
Globally, measles fell 60% from an estimated 873,000 deaths in 1999 to 345,000 in 2005.[17] Estimates for 2008
indicate deaths fell further to 164,000 globally, with 77% of the remaining measles deaths in 2008 occurring
within the South-East Asian region.[22]
Five out of six WHO regions have set goals to eliminate measles, and at the 63rd World Health Assembly in
May 2010, delegates agreed a global target of a 95% reduction in measles mortality by 2015 from the level
seen in 2000, as well as to move towards eventual eradication. However, no specific global target date for
eradication has yet been agreed as of May 2010.[23][24]

[edit]History and culture

[edit]  Y

The Antonine Plague, 165-180 AD, also known as the Plague of Galen, who described it, was
probably smallpox or measles. Disease killed as much as one-third of the population in some areas, and
decimated the Roman army.[25] The first scientific description of measles and its distinction from smallpox
and chickenpox is credited to the Persian physician, Muhammad ibn Zakariya ar-Razi (860-932), known to the
West as "Rhazes", who published a book entitled ÔO  
‘‘ ?‘? (in Arabic: *

‘
[26]
-‘O?
O).

Measles is an endemic disease, meaning that it has been continually present in a community, and many people
develop resistance. In populations that have not been exposed to measles, exposure to a new disease can be
devastating. In 1529, a measles outbreak in Cubakilled two-thirds of the natives who had previously survived
smallpox. Two years later measles was responsible for the deaths of half the population of Honduras, and had
ravaged Mexico, Central America, and the Inca civilization.[27]

In roughly the last 150 years, measles has been estimated to have killed about 200 million people
worldwide.[28] During the 1850s, measles killed a fifth of Hawaii's people.[29] In 1875, measles killed over
40,000 Fijians, approximately one-third of the population.[30] In the 19th century, the disease decimated
the Andamanese population.[31] In 1954, the virus causing the disease was isolated from an 11-year old boy
from the United States, David Edmonston, and adapted and propagated on chick embryo tissue culture.[32] To
date, 21 strains of the measles virus have been identified.[33] While at Merck, Maurice Hilleman developed the
first successful vaccine[34]. Licensed vaccines to prevent the disease became available in 1963.

[edit]$
Y .Y


‘?‘? 

?
Oë


?

Since the beginning of September, 2009, Johannesburg, a city in Gauteng, South Africa reported about 48
cases of measles. Soon after the outbreak, the Government ordered that all children be vaccinated.
Vaccination programs were then initiated in all schools and parents of young children were advised to have
them vaccinated.[35] Many people were not willing to have the vaccination done, as it is believed to be unsafe
and ineffective. The Health Department assured the public that their program was indeed safe. Speculation
arose as to whether or not new needles were being used.[36] By mid-October there were at least 940 recorded
cases, and 4 deaths.[37]
On February 19, 2009, 505 measles cases were reported in twelve provinces in the North of Vietnam,
with Hanoi accounting for 160 cases.[38] A high rate of complications includingmeningitis & encephalitis has
worried health workers[39] and the U.S. CDC recommended that all travelers be immune to measles.[40]

On The 1st of April 2009, an outbreak has happened in two schools in North Wales. Ysgol John
Bright and Ysgol Ffordd Dyffryn in Wales have had the outbreak and are making sure every pupil has had
the Measles vaccine.

In 2007, a large measles outbreak in Japan caused a number of universities and other institutions to close in an
attempt to contain the disease.[41][42]

Approximately 1000 cases of the disease were reported in Israel between August 2007 and May 2008 (in sharp
contrast to just some dozen cases the year before).[

 ]
Many children in ultra-Orthodox Jewish
communities were affected due to low vaccination coverage.[43][44] As of 2008 the disease is endemic in
the United Kingdom with 1,217 cases diagnosed in 2008 [45] and epidemics have been reported
in Austria, Italy and Switzerland. Low vaccination rates are responsible.[46]

In March 2010, Philippines declared an epidemic about the continuously rising cases of measles.[

 ]

[edit] YÑ Y

Indigenous measles were declared to have been eliminated in North, Central, and South America; the last
endemic case in the region was reported on November 12, 2002, with only Northern Argentina and
rural Canada, particularly in the provinces of Ontario, Quebec, and Alberta having minor endemic
status.[47] Outbreaks are still occurring, however, following importations of measles viruses from other world
regions. In June 2006, an outbreak in Boston resulted after a resident became infected in India,[48] and in
October 2007, a Michigan girl who had been vaccinated contracted the disease in Sweden.[49]

Between January 1 and April 25, 2008, a total of 64 confirmed measles cases were preliminarily reported in the
United States to the Centers for Disease Control and Prevention,[50][51]the most reported by this date for any
year since 2001. Of the 64 cases, 54 were associated with importation of measles from other countries into the
United States, and 63 of the 64 patients were unvaccinated or had unknown or undocumented vaccination
status.[52]

By July 9, 2008, a total of 127 cases were reported in 15 states (including 22 in Arizona),[53] making it the
largest U.S. outbreak since 1997 (when 138 cases were reported).[54] Most of the cases were acquired outside
of the United States and afflicted individuals who had not been vaccinated.

By July 30, 2008, the number of cases had grown to 131. Of these, about half involved children whose parents
rejected vaccination. The 131 cases occurred in 7 different outbreaks. There were no deaths, and 15
hospitalizations. 11 of the cases had received at least one dose of the measles vaccine. 122 of the cases
involved children who were unvaccinated or whose vaccination status was unknown. Some of these were
under the age of one year old and below the age when vaccination is recommended, but in 63 cases the
vaccinations had been refused for religious or philosophical reasons.

[edit]Additional images

Y Y
Y

Y
Y
YY
Y 3
YY
Y
Y

YY, 
Y#
Y

Y8
YY
Y$ 
Y
YY
Y
Y


 ]Y
YY
Y

Chickenpox
From Wikipedia, the free encyclopedia

#%‘‘#
?O› 
O


  
 "?%‘‘ 
 !

› 
O??"?6O ?
 
 !

Y Y        ,
Y'Y
Y6Y

YY
 Y, 6 )Y0  YY
Y0  Y)Y YYYY
Y YY
Y
5YÀ{
 Y

Y Y
  ! 

  "Y)Y .Y
Y Y Y YYÀ
 Y
Y


 

6



 
 Y
 Y
(
Y/ 
Y. Y Y

0
 @$ Y

0
 $" Y

  
  " Y

   $$" Y


   !" Y!2

! Y


  6  Y

6 .
  or  .
Y  is a highly contagious illness caused by primary infection with varicella zoster
virus (VZV).[1] It usually starts with vesicular skin rash mainly on the body and head rather than at the periphery
and become itchy, raw pockmarks, which mostly heal without scarring.

Chicken pox is spread easily through coughs or sneezes of ill individuals or through direct contact with
secretions from the rash. Following primary infection there is usually lifelong protective immunity from further
episodes of chickenpox.

Chickenpox is rarely fatal, although it is generally more severe in adult males than in adult females or children.
Pregnant women and those with a suppressed immune system are at highest risk of serious complications.
Chicken pox is now believed to be the cause of one third of stroke cases in children.[2] The most common late
complication of chicken pox is shingles, caused by reactivation of the varicella zoster virus decades after the
initial episode of chickenpox.

Chickenpox has been observed in other primates, including chimpanzees[3] and gorillas.[4]

6



Y%
& Y

Y'
YY Y

"Y# 
 Y

Y4  
Y

Y)

 
Y

m Y3 Y Y

 YYY

m "Y'

Y

Y). Y

m Y*
YY

m "YE Y

Y Y

m Y(
Y

m "YY

Y)
 Y

Y*  Y

Y'YY

$YY

Y45Y 6Y

[edit]Signs and symptoms

Chickenpox is a highly infectious disease that spreads from person to person by direct contact or by air from an
infected person's coughing or sneezing. Touching the fluid blister can also spread the disease. A person with
chickenpox is infectious from one to five days before the rash appears.[5] The contagious period continues until
all blisters have formed scabs, which may take 5 to 6 days at which point they are no longer contagious.[6] It
takes from 10 to 21 days after contact with an infected person for someone to develop chickenpox. Chickenpox
(varicella) is often heralded by a prodrome of anorexia, myalgia, nausea, fever, headache, sore throat, pain in
both ears, complaints of pressure in head or swollen face, andmalaise in adolescents and adults, while in
children the first symptom is usually the development of a papular rash, followed by development
of malaise, fever (a body temperature of 38 °C (100 °F), but may be as high as 42 °C (108 °F) in rare cases),
and anorexia. Rarely cough, rhinitis, abdominal pain, and gastrointestinal distress has been reported in patients
with varicella. Typically, the disease is more severe in adults.[7]

Y Y

,YY2 +Y
Y

 YY
Y
YYY
Y Y2
(YY
Y. 

Y
+Y
(YY

YVYYY
Y

[edit]Diagnosis

The diagnosis of varicella is primarily clinical, with typical early "prodromal" symptoms, and then the
characteristic rash. Confirmation of the diagnosis can be sought through either examination of the fluid within
the vesicles of the rash, or by testing blood for evidence of an acute immunologic response.

Vesicular fluid can be examined with a Tsanck smear, or better with examination for direct fluorescent antibody.
The fluid can also be "cultured", whereby attempts are made to grow the virus from a fluid sample. Blood tests
can be used to identify a response to acute infection (IgM) or previous infection and subsequent immunity
(IgG).[8]

Prenatal diagnosis of fetal varicella infection can be performed using ultrasound, though a delay of 5 weeks
following primary maternal infection is advised. A PCR (DNA) test of the mother's amniotic fluid can also be
performed, though the risk of spontaneous abortion due to the amniocentesis procedure is higher than the risk
of the baby developing foetal varicella syndrome.[9]

[edit]Epidemiology

Primary varicella is an endemic disease. Cases of varicella are seen throughout the year but more commonly in
winter and early spring. Varicella is one of the classic diseases of childhood, with the highest prevalence in the
4±10 year old age group. Like rubella, it is uncommon in preschool children. Varicella is highly communicable,
with an infection rate of 90% in close contacts. Most people become infected before adulthood but 10% of
young adults remain susceptible.

Historically, varicella has been a disease predominantly affecting preschool and school-aged children. In adults
the pock marks are darker and the scars more prominent than in children.[10]

[edit]Pathophysiology
Exposure to VZV in a healthy child initiates the production of host immunoglobulin G (IgG), immunoglobulin
M (IgM), and immunoglobulin A (IgA) antibodies; IgG antibodies persist for life and confer immunity. Cell-
mediated immune responses are also important in limiting the scope and the duration of primary varicella
infection. After primary infection, VZV is hypothesized to spread from mucosal and epidermal lesions to
local sensory nerves. VZV then remains latent in the dorsal ganglion cells of the sensory nerves. Reactivation
of VZV results in the clinically distinct syndrome of herpes zoster (i.e., ?O ‘?), and sometimes Ramsay Hunt
syndrome type II.[

 ]

[edit]0

Y
Y

Y
Y

Y

For pregnant women, antibodies produced as a result of immunization or previous infection are transferred via
the placenta to the fetus.[11] Women who are immune to chickenpox cannot become infected and do not need
to be concerned about it for themselves or their infant during pregnancy.[12]

Varicella infection in pregnant women can lead to viral transmission via the placenta and infection of the fetus.
If infection occurs during the first 28 weeks of gestation, this can lead to fetal varicella syndrome (also known
as   
‘‘‘?  ).[13] Effects on the fetus can range in severity from underdeveloped toes and
fingers to severe anal and bladder malformation. Possible problems include:

§ Damage to brain: encephalitis,[14] microcephaly, hydrocephaly, aplasia of brain

§ Damage to the eye: optic stalk, optic cap, and lens vesicles, microphthalmia, cataracts, chorioretinitis, optic
atrophy

§ Other neurological disorder: damage to cervical and lumbosacral spinal cord, motor/sensory deficits,
absent deep tendon reflexes, anisocoria/Horner's syndrome

§ Damage to body: hypoplasia of upper/lower extremities, anal and bladder sphincter dysfunction
§ Skin disorders: (cicatricial) skin lesions, hypopigmentation

Infection late in gestation or immediately following birth is referred to as " 
‘‘‘".[15] Maternal
infection is associated with premature delivery. The risk of the baby developing the disease is greatest
following exposure to infection in the period 7 days prior to delivery and up to 7 days following the birth. The
baby may also be exposed to the virus via infectious siblings or other contacts, but this is of less concern if the
mother is immune. Newborns who develop symptoms are at a high risk of pneumonia and other serious
complications of the disease.[9]

[edit] 

Y

‘
O ‘?
After a chickenpox infection, the virus remains dormant in the body's nerve tissues. The immune system keeps
the virus at bay, but later in life, usually as an adult, it can be reactivated and cause a different form of the virus
called shingles.[16]

[edit]Prevention

[edit] 
Y Y
The spread of chicken pox can be prevented by isolating affected individuals. Contagion is by exposure to
respiratory droplets, or direct contact with lesions, within a period lasting from three days prior to the onset of
the rash, to four days after the onset of the rash.[17] Therefore, avoidance of close proximity or physical contact
with affected individuals during that period will prevent contagion. The chicken pox virus (VZV) is susceptible to
disinfectants, notably chlorine bleach (i.e., sodium hypochlorite). Also, like all enveloped viruses, VZV is
sensitive to desiccation, heat and detergents. Therefore these viruses are relatively easy to kill.

[edit]

Y


‘%‘‘

A varicella vaccine was first developed by Michiaki Takahashi in 1974 derived from the Oka strain. It has been
available in the U.S. since 1995 to inoculate against the disease. Some countries require the varicella
vaccination or an exemption before entering elementary school. Protection is not lifelong and further
vaccination is necessary five years after the initial immunization.[18] The chickenpox vaccine is not part of the
routine childhood vaccination schedule in the UK. In the UK, the vaccine is currently only offered to people who
are particularly vulnerable to chickenpox.[19]

[edit]Treatment

Y

Y YD Y5 Y

Although there have been no formal clinical studies evaluating the effectiveness of topical application
of calamine lotion, a topical barrier preparation containing zinc oxide and one of the most commonly used
interventions, it has an excellent safety profile.[20] It is important to maintain good hygiene and daily cleaning
of skin with warm water to avoid secondary bacterial infection.[21] Scratching may also increase the risk of
secondary infection.[22] Addition of a small quantity of vinegar to the water is sometimes advocated. Painkillers
could be taken to prevent feeling itchy [23]

To relieve the symptoms of chicken pox, people commonly use anti-itching creams and lotions. These lotions
are not to be used on the face or close to the eyes. An oatmeal bath also might help ease discomfort.[24]

Varicella treatment mainly consists of easing the symptoms as there is no actual cure of the condition. Some
treatments are however available for relieving the symptoms while theimmune system clears the virus from
the body. As a protective measure, patients are usually required to stay at home while they are infectious to
avoid spreading the disease to others. Also, sufferers are frequently asked to cut their nails short or to
wear gloves to prevent scratching and to minimize the risk of secondary infections.

The condition resolves by itself within a couple of weeks but meanwhile patients must pay attention to their
personal hygiene.[25] The rash caused by varicella zoster virus may however last for up to one month, although
the infectious stage does not take longer than a week or two.[26] Also, staying in a cold surrounding can help in
easing the itching as heat and sweatmakes it worse. Calamine lotion may be tried as it may relieve the
symptoms because of its soothing, cooling effect on the skin.

Natural chicken pox remedies include pea water, baking soda, vitamin E oil, honey, herbal
tea or carrot and coriander. It is believed that the irritation of the skin can be relieved to some extent with water
in which fresh peas have been cooked.[27] A lotion made of baking soda with water can be sponged onto the
skin of the patients to ease the itching. Also, rubbing vitamin E oil or honey on the skin is thought to have a
healing effect on the marks that could remain after the infection has been cured. Some people claim that the
mild sedative effect ofgreen tea is effective in relieving the symptoms. It is not however known to what extent
these home remedies can actually help the patients cope better with their symptoms.

A varicella vaccine is available for people who have been exposed to the virus, but have not experienced
symptoms. The vaccine is more effective if administered within three days and up to five days after exposure. It
has been shown that the chicken pox vaccine may prevent or reduce the symptoms in 90% of cases, if given
within three days after exposure. People who have been exposed to the virus but who are contraindicated to
receive the vaccine, there is a medication available, called varicella zoster immunoglobulin or VZIG which may
prevent or reduce the symptoms after exposure. VZIG is primarily administered to individuals who are at risk of
developing complications due to its high costs and temporary protection. This type of treatment is only
recommended in newborns whose mothers have had chicken pox few days prior or after delivery, children
with leukemia or lymphoma, people with a poor immune system or pregnant women. VZIG is recommended to
be administered no later than 96 hours after exposure to the virus.

[edit]6 

Y

If oral acyclovir is started within 24 hours of rash onset it decreases symptoms by one day but has no effect on
complication rates. Use of acyclovir therefore is not currently recommended for immunocompetent individuals
(i.e., otherwise healthy persons without known immunodeficiency or those on immunosuppressive
medication).[28]

Treatment of chicken pox in children is aimed at symptoms whilst the immune system deals with the
virus.[29] With children younger than 12 years cutting nails and keeping them clean is an important part of
treatment as they are more likely to deep scratch their blisters. Children younger than 12 years old and older
than one month are not meant to receive antiviral medication if they are not suffering from another medical
condition which would put them at risk of developing complications.

Increased amounts of water are recommended to avoid dehydration, especially if the child develops fever.
Fever, headaches or pain can be relieved with painkillers such as ibuprofen orparacetamol. Children who are
older than one year may be administered antihistamine tablets or liquid medicines which are helpful in cases
when the child is not able to sleep because of the itching.

Acyclovir or immunoglobulin is generally prescribed in children who are at risk of complications from chicken
pox. They receive the same treatment as the one mentioned above plus antiviral medication additionally. The
category of children that are considered at risk to develop complications includes infants less than one month
old, those with a suppressed immune system, those who are taking steroids or immune suppressing
medication or children with severe heart, lung and skin conditions. Moreover, adults and teenagers are
considered at risk of complications and they are normally administered antiviral medication.

Aspirin is highly contraindicated in children younger than 16 years as it has been related with a potentially fatal
condition known as Reye's syndrome.

[edit]Ñ
Y

Infection in otherwise healthy adults tends to be more severe and active; treatment with
antiviral drugs (e.g. acyclovir) is generally advised, as long as it is started within 24±48 hours from rash
onset.[30]

Remedies to ease the symptoms of chicken pox in adults are basically the same as those used on children.
Moreover, adults are often prescribed antiviral medication as it is effective in reducing the severity of the
condition and the likelihood of developing complications. Antiviral medicines are not however aimed to kill the
virus, but to stop it from multiplying.

Adults are also advised to increase the water intake to reduce dehydration and to relieve headaches.
Painkillers such as paracetamol and ibuprofen are also recommended as they are effective in relieving itching
and other symptoms such as fever or pains. Antihistamines may be used in cases when the symptoms cause
the inability to sleep, as they are efficient for easing the itching and they are acting as a sedative.

As with children, antiviral medication is considered more useful for those adults who are more prone to develop
complications. These include pregnant women or people who have a poor immune system.[31]

Sorivudine, a nucleoside analogue has been found in few case reports effective in the treatment of primary
varicella in healthy adults. Larger scale clinical trials are needed to demonstrate the efficacy of this
medication.[32]

[edit]Prognosis
The duration of the visible blistering caused by varicella zoster virus varies in children usually from 4 to 7 days,
and the appearance of new blisters begins to subside after the 5th day. Chickenpox infection is milder in young
children, and symptomatic treatment, with sodium bicarbonate baths or antihistamine medication may ease
itching.[33] Paracetamol(acetaminophen) is widely used to reduce fever. Aspirin, or products containing aspirin,
must not be given to children with chickenpox as this risks causing Reye's Syndrome.[34]

In adults, the disease is more severe,[35] though the incidence is much less common. Infection in adults is
associated with greater morbidity and mortality due to pneumonia,[36]hepatitis, and encephalitis.[

 ]
In
particular, up to 10% of pregnant women with chickenpox develop pneumonia, the severity of which increases
with onset later in gestation. In England and Wales, 75% of deaths due to chickenpox are in
adults.[9] Inflammation of the brain, or encephalitis, can occur in immunocompromised individuals, although the
risk is higher with herpes zoster.[37] Necrotizing fasciitis is also a rare complication.[38]

Secondary bacterial infection of skin lesions, manifesting as impetigo, cellulitis, and erysipelas, is the most
common complication in healthy children. Disseminated primary varicella infection usually seen in the
immunocompromised may have high morbidity. Ninety percent of cases of varicella pneumonia occur in the
adult population. Rarer complications of disseminated chickenpox also include myocarditis, hepatitis,
and glomerulonephritis.[39]

Hemorrhagic complications are more common in the immunocompromised or immunosuppressed populations,

although healthy children and adults have been affected. Five major clinical syndromes have been
described: febrile purpura, malignant chickenpox with purpura, postinfectious purpura, purpura fulminans,
and anaphylactoid purpura. These syndromes have variable courses, with febrile purpura being the most
benign of the syndromes and having an uncomplicated outcome. In contrast, malignant chickenpox with
purpura is a grave clinical condition that has a mortality rate of greater than 70%. The etiology of these
hemorrhagic chickenpox syndromes is not known.[39]

Cholera
From Wikipedia, the free encyclopedia

Y Y/ 
Y, 6  JY

  2Y
Y 
   
 
Y
 "Y)Y Y
Y YY
Y6Y
YYY
Y Y
 YY
 6YY
Y Y/ YY  .YYY Y YÀ
 Y



6



 
 Y

Y
' 
Y4Y0 Y 
YYA   
Y

0
 $$
KY$$Y$$Y2Y

0
 $$ Y

  
  "$ Y

   $$$ $ Y


   !  Y


  #$$" Y

6
[1] is a severe bacterial infection caused by the bacteria %
 O ‘, which primarily affects
the small intestine. The main symptoms include profuse watery diarrhea and vomiting. Transmission is
primarily by the acquisition of the pathogen through contaminated drinking water or infected food. The severity
of the diarrhea and associated vomiting can lead to rapid dehydration and electrolyte loss, which can lead to
death. Cholera is a major cause of death in the world.
The study of cholera has been used as an example of early epidemiology. Study of the %O ‘ bacterium
has also shed light on many of the mechanisms used by bacteria to infect and survive in their hosts.

6



Y%
& Y

Y'
YY Y

"Y(Y

Y)

 
Y

m Y'    Y

m "Y   Y

§ "Y) Y
Y  YY     Y

Y# 
 Y

m Y4 
Y Y

m "Y) 
Y Y

Y). Y

Y Y

Y4  
Y

m Y) Y
 Y .  Y

Y*  Y

m Y8
YYY

m "Y?Y
 YY

m  Y(
YY

m Y8
Y
 Y  Y

m Y
Y

m Y?Y.  Y

Y>Y

$Y'YY

YY

"Y?
Y 
Y

 Y45Y 6Y

[edit]Signs and symptoms

The primary symptoms of cholera are profuse diarrhea, severe dehydration and abdominal pain. Cholera may
also cause vomiting. These symptoms start suddenly, usually one to five days after infection, and are the result
of a toxin produced by the vibrio cholerae bacterium that compels profuse amounts of fluid from the blood
supply into the small and large intestines.D.Kindersley (editor) (1989). ÑÑ ‘  . Random
House. ISBN 0-394-56528-2.</ref> An untreated cholera patient may produce several gallons of diarrhoeal
fluid a day.

[edit]Cause

TEM image of %
 O ‘

Most of the %O ‘ bacteria in the contaminated water consumed by the host do not survive the highly
acidic conditions of the human stomach.[2] The few bacteria that do survive conserve their energy and stored
nutrients during the passage through the stomach by shutting down much protein production. When the
surviving bacteria exit the stomach and reach the small intestine, they need to propel themselves through the
thick mucus that lines the small intestine to get to the intestinal wall where they can thrive. %O ‘ bacteria
start up production of the hollow cylindrical protein flagellin to make flagella, the curly whip-like tails that they
rotate to propel themselves through the mucus of the small intestine.

Once the cholera bacteria reach the intestinal wall, they do not need the flagella propellers to move any longer.
The bacteria stop producing the protein flagellin, thus again conserving energy and nutrients by changing the
mix of proteins which they manufacture in response to the changed chemical surroundings. On reaching the
intestinal wall, %O ‘ start producing the toxic proteins that give the infected person a watery diarrhea.
This carries the multiplying new generations of %O ‘ bacteria out into the drinking water of the next host
if proper sanitation measures are not in place.

The cholera toxin (CTX or CT) is an oligomeric complex made up of six protein subunits: a single copy of the A
subunit (part A), and five copies of the B subunit (part B), connected by a disulfide bond. The five B subunits
form a five-membered ring that binds to GM1 gangliosides on the surface of the intestinal epithelium cells. The
A1 portion of the A subunit is an enzyme that ADP-ribosylates G proteins, while the A2 chain fits into the
central pore of the B subunit ring. Upon binding, the complex is taken into the cell via receptor-mediated
endocytosis. Once inside the cell, the disulfide bond is reduced and the A1 subunit is freed to bind with a
human partner protein called ADP-ribosylation factor 6 (Arf6).[3] Binding exposes its active site, allowing it to
permanently ribosylate the Gs alpha subunit of the heterotrimeric G protein. This results in constitutive cAMP
production, which in turn leads to secretion of H2O, Na+, K+, Clí, and HCO3í into the lumen of the small intestine
and rapid dehydration. The gene encoding the cholera toxin is introduced into V. cholerae by horizontal gene
transfer. Virulent strains of V. cholerae carry a variant of lysogenic bacteriophage called CTXf or CTXij.

Cholera Toxin. The delivery region (blue) binds membrane carbohydrates to get into cells. The toxic part (red) is activated
inside the cell (PDB code: 1xtc).

Microbiologists have studied the genetic mechanisms by which the %O ‘ bacteria turn off the production
of some proteins and turn on the production of other proteins as they respond to the series of chemical
environments they encounter, passing through the stomach, through the mucous layer of the small intestine,
and on to the intestinal wall.[4] Of particular interest have been the genetic mechanisms by which cholera
bacteria turn on the protein production of the toxins that interact with host cell mechanisms to
pump chloride ions into the small intestine, creating an ionic pressure which prevents sodium ions from
entering the cell. The chloride and sodium ions create a salt-water environment in the small intestines, which
through osmosis can pull up to six liters of water per day through the intestinal cells, creating the massive
amounts of diarrhea. The host can become rapidly dehydrated if an appropriate mixture of dilute salt water and
sugar is not taken to replace the blood's water and salts lost in the diarrhea.

By inserting separate, successive sections of %O ‘ DNA into the DNA of other bacteria such as 
 ‘ that would not naturally produce the protein toxins, researchers have investigated the mechanisms by
which %O ‘ responds to the changing chemical environments of the stomach, mucous layers, and
intestinal wall. Researchers have discovered that there is a complex cascade of regulatory proteins that control
expression of %O ‘ virulence determinants. In responding to the chemical environment at the intestinal
wall, the %O ‘bacteria produce the TcpP/TcpH proteins, which, together with the ToxR/ToxS proteins,
activate the expression of the ToxT regulatory protein. ToxT then directly activates expression
of virulence genes that produce the toxins that cause diarrhea in the infected person and that permit the
bacteria to colonize the intestine.[4] Current research aims at discovering "the signal that makes the cholera
bacteria stop swimming and start to colonize (that is, adhere to the cells of) the small intestine."[4]

[edit]Pathophysiology

[edit] 
Y
Recent epidemiologic research suggests that an individual's susceptibility to cholera (and other diarrheal
infections) is affected by their blood type: those with type O blood are the most susceptible,[5][6] while those
with type AB are the most resistant. Between these two extremes are the A and B blood types, with type A
being more resistant than type B.[

 ]

About one million %O ‘ bacteria must typically be ingested to cause cholera in normally healthy adults,
although increased susceptibility may be observed in those with a weakened immune system, individuals with
decreased gastric acidity (as from the use of antacids), or those who are malnourished.

It has also been hypothesized that the cystic fibrosis genetic mutation has been maintained in humans due to a
selective advantage: heterozygous carriers of the mutation (who are thus not affected by cystic fibrosis) are
more resistant to %O ‘ infections.[7] In this model, the genetic deficiency in the cystic fibrosis
transmembrane conductance regulator channel proteins interferes with bacteria binding to
the gastrointestinal epithelium, thus reducing the effects of an infection.

[edit]
 
Y
Drawing of Death bringing the cholera, inuc

ÿ ‘

People infected with cholera suffer acute diarrhea. This highly liquid diarrhea, colloquially referred to as "rice-
water stool," is loaded with bacteria that can infect water used by other people.[8] Cholera is transmitted through
ingestion of water contaminated with the cholera bacterium, usually from feces or other effluent. The source of
the contamination is typically other cholera patients when their untreated diarrhea discharge is allowed to get
into waterways or into groundwater or drinking water supplies. Any infected water and any foods washed in the
water, as well as shellfish living in the affected waterway, can cause an infection. Cholera is rarely spread
directly from person to person. %O ‘ harbors naturally in the zooplankton of fresh, brackish, and salt
water, attached primarily to their chitinous exoskeleton.[9] Both toxic and non-toxic strains exist. Non-toxic
strains can acquire toxicity through a lysogenic bacteriophage.[10] Coastal cholera outbreaks typically
follow zooplankton blooms, thus making cholera a zoonotic disease.

x
c 

 
 
      

Cholera bacteria grown 
 encounter difficulty subsequently growing in humans without additional stomach
acid buffering. In a 2002 study at Tufts University School of Medicine, it was found that stomach acidity is a
principal agent that advances epidemic spread.[11] In their findings, the researchers found that human
colonization creates a hyperinfectious bacterial state that is maintained after dissemination and that may
contribute to epidemic spread of the disease. When these hyperinfectious bacteria underwent transcription
profiles, they were found to possess a unique physiological and behavioral state, characterized by high
expression levels of genes required for nutrient acquisition and motility, and low expression levels of genes
required for bacterial chemotaxis. Thus, the spread of cholera can be expedited by host physiology.

[edit]Diagnosis

In epidemic situations, a clinical diagnosis is made by taking a history of symptoms from the patient and by a
brief examination only. Treatment is usually started without or before confirmation by laboratory analysis of
specimens.

Stool and swab samples collected in the acute stage of the disease, before antibiotics have been administered,
are the most useful specimens for laboratory diagnosis. If an epidemic of cholera is suspected, the most
common causative agent is %
 O ‘ O1. If %O ‘ serogroup O1 is not isolated, the laboratory
should test for %O ‘ O139. However, if neither of these organisms is isolated, it is necessary to send
stool specimens to a reference laboratory. Infection with %O ‘ O139 should be reported and handled in
the same manner as that caused by %O ‘ O1. The associated diarrheal illness should be referred to as
cholera and must be reported.[12]

A number of special media have been employed for the cultivation for cholera vibrios. They are classified as
follows:

x
J

 

1. ё‘

 at pH 8.6

2.  ??
 O ‘

‘‘


 at pH 9.2

x
c   

1. ё‘
‘?‘
 
Ñ!: The colonies are very similar to those on nutrient agar.
2.  ?? ‘
Ô O ‘

 
?
‘‘
 wÔÔÑ!: Cholera vibrios produce small
translucent colonies with a greyish black centre.

3. Ô6
: This the mostly widely used medium. This medium contains thiosulphate, citrate, bile
salts and sucrose. Cholera vibrios produce flat 2±3 mm in diameter, yellow nucleated colonies.

Direct microscopy of stool is not recommended as it is unreliable. Microscopy is preferred only after
enrichment, as this process reveals the characteristic motility of %
 ? and its inhibition by
appropriate antiserum. Diagnosis can be confirmed as well as serotyping done by agglutination with specific
sera.

[edit]Prevention

Although cholera may be life-threatening, prevention of the disease is normally straightforward if proper
sanitation practices are followed. In the first world, due to nearly universal advancedwater treatment and
sanitation practices, cholera is no longer a major health threat. The last major outbreak of cholera in the United
States occurred in 1910-1911.[13][14] Travelers should be aware of how the disease is transmitted and what can
be done to prevent it. Effective sanitation practices, if instituted and adhered to in time, are usually sufficient to
stop an epidemic. There are several points along the cholera transmission path at which its spread may be
(and should be) halted:

Cholera hospital in Dhaka, showing typical O ‘
?.

§ Sterilization: Proper disposal and treatment of infected fecal waste water produced by cholera victims and
all contaminated materials (e.g. clothing, bedding, etc.) is essential. All materials that come in contact with
cholera patients should be sterilized by washing in hot water using chlorine bleach if possible. Hands that
touch cholera patients or their clothing, bedding, etc., should be thoroughly cleaned and disinfected with
chlorinated water or other effective anti-microbial agents.

§ Sewage: anti-bacterial treatment of general sewage by chlorine, ozone, ultra-violet light or other effective
treatment before it enters the waterways or underground water supplies helps prevent undiagnosed
patients from inadvertently spreading the disease.

§ Sources: Warnings about possible cholera contamination should be posted around contaminated water
sources with directions on how todecontaminate the water (boiling, chlorination etc.) for possible use.

§ Water purification: All water used for drinking, washing, or cooking should be sterilized by either
boiling, chlorination, ozone water treatment, ultra-violet light sterilization, or anti-microbal filtration in any
area where cholera may be present. Chlorination and boiling are often the least expensive and most
effective means of halting transmission. Cloth filters, though very basic, have significantly reduced the
 occurrence of cholera when used in poor villages in Bangladesh that rely on untreated surface water.
Better anti-microbial filters like those present in advanced individual water treatment hiking kits are most
effective. Public health education and adherence to appropriate sanitation practices are of primary
importance to help prevent and control transmission of cholera and other diseases.

A vaccine for cholera is available in some countries, but prophylactic usage is not currently recommended for
routine use by the Centers for Disease Control and Prevention (CDC).[15] During recent years, substantial
progress has been made in developing new oral vaccines against cholera. Two oral cholera vaccines, which
have been evaluated with volunteers from industrialized countries and in regions with endemic cholera, are
commercially available in several countries: a killed whole-cell %O ‘ O1 in combination with purified
recombinant B subunit of cholera toxin and a live-attenuated live oral cholera vaccine, containing the
genetically manipulated %O ‘ O1 strain CVD 103-HgR. The appearance of %O ‘ O139 has
influenced efforts in order to develop an effective and practical cholera vaccine since none of the currently
available vaccines is effective against this strain.[12] The newer vaccine (brand name:  ‘), an orally
administered inactivated whole cell vaccine, appears to provide somewhat better immunity and have fewer
adverse effects than the previously available vaccine.[15] This safe and effective vaccine is available for use by
individuals and health personnel. Work is under way to investigate the role of mass vaccination.[16]

Sensitive surveillance and prompt reporting allow for containing cholera epidemics rapidly. Cholera exists as a
seasonal disease in many endemic countries, occurring annually mostly during rainy seasons. Surveillance
systems can provide early alerts to outbreaks, therefore leading to coordinated response and assist in
preparation of preparedness plans. Efficient surveillance systems can also improve the risk assessment for
potential cholera outbreaks. Understanding the seasonality and location of outbreaks provide guidance for
improving cholera control activities for the most vulnerable. This will also aid in the developing indicators for
appropriate use of oral cholera vaccine.[17]

[edit]Treatment

Cholera patient being treated by medical staff in 1992.

In most cases cholera can be successfully treated with oral rehydration therapy (ORT). ORT is highly effective,
safe, and simple to administer: prompt replacement of water and electrolytes is the principal treatment for
cholera, as dehydration and electrolyte depletion occur rapidly. In situations where commercially produced
ORT sachets are too expensive or difficult to obtain, alternative homemade solutions using various formulas of
water, sugar, table salt, baking soda, and fruit offer less expensive methods of electrolyte repletion. In severe
cholera cases with significant dehydration, the administration of intravenous rehydration solutions may be
necessary.

Antibiotics shorten the course of the disease and reduce the severity of the symptoms; however, oral
rehydration therapy remains the principal treatment. Tetracycline is typically used as the primary antibiotic,
although some strains of %O ‘ have shown resistance. Other antibiotics that have been proven effective
against %O ‘ include cotrimoxazole, erythromycin, doxycycline, chloramphenicol,
andfurazolidone.[18] Fluoroquinolones such as norfloxacin also may be used, but resistance has been
reported.[19]

Rapid diagnostic assay methods are available for the identification of multi-drug resistant %O ‘.[20] New
generation antimicrobials have been discovered which are effective against %O ‘ in 
 studies.[21]

The success of treatment is significantly affected by the speed and method of treatment. If cholera patients are
treated quickly and properly, the mortality rate is less than 1%; however, with untreated cholera, the mortality
rate rises to 50±60%.[22][23]

[edit]Epidemiology

By 12 February 2009, the number of cases of infection by cholera in sub-Saharan Africa had reached 128,548 and the
number of fatalities, 4,053.
§ In 2000, some 140,000 cholera cases were officially notified to WHO. Africa accounted for 87% of these
cases.[24]

§ July - December 2007 - A lack of clean drinking water in Iraq has led to an outbreak of cholera.[25] As of 2
December 2007, the UN has reported 22 deaths and 4,569 laboratory-confirmed cases.[26]

§ August 2007 - The cholera epidemic started in Orissa, India. The outbreak has affected Rayagada,
Koraput and Kalahandi districts where more than 2,000 people have been admitted to hospitals.[27]

§ August - October 2008 - As of 29 October 2008, a total of 644 laboratory-confirmed cholera cases,
including eight deaths, had been verified in Iraq.[28]

§ March - April 2008 - 2,490 people from 20 provinces throughout Vietnam have been hospitalized with acute
diarrhea. Of those hospitalized, 377 patients tested positive for cholera.[29]

§ November 2008 - Doctors Without Borders reported an outbreak in a refugee camp in the Democratic
Republic of the Congo's eastern provincial capital of Goma. Some 45 cases were reportedly treated
between November 7 through 9th.

§ August 2008 - April 2009: In the +,,0Y1 "

Y
Y ., which is still continuing, an
estimated 96,591 people in thecountry have been infected with cholera and, by 16 April 2009, 4,201 deaths
had been reported.[30] According to the World Health Organization, during the week of 22±28 March 2009,
the "Crude Case Fatality Ratio (CFR)" had dropped from 4.2% to 3.7%.[30] The daily updates for the period
29 March 2009 to 7 April 2009, list 1748 cases and 64 fatalities, giving a weekly CFR of 3.66% (see table
above);[31]however, those for the period 8 April to 16 April list 1375 new cases and 62 deaths (and a
resulting CFR of 4.5%).[31] The CFR had remained above 4.7% for most of January and early February
2009.[32]

§ January 2009 - The Mpumalanga province of South Africa has confirmed over 381 new cases of Cholera,
bringing the total number of cases treated since November 2008 to 2276. 19 people have died in the
province since the outbreak.[33]
[edit] 
 Y
YY
Amplified fragment length polymorphism (AFLP) fingerprinting of the pandemic isolates of %
 O ‘ has
revealed variation in the genetic structure. Two clusters have been identified: Cluster I and Cluster II. For the
most part Cluster I consists of strains from the 1960s and 1970s, while Cluster II largely contains strains from
the 1980s and 1990s, based on the change in the clone structure. This grouping of strains is best seen in the
strains from the African Continent.[34]
[edit]History

Hand bill from the New York City Board of Health, 1832. The outdated public health advice demonstrates the lack of
understanding of the disease and its actual causative factors.

[edit]
Y
YY

Cholera likely has its origins in and is endemic to the Indian subcontinent. The disease spread by trade routes
(land and sea) to Russia, then to Western Europe, and from Europe to North America. Cholera is now no
longer considered a pressing health threat in Europe and North America due to filtering and chlorination of
water supplies, but still heavily affects populations in developing countries.

§ 1816-1826 - Y
Y

 : Previously restricted, the pandemic began in Bengal, and then
spread across India by 1820. 10,000British troops and countless Indians died during this pandemic.[35] The
cholera outbreak extended as far as China, Indonesia (where more than 100,000 people succumbed on
the island of Java alone) and the Caspian Sea before receding. Deaths in India between 1817 and 1860
are estimated to have exceeded 15 million persons. Another 23 million died between 1865 and 1917. [36]

§ 1829-1851 - 
Y
Y
  reached Russia (see Cholera Riots), Hungary (about 100,000
deaths) and Germany in 1831,London (more than 55,000 people died in the United
Kingdom)[37] and Paris in 1832. In London, the disease claimed 6,536 victims and came to be known as
"King Cholera"; in Paris, 20,000 succumbed (out of a population of 650,000) with about 100,000 deaths in
all ofFrance.[38] The epidemic reached Quebec, Ontario and New York in the same year and the Pacific
coast of North America by 1834.[39] The 1831 cholera epidemic killed 150,000 people in Egypt.[40] In 1846,
cholera struck Mecca, killing over 15,000 people.[41] A two-year outbreak began in England and Wales in
1848 and claimed 52,000 lives.[42] Cholera was found in Dundee in 1832. One influential UK pamphlet
explaining how to nurse cholera patients and prevent the disease was  
? 
O6O ‘ 
? (1832)
by the home economics writer Esther Copley.
§ 1849 - Second major outbreak in Paris. In London, it was the worst outbreak in the city's history, claiming
14,137 lives, over twice as many as the 1832 outbreak. Cholera hit Ireland in 1849 and killed many of
the Irish Famine survivors already weakened by starvation and fever.[43] In 1849 cholera claimed 5,308
lives in the port city of Liverpool, England, and 1,834 inHull, England.[38] An outbreak in North America took
the life of former U.S. President James K. Polk. Cholera, believed spread from ship(s) from England,
spread throughout theMississippi river system killing over 4,500 in St. Louis[38] and over 3,000 in New
Orleans[38] as well as thousands in New York.[38] Mexico was similarly attacked.[41] In 1849 cholera was
spread along the California, Mormon and Oregon Trails as 6,000 to 12,000[44] are believed to have died on
their way to the California Gold Rush, Utah and Oregon in the cholera years of 1849-1855.[38] It is believed
that over 150,000 Americans died during the two pandemics between 1832 and 1849.[45][46]

§ 1852-1860 -  Y
Y

  mainly affected Russia, with over a million deaths. In 1852, cholera
spread east to Indonesia and later invaded China and Japan in 1854. ThePhilippines were infected in 1858
and Korea in 1859. In 1859, an outbreak in Bengal once again led to the transmission of the disease
to Iran, Iraq, Arabia and Russia.[41] There were at least seven major outbreaks of cholera in Japan between
1858 and 1902. The Ansei outbreak of 1858-60, for example, is believed to have killed between 100,000
and 200,000 people in Tokyo alone.[47]

§ 1854 - Outbreak of cholera in Chicago took the lives of 5.5% of the population (about 3,500 people).[38][48] In
1853-4, London's epidemic claimed 10,738 lives. The Soho outbreak in London ended after removal of the
handle of the Broad Street pump by a committee instigated to action by ÿ
Y
".[49] This proved that
contaminated water (although it didn't identify the contaminant) was the main agent spreading cholera. It
would take almost 50 years for this message to be believed and acted upon. Building and maintaining a
safe water system was and is not cheap²but is absolutely essential.

§ 1863-1875 -   Y
Y

  spread mostly in Europe and Africa. At least 30,000 of the
90,000 Mecca pilgrims fell victim to the disease. Cholera claimed 90,000 lives in Russia in 1866.[50] The
epidemic of cholera that spread with the Austro-Prussian War (1866) is estimated to have claimed 165,000
lives in the Austrian Empire.[51] Hungary andBelgium both lost 30,000 people and in
the Netherlands 20,000 perished. In 1867, Italy lost 113,000 lives.[52]
1892 cholera outbreak in Hamburg, hospital ward

1892 cholera outbreak in Hamburg, disinfection team

§ 1866 - 1873 - Outbreaks in North America. It killed some 50,000 Americans.[45] In London, a localized
epidemic in the East End claimed 5,596 lives just as London was completing its major sewage and water
treatment systems²the East End was not quite complete. William Farr, using the work of John Snow et al.
as to contaminated drinking water being the likely source of the disease, was able to relatively quickly
identify the East London Water Company as the source of the contaminated water. Quick action prevented
further deaths.[38] Also a minor outbreak at Ystalyfera in South Wales. Caused by the local water works
using contaminated canal water, it was mainly its workers and their families who suffered, 119 died. In the
same year more than 21,000 people died in Amsterdam, The Netherlands. In the 1870s, cholera spread in
the US as epidemic from New Orleans along the Mississippi River and related ports of tributaries, with
thousands dying.

§ 1881-1896 -  Y
Y

  ; According to Dr A. J. Wall, the 1883-1887 epidemic cost 250,000
lives in Europe and at least 50,000 in Americas. Cholera claimed 267,890 lives
in Russia (1892);[53] 120,000 in Spain;[54] 90,000 in Japan and over 60,000 in Persia.[53]In Egypt cholera
claimed more that 58,000 lives. The 1892 outbreak in Hamburg killed 8,600 people. Although generally
held responsible for the virulence of the epidemic, the city government went largely unchanged. This was
the last serious European cholera outbreak.

§ 1899-1923 -  Y
Y

  had little effect in Europe because of advances in public health, but
major Russian cities (more than 500,000 people dying of cholera during the first quarter of the 20th
century)[55] and the Ottoman Empire were particularly hard hit by cholera deaths. The 1902-1904 cholera
epidemic claimed 200,000 lives in the Philippines.[56] 27 epidemics were recorded during pilgrimages
toMecca from the 19th century to 1930, and more than 20,000 pilgrims died of cholera during the 1907±
08 hajj.[55] The sixth pandemic killed more than 800,000 in India. The last outbreak in the United States was
 in 1910-1911 when the steamship  ‘
 brought infected people to New York City. Vigilant health
authorities isolated the infected on Swinburne Island. Eleven people died, including a health care worker
onSwinburne Island.[13][14][57]

§ 1961-1970s - 
 Y
Y
  began in Indonesia, called El Tor after the strain, and
reached Bangladesh in 1963, India in 1964, and the USSR in 1966. From North Africa it spread into Italy
by 1973. In the late 1970s, there were small outbreaks in Japan and in the South Pacific. There were also
many reports of a cholera outbreak near Baku in 1972, but information about it was suppressed in
theUSSR.

§ January 1991 to September 1994 - Outbreak in South America, apparently initiated when a ship
discharged ballast water. Beginning in Peruthere were 1.04 million identified cases and almost 10,000
deaths. The causative agent was an O1, El Tor strain, with small differences from the seventh pandemic
strain. In 1992 a new strain appeared in Asia, a non-O1, nonagglutinable vibrio (NAG) named O139
Bengal. It was first identified in Tamil Nadu, India and for a while displaced El Tor in southern Asia before
decreasing in prevalence from 1995 to around 10% of all cases. It is considered to be an intermediate
between El Tor and the classic strain and occurs in a new serogroup. There is evidence of the emergence
of wide-spectrum resistance to drugs such as trimethoprim, sulfamethoxazole and streptomycin.
[edit]
Y  
Y Y


‘6O '' O ‘
O

A persistent myth states that 90,000 people died in Chicago of cholera and typhoid fever in 1885, but this story
has no factual basis.[58] In 1885, there was a torrential rainstorm that flushed the Chicago River and its
attendant pollutants into Lake Michigan far enough that the city's water supply was contaminated. However,
because cholera was not present in the city, there were no cholera-related deaths, though the incident caused
the city to become more serious about its sewage treatment.

[edit]6
Y Y

The term O ‘ 
? was used in the 19th and early 20th centuries to describe both non-epidemic cholera
and other gastrointestinal diseases (sometimes epidemic) that resembled cholera. The term is not in current
use, but is found in many older references.[59] The other diseases are now known collectively as gastroenteritis.

[edit] Y  
Y

  
Y
In the past, people traveling in ships would hang a yellow quarantine flag if one or more of the crew members
suffered from cholera. Boats with a yellow flag hung would not be allowed to disembark at any harbor for an
extended period, typically 30 to 40 days.[60]. In modern international maritime signal flags the quarantine flag is
yellow and black.
[edit]$ Y

The Russian-born bacteriologist Waldemar Haffkine developed the first cholera vaccine around 1900. The
bacterium had been originally isolated thirty years earlier (1855) by Italian anatomist Filippo Pacini, but its exact
nature and his results were not widely known around the world.

One of the major contributions to fighting cholera was made by the physician and pioneer medical
scientist John Snow (1813±1858), who found a link between cholera and contaminated drinking water in
1854.[38] Dr Snow proposed a microbial origin for epidemic cholera in 1849. In his major "state of the art" review
of 1855, he proposed a substantially complete and correct model for the aetiology of the disease. In two
pioneering epidemiological field-studies, he was able to demonstrate that human sewage contamination was
the most probable disease vector in two major epidemics in London in 1854.[61] His model was not immediately
accepted, but it was seen to be the more plausible as medical microbiology developed over the next thirty
years or so.

Cities in developed nations made massive investment in clean water supply and well-separated sewage
treatment infractures was made between the mid-1850s and the 1900s. This eliminated the threat of cholera
epidemics from the major developed cities in the world. Robert Koch, 30 years later, identified %O ‘ with
a microscope as the bacillus causing the disease in 1885.

Cholera has been a laboratory for the study of evolution of virulence. The province of Bengal in British
India was partitioned into West Bengal and East Pakistan in 1947. Prior to partition, both regions had cholera
pathogens with similar characteristics. After 1947, India made more progress on public health than East
Pakistan (now Bangladesh). As a consequence,[‘
 ]
the strains of the pathogen that succeeded in
India had a greater incentive in the longevity of the host. They have become less virulent than the strains
prevailing in Bangladesh. These uninhibitedly draw upon the resources of the host population, thus rapidly
killing many victims.

More recently, in 2002, Alam et al. studied stool samples from patients at the International Centre for
Diarrhoeal Disease (ICDDR) in Dhaka, Bangladesh. From the various experiments they conducted, the
researchers found a correlation between the passage of %O ‘ through the human digestive system and
an increased infectivity state. Furthermore, the researchers found that the bacterium creates a hyper-infected
state where genes that control biosynthesis of amino acids, iron uptake systems, and formation of periplasmic
nitrate reductase complexes were induced just before defecation. These induced characteristics allow the
cholera vibrios to survive in the "rice water" stools, an environment of limited oxygen and iron, of patients with a
cholera infection.[11]

Y
Y

Yellow fever
From Wikipedia, the free encyclopedia

#Ñc‘ #
?O› 
O 
"?ÔOÑc‘ › 
O?? # ‘‘ 

#"?‘‘ ?
 
 !

U›

6



 
 Y

Y
Y 40Y 

YY
Y /Y.Y. Y" 2$$$LY
   Y

0
  Y

0
 $$ Y

  
  "$ Y

   $$  Y

 
   !" "Y
!Y


  #$$$Y

U

"Y is an acute viral hemorrhagic disease.[1] The virus is a 40 to 50 nm enveloped RNA virus with
positive sense of the Flaviviridaefamily.

The yellow fever virus is transmitted by the bite of female mosquitos (the yellow fever mosquito, Ñ? 
,
and other species) and is found in tropical and subtropical areas in South America and Africa, but not
in Asia.[2] The only known hosts of the virus are primates and several species of mosquito. The origin of the
disease is most likely to be Africa, from where it was introduced to South America through theslave trade in the
16th century. Since the 17th century, several major epidemics of the disease have been recorded in the
Americas, Africa and Europe. In the 19th century, yellow fever was deemed one of the most
dangerous infectious diseases.[3]

Clinically, yellow fever presents in most cases with fever, nausea, and pain and it generally subsides after
several days. In some patients, a toxic phase follows, in which liver damage with jaundice (giving the name of
the disease) can occur and lead to death. Because of the increased bleeding tendency (bleeding diathesis),
yellow fever belongs to the group of hemorrhagic fevers. The WHO estimates that yellow fever causes 200,000
illnesses and 30,000 deaths every year in unvaccinated populations;[4] around 90% of the infections occur in
Africa.[5]

A safe and effective vaccine against yellow fever has existed since the middle of the 20th century and some
countries require vaccinations for travelers.[6] Since no therapy is known, vaccination programs are, along with
measures to reduce the population of the transmitting mosquito, of great importance in affected areas. Since
the 1980s, the number of cases of yellow fever has been increasing, making it a   ??.[7]

6



Y%
& Y

Y'
YY Y

"Y(Y

Y   Y

Y)

 Y

Y# 
 Y

Y). Y

m YE  Y
 m "Y( Y.  Y

m  YEYY

Y Y

Y4  
Y

Y*  Y

$Y
Y

YY

"Y45Y 6Y

[edit]Signs and symptoms

Yellow fever begins after an incubation period of three to six days. Most cases only cause a mild infection with
fever, headache, chills, back pain, loss of appetite, nausea and vomiting.[8]In these cases the infection lasts
only three to four days. 15% of cases enter a second, toxic phase of the disease with recurring fever, this time
accompanied by jaundice due to liver damage, as well as abdominal pain. Bleeding in the mouth, the eyes and
in the gastrointestinal tract can cause vomitus containing blood (giving the name 
.Y ).[9] The toxic
phase is fatal in approximately 20% of cases.[10]

Surviving the infection causes life-long immunity[11] and normally there is no remaining organ damage.[12]

[edit]Cause

U  




( 
 
 

+IY +Y3EYK>Y

?  IY ?. .   Y

+IY ›
 Y

' IY U  



Y

Yellow fever is caused by the yellow fever virus, a 40 to 50 nm wide enveloped RNA virus belonging to the
family Flaviviridae. The positive sensesingle-stranded RNA is approximately 11,000 nucleotides long and has a
single open reading frame encoding a polyprotein. Host proteases cut this polyprotein into three structural (C,
prM, E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration
corresponds to the arrangement of the protein coding genes in the genome.[13] The viruses infect amongst
others monocytes, macrophages anddendritic cells. They attach to the cell surface via specific receptors and
are taken up by an endosomal vesicle. Inside the endosome, the decreasedpH induces the fusion of the
endosomal membrane with the virus envelope. Thus, the capsid reaches the cytosol, decays and releases the
genome. Receptor binding as well as membrane fusion are catalyzed by the protein E, which changes its
conformation at low pH, which causes a rearrangement of the 90 homodimers to 60 homotrimers.[13]

After entering the host cells, the viral genome is replicated in the rough endoplasmic reticulum (ER) and in the
so-called vesicle packets. At first, an immature form of the virus particle is produced inside the ER, whose M-
protein is not yet cleaved to its mature form and is therefore denoted as prM (? ) and forms a
complex with protein E. The immature particles are processed in the Golgi apparatus by the host protein furin,
which cleaves prM to M. This releases E from the complex which can now take its place in the mature,
infectious virion.[13]

[edit]Transmission

Ñ? 
 feeding

Adults of the yellow fever mosquitoÑ? 
. The male on the left, females on the right. Only the female mosquito bites
and can transmit the disease
The yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Ñ? 
, but
other mosquitos such as the " tiger mosquito" (Ñ?‘

?) can also serve as a vector for the virus. Like
other Arboviruses which are transmitted via mosquitos, the yellow fever virus is taken up by a female mosquito
which sucks the blood of an infected person. Viruses reach the stomach of the mosquito, and if the virus
concentration is high enough, the virions can infect epithelial cells and replicate there. From there they reach
the haemocoel (the blood system of mosquitos) and from there the salivary glands. When the mosquito sucks
blood the next time, it injects its saliva into the wound, and thus the virus reaches the blood of the bitten
person. There are also indications for vertical infection of the yellow fever virus withinÑ 
, i.e., the
transmission from a female mosquito to her eggs and then larvae. This infection of vectors without a previous
blood meal seems to play a role in single, sudden breakouts of the disease.[14]

There are three epidemiologically different infectious cycles,[7] in which the virus is transmitted from mosquitos
to humans or other primates. In the urban cycle, only the yellow fever mosquito Ñ? 
 is involved,
which is well adapted to urban centres and can also transmit other diseases
including Dengue and Chikungunya. The urban cycle is responsible for the major outbreaks of yellow fever that
occur in Africa. Except in an outbreak in 1999 in Bolivia, this urban cycle no longer exists in South America and
is only present in Africa.

Besides the urban cycle there is, both in Africa and South America, a sylvatic cycle (Forest cycle
or Jungle cycle), where Ñ?? (in Africa) or mosquitos of the genus   ? and


O? (in
South America) serve as a vector. In the jungle, mainly non-human primates get infected; the disease is mostly
asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way humans can
infect themselves, which explains the low incidence of yellow fever cases on this continent. People who
become infected in the jungle can carry the virus to urban centres, where Ñ? 
 acts as a vector. It is
because of this sylvatic cycle that yellow fever cannot be eradicated.[7]

In Africa there is a third infectious cycle, also known as savannah cycle or intermediate cycle, which occurs
between the jungle and urban cycle. Different mosquitos of the genus Ñ? are involved. In recent years this
is the most common form of yellow fever seen in Africa.[4]

[edit]Pathogenesis

After transmission of the virus from a mosquito the viruses replicate in the lymph nodes and infect dendritic
cells in particular. From there they reach the liver and infect hepatocytes(probably indirectly via Kupffer cells),
which leads to eosinophilic degradation of these cells and to the release of cytokines. Necrotic masses
(Councilman bodies) appear in thecytoplasm of hepatocytes.[6][15]
When the disease takes a deadly course, a cardiovascular shock and multi organ failure with strongly
increased cytokine levels (cytokine storm) follow.[10]

[edit]Diagnosis

Yellow fever is a clinical diagnosis, which often relies on the whereabouts of the diseased person during
the incubation time. Mild courses of the disease can only be confirmed virologically. Since also mild courses of
yellow fever can significantly contribute to regional outbreaks, every suspected yellow fever has to be treated
seriously (six to ten days after leaving the affected area symptoms of fever, pain, nausea and vomiting).

If yellow fever is suspected, the virus can be confirmed until six to ten days after the illness. A direct
confirmation can be obtained by Reverse transcription polymerase chain reactionwhere the genome of the
virus is amplified.[5] Another direct approach is the isolation of the virus and its growth in cell culture using blood
plasma; this can take one to four weeks.

Serologically an enzyme linked immunosorbent assay during the acute phase of the disease using
specific IgM against yellow fever or an increase in specific IgG-titer (compared to an earlier sample) can
confirm yellow fever. Together with clinical symptoms, the detection of IgM or a fourfold increase in IgG-titer is
considered sufficient indication for yellow fever. Since these tests can cross-react with other Flaviviruses,
like Dengue virus, these indirect methods can never prove yellow fever infection. Liver biopsy can
verify inflammation and necrosis of hepatocytes and detect viral antigens. Because of the bleeding tendency of
yellow fever patients, a biopsy is only advisable  ?
 
 to confirm the cause of death.

In a differential diagnosis, infections with yellow fever have to be distinguished from other feverish illnesses
like malaria. Other viral hemorrhagic fever, such as Ebola virus, Lassa virus,Marburg virus or Junin virus have
to be excluded as cause.

[edit]Prevention

Personal prevention of yellow fever includes vaccination as well as avoidance of mosquito bites in areas where
yellow fever is endemic. Institutional measures for prevention of yellow fever include vaccination programmes
and measures of controlling mosquitos.

[edit]


Y
Injection of protective vaccination into thedeltoid muscle

The cover of a certificate that confirms that the holder has been vaccinated against yellow fever


‘‘‘ 

For journeys into affected areas, vaccination is highly recommended since mostly non-native people are
affected by severe cases of yellow fever. The protective effect is established 10 days after vaccination in 95%
of the vaccinated people[16] and lasts for at least 10 years (even 30 years later, 81% of patients retained the
immunity). The attenuated live vaccine (stem 17D) was developed in 1937 by Max Theiler[16] from a diseased
patient in Ghana and is produced in chicken eggs. WHO recommends routine vaccinations for people living in
endemic areas between the 9th and 12th month after birth.[5]

In about 20% of all cases,[17] mild, flu-like symptoms may develop. In rare cases (less than one in 200,000 to
300,000[16]), the vaccination can cause YEL-AVD ( ‘‘ ?? 
?
 ??),
which is fatal in 60% of all cases. It is probably due to a genetic defect in the immune system. But in some
vaccination campaigns, a 20 fold higher incidence rate has been reported. Age is an important risk factor; in
children the complication rate is less than one case per 10 million vaccinations. Another possible side effect is
an infection of the nervous system that occurs in one in 200,000 to 300,000 of all cases, causing YEL-AND
( ‘‘ ?? 

 ??), which can cause meningoencephalitis and is less than
5%[16] of all cases fatal.[5][10]

In 2009, the largest mass vaccination against yellow fever commenced in West Africa,
specifically Benin, Liberia and Sierra Leone.[18][19]When it is completed in 2015, more than 12 million people will
have been vaccinated against the disease.[18] According to the World Health Organization, the mass
vaccination cannot eliminate yellow fever because of the massive number of infected mosquitoes in urban
areas of the target countries, but it will significantly reduce the number of people infected.[18] However, the
WHO plans to continue the vaccination campaign in another five African countries²Central African
Republic, Ghana, Guinea, Ivory Coast and Nigeria²and claimed that approximately 160 million people in the
continent could be at risk unless the organization acquires additional funding.[20]

[edit]6 
 Y


Y
Some countries in Asia are theoretically in danger of yellow fever epidemics (mosquitoes with the capability to
transmit yellow fever and susceptible monkeys are present), even though the disease does not yet occur there.
To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors, if they
have passed through yellow fever areas. Vaccination has to be proven in a vaccination certificate which is valid
10 days after the vaccination and lasts for 10 years. A list of the countries which require yellow fever
vaccination is published by the WHO.[21] If the vaccination cannot be conducted for some reasons, dispensation
is possible. In this case an exemption certificate issued by a WHO approved vaccination center is required.

Even though 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in
many of these countries fewer than 50% of their population is vaccinated.[5]

[edit]
 Y

Y

Information campaign for prevention of Dengue and yellow fever in Paraguay

Besides vaccination, control of the yellow fever mosquito Ñ? 
 is of major importance, especially
because the same mosquito can also transmit Dengue and Chikungunya disease. Ñ? 
 breeds
preferentially in water, for example in installations by inhabitants of areas with precarious drinking water supply,
or in domestic waste; especially tires, cans and plastic bottles. Especially in proximity to urban centres of
developing countries these conditions are very common and make a perfect habitat forÑ? 
. Two
strategies are employed to fight the mosquito:

One approach is to kill the developing larva. Measures are taken to reduce water build-up (the habitat of the
larva), and larvicides are used as well as larva-eating fish and copepods, which reduce the number of larva and
thus indirectly the number of disease-transmitting mosquitos. For many years, copepods of the
genus ?  ‘ ? have been used in Vietnam for fighting Dengue fever (yellow fever does not occur in Asia),
with the effect that in the affected areas no cases of Dengue fever have occurred since 2001. Similar
mechanisms are probably also effective against yellow fever. Pyriproxyfen is recommended as a chemical
larvicide, mainly because it is safe for humans and effective even in small doses.[5]

Besides larva, the adult yellow fever mosquitos are also targeted. The curtains and lids of water tanks are
sprayed with insecticides. Spraying insecticides inside houses is another measure, although it is not
recommended by the WHO. Similar to the malaria carrier, the Ñ O‘? mosquito, insecticide
treated mosquito nets are used successfully against Ñ? 
.[5]

[edit]Treatment

For yellow fever there is, like for all diseases caused by Flaviviruses, no causative cure. Hospitalization is
advisable and intensive care may be necessary because of rapid deterioration in some cases. Different
methods for acute treatment of the disease have been shown to not be very successful; passive immunisation
after emergence of symptoms is probably without effect. Ribavirin and other antiviral drugs as well as treatment
with interferons do not have a positive effect in patients.[10] A symptomatic treatment includes rehydration and
pain relief with drugs like paracetamol. Acetylsalicylic acid (for example Ñ?) should not be given because of
its haemodiluting effect, which can be devastating in the case of inner bleeding that can occur with yellow fever.

[edit]Epidemiology
Endemic range of yellow fever in South America (2009).

Endemic range of yellow fever in Africa (2009).

Yellow fever is endemic in tropical and subtropical areas of South America and Africa. Even though the main
vector Ñ? 
 also occurs in Asia, in the Pacific and the Middle East, yellow fever does not occur in
these areas; the reason for this is unknown. Worldwide there are about 600 million people living in endemic
areas and the official estimations of the WHO amount to 200,000 cases of disease and 30,000 deaths a year;
the number of officially reported cases is far lower. An estimated 90% of the infections occur on the African
continent.[5] In 2008, the largest number of cases was recorded in Togo.

Phylogenetic analysis identified seven genotypes of yellow fever viruses, and it is assumed that they are
differently adapted to humans and to the vector Ñ? 
. Five genotypes occur solely in Africa, and is
assumed that the West Africa±genotype I is especially virulent or infectious, because this type is often
associated with major outbreaks of yellow fever. In South America two genotypes have been identified.[7]
[edit]History


‘? ?
   ‘‘ ‘‘ › )(.

Carlos Finlay

Walter Reed

The evolutionary origins of yellow fever most likely lie in Africa.[22] It is thought that the virus originated in East
or Central Africa and spread from there to West Africa. The virus as well as the vector Ñ 
 were probably
brought to South America by ship after 1492. The first probable outbreak of the disease was in 1648
in Yucatan, where the illness was termed  (black vomit). At least 25 major outbreaks followed, such as
in Philadelphia 1793, where several thousand people died and the American administration as well as George
Washington had to flee the city.[23] Yellow fever epidemics in North America caused some 100,000-150,000
deaths.[24] Major outbreaks also occurred in Europe, e.g. in 1821 in Barcelona with several thousand victims. In
1878, about 20,000 people died in an epidemic in the Mississippi River Valley and the last major outbreak in
the US occurred in 1905 in New Orleans.[7] In colonial times, West Africa became known as "the white man's
grave" because of malaria and yellow fever.[25]

Carlos Finlay, a Cuban doctor and scientist, first proposed in 1881 that yellow fever may be transmitted
by mosquitoes rather than direct human contact.[26] Since the losses in the invasion of Cuba in the 1890s due to
yellow fever were thirteenfold higher than the losses due to military operations, further experiments conducted
by a team under Walter Reed successfully proved the ƎMosquito HypothesisƎ. Yellow fever was thus the first
virus shown to be transmitted by mosquitos. The physician William Gorgas then applied these insights and
eradicated yellow fever from Havana and fought yellow fever during the construction of the Panama Canal ±
after a French effort to build the canal had failed due, among other reasons, to the high incidence of yellow
fever and malaria.[7]

Although Dr. Reed received much of the credit in history books for "beating" yellow fever, Reed himself credited
Dr. Finlay with the discovery of the yellow fever vector, and thus how it might be controlled. Dr. Reed often
cited Finlay's papers in his own articles and gave him credit for the discovery, even in his personal
correspondence.[27] The acceptance of Finlay's work was one of the most important and far-reaching effects of
the Walter Reed Commission of 1900.[28] Applying methods first suggested by Finlay, yellow fever was
eradicated in Cuba and later in Panama, allowing completion of the of the Panama Canal.

In 1927, the yellow fever virus was isolated in West Africa, which led to the development of two vaccines in the
1930s. The vaccine D17 was developed by the South African microbiologist Max Theiler at the Rockefeller
Institute. Following the work of Ernest Goodpasture, he used chicken eggs to culture the virus and won a Nobel
Prize for this achievement in 1951. A French team developed the vaccine FNV (›O
 ),
which was extracted from mouse brain tissue ± but since it was associated with a higher incidence
of encephalitis, FNV was not recommended after 1961. 17D on the other hand is still in use and over 400
million doses have been distributed. Since little has been invested in the development of new vaccines, the 60
year old technology cannot adopt fast enough to a yellow fever epidemic. Newer vaccines based on vero
cells are in development and should replace 17D at some point.[5]

Using vector control and strict vaccination programs, the urban cycle of yellow fever has been eradicated from
South America and since 1943 ± apart from an urban outbreak in Santa Cruz de la Sierra (Bolivia) ± there has
been no yellow fever transmission by Ñ 
 reported. Since the 1980s, the number of yellow fever cases
has been increasing again and Ñ 
 has returned to the urban centres of South America; partly because
the vector control program was abandoned. Even though no new urban cycle has yet established itself, it is
feared that this might happen at any point. An outbreak in Paraguay in 2008 was first thought to be urban in
nature, but this turned out to not be the case.[5]
In Africa on the other hand, virus eradication programs have mostly used vaccination, but have been
unsuccessful since the sylvatic cycle could not be eradicated. After the measures to fight yellow fever were
abandoned since few countries have established regular vaccination programs, the virus could spread again.[5]

Brucellosis
From Wikipedia, the free encyclopedia


  

6



 
 Y

0
 "  Y

0
 $" Y

  
   Y

   $$$ Y


   !" Y
 
  #$$"$$ Y



, also called 

Y, 
Y, {
Y, {
Y, {

Y
,  .Y, or 


Y,[1][2] is a highly contagious zoonosis caused by ingestion
of unsterilized milk or meat from infected animals, or close contact with their secretions. Transmission from
human to human, for example through sexual contact or from mother to child, is exceedingly rare, but
possible.[3] ‘‘ spp. are small, Gram-negative, non-motile, non-spore-forming rods, which function as
facultative intracellular parasites that cause chronic disease, which usually persists for life. Symptoms include
profuse sweating and joint and muscle pain. Brucellosis has been recognized in animals including humans
since the 19th century.

6



Y%
& Y

Y*  YYY

"Y@ Y Y Y

m "Y@ Y YY

m ""Y@ Y Y3Y

m " Y@ Y Y
Y+YM/YY

m "Y@ Y Y
Y

Y@ Y Y
Y

m Y' Y

m "Y YY. Y

m  Y@ 
Y/Y

Y)YYY

Y'YY

YY

Y45Y 6Y

[edit]History and nomenclature

The disease now called brucellosis, under the name "Malta fever", first came to the attention of British medical
officers in Malta during the Crimean War in the 1850s. The causal relationship between organism and disease
was first established by Dr. David Bruce in 1887.[4][5]
In 1897, Danish veterinarian Bernhard Bang isolated ‘‘

? as the agent, and the additional name
"Bang's disease" was assigned. In modern usage, "Bang's disease" is often shortened to just "
"
when ranchers discuss the disease or vaccine.

Maltese doctor and archaeologist Sir Themistocles Zammit earned a knighthood for identifying unpasteurized
milk as the major source of the pathogen in 1905, and it has since become known as Malta Fever. In cattle this
disease is also known as 
 Y 
and 
 Y 
.

The popular name "undulant fever" originates from the characteristic undulance (or "wave-like" nature) of the
fever which rises and falls over weeks in untreated patients. In the 20th century, this name, along with
"brucellosis" (after ‘‘, named for Dr Bruce), gradually replaced the 19th century names "Mediterranean
fever" and "Malta fever".

In 1989, neurologists in Saudi Arabia discovered

 

, a neurological involvement in
brucellosis.[6][7]

The following obsolete names have previously been applied to brucellosis:

§ ‘‘??
§ Bruce's septicemia
§ Chumble fever
§ continued fever
§ Crimean fever
§ Cyprus fever
§ 
?‘
??
§ 
?‘?
§ Fist of mercy

§ goat fever

§ ‘
???

§ melitococcosis
§ milk sickness

§ mountain fever
§ Neapolitan fever

§ Satan's fever

§ slow fever
[edit]Brucellosis in animals
Disease incidence map of Brucella melitensis infections in animals in Europe during the first half of 2006. never

reported not reported in this period confirmed clinical disease confirmed infection no information

Species infecting domestic livestock are ‘
?? (goats and sheep, see Brucella melitensis), ?? (pigs,
see Swine brucellosis), 

? (cattle and bison),  ? (sheep), and ? (dogs). 

? also
infects bison and elk in North America and ?? is endemic in caribou. ‘‘ species have also been
isolated from several marine mammal species (pinnipeds and cetaceans).

[edit]

Y
Y
Y

The bacterium ‘‘

? is the principal cause of brucellosis in cattle. The bacteria are shed from an
infected animal at or around the time of calving or abortion. Once exposed, the likelihood of an animal
becoming infected is variable, depending on age, pregnancy status, and other intrinsic factors of the animal, as
well as the amount of bacteria to which the animal was exposed.[8] The most common clinical signs of cattle
infected with ‘‘

? are high incidences of abortions, arthritic joints and retained after-birth. There are
two main causes for spontaneous abortion in animals. The first is due to erythritol, which can promote
infections in the fetus and placenta. Second is due to the lack of anti-Brucella activity in the amniotic fluid.
Males can also harbor the bacteria in their reproductive tracts, namely seminal vesicles, ampullae, testicles,
and epididymides.

Dairy herds in the USA are tested at least once a year with the Brucella Milk Ring Test (BRT).[9] Cows that are
confirmed to be infected are often killed. In the United States, veterinarians are required to vaccinate all young
stock, thereby further reducing the chance of zoonotic transmission. This vaccination is usually referred to as a
"calfhood" vaccination. Most cattle receive a tattoo in their ear serving as proof of their vaccination status. This
tattoo also includes the last digit of the year they were born.[10]

Canada declared their cattle herd brucellosis-free on September 19, 1985. Brucellosis ring testing of milk and
cream, as well as testing of slaughter cattle, ended April 1, 1999. Monitoring continues through auction market
testing, standard disease reporting mechanisms, and testing of cattle being qualified for export to countries
other than the USA.[11]

The first state±federal cooperative efforts towards eradication of brucellosis caused by ‘‘

? in the
U.S. began in 1934.

[edit]

Y
Y0

Y

Ireland was declared free of brucellosis on 1 July 2009. The disease had troubled the country's farmers and
veterinarians for several decades.[12][13] The Irish government submitted an application to the European
Commission, which verified that Ireland had been liberated.[13] Brendan Smith, Ireland's Minister for Agriculture,
Fisheries and Food, said the elimination of brucellosis was "a landmark in the history of disease eradication in
Ireland".[12][13] Ireland's Department of Agriculture, Fisheries and Food intends to reduce its brucellosis
eradication programme now that eradication has been confirmed.[12][13]

[edit]

Y
Y Y YU

"
YY
Wild bison and elk in the Greater Yellowstone Area (GYA) are the last remaining reservoir of ‘‘


? in the U.S. The recent transmission of brucellosis from cattle to elk in Idaho and Wyoming illustrates
how brucellosis in domestic cattle around the GYA may negatively affect wildlife. Eliminating brucellosis from
this area is a challenge, because these animals are on public land and there are many viewpoints involved in
the management of these animals.

[edit]

Y
Y Y

The causative agent of brucellosis in dogs is ‘‘?. It is transmitted to other dogs through breeding
and contact with aborted fetuses. Brucellosis can occur in humans that come in contact with infected aborted
tissue or semen. The bacteria in dogs normally infect the genitals and lymphatic system, but can also spread to
the eye, kidney, and intervertebral disc(causing discospondylitis). Symptoms of brucellosis in dogs include
abortion in female dogs and scrotal inflammation and orchitis (inflammation of the testicles) in males. Fever is
uncommon. Infection of the eye can cause uveitis, and infection of the intervertebral disc can cause pain or
weakness. Blood testing of the dogs prior to breeding can prevent the spread of this disease. It is treated with
antibiotics, as with humans, but it is difficult to cure.[14]

[edit]Brucellosis in humans
[edit]   Y
Granuloma and necrosis in the liver of a guinea pig infected with ‘‘??

Brucellosis in humans is usually associated with the consumption of unpasteurized milk and soft cheeses made
from the milk of infected animals, primarily goats, infected with ‘‘‘
?? and with occupational
exposure of laboratory workers, veterinarians and slaughterhouse workers. Some vaccines used in livestock,
most notably 

? strain 19, also cause disease in humans if accidentally injected. Brucellosis induces
inconstant fevers, sweating, weakness, anaemia, headaches, depression and muscular and bodily pain.

The symptoms are like those associated with many other febrile diseases, but with emphasis on muscular pain
and sweating. The duration of the disease can vary from a few weeks to many months or even years. In the
first stage of the disease, septicaemia occurs and leads to the classic triad of undulant fevers, sweating (often
with characteristic smell, likened to wet hay) and migratory arthralgia and myalgia. In blood tests, is
characteristic the leukopenia and anaemia, some elevation of AST and ALT and positivity of classic Bengal
Rose and Huddleson reactions. This complex is, at least in Portugal, known as the Malta fever. During
episodes of Malta fever, melitococcemia (presence of brucellae in blood) can usually be demonstrated by
means of blood culture in tryptose medium or Albini medium. If untreated, the disease can give origin to
focalizations or become chronic. The focalizations of brucellosis occur usually in bones and joints and
spondylodiscitis of lumbar spine accompanied by sacroiliitis is very characteristic of this disease. Orchitis is
also frequent in men.

Diagnosis of brucellosis relies on:

1. Demonstration of the agent: blood cultures in tryptose broth, bone marrow cultures. The growth of
brucellae is extremely slow (they can take until 2 months to grow) and the culture poses a risk to
laboratory personnel due to high infectivity of brucellae.

2. Demonstration of antibodies against the agent either with the classic Huddleson, Wright and/or Bengal
Rose reactions, either with ELISA or the 2-mercaptoethanol assay for IgM antibodies associated with
chronic disease
3. Histologic evidence of granulomatous hepatitis (hepatic biopsy)
 4. Radiologic alterations in infected vertebrae: the Pedro Pons sign (preferential erosion of antero-
superior corner of lumbar vertebrae) and marked osteophytosis are suspicious of brucellic spondylitis.

The disease's sequelae are highly variable and may include granulomatous
hepatitis, arthritis, spondylitis, anaemia, leukopenia, thrombocytopenia, meningitis, uveitis, optic
neuritis,endocarditis and various neurological orders collectively known as neurobrucellosis.

[edit] 
Y
Y

Y
Antibiotics like tetracyclines, rifampicin and the aminoglycosides streptomycin and gentamicin are effective
against Brucella bacteria. However, the use of more than one antibiotic is needed for several weeks, because
the bacteria incubate within cells.

The gold standard treatment for adults is daily intramuscular injections of streptomycin 1 g for 14 days and
oral doxycycline 100 mg twice daily for 45 days (concurrently). Gentamicin5 mg/kg by intramuscular
injection once daily for 7 days is an acceptable substitute when streptomycin is not available or difficult to
obtain.[15] Another widely used regimen is doxycycline plus rifampin twice daily for at least 6 weeks. This
regimen has the advantage of oral administration. A triple therapy of doxycycline, together with rifampin and
cotrimoxazole has been used successfully to treat neurobrucellosis.[16] Doxycycline is able to cross the blood±
brain barrier, but requires the addition of two other drugs to prevent relapse. Ciprofloxacin and co-trimoxazole
therapy is associated with an unacceptably high rate of relapse. In brucellic endocarditis surgery is required for
an optimal outcome. Even with optimal antibrucellic therapy relapses still occur in 5±10 percent of patients with
Malta fever. The main way of preventing brucellosis is by using fastidious hygiene in producing raw milk
products, or bypasteurizing all milk that is to be ingested by human beings, either in its unaltered form or as a
derivate, such as cheese. Experiments have shown that cotrimoxazol and rifampin are both safe drugs to use
in treatment of pregnant women who have Brucellosis.

[edit]

Y"Y

In 1954, ?? became the first agent weaponized by the United States at its Pine Bluff Arsenal in
Arkansas. ‘‘ species survive well in aerosols and resist drying. ‘‘ and all other remaining biological
weapons in the U.S. arsenal were destroyed in 1971±72 when the U.S. offensive biological weapons (BW)
program was discontinued.[17]

The United States BW program focused on three agents of the ‘‘ group:

§ Porcine Brucellosis (Agent US)

§ Bovine Brucellosis (Agent AB)

§ Caprine Brucellosis (Agent AM).

Agent US was in advanced development by the end of World War II. When the U.S. Air Force (USAF) wanted a
biological warfare capability, the Chemical Corps offered Agent US in theM114 bomblet, based after the 4-
pound bursting bomblet developed for anthrax in World War II. Though the capability was developed,
operational testing indicated that the weapon was less than desirable, and the USAF termed it an interim
capability until replaced by a more effective biological weapon. The main drawbacks of the M114 with Agent
US was that it was incapacitating (the USAF wanted "killer" agents), the storage stability was too low to allow
for storing at forward air bases, and the logistical requirements to neutralize a target were far higher than
originally anticipated, requiring unreasonable logistical air support.

Agents US and AB had a median infective dose of 500 org/person, and AM was 300 org/person. The rate-of-
action was believed to be 2 weeks, with a duration of action of several months. The lethality estimate was
based on epidemiological information at 1±2%. AM was always believed to be a more virulent disease, and a
3% fatality rate was expected.

Schick test
From Wikipedia, the free encyclopedia

A boy receives an injection of diluted toxin for the Schick test in 1915.

The  .Y, invented between 1910 and 1911[1] is a test used to determine whether or not a person is
susceptible to diphtheria.[2] It was named after its inventor, Béla Schick (1877±1967), a Hungarian-born
American pediatrician.

The test is a simple procedure. A small amount (0.1 ml) of diluted (1/50 MLD) diphtheria toxin is injected
intradermally into the arm of the person. If a person does not have enough antibodies to fight it off, the skin
around the injection will become red and swollen, indicating a positive result. This swelling disappears after a
few days. If the person has an immunity, then little or no swelling and redness will occur, indicating a negative
result.

Results can be interpreted as:

1. Positive: when the test results in a wheal of 5±10 mm diameter

2. Pseudo-positive: when there is only a red colored inflammation and it disappears rapidly

3. Negative reaction:

4. pseudo negative reaction:

The test was created when immunizing agents were scarce and not very safe, however as newer and
safer toxoids were made available there was no more requirement for susceptibility tests.

Almaty
From Wikipedia, the free encyclopedia

    
   
   
 
 )   YÀ{
 Y
Y Y 
2Y55


 YYYYY
Y6Y
YY
Y 

Y Y
 Y  'Y Y. Y+
Y

Ñ
-./012
-./0-10

Y
›Y
Y

Y

Y
 Y

 Y

- Y Y176
Y

( IY  NÙ Ǝ>YN ÙƎ4( IY

 NÙ Ǝ>YN ÙƎ4Y

 
 Y176
Y


  Y

›   $<
Y Y@(Y

›  Y

0
%
& Y

w  Y

Ñ%& 6
7
YM . Y

Ñ Y

"
Ô "Y6 Y"YDY Y

 Y $$<2$$YY2$<2YY

 Y"$$Y

%
 

&
Ô 2"$2 Y

"
Y
 Y 2"!6 Y$2 !DY Y
 Ô$   C (KYC (KY

 
  $$$$$<$$$ Y

Ñ
% &  KY"%&Y

0
3*  -Y

u
   Y

 
I!!/// 67

Y

Ñ
 (Kazakh: 234567 / Ñ
8 / ϯΕ΍ ϡϝ ΍ ), also known by its former name ёÑ
 (Russian: /012/32,
until 1992) and % (Russian: 456789, until 1921), is the largest city in Kazakhstan, with a population of
1,348,500 (as of 1 September 2008),[2] which represents 9% of the population of the country.

It was the capital of Kazakhstan (and its predecessor, the Kazakh SSR) from 1929 to 1997. Despite losing its
status as the capital to Astana, Almaty remains the major commercial center of Kazakhstan.

6



Y%
& Y

Y  Y

"Y*  Y

m "Y)
 Y Y

m ""Y0 Y
Y

m " Y
<
Y Y

m "Y? YYE Y

m "Y"$
Y Y Y

§ "Y YY
Y. YYYY,Y,Y33Y

§ ""Y Y Y,Y,Y33Y

§ " Y YYYY"$$$Y

m "Y"Y Y Y

Y( Y

Y#

Y

Y4 Y

Y'

Y
 m Y1O6Y OY

m "Y? Y

YC .  YY Y

Y'Y

Y8  Y  Y

$Y'YY

YY

"Y45Y 6Y

m "Y8  9Y

m ""Y .9Y

[edit]Toponomy

The name "Almaty" derives from the Kazakh word for 'apple' (ɚɥɦɚ), and thus is often translated as "full of
apples;" ‘ is also 'apple' in other Turkic languages, as well as in Hungarian. The older Soviet-
era Russian version of its name, Alma-Ata, originates from the saint's tomb, buried in an apple orchard,
whence the name, "Saint of the Apple (orchard)" or "Father of Apples".[

 ]
"Ata" standing for father in
Kazakh and many other Turkic languages, also stands for a saint or a priest, as the term "padre" in
the Romance languages. The old name for the new capital of Kazakhstan, Astana was Akmolinsk/Akmola--,
"White Shrine/Mausoleum", a reference to another saint's burial ground.

In fact, in the region surrounding Almaty, there is a great genetic diversity among the wild apples; the region is
thought to be the ancestral home of the apple, and the wild ‘???, is considered a likely candidate for
the ancestor of the modern domestic apple. The area is often visited by researchers and scientists from around
the world in order to learn more about the complex systems of genetics, and also to discover the true
beginnings of the domestic apple.

[edit]History

[edit]   YÑ
Y

During 1000±900 BCE in the Bronze Age the first farmers and cattle-breeders established settlements on the
territory of Almaty.

During the Saka¶s period (from 700 BCE to the beginning of the Common Era), these lands were chosen for
residence by Saka tribes and later Uisun tribes inhabiting the territory north of the Tian Shan mountain range.
The evidences of these times are numerous burial tumuli and ancient settlements, especially giant burial
mounds of Saka tsars. The most famous archaeological finds are the Golden man from the Issyk Kurgan,
Zhalauly treasure, Kargaly diadem, Zhetysu arts bronze (boilers, lamps and altars). During the period of Saka
and uisun governance, Almaty became the early education center.[3]

Silver dirham coin minted in Almaty in 684 CE

[edit]{
YÑY

The next stage of Almaty evolution is attributed to the Middle Ages (8±10th centuries) and is characterized by
city culture development, transfer to a settled way of living, farming and handicraft development, and the
emergence of a number of towns and cities in the territory of Zhetysu.

In 10±14th centuries, settlements in the territory of the so called "Big Almaty" became part of the trade routes of
the Silk Road. At that time, Almaty became one of the trade, craft and agricultural centers on the Silk Road and
possessed an official mint. The city was first mentioned as ё
 in books from the 13th century.

[edit]½- 9½0 Y

Y

In the 15th±18th centuries, the city was on the way to degradation as trade activities were decreasing on this
part of the Silk Road. Notwithstanding, this period was saturated with very important political events that had
significant impact on the history of Almaty and Kazakhstan as a whole. It was a period of crucial ethnic and
political transformations. The Kazakh state and nation were founded here, close to Almaty.

These lands also witnessed the tragic developments related to the Dzungar intervention and rigorous efforts of
the Kazakh to protect their land and preserve independence. In 1730 the Kazakh defeated the Dzungar in the
Anyrakay mountains, 70 km to north-west from Almaty. It was a critical moment of the Patriotic War between
Kazakhs and Dzungars.

[edit] 

Y Y

Y
Zenkov Cathedral, a 19th-century Russian Orthodox cathedral located in Panfilov Park, is the second tallest wooden
building in the world.[4]

On 4 February 1854 the modern history of the city began with the strengthening of the Russian
piedmont Fort % nearby the Zailiysky Alatau mountain range between Bolshaya and Malaya Almatinka
rivers. The construction of the Verniy Fort was almost finished by autumn 1854. It was a fenced pentagon and
one of its sides was built along the Malaya Almatinka. Later, wood fence was replaced with the wall of brick
with embrasures. Main facilities were erected around the big square for training and parading.[5]

In 1855 the first displaced Kazakh appeared in Verniy. Since 1856, Verniy started accepting Russian peasants.
They founded the Bolshaya Almatinskaya Stanitsa (Cossack village) nearby the fortification. The inflow of
migrants was increasing and led to construction of the Malaya Almatinskaya Stanitsa and Tatarskaya
(Tashkentskaya) sloboda. It was the place of settlement for Tatar mechants and craftsmen.

In 1867 the Verniy Fort was transformed into the town and called ё
?. However, the population did not
like the new name of the town and soon the town was re-named as Verniy.

According to the First City Plan, the city perimeters were 2 km on the south along Almatinka river, and 3 km on
the west. The new city area was divided into residential parts, and the latter ² into districts. Three categories
of the city buildings were distinguished. Buildings of the first and second categories were two-storied or, at
least, one-storied constructions with the high semi-basement. Buildings of categories I and II were erected
around and in the center of the city, others ² on the outskirts.

On 28 May 1887, at 4 a.m., an earthquake almost totally destroyed Verniy in 11±12 minutes. Brick buildings
were mostly damaged. As a result, people were inclined to build up one-storied construction made of wood
or  .

[edit]+, Y
YÑ
Y
Holiday Inn

x
Ñ 
 
 ÷ ÷ 00

Samal

In 1921, the joint solemn sitting was summoned for the participation of the representative of government
regional and sub-regional institutions, professional trades, the Muslim people to make a decision to assign a
new name to Verniy ² ёÑ
.

In 1926, the Council of Labour and Defence approved the construction of the Turkestan-Siberia Railwayrailway
that was a crucial element of the republic reconstruction, specifically on the east and southeast of the republic.
The Turkestan-Siberia Railway construction was also a decisive economic aspect that foreordained the destiny
of Alma-Ata as a capital of Kazakh ASSR. In 1930 the construction of the highway and railway to the Alma-Ata
station was completed.

On 2 March 1927, It was the initiative of the Central Executive Committee of the Kazakh Republic to transfer
the capital from Kyzyl-Orda to Alma-Ata. The VI Kazakhstani Congress approved this initiative.[6]

On 29 April 1927, it was officially decided on the sitting of the Russian SFSR Committee to transfer the capital
of the Kazakh Autonomous Soviet Socialist Republic from Kyzyl-Orda to Alma-Ata.
Besides, the Alma-Ata airport was opened in 1930 and people from the capital of Kazakhstan could fly now
from Alma-Ata to Moscow. Alma-Ata became the air gate to Kazakhstan. Transformation of the small town into
the capital of the Republic was supplied by the large-scaled construction of new administrative and government
facilities and housing.

The Central Mosque of Almaty.

Given the transfer of the capital of Kazakhstan to Alma-Ata, in 1936 the Architecture and Planning Bureau
elaborated the General Plan aimed at re-creating Alma-Ata as the new cultural and comfortable capital of
Kazakhstan. The Plan was based on the existing rectangular system of districts that would further be
strengthened and reconstructed.

x
Ñ  ÷ ÷ 00

During World War II the city territory was changed to a large extent. To organize the home front and
concentrate industrial and material resources, the residential stock was compressed to arrange
accommodation for 26,000 persons evacuated. Alma-Ata hosted over 30 industrial facilities from the front
areas, 8 evacuated hospitals, 15 institutes, universities and technical schools, around 20 cultural institutions,
etc. Motion pictureproduction companies from Leningrad, Kiev and Moscow were also evacuated to Alma-Ata.

 
?‘  ‘
, over 52,000 Alma-Ata residents were awarded. 48 residents were granted the
title of    ÔO

å . Threerifle divisions were raised in Alma-Ata , including the well-known 8th
Guards Rifle Division 'Panfilov', along with 2 rifle battalions and 3 aviation regiments that were raised on the
bases of the air club of Alma-Ata.
x
Ñ 

Furmanov street

From 1966 to 1971, 1,400,000 square meters of public and cooperative housing were put into operation.
Annually, around 300,000 square meters of dwellings were under construction. It was the period of
constructing earthquake-proof multi-storied buildings. Construction unification and type-design practice
diversified architectural forms. At that time lots of schools, hospitals, cultural and entertainment facilities were
constructed, including Lenin¶s Palace, Kazakhstan Hotel, and the ³Medeo´ sports complex.

The Medeu Dam, designed to protect the city of Almaty and the Medeo skating rink from
catastrophic mudflows, was built in 1966 and reinforced a number of times in the 1960s and 1970s.

The supersonic transport Tupolev Tu-144 went into service on 26 December 1975, flying mail and freight
between Moscow and Alma-Ata in preparation for passenger services, which commenced in November 1977.
The Aeroflot flight on 1 June 1978 was the Tu-144's 55th and last scheduled passenger service.

Since 1981, the underground Almaty Metro construction project has been developed.

On 16 December 1986 Jeltoksan riot took place in response to General Secretary Mikhail Gorbachev's
dismissal of Dinmukhamed Kunayev.
Hotel Kazakhstan

In 1993 the government made a decision to rename Alma-Ata. The new name of the city is ё
.

In 1997 the President of the Republic of Kazakhstan Nursultan Nazarbayev approved the Decree to transfer
the capital from Almaty to Astana.[7]

Dostyk Hotel

On 1 July 1998 a Law was passed concerning the special status of Almaty as a scientific, cultural, historical,
financial and industrial center.

[edit]+½Y
YÑ
Y
The new 2030 General Plan of Almaty was developed in 1998 and aims at forming ecologically safe, secure
and socially comfortable living conditions. The main objective is to promote Almaty¶s image as a garden-city.
One of the components of the General Plan is to continue multi-storied and individual construction, reorganize
industrial territories, improve transport infrastructure and launch Almaty Metro.[

 ]

[edit]Climate

Almaty features a humid continental climate with very warm summers and cold winters. Its wettest months are
April and May, during which about a third of the city¶s annual precipitation is received. August and September
are the driest months where on average under 30 mm (1.18 in) of precipitation is seen.
 %
& Ñ

   4  ›  Ñ  4  4 Ñ



"Y $Y "$Y "Y Y  Y Y "Y Y

)
  5 %5›&
Y "Y "Y Y "Y $"Y "Y $Y $$Y

9$"Y Y $Y "Y "Y "Y "Y "Y " Y
Ñ  5 %5›&
 Y  Y Y  Y $Y $Y Y  Y Y

9Y 9 Y ""Y Y Y "$Y " Y ""Y Y

 5 %5›&
" "Y "Y  Y  Y Y Y Y "Y  Y

9Y 9"Y 9"Y Y $Y "Y Y  Y "Y

Ñ5 %5›&
Y "Y " Y  Y $Y Y Y  Y ""Y

9 $Y 9 Y 9"Y 9$Y 9$Y "$Y  Y Y 9 $Y

)
5 %5›&
9"""Y 9 Y 9"Y "Y Y  Y Y $Y "Y

Y Y "Y Y $Y Y Y "Y "Y


 %
 &
 Y Y "Y  Y Y "Y Y $Y Y

 ! "#Y

[edit]Demographics


O  ?ë

.![

 ]

:

§ Kazakh 51.5 %
§ Russian 30.0 %
§ Uyghur 5.8 %
§ Tatar 2.0 %
§ Korean 2.0 %
§ Ukrainian 1.0 %
§ German 1.0 %
§ Indians 1.0 %
§ Chinese 1.0 %
§ Others : 5%

According to the USSR Census of 1989, population of Almaty was 1,071,900; Kazakhstan Census of 1999
reported 1,129,400.[8]

[edit]Economy
Almaty business centre

Almaty is also developing as the regional financial and business centre ² RFCA.[

 ]
.

Air Astana is headquartered in the Air Astana Centre 1 in Almaty.[9] Prior to their dissolution, Air
Kazakhstan[10] and Kazakhstan Airlines[11]were also headquartered in Almaty.

[edit]Sights

[edit]ö .Y Y

Downtown Almaty as seen from Kok Tobe

An aerial tramway line connects downtown Almaty with a popular recreation area the top of Kök
Töbe (Kazakh: Ʉԧɤɬԧɛɟ, which means 'Green Hill'), a mountain just to the southeast. The city television
tower, Alma-Ata Tower, is located on the hill, as well as a variety of amusement-park type attractions and
touristy restaurants.

[edit] 

Y
A section of the Zodiac Fountain (1979)

According to the city's Department of Natural Resources and Resource Use Management,[12] as of 2007 the
city has 125 fountain groups or isolated fountains. Among them is the "Oriental Calendar" Fountain, whose 12
sculpture figures represent the 12 animals of the Kazakh 12-year animal cycle (similar to its Chinese
counterpart).

[edit]Universities of Almaty

§ International IT University (IITU)

§ Kazakh-British Technical University (KBTU)
§ Kazakh National Medical University

§ Almaty Institute of Power Engineering and Telecommunications

§ Kazakh National Technical University (KazNTU)
§ Al-Farabi Kazakh National University (KazUU)
§ Suleyman Demirel University (SDU)
§ KIMEP (Kazakhstan Institute of Management, Economics, and Strategic Research)

§ Kazakh-American University (KAU)

§ Kazakh Academy of Sciences

§ Kazakh Academy of Labour and Social Relations

§ Almaty State University (named after Abay)

§ Turan University

§ Kazakhstan University of Global Relationships and Languages (ɄɚɡɍɆɈɢɆə)

§ Central Asian University (ɐȺɍ)

§ Kazakh-German University (Ʉɇɍ)

Apple Town

 
O
‘?u?
 ?
?* O?


Medeo, with bandy goals

[edit]Sports

The historic bandy team Dinamo won the Soviet Championships in 1977 and 1990 and the European Cup in
1978. Their home ground was Medeo, where bandy will be the only sport at the 2011 Winter Asian Games.

[edit]Olympic aspirations

Almaty was an official candidate to host the XXII Olympic Winter Games in 2014,[13] but was eliminated from
consideration after it failed to be included in the "short list" of candidate cities. Almaty won its bid to host
the 2011 Winter Asian Games. The city is exploring possible future bids, such as the 2018 Winter Olympics.
However, the city failed to submit a bid as an applicant city for the 2018 games.

Y
Y

Bronchitis
From Wikipedia, the free encyclopedia

D


 ?
O
 O ‘
?


 

6



 
 Y

Y

Y 
Y
/YY
 Y

0
 ÿ"$9ÿ"2Yÿ"Y

0
 2YY

  
  "  Y

   $$$ Y


    !"$ Y


  #$$ Y

Y Y   
 
 "Y
)Y
Y .Y
Y Y Y 
Y YYCY Y Y
Y
Y

YY.À  Y


  is inflammation of the mucous membranes of the bronchi, the airways that carry airflow from
the trachea into the lungs. Bronchitis can be classified into two categories, acute and chronic, each of which
has unique etiologies, pathologies, and therapies.

Acute bronchitis is characterized by the development of a cough, with or without the production
of sputum, mucus that is expectorated(coughed up) from the respiratory tract. Acute bronchitis often occurs
during the course of an acute viral illness such as the common cold orinfluenza. Viruses cause about 90% of
cases of acute bronchitis while bacteria account for less than 10%.[1]

Chronic bronchitis, a type of chronic obstructive pulmonary disease, is characterized by the presence of a
productive cough that lasts for 3 months or more per year for at least 2 years. Chronic bronchitis most often
develops due to recurrent injury to the airways caused by inhaled irritants. Cigarette smoking is the most
common cause, followed by air pollution and occupational exposure to irritants, and cold air.

6



Y%
& Y

Y(   Y

m YY
 Y

m "Y(
 Y
 Y

m  Y)Y Y
 Y

"YY

Y45Y 6Y

[edit]Classification

[edit]ÑY
 Y


‘Ñ

 O
?

Acute bronchitis is most often caused by viruses that infect the epithelium of the bronchi, resulting in
inflammation and increased secretion of mucus. Cough, a common symptom of acute bronchitis, develops in
an attempt to expel the excess mucus from the lungs. Other common symptoms include sore throat, runny
nose, nasal congestion (coryza), low-gradefever, pleurisy, malaise, and the production of sputum.[1]

Acute bronchitis often develops during the course of an upper respiratory infection (URI) such as the common
cold or influenza.[1] About 90% of cases of acute bronchitis are caused by viruses,
including rhinoviruses, adenoviruses, and influenza. Bacteria, including   ‘? , 6O‘ 
 , and  
‘‘
???, account for about 10% of cases.[1]

Treatment for acute bronchitis is primarily symptomatic. Non-steroidal anti-inflammatory drugs (NSAIDs) may
be used to treat fever and sore throat. Decongestants can be useful in patients with nasal congestion,
and expectorants may be used to loosen mucus and increase expulsion of sputum. Cough suppressants may
be used if the cough interferes with sleep or is bothersome, although coughing may be useful in expelling
sputum from the airways. Even with no treatment, most cases of acute bronchitis resolve quickly.[1]

Only about 5-10% of bronchitis cases are caused by a bacterial infection. Most cases of bronchitis are caused
by a viral infection and are "self-limited" and resolve themselves in a few weeks.[2] As most cases of acute
bronchitis are caused by viruses, antibiotics should not be used since they are only effective against bacteria.
Using antibiotics in patients who do not have bacterial infections promotes the development of antibiotic-
resistant bacteria, which may lead to greater morbidity and mortality. Antibiotics should only be prescribed if
microscopic examination of Gram stained sputum shows large numbers of bacteria present.

[edit]6 
Y
 Y


‘6O 
 O
?

Chronic bronchitis, a type of chronic obstructive pulmonary disease, is defined by a productive cough that lasts
for 3 months or more per year for at least 2 years.[3] Other symptoms may include wheezing and shortness of
breath, especially upon exertion. The cough is often worse soon after awakening, and the sputum produced
may have a yellow or green color and may be streaked with blood.[1]

Chronic bronchitis is caused by recurring injury or irritation to the respiratory epithelium of the bronchi, resulting
in chronic inflammation, edema (swelling), and increased production of mucus by goblet cells.[1] Airflow into and
out of the lungs is partly blocked because of the swelling and extra mucus in the bronchi or due to
reversible bronchospasm.[4]

Most cases of chronic bronchitis are caused by smoking cigarettes or other forms of tobacco. Chronic
inhalation of irritating fumes or dust from occupational exposure or air pollution may also be causative. About
5% of the population has chronic bronchitis, and it is two times more common in males than females.[1]

Chronic bronchitis is treated symptomatically. Inflammation and edema of the respiratory epithelium may be
reduced with inhaled corticosteroids. Wheezing and shortness of breath can be treated by
reducing bronchospasm (reversible narrowing of smaller bronchi due to constriction of the smooth muscle)
with bronchodilators such as inhaled ȕ-Adrenergic agonists (e.g.,albuterol) and
inhaled anticholinergics (e.g., ipratropium bromide). Hypoxemia, too little oxygen in the blood, can be treated
with supplemental oxygen.[1] However, oxygen supplementation can result in decreased respiratory drive
leading to increased blood levels of carbon dioxide and subsequent respiratory acidosis.
The most effective method of preventing chronic bronchitis and other forms of COPD is to avoid smoking
cigarettes and other forms of tobacco.[1]

On pulmonary tests, a bronchitic (bronchitis) may present a decreased FEV1 and FEV1/FVC. However, unlike
the other common obstructive disorders, asthma and emphysema, bronchitis rarely causes a high residual
volume. This is because the air flow obstruction found in bronchitis is due to increased resistance, which does
not generally cause the airways to collapse prematurely and trap air in the lungs.[

 ]

[edit]  Y
Y
 Y
Protracted bacterial bronchitis is defined as a cough of more than 8 weeks, with a positive bronchoalveolar
lavage (BAL), that resolves with antibiotics.[5] It is usually caused bystreptococcus pneumoniae, haemophilus
influenzae, or moraxella catarrhalis.[5]

Meningitis
From Wikipedia, the free encyclopedia

   

6



 
 Y

Y
0 
YY
YY.Y IYY2Y
 2YY Y

Y

0
 +$$<+$ Y

0
 "$< ""Y


  
  "" Y

   $$$$ Y


   !" Y

! $
! $Y


  #$$ Y

{

 is inflammation of the protective membranes covering the brain and spinal cord, known collectively
as the meninges.[1] The inflammation may be caused by infection with viruses, bacteria, or
other microorganisms, and less commonly by certain drugs.[2] Meningitis can be life-threatening because of the
inflammation's proximity to the brain and spinal cord; therefore the condition is classified as a medical
emergency.[1][3]

The most common symptoms of meningitis are headache and neck stiffness associated
with fever, confusion or altered consciousness, vomiting, and an inability to tolerate light (photophobia) or loud
noises (phonophobia). Sometimes, especially in small children, onlynonspecific symptoms may be present,
such as irritability and drowsiness. If a rash is present, it may indicate a particular cause of meningitis; for
instance, meningitis caused by meningococcal bacteria may be accompanied by a characteristic rash.[1][4]

A lumbar puncture may be used to diagnose or exclude meningitis. This involves inserting a needle into
the spinal canal to extract a sample of cerebrospinal fluid (CSF), the fluid that envelops the brain and spinal
cord. The CSF is then examined in a medical laboratory.[3] The usual treatment for meningitis is the prompt
application of antibiotics and sometimes antiviral drugs. In some situations, corticosteroid drugs can also be
used to prevent complications from overactive inflammation.[3][4] Meningitis can lead to serious long-term
consequences such asdeafness, epilepsy, hydrocephalus and cognitive deficits, especially if not treated
quickly.[1][4] Some forms of meningitis (such as those associated with meningococci,   O‘?
‘  type B, pneumococci or mumps virus infections) may be prevented byimmunization.[1]

6



Y%
& Y

Y'
YY Y

m Y(  YY

m "Y4 Y  Y

"Y(Y
 m "Y@ Y

m ""Y Y

m " YE Y

m "Y)  Y

m "Y>9  Y

Y0
 Y

Y# 
 Y

m Y@YYY 

Y

m "Y-YY

m  Y)Y

Y). Y

Y Y

m Y3  YY

m "Y@ Y 
 Y

§ "Y   Y

§ ""Y' Y

m  YE Y 
 Y

m Y?
Y 
 Y

Y)
 Y

Y4  
Y

Y*  Y

$Y'YY

YY

"Y45Y 6Y

[edit]Signs and symptoms

[edit]6


YY

In adults, a severe headache is the most common symptom of meningitis ± occurring in almost 90% of cases of
bacterial meningitis, followed by nuchal rigidity (inability to flex the neck forward passively due to increased
neck muscle tone and stiffness).[5] The classic triad of diagnostic signs consists of nuchal rigidity, sudden high
fever, and altered mental status; however, all three features are present in only 44±46% of all cases of bacterial
meningitis.[5][6] If none of the three signs is present, meningitis is extremely unlikely.[6] Other signs commonly
associated with meningitis include photophobia (intolerance to bright light) and phonophobia (intolerance to
loud noises). Small children often do not exhibit the aforementioned symptoms, and may only be irritable and
looking unwell.[1] In infants up to 6 months of age, bulging of the fontanelle (the soft spot on top of a baby's
head) may be present. Other features that might distinguish meningitis from less severe illnesses in young
children are leg pain, cold extremities, and abnormal skin color.[7]

Nuchal rigidity occurs in 70% of adult cases of bacterial meningitis.[6] Other signs of meningism include the
presence of positive Kernig's sign or Brudzinski's sign. Kernig's sign is assessed with the patient lying supine,
with the hip and knee flexed to 90 degrees. In a patient with a positive Kernig's sign, pain limits passive
extension of the knee. A positive Brudzinski's sign occurs when flexion of the neck causes involuntary flexion of
the knee and hip. Although Kernig's and Brudzinski's signs are both commonly used to screen for meningitis,
the sensitivity of these tests is limited.[6][8] They do, however, have very good specificity for meningitis: the signs
rarely occur in other diseases.[6] Another test, known as the "jolt accentuation maneuver" helps determine
whether meningitis is present in patients reporting fever and headache. The patient is told to rapidly rotate his
or her head horizontally; if this does not make the headache worse, meningitis is unlikely.[6]

Meningitis caused by the bacterium D?? 
? (known as "meningococcal meningitis") can be
differentiated from meningitis with other causes by a rapidly spreadingpetechial rash which may precede other
symptoms.[7] The rash consists of numerous small, irregular purple or red spots ("petechiae") on the
trunk, lower extremities, mucous membranes, conjuctiva, and (occasionally) the palms of the hands or soles of
the feet. The rash is typically non-blanching: the redness does not disappear when pressed with a finger or a
glass tumbler. Although this rash is not necessarily present in meningococcal meningitis, it is relatively specific
for the disease; it does, however, occasionally occur in meningitis due to other bacteria.[1] Other clues as to the
nature of the cause of meningitis may be the skin signs of hand, foot and mouth disease and genital herpes,
both of which are associated with various forms of viral meningitis.[9]

[edit]
Y 

Y

A severe case of meningococcal meningitis in which the petechial rash progressed to gangrene and requiredamputation of
all limbs. The patient,Charlotte Cleverley-Bisman, survived the disease and became a poster child for a meningitis
vaccination campaign in New Zealand.
People with meningitis may develop additional problems in the early stages of their illness. These may require
specific treatment, and sometimes indicate severe illness or worse prognosis. The infection may trigger sepsis,
a systemic inflammatory response syndrome of falling blood pressure,fast heart rate, high or abnormally low
temperature and rapid breathing. Very low blood pressure may occur early, especially but not exclusively in
meningococcal illness; this may lead to insufficient blood supply to other organs.[1] Disseminated intravascular
coagulation, the excessive activation of blood clotting, may cause both the obstruction of blood flow to organs
and a paradoxical increase of bleeding risk. In meningococcal disease, gangrene of limbs can occur.[1] Severe
meningococcal and pneumococcal infections may result in hemorrhaging of the adrenal glands, leading
to Waterhouse-Friderichsen syndrome, which is often lethal.[10]

The brain tissue may swell, with increasing pressure inside the skull and a risk of swollen brain tissue getting
trapped. This may be noticed by a decreasing level of consciousness, loss of the pupillary light reflex,
and abnormal positioning.[4] Inflammation of the brain tissue may also obstruct the normal flow of CSF around
the brain (hydrocephalus).[4] Seizures may occur for various reasons; in children, seizures are common in the
early stages of meningitis (30% of cases) and do not necessarily indicate an underlying cause.[3] Seizures may
result from increased pressure and from areas of inflammation in the brain tissue.[4] Focal seizures (seizures
that involve one limb or part of the body), persistent seizures, late-onset seizures and those that are difficult to
control with medication are indicators of a poorer long-term outcome.[1]

The inflammation of the meninges may lead to abnormalities of the cranial nerves, a group of nerves arising
from the brain stem that supply the head and neck area and control eye movement, facial muscles and hearing,
among other functions.[1][6] Visual symptoms and hearing loss may persist after an episode of meningitis (see
below).[1] Inflammation of the brain (encephalitis) or its blood vessels (cerebral vasculitis), as well as the
formation of blood clots in the veins (cerebral venous thrombosis), may all lead to weakness, loss of sensation,
or abnormal movement or function of the part of the body supplied by the affected area in the brain.[1][4]

[edit]Causes

Meningitis is usually caused by infection from viruses or micro-organisms. Most cases are due to infection with
viruses,[6] with bacteria, fungi, and parasites being the next most common causes.[2] It may also result from
various non-infectious causes.[2]

[edit]
Y

The types of bacteria that cause bacterial meningitis vary by age group. In premature babies and newborns up
to three months old, common causes are  ?

  (subtypes III which normally inhabit
the vagina and are mainly a cause during the first week of life) and those that normally inhabit the digestive
tract such as ?OO ‘ (carrying K1 antigen).u?
  
? (serotype IVb) may affect the
newborn and occurs in epidemics. Older children are more commonly affected by D??
 
? (meningococcus),


 ?  (serotypes 6, 9, 14, 18 and 23) and those under five
by   O‘?‘  type B (in countries that do not offer vaccination, see below).[1][3] In adults, D
 
? and
  together cause 80% of all cases of bacterial meningitis, with increased risk
of u  
? in those over 50 years old.[3][4] Since the pneumococcal vaccine was introduced, however,
rates of pneumococcal meningitis have declined in children and adults.[11]

Recent trauma to the skull gives bacteria in the nasal cavity the potential to enter the meningeal space.
Similarly, individuals with a cerebral shunt or related device (such as anextraventricular drain or Ommaya
reservoir) are at increased risk of infection through those devices. In these cases, infections
with staphylococci are more likely, as well as infections bypseudomonas and other Gram-negative bacilli.[3] The
same pathogens are also more common in those with an impaired immune system.[1] In a small proportion of
people, an infection in the head and neck area, such as otitis media or mastoiditis, can lead to
meningitis.[3] Recipients of cochlear implants for hearing loss are at an increased risk of pneumococcal
meningitis.[12]

Tuberculous meningitis, meningitis due to infection with  



‘ ??, is more common in those
from countries where tuberculosis is common, but is also encountered in those with immune problems, such
as AIDS.[13]

Recurrent bacterial meningitis may be caused by persisting anatomical defects, either congenital or acquired,
or by disorders of the immune system.[14] Anatomical defects allow continuity between the external environment
and the nervous system. The most common cause of recurrent meningitis is skull fracture,[14] particularly
fractures that affect the base of the brain or extend towards the sinuses and petrous pyramids.[14] A literature
review of 363 reported cases of recurrent meningitis showed that 59% of cases are due to such anatomical
abnormalities, 36% due to immune deficiencies (such as complement deficiency, which predisposes especially
to recurrent meningococcal meningitis), and 5% due to ongoing infections in areas adjacent to the meninges.[14]

[edit]ÑY

The term ?
 
? refers loosely to all cases of meningitis in which no bacterial infection can be
demonstrated. This is usually due to viruses, but it may be due to bacterial infection that has already been
partially treated, with disappearance of the bacteria from the meninges, or by infection in a space adjacent to
the meninges (e.g. sinusitis). Endocarditis(infection of the heart valves with spread of small clusters of bacteria
through the bloodstream) may cause aseptic meningitis. Aseptic meningitis may also result from infection
withspirochetes, a type of bacteria that includes Ô ‘‘ (the cause of syphilis) and  ‘

   (known for causing Lyme disease). Meningitis may be encountered incerebral malaria (malaria
infecting the brain). Fungal meningitis, e.g. due to 6 
 ?  ?, is typically seen in people with
immune deficiency such as AIDS. Amoebic meningitis, meningitis due to infection with amoebae such
as D ‘ ‘, is contracted from freshwater sources.[2]
[edit]

Y

Viruses that can cause meningitis include enteroviruses, herpes simplex virus type 2 (and less commonly type
1), varicella zoster virus (known for causing chickenpox and shingles),mumps virus, HIV, and LCMV.[9]

[edit] Y
A parasitic cause is often assumed when there is a predominance of eosinophils in the CSF. The most
common parasites implicated are Ñ  ?
  ‘?
?? and w
O ?

? . Tuberculosis, syphilis, cryptococcosis, and coccidiodomycosis are rare causes of eosinophilic
meningitis that may need to be considered.[15][16][17]

[edit](
&
 Y

Meningitis may occur as the result of several non-infectious causes: spread of cancer to the meninges
(‘ 
 
?)[18] and certain drugs (mainly non-steroidal anti-inflammatory
drugs, antibiotics and intravenous immunoglobulins).[19] It may also be caused by several inflammatory
conditions such as sarcoidosis (which is then called neurosarcoidosis), connective tissue disorders such
as systemic lupus erythematosus, and certain forms of vasculitis (inflammatory conditions of the blood vessel
wall) such as Behçet's disease.[2]Epidermoid cysts and dermoid cysts may cause meningitis by releasing irritant
matter into the subarachnoid space.[2][14] Mollaret's meningitis is a syndrome of recurring episodes of aseptic
meningitis; it is now thought to be caused by herpes simplex virus type 2. Rarely, migraine may cause
meningitis, but this diagnosis is usually only made when other causes have been eliminated.[2]

[edit]Mechanism

The meninges comprise three membranes that, together with the cerebrospinal fluid, enclose and protect
the brain and spinal cord (the central nervous system). The pia mater is a very delicate impermeable
membrane that firmly adheres to the surface of the brain, following all the minor contours. The arachnoid
mater (so named because of its spider-web-like appearance) is a loosely fitting sac on top of the pia mater.
The subarachnoid space separates the arachnoid and pia mater membranes, and is filled with cerebrospinal
fluid. The outermost membrane, the dura mater, is a thick durable membrane, which is attached to both the
arachnoid membrane and the skull.

In bacterial meningitis, bacteria reach the meninges by one of two main routes: through the bloodstream or
through direct contact between the meninges and either the nasal cavity or the skin. In most cases, meningitis
follows invasion of the bloodstream by organisms that live upon mucous surfaces such as the nasal cavity. This
is often in turn preceded by viral infections, which break down the normal barrier provided by the mucous
surfaces. Once bacteria have entered the bloodstream, they enter the subarachnoid space in places where
theblood-brain barrier is vulnerable²such as the choroid plexus. Meningitis occurs in 25% of newborns with
bloodstream infections due to group B streptococci; this phenomenon is less common in adults.[1] Direct
contamination of the cerebrospinal fluid may arise from indwelling devices, skull fractures, or infections of the
nasopharynx or the nasal sinuses that have formed a tract with the subarachnoid space (see above);
occasionally, congenital defects of the dura mater can be identified.[1]

The large-scale inflammation that occurs in the subarachnoid space during meningitis is not a direct result of
bacterial infection but can rather largely be attributed to the response of theimmune system to the entrance of
bacteria into the central nervous system. When components of the bacterial cell membrane are identified by the
immune cells of the brain (astrocytesand microglia), they respond by releasing large amounts of cytokines,
hormone-like mediators that recruit other immune cells and stimulate other tissues to participate in an immune
response. The blood-brain barrier becomes more permeable, leading to "vasogenic" cerebral edema (swelling
of the brain due to fluid leakage from blood vessels). Large numbers of white blood cells enter the CSF,
causing inflammation of the meninges, and leading to "interstitial" edema (swelling due to fluid between the
cells). In addition, the walls of the blood vessels themselves become inflamed (cerebral vasculitis), which leads
to a decreased blood flow and a third type of edema, "cytotoxic" edema. The three forms of cerebral edema all
lead to an increased intracranial pressure; together with the lowered blood pressure often encountered in acute
infection, this means that it is harder for blood to enter the brain, and brain cells are deprived of oxygen and
undergo apoptosis (automated cell death).[1]

It is recognized that administration of antibiotics may initially worsen the process outlined above, by increasing
the amount of bacterial cell membrane products released through the destruction of bacteria. Particular
treatments, such as the use of corticosteroids, are aimed at dampening the immune system's response to this
phenomenon.[1][4]

[edit]Diagnosis

%"$&

›         

Ô    w
     

)0>2Y
Ñ

 /Y


Y
YPY $$!QY

2Y
Ñ
 Y YY


Y
HY $$!QY

Ô
  /Y

Y
YY
 )0>2YHY $$!QY

›  /Y


Y HY $$!QY

 Y
    /Y


Y
Y

[edit]
YY
Y 
Y
In someone suspected of having meningitis, blood tests are performed for markers of inflammation (e.g. C-
reactive protein,complete blood count), as well as blood cultures.[3][21]

The most important test in identifying or ruling out meningitis is analysis of the cerebrospinal fluid
through lumbar puncture(LP, spinal tap).[22] However, lumbar puncture is contraindicated if there is a mass in
the brain (tumor or abscess) or theintracranial pressure (ICP) is elevated, as it may lead to brain herniation. If
someone is at risk for either a mass or raised ICP (recent head injury, a known immune system problem,
localizing neurological signs, or evidence on examination of a raised ICP), a CT or MRI scan is recommended
prior to the lumbar puncture.[3][21][23] This applies in 45% of all adult cases.[4] If a CT or MRI is required before
LP, or if LP proves difficult, professional guidelines suggest that antibiotics should be administered first to
prevent delay in treatment,[3] especially if this may be longer than 30 minutes.[21][23] Often, CT or MRI scans are
performed at a later stage to assess for complications of meningitis.[1]

In severe forms of meningitis, monitoring of blood electrolytes may be important; for example, hyponatremia is
common in bacterial meningitis, due to a combination of factors including dehydration, the inappropriate
excretion of the antidiuretic hormone (SIADH), or overly aggressive intravenous fluid administration.[4][24]

[edit] Y
Y
A lumbar puncture is done by positioning the patient, usually lying on the side, applying local anesthetic, and
inserting a needle into the dural sac (a sac around the spinal cord) to collect cerebrospinal fluid (CSF). When
this has been achieved, the "opening pressure" of the CSF is measured using a manometer. The pressure is
normally between 6 and 18 cm water (cmH2O);[22] in bacterial meningitis the pressure is typically
elevated.[3][21] The initial appearance of the fluid may prove an indication of the nature of the infection: cloudy
CSF indicates higher levels of protein, white and red blood cells and/or bacteria, and therefore may suggest
bacterial meningitis.[3]
Gram stain of meningococci from a culture showing Gram negative (pink) bacteria, often in pairs

The CSF sample is examined for presence and types of white blood cells, red blood cells, protein content
and glucose level.[3] Gram stainingof the sample may demonstrate bacteria in bacterial meningitis, but absence
of bacteria does not exclude bacterial meningitis as they are only seen in 60% of cases; this figure is reduced
by a further 20% if antibiotics were administered before the sample was taken, and Gram staining is also less
reliable in particular infections such as listeriosis. Microbiological culture of the sample is more sensitive (it
identifies the organism in 70±85% of cases) but results can take up to 48 hours to become available.[3] The
type of white blood cell predominantly present (see table) indicates whether meningitis is bacterial (usually
neutrophil-predominant) or viral (usually lymphocyte-predominant),[3] although in the beginning of the disease
this is not always a reliable indicator. Less commonly, eosinophils predominate, suggesting parasitic or fungal
etiology, among others.[16]

The concentration of glucose in CSF is normally above 40% that in blood. In bacterial meningitis it is typically
lower; the CSF glucose level is therefore divided by the blood glucose (CSF glucose to serum glucose ratio). A
ratio ”0.4 is indicative of bacterial meningitis;[22] in the newborn, glucose levels in CSF are normally higher, and
a ratio below 0.6 (60%) is therefore considered abnormal.[3] High levels of lactate in CSF indicate a higher
likelihood of bacterial meningitis, as does a higher white blood cell count.[22]

Various more specialized tests may be used to distinguish between various types of meningitis. A latex
agglutination test may be positive in meningitis caused by


 ? , D??
 
?,   O‘?‘ , ?OO ‘ and  ?

 ; its routine use is not
encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic.
Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is of
limited use unless other tests have been unhelpful.[3] Polymerase chain reaction (PCR) is a technique used to
amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA in cerebrospinal
fluid; it is a highly sensitive and specific test since only trace amounts of the infecting agent's DNA is required.
It may identify bacteria in bacterial meningitis and may assist in distinguishing the various causes of viral
meningitis (enterovirus, herpes simplex virus 2 and mumps in those not vaccinated for
this).[9] Serology (identification of antibodies to viruses) may be useful in viral meningitis.[9] If tuberculous
meningitis is suspected, the sample is processed for Ziehl-Neelsen stain, which has a low sensitivity, and
tuberculosis culture, which takes a long time to process; PCR is being used increasingly.[13] Diagnosis of
cryptococcal meningitis can be made at low cost using an India ink stain of the CSF; however, testing for
cryptococcal antigen in blood or CSF is more sensitive, particularly in persons with AIDS.[25][26][27]

A diagnostic and therapeutic conundrum is the "partially treated meningitis", where there are meningitis
symptoms after receiving antibiotics (such as for presumptive sinusitis). When this happens, CSF findings may
resemble those of viral meningitis, but antibiotic treatment may need to be continued until there is definitive
positive evidence of a viral cause (e.g. a positive enterovirus PCR).[9]

[edit]   Y
Meningitis can be diagnosed after death has occurred. The findings from a post mortem are usually a
widespread inflammation of the pia mater and arachnoid layers of the meninges covering the brain and spinal
cord. Neutrophil leucocytes tend to have migrated to the cerebrospinal fluid and the base of the brain, along
with cranial nerves and the spinal cord, may be surrounded with pus²as may the meningeal vessels.[28]

[edit]Prevention

For some causes of meningitis, prophylaxis can be provided in the long term with vaccine, or in the short term
with antibiotics.

Since the 1980s, many countries have included immunization against   O‘?‘  type B in their
routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of meningitis
in young children in those countries. In the countries where the disease burden is highest, however, the
vaccine is still too expensive.[29][30] Similarly, immunization against mumps has led to a sharp fall in the number
of cases of mumps meningitis, which prior to vaccination occurred in 15% of all cases of mumps.[9]

Meningococcus vaccines exist against groups A, C, W135 and Y.[31] In countries where the vaccine for
meningococcus group C was introduced, cases caused by this pathogen have decreased substantially.[29] A
quadrivalent vaccine now exists, which combines all four vaccines. Immunization with the ACW135Y vaccine
against four strains is now a visa requirement for taking part in the Hajj.[32] Development of a vaccine against
group B meningococci has proved much more difficult, as its surface proteins (which would normally be used to
make a vaccine) only elicit a weak response from the immune system, or cross-react with normal human
proteins.[29][31] Still, some countries (New Zealand, Cuba, Norway and Chile) have developed vaccines against
local strains of group B meningococci; some have shown good results and are used in local immunization
schedules.[31] In Africa, the current approach for prevention and control of meningococcal epidemics is based
on early detection of the disease and emergency reactive mass vaccination of the at-risk population with
bivalent A/C or trivalent A/C/W135 polysaccharide vaccines.[33]
Routine vaccination against


 ?  with the pneumococcal conjugate vaccine (PCV),
which is active against seven common serotypes of this pathogen, significantly reduces the incidence of
pneumococcal meningitis.[29][34] The pneumococcal polysaccharide vaccine, which covers 23 strains, is only
administered in certain groups (e.g. those who have had a splenectomy, the surgical removal of the spleen); it
does not elicit a significant immune response in all recipients, e.g. small children.[34]

Childhood vaccination with Bacillus Calmette-Guérin has been reported to significantly reduce the rate of
tuberculous meningitis, but its waning effectiveness in adulthood has prompted a search for a better vaccine.[29]

Short-term antibiotic prophylaxis is also a method of prevention, particularly of meningococcal meningitis. In

cases of meningococcal meningitis, prophylactic treatment of close contacts with antibiotics
(e.g. rifampicin, ciprofloxacin or ceftriaxone) can reduce their risk of contracting the condition, but does not
protect against future infections.[21][35]

[edit]Treatment

[edit]0

Y 
Y
Meningitis is potentially life-threatening and has a high mortality rate if untreated;[3] delay in treatment has been
associated with a poorer outcome.[4] Thus treatment with wide-spectrum antibiotics should not be delayed while
confirmatory tests are being conducted.[23] If meningococcal disease is suspected in primary care, guidelines
recommend that benzylpenicillin be administered before transfer to hospital.[7] Intravenous fluids should be
administered if hypotension (low blood pressure) or shock are present.[23] Given that meningitis can cause a
number of early severe complications, regular medical review is recommended to identify these complications
early,[23] as well as admission to an intensive care unit if deemed necessary.[4]

Mechanical ventilation may be needed if the level of consciousness is very low, or if there is evidence
of respiratory failure. If there are signs of raised intracranial pressure, measures to monitor the pressure may
be taken; this would allow the optimization of the cerebral perfusion pressure and various treatments to
decrease the intracranial pressure with medication (e.g.mannitol).[4] Seizures are treated
with anticonvulsants.[4] Hydrocephalus (obstructed flow of CSF) may require insertion of a temporary or long-
term drainage device, such as a cerebral shunt.[4]

[edit]
Y 

Y
x
Ñ  

Structural formula of ceftriaxone, one of the third-generation cefalosporin antibiotics recommended for the initial treatment of
bacterial meningitis.

Empiric antibiotics (treatment without exact diagnosis) must be started immediately, even before the results of
the lumbar puncture and CSF analysis are known. The choice of initial treatment depends largely on the kind of
bacteria that cause meningitis in a particular place. For instance, in the United Kingdom empirical
treatment consists of a third-generation cefalosporin such as cefotaxime or ceftriaxone.[21][23] In the USA, where
resistance to cefalosporins is increasingly found in streptococci, addition of vancomycin to the initial treatment
is recommended.[3][4][21] Empirical therapy may be chosen on the basis of the age of the patient, whether the
infection was preceded by head injury, whether the patient has undergone neurosurgery and whether or not a
cerebral shunt is present.[3] For instance, in young children and those over 50 years of age, as well as those
who are immunocompromised, addition of ampicillin is recommended to cover u?

  
?.[3][21] Once the Gram stain results become available, and the broad type of bacterial cause is
known, it may be possible to change the antibiotics to those likely to deal with the presumed group of
pathogens.[3]

The results of the CSF culture generally take longer to become available (24±48 hours). Once they do, empiric
therapy may be switched to specific antibiotic therapy targeted to the specific causative organism and its
sensitivities to antibiotics.[3] For an antibiotic to be effective in meningitis, it must not only be active against the
pathogenic bacterium, but also reach the meninges in adequate quantities; some antibiotics have inadequate
penetrance and therefore have little use in meningitis. Most of the antibiotics used in meningitis have not been
tested directly on meningitis patients in clinical trials. Rather, the relevant knowledge has mostly derived from
laboratory studies in rabbits.[3]

Tuberculous meningitis requires prolonged treatment with antibiotics. While tuberculosis of the lungs is typically
treated for six months, those with tuberculous meningitis are typically treated for a year or longer.[13] In
tuberculous meningitis there is a strong evidence base for treatment with corticosteroids, although this
evidence is restricted to those without AIDS.[36]

x
m 

Adjuvant treatment with corticosteroids (usually dexamethasone) has been shown in some studies to reduce
rates of mortality, severe hearing loss and neurological damage in adolescents and adults from high income
countries which have low rates of HIV.[37] The likely mechanism is suppression of overactive
inflammation.[38] Professional guidelines therefore recommend the commencement of dexamethasone or a
similar corticosteroid just before the first dose of antibiotics is given, and continued for four days.[21][23] Given
that most of the benefit of the treatment is confined to those with pneumococcal meningitis, some guidelines
suggest that dexamethasone be discontinued if another cause for meningitis is identified.[3][21]

Adjuvant corticosteroids have a different role in children than in adults. Though the benefit of corticosteroids
has been demonstrated in adults as well as in children from high-income countries, their use in children
from low-income countries is not supported by evidence; the reason for this discrepancy is not clear.[39] Even in
high-income countries, the benefit of corticosteroids is only seen when they are given prior to the first dose of
antibiotics, and is greatest in cases of  ‘  meningitis,[3][40] the incidence of which has decreased
dramatically since the introduction of the Hib vaccine. Thus, corticosteroids are recommended in the treatment
of pediatric meningitis if the cause is  ‘  and only if given prior to the first dose of antibiotics, whereas
other uses are controversial.[3]

A 2010 analysis of previous studies has shown that the benefit from steroids may not be as significant as
previously found. The one possible significant benefit is reduction of hearing loss in survivors.[41]

[edit]

Y 

Y
Viral meningitis typically requires supportive therapy only; most viruses responsible for causing meningitis are
not amenable to specific treatment. Viral meningitis tends to run a more benign course than bacterial
meningitis. Herpes simplex virus and varicella zoster virus may respond to treatment with antiviral drugs such
as aciclovir, but there are no clinical trials that have specifically addressed whether this treatment is
effective.[9] Mild cases of viral meningitis can be treated at home with conservative measures such as fluid,
bedrest, and analgesics.[42]

[edit]

Y 

Y
Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of highly dosed antifungals,
such as amphotericin B and flucytosine.[25][43]

[edit]Prognosis

Untreated, bacterial meningitis is almost always fatal. Viral meningitis, in contrast, tends to resolve
spontaneously and is rarely fatal. With treatment, mortality (risk of death) from bacterial meningitis depends on
the age of the patient and the underlying cause. Of the newborn patients, 20±30% may die from an episode of
bacterial meningitis. This risk is much lower in older children, whose mortality is about 2%, but rises again to
about 19±37% in adults.[1][4] Risk of death is predicted by various factors apart from age, such as the pathogen
and the time it takes for the pathogen to be cleared from the cerebrospinal fluid,[1] the severity of the
generalized illness, decreased level of consciousness or abnormally low count of white blood cells in the
CSF.[4] Meningitis caused by  ‘  and meningococci has a better prognosis compared to cases
caused by group B streptococci, coliforms and
 .[1] In adults, too, meningococcal meningitis has a
lower mortality (3±7%) than pneumococcal disease.[4]
In children there are several potential disabilities which result from damage to the nervous
system. Sensorineural hearing loss, epilepsy, learning and behavioral difficulties, as well as decreased
intelligence, occur in about 15% of survivors.[1] Some of the hearing loss may be reversible.[44] In adults, 66% of
all cases emerge without disability. The main problems aredeafness (in 14%) and cognitive impairment (in
10%).[4]

[edit]Epidemiology

Demography of meningococcalmeningitis. meningitis belt epidemic zones sporadic cases only

Disability-adjusted life year for meningitis per 100,000 inhabitants in 2002.[45]

no data ” 10 10-25 25-50 50-75 75-100 100-200 200-300 300-400 400-500 500-1000 1000-1500 • 1500

Although meningitis is a notifiable disease in many countries, the exact incidence rate is unknown.[9] Bacterial
meningitis occurs in about 3 people per 100,000 annually in Western countries. Population-wide studies have
shown that viral meningitis is more common, at 10.9 per 100,000, and occurs more often in the summer. In
Brazil, the rate of bacterial meningitis is higher, at 45.8 per 100,000 annually.[6] Sub-Saharan Africa has been
plagued by large epidemics of meningococcal meningitis for over a century,[46] leading to it being labeled the
"meningitis belt". Epidemics typically occur in the dry season (December to June), and an epidemic wave can
last two to three years, dying out during the intervening rainy seasons.[47] Attack rates of 100-800 cases per
100,000 are encountered in this area,[48] which is poorly served by medical care. These cases are
predominantly caused by meningococci.[6] The largest epidemic ever recorded in history swept across the
entire region in 1996±1997, causing over 250,000 cases and 25,000 deaths.[49]
Meningococcal disease occurs in epidemics in areas where many people live together for the first time, such as
army barracks during mobilization, college campuses[1] and the annual Hajj pilgrimage.[32]Although the pattern
of epidemic cycles in Africa is not well understood, several factors have been associated with the development
of epidemics in the meningitis belt. They include: medical conditions (immunological susceptibility of the
population), demographic conditions (travel and large population displacements), socioeconomic conditions
(overcrowding and poor living conditions), climatic conditions (drought and dust storms), and concurrent
infections (acute respiratory infections).[48]

There are significant differences in the local distribution of causes for bacterial meningitis. For instance,
while D 
? groups B and C cause most disease episodes in Europe, group A is found in Asia and
continues to predominate in Africa, where it causes most of the major epidemics in the meningitis belt,
accounting for about 80% to 85% of documented meningococcal meningitis cases.[48]

[edit]History

Some suggest that Hippocrates may have realized the existence of meningitis,[6] and it seems that meningism
was known to pre-Renaissance physicians such as Avicenna.[50] The description of tuberculous meningitis, then
called "dropsy in the brain", is often attributed to Edinburgh physician Sir Robert Whytt in a posthumous report
that appeared in 1768, although the link with tuberculosis and its pathogen was not made until the next
century.[50][51]

It appears that epidemic meningitis is a relatively recent phenomenon.[52] The first recorded major outbreak
occurred in Geneva in 1805.[52][53]Several other epidemics in Europe and the United States were described
shortly afterward, and the first report of an epidemic in Africa appeared in 1840. African epidemics became
much more common in the 20th century, starting with a major epidemic sweeping Nigeria andGhana in 1905±
1908.[52]

The first report of bacterial infection underlying meningitis was by the Austrian bacteriologist Anton
Weichselbaum, who in 1887 described the  ?.[54] Mortality from meningitis was very high (over
90%) in early reports. In 1906, antiserum was produced in horses; this was developed further by the American
scientist Simon Flexner and markedly decreased mortality from meningococcal disease.[55][56] In
1944,penicillin was first reported to be effective in meningitis.[57] The introduction in the late 20th century
of   O‘? vaccines led to a marked fall in cases of meningitis associated with this pathogen,[30] and in
2002 evidence emerged that treatment with steroids could improve the prognosis of bacterial meningitis.[38][39][56]

Y
Y

Spina bifida
From Wikipedia, the free encyclopedia

 
 


6



 
 Y

0
 A$2YA$Y

0
 2YY

0  "$ Y

  
  " $ Y


   
! Y


  6 Y
 
Y (Latin: "split spine") is a developmental birth defect caused by the incomplete closure of
the embryonic neural tube. Somevertebrae overlying the spinal cord are not fully formed and remain unfused
and open. If the opening is large enough, this allows a portion of the spinal cord to protrude through the
opening in the bones. There may or may not be a fluid-filled sac surrounding the spinal cord. Other neural tube
defects include anencephaly, a condition in which the portion of the neural tube which will become
the cerebrum does not close, and encephalocele, which results when other parts of the brain remain unfused.

Spina bifida malformations fall into four categories: ?
 ‘
, ?
 ?

 ‘  ‘!,  ‘ and‘  ‘. The most common location of the malformations is
the lumbar and sacral areas . Myelomeningocele is the most significant form and it is this that leads to disability
in most affected individuals. The terms spina bifida and myelomeningocele are usually used interchangeably.

Spina bifida can be surgically closed after birth, but this does not restore normal function to the affected part of
the spinal cord. Intrauterine surgery for spina bifida has also been performed and the safety and efficacy of this
procedure is currently being investigated. The incidence of spina bifida can be decreased by up to 75% when
daily folic acid supplements are taken   to conception.

6



Y%
& Y

Y(   Y

m Y' Y  YY

m "Y' Y  Y  Y

m  Y0 
Y

m Y0  
Y

"Y'
YY Y

Y)

 
Y

Y). Y

m Y)
 Y 
Y

Y Y

m Y?Y
 Y  Y Y

Y4  
Y

Y'  YYY

m Y0 Y

m "Y>YY

Y'YY
YY

$Y45Y 6Y

[edit]Classification

[edit] 
YY 
Y

X-ray image of Spina bifida occulta in S-1

Unfused arch of C1 at CT.

‘
 is Latin for "hidden." This is one of the mildest forms of spina bifida.[1]

In occulta, the outer part of some of the vertebrae are not completely closed.[2] The split in the vertebrae is so
small that the spinal cord does not protrude. The skin at the site of the lesion may be normal, or it may have
some hair growing from it; there may be a dimple in the skin, alipoma, a dermal sinus or a birthmark.[3]

Many people with the mildest form of this type of spina bifida do not even know they have it, as the condition is
asymptomatic in most cases.[3] A systematic review of radiographic research studies found no relationship
between spina bifida occulta and back pain.[4] More recent studies not included in the review support the
negative findings.[5][6][7]

However, other studies suggest spina bifida occulta is not always harmless. One study found that among
patients with back pain, severity is worse if spina bifida occulta is present.[8][9]

[edit] 
YYY
In spina bifida cystica, a cyst protrudes through the defect in the vertebral arch. These conditions can be
diagnosed in utero on the basis of elevated levels of alpha-fetoprotein, after amniocentesis, and by ultrasound
imaging. Spina bifida cystica may result in hydrocephalus and neurological deficits.[

 ]

[edit]{

 
Y

The least common form of spina bifida is a posterior 


 
 (or 


Y).

In a   Y 

 
, the vertebrae develop normally, however the meninges are forced into the gaps
between the vertebrae. As the nervous system remains undamaged, individuals with meningocele are unlikely
to suffer long-term health problems, although there are reports of tethered cord. Causes of meningocele
include teratoma and other tumors of the sacrococcyx and of the presacral space, and Currarino syndrome,
Bony defect with outpouching of meninges.[10]

[edit]{


 
Y

Myelomeningocele in the lumbar area.

(1) External sac with cerebrospinal fluid.
(2) Spinal cord wedged between the vertebrae.
In this, the most serious and common[11] form, the unfused portion of the spinal column allows the spinal cord to
protrude through an opening. The meningeal membranes that cover the spinal cord form a sac enclosing the
spinal elements. Spina bifida with myeloschisis is the most severe form of spina bifida cystica. In this defect,
the involved area is represented by a flattened, plate-like mass of nervous tissue with no overlying membrane.
The exposure of these nerves and tissues make the baby more prone to life-threatening infections.[12]

The protruded portion of the spinal cord and the nerves which originate at that level of the cord are damaged or
not properly developed. As a result, there is usually some degree of paralysis and loss of sensation below the
level of the spinal cord defect. Thus, the higher the level of the defect the more severe the associated nerve
dysfunction and resultant paralysis. People may have ambulatory problems, loss of sensation, deformities of
the hips, knees or feet and loss of muscle tone. Depending on the location of the lesion, intense pain may
occur originating in the lower back, and continuing down the leg to the back of the knee.[

 ]

Many individuals with spina bifida will have an associated abnormality of the cerebellum, called the Arnold
Chiari II malformation. In affected individuals the back portion of the brain is displaced from the back of the skull
down into the upper neck. In approximately 90 percent of the people with
myelomeningocele, hydrocephalus will also occur because the displaced cerebellum interferes with the normal
flow ofcerebrospinal fluid.[

 ]

The myelomeningocele (or perhaps the scarring due to surgery) tethers the spinal cord. In some individuals this
causes significant traction on the spinal cord and can lead to a worsening of the paralysis, scoliosis, back pain,
or worsening bowel and/or bladder function.[13]

[edit]Signs and symptoms

Children with spina bifida often have hydrocephalus, which consists of excessive accumulation of cerebrospinal
fluid in the ventricles of the brain.[14]

According to the Spina Bifida Association of America (SBAA), over 73 percent of people with spina bifida
develop an allergy to latex, ranging from mild to life-threatening. The common use of latex in medical facilities
makes this a particularly serious concern. The most common approach to avoid developing an allergy is to
avoid contact with latex-containing products such as examination gloves, condoms, catheters, and many of the
products used by dentists.[2]

[edit]Pathophysiology

Spina bifida is caused by the failure of the neural tube to close during the first month of embryonic development
(often before the mother knows she is pregnant).

Normally the closure of the neural tube occurs around 28 days after fertilization.[15] However, if something
interferes and the tube fails to close properly, a neural tube defect will occur. Medications such as
some anticonvulsants, diabetes, having a relative with spina bifida, obesity, and an increased body temperature
from fever or external sources such as hot tubs and electric blankets can increase the chances a woman will
conceive a baby with a spina bifida. However, most women who give birth to babies with spina bifida have
none of these risk factors, and so in spite of much research, it is still unknown what causes the majority of
cases.[

 ]

The varying prevalence of spina bifida in different human populations and extensive evidence from mouse
strains with spina bifida suggests a genetic basis for the condition. As with other human diseases such
as cancer, hypertension and atherosclerosis (coronary artery disease), spina bifida likely results from the
interaction of multiple genes and environmental factors.

Research has shown that lack of folic acid (folate) is a contributing factor in the pathogenesis of neural tube
defects, including spina bifida. Supplementation of the mother's diet with folate can reduce the incidence of
neural tube defects by about 70 percent, and can also decrease the severity of these defects when they
occur.[16][17][18] It is unknown how or why folic acid has this effect.

Spina bifida does not follow direct patterns of heredity like muscular dystrophy or haemophilia. Studies show
that a woman who has had one child with a neural tube defect such as spina bifida, has about a three percent
risk of having another child with a neural tube defect. This risk can be reduced to about one percent if the
woman takes high doses (4 mg/day) of folic acid before and during pregnancy. For the general population, low-
dose folic acid supplements are advised (0.4 mg/day).[

 ]

[edit]Prevention

There is no single cause of spina bifida nor any known way to prevent it entirely. However, dietary
supplementation with folic acid has been shown to be helpful in preventing spina bifida (see above). Sources of
folic acid include whole grains, fortified breakfast cereals, dried beans, leaf vegetables and fruits.[19]

Folate fortification of enriched grain products has been mandatory in the United States since 1998. The U.S.
Food and Drug Administration, Public Health Agency of Canada[20] and UK recommended amount of folic acid
for women of childbearing age and women planning to become pregnant is at least 0.4 mg/day of folic acid
from at least three months beforeconception, and continued for the first 12 weeks of pregnancy.[21] Women who
have already had a baby with spina bifida or other type of neural tube defect, or are
taking anticonvulsantmedication should take a higher dose of 4±5 mg/day.[21]

Certain mutations in the gene VANGL1 are implicated as a risk factor for spina bifida: these mutations have
been linked with spina bifida in some families with a history of spina bifida.[22]

[edit] 

Y

Y
Neural tube defects can usually be detected during pregnancy by testing the mother's blood (AFP screening) or
a detailed fetal ultrasound. Spina bifida may be associated with other malformations as in dysmorphic
syndromes, often resulting in spontaneous miscarriage. However, in the majority of cases spina bifida is an
isolated malformation.

Genetic counseling and further genetic testing, such as amniocentesis, may be offered during the pregnancy as
some neural tube defects are associated with genetic disorders such astrisomy 18. Ultrasound screening for
spina bifida is partly responsible for the decline in new cases, because many pregnancies are terminated out of
fear that a newborn might have a poor future quality of life. With modern medical care, the quality of life of
patients has greatly improved.[15]

[edit]Treatment

There is no known cure for nerve damage due to spina bifida. To prevent further damage of the nervous tissue
and to prevent infection, pediatric neurosurgeons operate to close the opening on the back. During the
operation for spina bifida cystica, the spinal cord and its nerve roots are put back inside the spine and covered
with meninges. In addition, a shunt may be surgically installed to provide a continuous drain for the
cerebrospinal fluid produced in the brain, as happens with hydrocephalus. Shunts most commonly drain into
the abdomen. However, if spina bifida is detected during pregnancy, then open fetal surgery can be
performed.[

 ]

Most individuals with myelomeningocele will need periodic evaluations by specialists including orthopedists to
check on their bones and muscles, neurosurgeons to evaluate the brain and spinal cord and urologists for the
kidneys and bladder. Such care is best begun immediately after birth. Most affected individuals will require
braces, crutches, walkers or wheelchairs to maximize their mobility. As a general rule, the higher the level of
the spina bifida defect the more severe the paralysis, but paralysis does not always occur. Thus, those with low
levels may need only short leg braces while those with higher levels do best with a wheelchair, and some may
be able to walk unaided. Many will need to manage their urinary system with a program of catheterization. Most
will also require some sort of bowel management program, though some may be virtually unaffected.[

 ]

[edit]
YY


Y
Y

Management of Myelomeningocele Study (MOMS)[23] is a phase III clinical trial to evaluate the safety and
efficacy of fetal surgery to close a myelomeningocele. This involves surgically opening the pregnant mother's
abdomen and uterus to operate on the fetus. This route of access to the fetus is called "open fetal surgery".
Fetal skin grafts are used to cover the exposed spinal cord, to protect it from further damage caused by
prolonged exposure to amniotic fluid. The fetal surgery may decrease some of the damaging effects of the
spina bifida, but at some risk to both the fetus and the pregnant woman.
In contrast to the open fetal operative approach tested in the MOMS, a minimally invasive approach has been
developed by the German Center for Fetal Surgery & Minimally Invasive Therapy at the University of Bonn,
Germany.[24] This minimally invasive approach uses three small tubes (trocars) with an external diameter of
5 mm that are directly placed via small needle punctures through the maternal abdominal wall into the uterine
cavity. Via this route, the unborn can be postured and its spina bifida defect be closed using small instruments.
In contrast to open fetal surgery for spina bifida, the fetoscopic approach results in less trauma to the mother as
large incisions of her abdomen and uterus is not required.

[edit]Epidemiology

Spina bifida is one of the most common birth defects, with an average worldwide incidence of 1±2 cases per
1000 births, but certain populations have a significantly greater risk.

In the United States, the average incidence is 0.7 per 1000 live births. The incidence is higher on the East
Coast than on the West Coast, and higher in whites (1 case per 1000 live births) than in blacks (0.1±0.4 case
per 1000 live births). Immigrants from Ireland have a higher incidence of spina bifida than do
nonimmigrants.[25][26]

The highest incidence rates worldwide were found in Ireland and Wales, where 3±4 cases of
myelomeningocele per 1000 population have been reported during the 1970s, along with more than six cases
of anencephaly (both live births and stillbirths) per 1000 population. The reported overall incidence of
myelomeningocele in the British Isles was 2±3.5 cases per 1000 births.[25][26] Since then, the rate has fallen
dramatically with 0.15 per 1000 live births reported in 1998[15], though this decline is partially accounted for by
the fact that some foetuses are aborted when tests show signs of spina bifida (see Pregnancy
screening below).

Parents of children with spina bifida have an increased risk of having a second child with a neural tube
defect.[25][26]

This condition is more likely to appear in females; the cause for this is unknown.[

 ]