Académique Documents
Professionnel Documents
Culture Documents
REVIEW ARTICLE
INFLAMMATORY RESPONSE IN INFECTIVE ENDOCARDITIS
E. DEVIRI and B.E. GLENVILLE
Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel
Received January 10, 2007 Accepted June 8, 2007
Endocarditis remains a devastating disease with a high mortality despite timely diagnosis
and treatment. The mainstays of treatment include appropriate antibiotics and when indicated,
removal of the septic focus. This sounds extremely simple and belies the necessity for a sophisticated
multidisciplinary approach to its treatment, the success of which depends not just on the right antibiotic
at the right dosage via the right portal, but also on a profound understanding of the inflammatory and
infective pathophysiology at work. This review aims at assisting both the clinician and the lab-based
physician in the task.
arthritis, vasculitis, splenomegaly, splenic infarcts
cutaneous and ocular signs cannot be explained
alone by the presence of circulating bacteria (7).
Understanding the inflammatory response
and the interaction between the bacterium, white
blood cells, platelets and endothelial cells and the
role of various cytokines may explain some of the
pathophysiological findings associated with infective
endocarditis. In addition, a better understanding of
the inflammatory response to infective endocarditis
may improve the diagnosis rate (especially in cases
of culture negative endocardi), the follow up of the
activity of the disease, the treatment, and above all
the survival and cure rate.
Animal studies
The vegetation
Data based on experimental endocarditis
Infective endocarditis is characterized by a
combination of systemic and local findings. The
central lesion is the vegetation which is an infected
fibrin platelet thrombus which forms on the surface
of damaged cardiac valves.
It is well recognized that the normal endothelium
Key words: infective endocarditis, blood culture negative endocarditis vegetation, inflammatory markers
Mailing address:
Prof. Brian E. Glenville,
Emek Refaim 13/2,
Jerusalem 93104, Israel
Fax: ++972 02561 8808
e-mail: bg@66harley.com
1721-727 (2007)
57
58
E. DEVIRI ET AL.
Eur. J. Inflamm.
59
60
E. DEVIRI ET AL.
61
Eur. J. Inflamm.
3.
4.
5.
62
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
E. DEVIRI ET AL.
1933.
Raoult D., J.P. Casalta, H. Richet, M. Khan, E.
Bernit, C. Rovery, S. Branger, F. Gouriet, G.
Imbert, E. Bothello, F. Collart and G. Habib.
2005. Contribution of systematic serological testing
in diagnosis of infective endocarditis. J. Clin.
Microbiol. 43:5238.
Brown M. and G.E. Griffin. 1998. Immune
responses in endocarditis. Heart 79:1.
Baddour L.M. 1994. Virulence factors among grampositive bacteria in experimental endocarditis. Infect.
Immun. 62:2143.
Garrison P.K. and L.R. Freedman. 1970.
Experimental endocarditis I. Staphylococcal
endocarditis in rabbits resulting from placement of
a polyethylene catheter in the right side of the heart.
Yale J. Biol. Med. 42:394.
Durack D.T. and P.B. Besson. 1972. Experimental
bacterial endocarditis. I. Colonization of a sterile
vegetation. Br. J. Exp. Pathol. 53:44.
Drake T.A. and M. Pang. 1989. Effects of
interleukin-1, lipopolysaccharide, and streptococci
on procoagulant activity of cultured human cardiac
valve endothelial and stromal cells. Infect. Immun.
57(2):507.
Veltrop M.H.A.M., H. Beekhuizen and J.
Thompson. 1999. Bacterial species- and straindependent induction of tissue factor in human
vascular endothelial cells. Infect. Immun. 67:6130.
Yeaman M.R., S.M. Puentes, D.C. Norman and
A.S. Bayer. 1992. Partial characterization and
staphylocidal activity of thrombin-induced platelet
microbicidal protein. Infect. Immun. 60:1202.
Kupferwasser L.I., M.R. Yeaman, S.M.
Shapiro, C.C. Nast and A.S. Bayer. 2002. In
vitro susceptibility to thrombin-induced platelet
microbicidal protein is associated with reduced
disease progression and complication rates in
experimental staphylococcus aureus endocarditis.
Circulation 105:746.
Dhawan V.K., A.S. Bayer and M.R. Yeaman.
1998. In vitro resistance to thrombin-induced platelet
microbicidal protein is associated with enhanced
progression and hematogenous dissemination in
experimental staphylococcus aureus infective
endocarditis. Infect. Immun. 66:3476.
Eur. J. Inflamm.
26. Toy P.T., L.W. Lai, T.A. Drake and M.A. Sande.
1985. Effect of fibronectin on adherence of
Staphylococcus aureus to fibrin thrombi in vitro.
Infect. Immun. 48:83.
27. Kuypers J.M. and R.A. Proctor. 1989. Reduced
adherence to traumatized rat heart valves by a
low-fibronectin-binding mutant of Staphylococcus
aureus. Infect. Immun. 57:2306.
28. Cheung A.L., M.R. Yeaman, P.M. Sullam, M.D.
Witt and A.S. Bayer. 1994. Role of the sar locus of
Staphylococcus aureus in induction of endocarditis
in rabbits. Infect. Immun. 62:1719.
29. Munro C.L. and F.L. Macrina. 1993. Sucrosederived exopolysaccharides of Streptococcus mutans
V403 contribute to infectivity in endocarditis. Mol.
Microbiol. 8:133.
30. Shun C.T., S.Y. Lu, C.Y. Yeh, C.P. Chiang, J.S.
Chia and J.Y. Chen. 2005. Glucosyltransferases of
viridans streptococci are modulins of interleukin-6
induction in infective endocarditis. Infect. Immun.
73:3261.
31 Yeh C.Y., J.Y. Chen and J.S. Chia. 2006.
Glucosyltransferases of viridans group streptococci
modulate interleukin-6 and adhesion molecule
expression in endothelial cells and augment
monocytic cell adherence. Infect. Immun. 74:1273.
32. Schlievert P.M., P.J. Gahr, A.P. Assimacopoulos,
M.M. Dinges, J.A. Stoehr, J.W. Harmala, H. Hirt
and G.M. Dunny. 1998. Aggregation and binding
substances enhance pathogenicity in rabbit models
of Enterococcus faecalis endocarditis. Infect. Immun.
66:218.
33. Young L.S., J.O. Cisar, J.L. Bryant, M.A.
Eckhaus and A.L. Sandberg. 2006. Resistance
of Streptococcus gordonii to polymorphonuclear
leukocyte killing is a potential virulence determinant
of infective endocarditis. Infect. Immun. 74(6):3148.
34. Lamas C.C. and S.J. Eykyn. 2003. Blood culture
negative endocarditis: analysis of 63 cases presenting
over 25 years. Heart 89:258.
35. Gouriet F., E. Bothelo-Nevers, B. Coulibaly,
D. Raoult and J.P. Casalta. 2006. Evaluation of
sedimentation rate, rheumatoid factor, C-reactive
protein, and tumor necrosis factor for the diagnosis
of infective endocarditis. Clin. Vaccine Immunol. 13:
301.
63
Key words: elastase two, severe congenital neutropenia, polymerase chain reaction, polymorphonueclear, reverse
transcription
Mailing address:
G. Ahangari, MT, Ph.D.,
Department of Molecular Medicine and Immunology,
National Institute for Genetic Engineering and Biotechnology,
P.O. Box: 14155-6343, Teheran, Iran
Tel: ++9821 44580384 Fax: ++9821 44580399
e-mail: ghah@nrcgeb.ac.ir
1721-727 (2007)
65
66
G. AHANGARI ET AL.
RESULTS
The aim of this study is to determine mutational
change in different exons of
Elastase II gene at RNA level in patients with
67
Eur. J. Inflamm.
Table I. Results of the mutational analysis of the ELA2 gene in 5 severe congenital neutropenia patients
and 20 healthy individuals by bidirectional capillary sequencing.
Patient
Exon number
RNA changes
TCT>GTC
1
4
Ala 22 Glu
Glu and Leu
GCG>GGA
Insertion of 5
neucleotide
GCG>GCA
Ala 44Gln
0/20
TGT>TTG
Cys196Leu
0/20
AAT>GAA
Asn45Gln
0/20
4
5
4
2
Healthy
control
0/20
0/20
68
G. AHANGARI ET AL.
69
polymorphism
Eur. J. Inflamm.
EXON1
EXON2
EXON3
EXON4
EXON5
Fig. 3. Schematic diagram showing the location of mutations in the ELAII gene in severe congenital neutropenia.
70
G. AHANGARI ET AL.
Eur. J. Inflamm.
25.
26.
27.
28.
29.
71
1721-727 (2007)
73
74
K. LAKOTA ET AL.
75
Eur. J. Inflamm.
under UV illumination.
RESULTS
SAA dose dependent stimulation of IL-6 in
HUVEC and HCAEC
To determine whether and to what extent SAA
increases the inflammatory response in HUVEC
and HCAEC, released protein levels of IL-6 of
supernatants were measured by ELISA (Fig. 1, panel
A) following a 24 h period of incubation with SAA,
and isolated the RNA and performed RT-PCR (Fig.
1, panels B and C).
Firstly, confluent cultures of normal human
HUVEC and HCAEC were incubated with SAA in
varying concentrations from 0-2000 nM. We then
examined the effect of SAA increasing doses on IL6 protein levels (Fig. 1 panel A) and on IL-6 mRNA
expression (Fig. 1 panels B and C) and compared
them in HUVEC and HCAEC. The results showed
that HCAEC strikingly elevated both IL-6 released
protein and mRNA expression following SAA
stimulation. HCAEC already exhibited a significant
increase of IL-6 protein following stimulation with
the lowest SAA concentration of 10 nM (p<0.05)
and in contrast there was no such significant increase
of IL-6 found in HUVEC at this concentration. At
the highest SAA concentration of 2000 nM, IL-6
released protein levels on HCAEC were 4 fold higher
than on HUVEC. These significant differences were
not only confirmed by the IL-6 mRNA expression
levels following RT-PCR in HUVEC (Fig. 1, panel
B-middle) and HCAEC (Fig. 1, panel C-middle), but
ICAM-1
VCAM-1
E-selectin
Ta
Cycle #
Fragm. size
59C
25
838 bp
51C
30
628 bp
35C
35
187 bp
50C
30
303 bp
56C
30
646 bp
60C
30
1002 bp
58C
30
255 bp
Ta, temperature
of annealing;
Cycle #, number
of#,cycles
used
in PCR;
Fragm.
size
Ta, temperature
of annealing
Cycle
number
of cycles
used in
PCR size, fragment
Fragm.
size, fragment size
76
K. LAKOTA ET AL.
A.
A.
IL-6 ELISA of supernatants
**
**
2500
2500
**
(pg/ml)
IL-6IL-6
(pg/ml)
2000
2000
**
**
1500
**
1000
SAA 100nM
SAA 500nM
**
SAA 500nM
SAA 1000nM
** **
500
SAA 1000nM
SAA 2000nM
*
** **
HUVEC
B.
HCAEC
HCAEC
C.
HUVEC
1
SAA 2000nM
HUVEC
800bp
HCAEC
-actin
2652bp
800bp
IL-6
2652bp
M
838bp
IL-6
2652bp
M
800bp
800bp
IL-8
200bp
SAA 0nM
SAA 10nM
SAA 10nM
SAA 100nM
**
** **** **
500
SAA 0nM
1000
2652bp
**
**
1500
-actin
**
**
**
**
**
150bp
628 bp
IL-8
200bp
150bp
+
187 bp
77
Eur. J. Inflamm.
A.
B.
2652bp
800bp
sICAM-1 (ng/ml)
**
30
25
**
**
**
SAA 100nM
2000bp
838 bp
VCAM-1
2652bp
+
1002 bp
800bp
ICAM-1
2652bp
800bp
HCAEC
-actin
M
SAA 0nM
M
ICAM-1
M
800bp
+
646 bp
SAA 500nM
15
SAA 1000nM
SAA 2000nM
**
0
HUVEC
HCAEC
**
60
sVCAM-1 (ng/ml)
800bp
SAA 10nM
**
20
SAA 0nM
**
50
**
40
**
30
20
800bp
35
VCAM-1
40
10
C.
HUVEC
-actin
**
**
10
**
SAA 10nM
SAA 100nM
SAA 500nM
SAA 1000nM
SAA 2000nM
0
HUVEC
HCAEC
E-selecin
350bp
250bp
E-selecin
350bp
250bp
+
255 bp
Fig.
2. Expression of adhesion molecules with increasing
Fig. 2. Expression of adhesion molecules with increasing concentrations of SAA.
A: sICAM-1 and sVCAM-1
concentrations
of ELISA
SAA.of supernatants from HUVEC and HCAEC treated with
different doses of SAA (mean + SD of three separate experiments) *p<0,05; **p<0,01
A:
sICAM-1
and
sVCAM-1
ELISA
of supernatants
from
compared with basal levels of expression (analysis
of variance)
B: representative experiment
(from two separate
experiments
performed)
of VCAM-1,
ICAM-1, E-selectin
and
-actin
HUVEC
and
HCAEC
treated
with
different
doses
of
SAAPCR
from HUVEC (concentrations of SAA: Lane 1) 0nM, 2) 10nM, 3) 100nM, 4) 500nM, 5)
1000nM, 6)+
2000nM)
experiment (from
three separate experiments
(mean
SD C:ofrepresentative
three separate
experiments)
*p<0,05;
performed) of VCAM-1, ICAM-1, E-selectin and -actin PCR from HCAEC (concentrations of
**p<0,01
compared
with
basal
levels
of
expression
SAA: Lane 1) 0nM, 2) 10nM, 3) 100nM, 4) 500nM, 5) 1000nM, 6) 2000nM). - negative PCR
reaction, + positive
control.
(analysis
of IL-1
variance)
B: representative experiment
(from two separate experiments performed) of VCAM1, ICAM-1, E-selectin and -actin PCR from HUVEC
(concentrations of SAA: Lane 1) 0nM, 2) 10nM, 3) 100nM,
4) 500nM, 5) 1000nM, 6) 2000nM) C: representative
experiment (from three separate experiments performed)
of VCAM-1, ICAM-1, E-selectin and -actin PCR from
HCAEC (concentrations of SAA: Lane 1) 0nM, 2) 10nM,
3) 100nM, 4) 500nM, 5) 1000nM, 6) 2000nM). - negative
PCR reaction, + positive IL-1 control.
78
K. LAKOTA ET AL.
A.
-actin
2652bp
M
800bp
300bp
HCAEC
-actin
2000bp
800bp
SAA
400bp
B.
HUVEC
+
838 bp
SAA
400bp
+
303 bp
200bp
Fig. 3. Expression
of SAA with increasing
concentrations
of concentrations
SAA.
Fig. 3. Expression
of SAA with
increasing
of SAA.
A: RT-PCR
representative
experiment
(from
three
separate
experiments
performed)experiments
of -actin andperformed)
SAA PCR fromofHUVEC
A: RT-PCR representative experiment (from three separate
-actin
(concentrations of SAA: Lane 1) 0nM, 2) 10nM, 3) 100nM, 4) 500nM, 5) 1000nM, 6) 2000nM) B: RT-PCR representative
and SAA PCR from HUVEC (concentrations of SAA: Lane 1) 0nM, 2) 10nM, 3) 100nM, 4)
experiment (from three separate experiments performed) of -actin and SAA PCR from HCAEC (concentrations of
500nM,
6) 2000nM)
B: 5)
RT-PCR
experiment
(from three
separate
SAA: Lane
1) 0nM,5)
2) 1000nM,
10nM, 3) 100nM,
4) 500nM,
1000nM,representative
6) 2000nM). - negative
PCR reaction,
+ positive
IL-1
experiments
performed)
of
-actin
and
SAA
PCR
from
HCAEC
(concentrations
of
SAA:
Lane
control.
Eur. J. Inflamm.
7.
8.
9.
ACKNOWLEDGEMENTS
We thank all members of the Laboratory for
Immunology, Department of Rheumatology,
University Medical Centre, Ljubljana for their
cooperation during the execution of our work.
Support for this study was obtained by the Marie
Curie International Reintegration Grant MC-IRG #
028414 to S. S-S.
10.
11.
REFERENCES
1.
2.
3.
4.
5.
6.
12.
13.
14.
15.
16.
17.
79
Chait A., C.Y. Han, J.F. Oram and J.W. Heinecke.
2005. Thematic review series: The immune
system and atherogenesis. Lipoprotein-associated
inflammatory proteins: markers or mediators of
cardiovascular disease? J. Lipid Res. 46:389.
Rosenberg R.D. and W.C. Aird. 1999. Vascularbed--specific hemostasis and hypercoagulable states.
N. Eng. J. Med. 340:1555.
Urieli-Shoval S., P. Cohen, S. Eisenberg and Y.
Matzner. 1998. Widespread expression of serum
amyloid A in histologically normal human tissues.
Predominant localization to the epithelium. J.
Histochem. Cytochem. 46:1377.
Meek R.L., S. Urieli-Shoval and E.P. Benditt.
1994. Expression of apolipoprotein serum amyloid A
mRNA in human atherosclerotic lesions and cultured
vascular cells: implications for serum amyloid A
function. Proc. Natl. Acad. Sci. USA 91:3186.
Yamada T., T. Kakihara, T. Kamishima, T.
Fukuda and T. Kawai. 1996. Both acute phase
and constitutive serum amyloid A are present in
atherosclerotic lesions. Pathol. Int. 46:797.
Maier W., L.A. Altwegg, R. Corti, S. Gay, M.
Hersberger, F.E. Maly, G. Sutsch, M. Roffi, M.
Neidhart, F.R. Eberli, F.C. Tanner, S. Gobbi,
A. von Eckardstein and T.F. Luscher. 2005.
Inflammatory markers at the site of ruptured plaque
in acute myocardial infarction: locally increased
interleukin-6 and serum amyloid A but decreased
C-reactive protein. Circulation 111:1355.
Uhlar C.M., C.J. Burgess, P.M. Sharp and A.S.
Whitehead. 1994. Evolution of the serum amyloid
A (SAA) protein superfamily. Genomics 19:228.
KluveBeckerman B., M.L. Drumm and M.D.
Benson. 1991. Nonexpression of the human serum
amyloid A three (SAA3) gene. DNA Cell Bio. 10:651.
Lowell C.A., R.S. Stearman and J.F. Morrow.
1986. Transcriptional regulation of serum amyloid A
gene expression. J. Biol. Chem. 261:8453.
Jiang S.L., G. Lozanski, D. Samols and I.
Kushner. 1995. Induction of human serum amyloid
A in Hep3B cells by IL-6 and IL-1 involves both
transcriptional and post- transcriptional mechanisms.
J. Immunol. 154:825.
Jensen L.E. and A.S. Whitehead. 1998. Regulation
of serum amyloid A protein expression during the
80
18.
19.
20.
21.
22.
23.
24.
25.
26.
K. LAKOTA ET AL.
Eur. J. Inflamm.
81
1721-727 (2007)
83
84
G. STASSI ET AL.
RESULTS
The effects of different concentrations of live H.
pylori on cytokine release by PBMC are reported in
Fig. 1. The results demonstrate that the production
of GRO- and TNF- was dose-dependent. In
particular, a significant differential stimulation
was evident at a concentration of 1x109 CFU/mL.
In a second series of experiments, we examined
how treatment with killed H. pylori or/and live H.
pylori infection may differentially influence the in
vitro cytokine release by PBMC. Results reported
in Fig. 2 show that infection with live H. pylori
triggers PBMC to release marked amounts of GRO compared with those induced by killed H. pylori
(1972 414 pg/mL vs 642 121 pg/mL; p<0.05).
85
Eur. J. Inflamm.
4000
Gro-alpha
3500
TNF-alpha
3000
pg/mL
2500
2000
1500
1000
500
0
10^5
10^7
10^9
Fig.1
Fig. 1. Effects of Helicobacter pylori concentration on GRO-alpha and TNF-alpha production by PBMC. Results represent
the means of five experiments using PBMC of 5 different donors. Data are shown as mean + standard deviation.
3000
2500
GRO-alpha (pg/mL)
2000
1500
1000
500
0
H.p live
H.p live+Ab-TNF
alpha
H.p killed
Fig.2
H.p
killed+H.p.live
H.p killed+H.p
live+ Ab-TNF
alpha
Fig. 2. Production of GRO-alpha by PBMC after treatment with live, killed and killed+live Helicobacter pylori in
presence or not of monoclonal antibodies vs TNF-alpha. Results represent the means of 5 experiments using PBMC of 5
different donors. Data are shown as mean + standard deviation.
86
G. STASSI ET AL.
4000
3500
3000
2500
2000
1500
1000
500
0
Fig.3
H.p live
H.p live+Ab-GRO
alpha
H.p killed
H.p killed+AbGROalpha
Fig. 3. Production of TNF-alpha by PBMC after treatment with live, killed and killed+live Helicobacter pylori in
presence or not of monoclonal antibodies vs GRO-alpha. Results represent the means of 5 experiments using PBMC of 5
different donors. Data are shown as mean + standard deviation.
87
Eur. J. Inflamm.
4.
5.
6.
7.
88
8.
9.
10.
11.
12.
13.
G. STASSI ET AL.
170:5309.
Geiser T., B Dewald., M.U. Ehrengruber, I. ClarkLewis and M. Baggiolini. 1993. The interleukin8-related chemotactic cytokines GRO-, GRO-,
and GRO- activate human neutrophil and basophil
leukocytes. J. Biol. Chem. 268:15419.
Richmond A. and H.G. Thomas. 1986. Purification
of melanoma growth stimulatory activity. J. Cell.
Physiol. 129:375.
Strieter R.M., P.J. Polverini, S.L., Kunkel, S.D.
Arenberg, M.D. Burdick, J. Kasper, J. Dzuiba, J.
Van Damme, A. Walz and D. Marriott. 1995. The
functional role of the ELR motif in CXC chemokinemediated angiogenesis. J.Biol. Chem. 270:27348.
Stassi G., A. Arena, A. Speranza, D. Iannello and
P. Mastroeni. 2002. Different modulation by live or
killed Helicobacter pylori on cytokine production
from peripheral blood mononuclear cells. New
Microbiol. 25:247.
Boyum A. 1968. Isolation of mononuclear cells and
granulocytes from human blood. Scand. J. Clin. Lab.
Invest. 21:77.
Haeberle H.A., M. Kubin, K.B. Bamford,
R. Garofano, D.J. Graham, F. El-zaatari, R.
Karttunen, S.E. Crowe, V.E. Reyesand and P.B
Ernst. 1997. Differential stimulation of interleukin12 and interleukin-10 by live and killed Helicobacter
pylori in vitro and association of interleukin-12
production with gamma interferon- producing T
14.
15.
16.
17.
18.
19.
Key words: plaque psoriasis, calcitriol, vitamin D3 analogue, topical treatment, dosing device
Mailing address: Prof. G.A. Vena, M.D.
Department of Internal Medicine, Immunology and
Infectious Diseases,
2nd Dermatology Clinic, University of Bari,
Piazza Giulio Cesare, 11
70124 Bari, Italy Tel/fax: ++39 080 5478 920
e-mail: g.vena@dermatologia.uniba.it
1721-727 (2007)
89
90
(pruritus/burning).
Changes of clinical parameters in each group were
analysed under a statistical point of view by the Wilcoxon
matched-pairs signed-ranks test, whereas differences
between the two groups at each visit were evaluated using
the Mann-Whitney U test (significance for p values <0.05
in both cases).
At the end of treatment, regardless of its duration,
patients and dermatologists gave their independent
opinion about the efficacy of the study treatment, rating it
on the basis of a 4-point scale. Patients were also asked to
score the acceptability of treatment.
Details of adverse events (AEs) were obtained
throughout the study period.
RESULTS
The study was conducted between October 2005
and May 2006. A total of 201 patients (109 males)
aged 18 to 80 years (mean age, 42.2) with chronic
plaque psoriasis were enrolled and received study
treatment. Of these, 100 patients were required
to use the dosing device and 101 patients entered
the unstandardized-dose treatment with calcitriol
ointment. At the baseline, clinical parameters did not
significantly differ between the two groups (Table
I) with the exception of BSA affected of the trunk
which was greater in the group of patients who did
not use the dosing device as compared to the other
group. No relevant inter-group differences were
observed in the distribution of the gender of patients
and affected sites nor in the type of emollient used
throughout the study period (Table I).
Eight patients (four patients in each group)
withdrew from the study after W4 and did not undergo
clinical assessment at W12 visit. Three patients were
lost to follow-up; reasons for discontinuation in the
other cases were treatment-related AEs in four cases
(two in each group) and lack of efficacy in another
patient.
Independently of the use of the dosing device,
calcitriol ointment caused a significant improvement
of psoriasis lesions at W4 and W12 and reduced both
the severity of signs and symptoms (Fig. 1), and the
extent of BSA affected (Fig. 2). Clinical response
after both 4 weeks and 12 weeks did not significantly
differ between the two groups.
In general, calcitriol ointment was well tolerated.
No serious AEs were observed. Local AEs such as
irritation and pruritus occurred in 12 subjects (of
91
Eur. J. Inflamm.
Table I. General characteristics and baseline clinical parameters. At the baseline, no significant inter-group differences
were observed in the distribution of the gender of patients and clinical parameters with the exception of BSA affected of
the trunk which was greater in the group of patients who did not use the dosing device as compared to the other group
(*p<0.05 Mann-Whitney U test). The type of emollient used throughout the study period did not differ between the two
groups. BSA affected and severity score are reported as mean value along with standard deviation (SD).
CALCITRIOL WITH
DOSING DEVICE
CALCITRIOL WITHOUT
DOSING DEVICE
100
101
Gender (n)
- Male
- Female
52
48
57
44
47
80
76
58
39
85
82
63
8.2 (15.1)
12.5 (12.4)
11.4 (12.15)
7.9 (11.8)*
4.35 (7.03)
12.1 (11.4)
12.4 (12.3)
12.7 (15.3)*
2.1 (0.7)
2.5 (0.8)
2.0 (0.9)
1.8 (0.8)
2.1 (0.7)
2.4 (0.6)
1.8 (0.75)
1.9 (0.8)
48
52
50
51
92
100
90
week4
week 12
80
% improvement
70
89
85
80
62
60
50
47
45
44
40
30
29
20
10
0
erythema
scaling
thickness
symptoms
100
90
week 4
89
88
week 12
82
80
% improvement
70
65
60
48
50
40
50
53
31
30
20
10
80
72
week 4
70
0
thickness
60
symptoms
Fig. 1. Change in the severity of signs and symptoms during treatment with calcitriol
Fig.
1.applied
Change
the severity
of device.
signs and symptoms
ointment
with (A)inor without
(B) the dosing
Variation of clinical parameters as compared to baseline in each group: p<0.01 at W4, p<0.001 at W12;
during
treatment
with
calcitriol
ointment
applied
differences of parameters between the two patient subgroups at each visit:
p>0.05. with (A)
or without (B) the dosing device.
Variation of clinical parameters as compared to baseline
in each group: p<0.01 at W4, p<0.001 at W12;
differences of parameters between the two patient
subgroups at each visit: p>0.05.
13
% reduction
scaling
50
50
40
30
28
25
23
19
20
10
0
head
upper limbs
lower limbs
80
69
70
trunk
74
week 4
68
week 12
60
% reduction
erythema
69
week 12
63
55
50
40
30
31
24
33
27
20
10
0
head
upper limbs
lower limbs
trunk
Fig. 2. Change in the extent of affected skin areas during treatment with calcitriol
Fig. 2.
Change
the extent
affected
ointment
applied
with (A)in
or without
(B) the of
dosing
device. skin areas during
Variation of affected BSA as compared to baseline in each group: p<0.01 at W4, p<0.001 at W12;
differences of values between the two patient subgroups at each visit: p>0.05.
14
12, efficacy of treatment was independently assessed by dermatologists (D) and patients
(P), and P were asked to judge the acceptability of treatment. Positive ratings were
reported in the majority of cases with a similar frequency in the two treatment groups.
Table II. Overall assessment of efficacy and acceptability at the end treatment. At week
12, efficacy of treatment was independently
assessed by dermatologists (D) and patients
Eur. J. Inflamm.
93
Table II. Overall assessment of efficacy and acceptability at the end treatment. At week
(P), and P were asked toCALCITRIOL
judge the acceptability
of treatment.
Positive
ratings were
CALCITRIOL
WITHOUT
WITH
12, efficacy of treatment was independently assessed by dermatologists
(D)
and patients
reported in the majority of cases
with DEVICE
a similar frequency in the
two treatment
groups.
DEVICE
DOSING
(P),
and
asked
to judge
the acceptability
treatment.
Positive
ratings
were
Table
II. POverall
assessment
of efficacy
and
acceptability
at DOSING
the end
treatment.
At week
Table II. Overall assessment
ofwere
efficacy
and
acceptability
at the
endoftreatment.
At
week
12,
efficacy
of treatment was
reported
in the
majority of
cases
with a similar
frequency
in the two treatment
groups.
12,
efficacy
of
treatment
was
independently
assessed
by
dermatologists
(D)
and
patients
independently assessed by dermatologists (D) and patients (P), and P were asked to judge the acceptability of treatment.
(P), and P were asked to judge the acceptability of treatment. Positive ratings were
Positive ratings were reported in the majority of cases with a similar frequency in the two treatment groups.
reported in the majority ofCALCITRIOL
cases with a similar
frequencyCALCITRIOL
in the two treatment
groups.
WITHOUT
WITH
EFFICACY
D (%)
P (%)
D (%)
P (%)
DOSING DEVICE
DOSING DEVICE
CALCITRIOL WITHOUT
CALCITRIOL WITH
DOSING DEVICE
DOSING DEVICE
CALCITRIOL WITHOUT
CALCITRIOL WITH
Excellent
28
30
23
26
DEVICE
DEVICE
EFFICACY
D DOSING
(%)
P (%)
DDOSING
(%)
P (%)
Good
EFFICACY
D52
(%)
P 46
(%)
D54
(%)
P 49
(%)
Moderate
EFFICACY
Excellent
D16
(%)
28
P 13
(%)
30
D18
(%)
23
P 15
(%)
26
Poor
Excellent
Good
4
28
52
11
30
46
5
23
54
10
26
49
Good
Excellent
Moderate
52
28
16
46
30
13
54
23
18
49
26
15
ACCEPTABILITY
Moderate
Good
Poor
16
52
4
13
46
11
18
54
5
Poor
Moderate
4
16
11
13
5
18
Excellent
Poor
ACCEPTABILITY
11
P (%)
37
P (%)
P (%)
10
15
30
P (%)
Good
ACCEPTABILITY
P 41
(%)
P 43
(%)
Moderate
ACCEPTABILITY
Excellent
P 15
(%)
37
P 18
(%)
30
Poor
Excellent
Good
7
37
41
9
30
43
Good
Excellent
Moderate
41
37
15
43
30
18
Moderate
Good
15
41
15
49
10
10
18
43
ACKNOWLEDGEMENTS
The authors thank Dr Monica Carbonara (Bari,
Italy) for her support in the statistical analysis.
REFERENCES
1.
2.
3.
15
94
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Eur. J. Inflamm.
95
and assessment of the adjuvant basic use of ureabased emollients. Eur. J. Inflamm. 3:37.
1721-727 (2007)
97
98
Table I. Changes in the parameters studied before and after 30 days treatment with cavedilol 12.5
Table I. Changes in the parameters studied before and after 30 days treatment with cavedilol 12.5 mg daily ( means
SD, n: 25). mg daily ( means SD, n: 25).
Parameters
After
Treatment
128.9513.3
Units
Changes %
SBP
Before
Treatment
168.3329.7
mmHg
23.4
Statistical
Significance
p<0.001
DBP
97.9115.87
81.256.95
mm/Hg
-17.0
p~0.001
LVESD
3.340.62
3.200.62
Cm
-4.19
p<0.001
LVEDD
5.060.57
4.860.62
Cm
-3.95
p~0.001
65.948.82
+3.56
p~0.05
3.5230.47
Cm
-3.69
p~0.05
msec
-11.79
p~0.01
pg/mL
+ 21.18
LVEF
LAD
P-Waves
63.677.53
3.6580.47
133.3336.21 117.6014.64
Duration
ANP
37.6016.34
45.8324.54
p>0.1
WT= p<0.01
ANP/SBP
0.2360.11
0.3460.20
+46.6
p~0.001
SBP, systolic blood pressure; DBP, diastolic blood pressure; LVESD, left ventricular end systolic diameter; LVEDD,
SBP, systolic blood pressure; DBP, diastolic blood pressure; LVESD, left ventricular end systolic
left ventriculardiameter;
end diastolic
diameter;
LVEF,left
ejectionLVEF,left
fracture; ventricular
LAD, left atrial
LVEDD,
left ventricular
endventricular
diastolic diameter;
ejectiondiameter;
fracture; ANP, atrial
natriuretic peptide
concentration);
WT,
Wilcoxon
test. peptide (plasma concentration); WT, Wilcoxon
LAD,(plasma
left atrial
diameter; ANP,
atrial
natriuretic
test.
ANP/SBP
0,7
P < 0,01
0,6
0,5
Eur. J. Inflamm.
BEFORE
TREATMENT
DURING
TREATMENT
0,4
0,3
ANP/SBP0,2
0,1
0,7
P < 0,01
CARVEDILOL
0,6
0,5
BEFORE
TREATMENT
DURING
TREATMENT
0,4
Fig 1.
0,3
0,2
0,1
0
CARVEDILOL
Fig 1.
P < 0,001
180
160
140
167
120
126
P < 0,001
100
BEFORE TREATMENT
DURING TREATMENT
80
168
60
129
40
20
0
CARVEDILOL
SBP
P < 0,001
CARVEDILOL
DBP
180
Fig. 2. Blood pressure changes on treatment with
160
carvedilol 12.5 mg daily for 30 days.
140
120
167
126
P < 0,001
99
CARVEDILOL
129
CARVEDILOL
100
2.
3.
4.
Eur. J. Inflamm.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
101
of bisoprolol and levels of plasma atrial natriuretic
peptide in hypertensive patients. Fundam. Clin.
Pharmacol. 16:361.
Marteau J., M. Zaiou, G. Siest et al. 2005. Genetic
determinants of blood pressure regulation. J.
Hypertension 23:2117.
Shields P. and C. Glembotski. 1989. Regulation
of atrial natriuretic factor-secretion from neonatal
rat primary atrial cultures by activators of protein
kinases A and C. Biol. Chem. 264:9322.
Ohta Y., K. Watanabe and M. Nakazawa. 2000.
Carvedilol enhances atrial and brain natriuretic
peptide mRNA expression and release in rat heart. J.
Cardiovasc. Pharmacol. 36(S):19.
Yoshimoto T., M. Naruse and A. Tanabe. 1998.
Potentiation of natriuretic peptide action by betaadrenergic blocker carvedilol in hypertensive rats:
a new anti-hypertensive mechanism. Endocrinology
139:81.
Papadopoulos C.L., B. Kokkas, P. Kotridis et al.
1995. Plasma atrial natriuretic peptide in essential
hypertension after angiotensin coverting enzyme
inhibition. Intern. J. Angiology 4:44.
Kotridis P., B. Kokkas, M. Karamouzis et al.
2002. Plasma atrial natriuretic peptide in essential
hypertension after treatment with irbesartan. Blood
Pressure 11:91.
Kotridis P., B. Kokkas, P. Kyriakou et al.
2003. Plasma atrial natriuretic peptide in essential
hypertension after treatment with terazocin. Eur. J.
Drug Metabol. Pharmacokin. 28:143.
Papadopoulos C.L., B. Kokkas, P. Kotridis et
al. 1992. The effect of prolong treatment with the
1-blocker bisoprolol on atrial natriuretic peptide
plasma levels in hypertensive patients. Arterial
Pressure (Gr) 1:201.
1721-727 (2007)
103
104
M. SPERANDEO ET AL.
complications and verify the value of renal RI and PI in identifying early stages of diabetic
nephropathy.
105
Eur. J. Inflamm.
Table
of the two study groups.
Table I. Characteristics
of I.theCharacteristics
two study groups.
p
Diabetic Group
Healthy Controls
(n=262)
(n=100)
201 (76.7%)
74 (74.0%)
NS
NS
NS
Table II. Characteristics of the three groups of type 2 diabetic patients studied.
Group I
Group II
Group III
(n=145)
(n=45)
(n=72)
Mean age
107 (73.8%)
35 (77.8%)
59 (81.9%)
0.84+/-0.16
0.98+/-0.15
1.85+/-0.28
Years
diagnosis
Microalbuminuria
(mg/day)
Serum creatinine
mg/dl
Glycosylated
hemoglobin (%)
Table II. Characteristics of the three groups of type 2 diabetic patients studied.
F 65.5+/-9.5
F 29+/ 5
GFR estimated by F 75.5+/-15.5
Cocroft-Gault
M 103+/-24
M 84+/16
M 39.5+/-7.5
formula (ml/min)
F: female patients
M: male patients
Table III. Resistance and Pulsatility indices in the renal arteries of type-2 diabetics and healthy controls.
Resistance Index
Group I
Group II
Group III
Controls
(n=145)
(n=45)
(n=72)
(n=100)
(I.R.)
Pulsatility Index
(I.P)
REFERENCES
106
M. SPERANDEO ET AL.
Fig. 1. Intrarenal eco colour Doppler in a normal subject, within normal range. Resistive Index (R.I)= 0.63 and Pulsatily
Index (P.I)=1.00
Fig. 2. Intrarenal eco colour Doppler in a diabetic patient without microalbuminuria. Both indexes resulted to be
increased (R.I.= 0.65 and P.I.= 1)
Fig. 3. Intrarenal eco colour Doppler in a diabetic patient with microalbuminuria and Nephropathy. Further increased
R.I. and P.I value ( R:I:=0.86 and P.I.=1.86)
107
Eur. J. Inflamm.
RESULTS
As shown in Table I, the diabetic and control
groups were not significantly different in terms of
sex, age, or body-mass indices. Based on the results
of enrolment lab work, the 262 diabetic patients
were divided into three subgroups: Group I included
145 patients (38 males, 107 females) with normal
renal function and no signs of microalbuminuria;
Group II included 45 patients (35 males, 10 females)
with microalbuminuria but normal renal function;
and Group III contained 72 patients (13 males,
59 females) with microalbuminuria and renal
insufficiency. The characteristics of these three
subgroups are summarized in Table II
According to the estimation of GFR by the
Cocoroft-Gault formula, the division in the three
groups did not change, as reported in Table II
The mean age of Group I patients was significantly
lower than those of the other two groups (p<0.001).
The three groups were also significantly different
(p<0.001) in terms of the duration of diabetes (years
since diagnosis), and this variable was significantly
correlated with the severity of the disease. There
108
M. SPERANDEO ET AL.
Eur. J. Inflamm.
8.
9.
10.
11.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
12.
13.
14.
15.
16.
17.
18.
19.
109
chronic renal failure. Nephrol. Dial. Transplant 12:
1376.
Radermacher J., S. Ellis and H. Haller. 2002.
Renal resistance index and progression of renal
disease. Hypertension 39:699.
Platt J.F., J.M. Rubin and J.H. Ellis. 1994.
Diabetic nephropathy: evaluation with renal duplex
doppler US. Radiology 190:343.
Fioretto P., M. Sambataro, C. Abaterusso,
M. Mauer, E. Brocco, M. Velussi, et al. 1996.
Patterns of renal injury in NIDDM patients with
microalbuminuria. Diabetologia 39:1569.
Ahmet S., D. Hasan, Z. Ali, T. Mnir and H. Resit.
1999. Value of resistive index in patients with clinical
diabetic nephropathy. Investigative Radiology 34:
718.
Mostbeck G.H., T. Zontsich and K. Turetschek.
2001. Ultrasound of the kidney: obstruction and
medical diseases. Eur. Radiol. 11:1878.
Kim S.H., W.H. Kim, B.I. Choi and C.W. Kim.
1992. Duplex Doppler US in patients with medical
renal disease: resistive index vs serum creatinine
level. Clinical Radiology 5:85.
Bude R.O. and J.M. Rubin. 1999. Relationship
between the resistive index and vascular compliance
and resistance. Radiology 211:411.
Brkljai B., V. Mrzljak, I. Drinkovi, D. Soldo,
M. Sabljar-Matovinovi and A. Hebrang. 1994.
Renal vascular resistance in diabetic nephropathy:
Duplex Doppler US Evaluation. Radiology 192:549.
Cockcroft D.W. and M.H. Gault. 1976. Prediction
of creatinine clearance from serum creatinine.
Nephron. 16:31.
Nosadini R., M. Velussi, E. Brocco, C. Abaterusso,
A. Carraro, F. Piarulli, et al. 2006. Increased
renal arterial resistance predicts the course of renal
function in type 2 diabetes with microalbuminuria.
Diabetes 55(49):476.
Sperandeo M., G. DAmico, A. Varriale, G.
Sperandeo, M.A. Annese and M. Correra. 1996.
Renal Duplex Doppler Sonography in patients with
insulin dependent diabetes complicated by early
nephropathy. Arch. It. Urol. LXVIII(S):183.
Nosadini R., M. Velussi, E. Brocco, C.
Abaterusso, F. Piarulli, G. Morgia, et al. 2005.
Altered transcapillary escape of albumin and
110
M. SPERANDEO ET AL.
1721-727 (2007)
111
112
A. DANIILIDIS ET AL.
Eur. J. Inflamm.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
REFERENCES
1.
13.
113
1499.
Clerici G., A. Cutuli and G.C. Renzo. 2001.
Delayed interval delivery of a second twin. Eur. J.
Obstet. Gynecol. Reprod. Biol. 1:121.
Van Doorn H.C., G. Van Wezel-Meijler, H.P. Van
Geijn and G.A. Dekker. 1999. Delayed interval
delivery in multiple pregnancies, is optimism
justified? Acta Obstet. Gynecol. Scand. 78:710.
Porreco R.P., E.D. Sabin, K.D. Heyborne and
G.L. Lindsay. 1998. Delayed interval delivery in
multiple pregnancy. Am. J. Obstet. Gynecol. 178:20.
Van der Straeten F.M., K. De Ketelaere and
M. Temmerman. 2001. Delayed interval delivery
in multiple pregnancies. Eur. J. Obstet. Gynecol.
Reprod. Biol. 1:85.
Benden D., M. Miller and N. Hatoum. 2001. 39
day delay in delivery of twins. A case report. Reprod.
Med. 12:1071.
Hamersley S.L., S.K. Coleman, N.K. Bergauer,
L.M. Bartholomew and T.L. Pinckert. 2002.
Delayed interval delivery in twin pregnancies. J.
Reprod. Med. 2:125.
Kirson B. 2002. Interval delivery and aggressive
tocolysis in high order multiple gestation. A report of
three cases. J. Reprod. Med. 10:867.
Zhang J., C.D. Johnson and M. Hoffman. 2003.
Cervical cerclage in delayed interval delivery in a
multifetal pregnancy: a review of seven case series.
Eur. J. Obstet. Gynecol. Reprod. Biol. 2:126.
Fayad S., A. Bongain, P. Holhfeld, E. Janky, M.
Durand-Reville, L. Eines, J.P. Schaaps and J.Y.
Gillet. 2003. Delayed delivery of second twin:
a multicentre study of 35 cases. Eur. J. Obstet.
Gynecol. Reprod. Biol. 1:16.
Zhang J., B. Hamilton, J. Martin and A. Trumble.
2004. Delayed interval delivery and infant survival:
a population-based study. Am. J. Obstet. Gynecol. 2:
470.
Ovelese Y., C.V. Ananth, J.C. Smulian and A.M.
Vintzileos. 2005. Delayed interval delivery in twin
pregnancies in the United States: impact on perinatal
mortality and morbidity. Am. J. Obstet. Gynecol. 2:439.
Cristinelli S., J. Eresson, M. Andre and P.
Monnier-Barbarino. 2005. Management of
delayed-interval delivery in multiple gestations.
Fetal Diagn. Ther. 4:285.
114
A. DANIILIDIS ET AL.