We read with great interest the paper by Gao et al, where the
authors elegantly prove the efficacy of a CD40 antisense oligonucleotide
for the treatment of trinitrobenzene sulphonic acid (TNBS)-induced colitis
in rats.[1] Their results are in keeping with previous reports in which
immunoblockade of CD40 ligand (L) was also able to ameliorate experimental
colitis. The authors conclude that inte...
We read with great interest the paper by Gao et al, where the
authors elegantly prove the efficacy of a CD40 antisense oligonucleotide
for the treatment of trinitrobenzene sulphonic acid (TNBS)-induced colitis
in rats.[1] Their results are in keeping with previous reports in which
immunoblockade of CD40 ligand (L) was also able to ameliorate experimental
colitis. The authors conclude that interruption of interactions between
CD40 bearing monocytes and endothelial cells and CD40L positive T-cells is
crucial for the beneficial effect exerted by CD40 antisense
oligonucleotide in TNBS-induced experimental colitis.
In the last few years we have been investigating the role of the
CD40/CD40L pathway in the pathogenesis of inflammatory bowel disease (IBD).[2] We and others have recently shown that, beside endothelial cells and
monocytes, also human intestinal fibroblasts (HIF) express CD40 on their
surface.[3,4] HIF significantly up-regulate CD40 expression, both at the
mucosal and submucosal levels, in patients with active IBD. Moreover, we
and others have shown that co-culture of CD40 expressing HIF with CD40L T-
cells induces fibroblast activation, leading to chemokine and cytokine
production, cell adhesion molecule up-regulation and activation of the
intracellular signaling machinery, by triggering MAP kinases and NFƒÛB
activation. All these events are biologically relevant for the
inflammatory process, since fibroblast-derived chemokines mediated T-cell
recruitment.[3,4] Another intriguing observation is the demonstration
that CD40L T-cells modulate collagen synthesis by HIF, thus suggesting a
potential involvement of the CD40/CD40L pathway in stricture formation in
Crohn's disease (CD).[5] Therefore, blockade of HIF CD40 is also another
potential mechanism of the CD40 antisense therapeutic efficacy.
We have also shown that platelets express high levels of biologically
active surface CD40 in a constitutive manner.[6] This molecule provides a
novel pathway for platelet activation, as shown by the observation of
RANTES release after platelet stimulation. These events are
particularly relevant at sites of intense immune activation, where local
inflamed endothelial cells retain RANTES on their surface and mediate T-
cell adhesion, thus locally amplifying the inflammatory response.
Moreover, Vowinkel et al recently showed that the CD40/CD40L system also
plays a critical role in mediating platelet adhesion to and activation of
intestinal microvasculature or leukocytes.[7]
Gao et al suggest that CD40L positive T-cells could stimulate CD40
endothelium, and that CD40 antisense could prevent such cell interaction.
Recently we have described that beside T-cells, also activated platelet
express CD40L.[8] Platelets display enhanced levels of membrane bound
CD40L in CD and ulcerative (UC) patients, and secrete higher amounts of
soluble CD40L, compared to healthy controls.[9] These phenomena have
biological relevance in terms of intestinal microvascular activation,
since IBD activated platelets trigger chemokine production, VCAM-1, ICAM-1
and CD40L up-regulation, and T-cell adhesion to the gut endothelium.[8,10] Therefore, abrogation of endothelial or platelet CD40 expression
would not only block T-cell-endothelial interactions but also interrupt
platelet-endothelial and platelet-leukocyte cell cross-talk in the gut
microvasculature.
Taken together, all these observations suggest that the CD40
antisense oligonucleotide used by Gao et al exerts its beneficial effect
not only disrupting the interaction between CD40 bearing monocytes and
endothelial cells and CD40L positive T-cells, but also acting on a much
wide array of cell types able to express either CD40 or CD40L. In
conclusion, the use of CD40 antisense oligonucleotides appears to be a
very promising therapeutic approach to turn off intestinal inflammation,
by disconnecting a crucial and almost ubiquitous communication system used
by multiple cell types during inflammation.
References
1. Gao D, Wagner AH, Fankhaenel S, Stojanovic T, Schweyer S, Panzner
S, Hecker M. 2005. CD40 antisense oligonucleotide inhibition of
trinitrobenzene sulphonic acid induced rat colitis. Gut 54: 70-7.
2. Danese S, Sans M, Fiocchi C. 2004. The CD40/CD40L costimulatory pathway
in inflammatory bowel disease. Gut 53: 1035-43.
3. Vogel JD, West GA, Danese S, De La Motte C, Phillips MH, Strong SA,
Willis J, Fiocchi C. 2004. CD40-mediated immune-nonimmune cell
interactions induce mucosal fibroblast chemokine leading to T-cell
trasmigration. Gastroenterology: 63-80.
4. Gelbmann CM, Leeb SN, Vogl D, Maendel M, Herfarth H,
Scholmerich J, Falk W, Rogler G. 2003. Inducible CD40 expression mediates
NFkappaB activation and cytokine secretion in human colonic fibroblasts.
Gut 52: 1448-56.
5. Vogel JD. 2001. Collagen synthesys by human intestinal fibroblasts is
modulated by T-cells through the CD40/CD40 ligand pathway.
Gastroenterology. A719.
6. Danese S, de la Motte C, Reyes BM, Sans M, Levine AD, Fiocchi C. 2004.
Cutting edge: T-cells trigger CD40-dependent platelet activation and
granular RANTES release: a novel pathway for immune response
amplification. J Immunol 172: 2011-5.
7. Vowinkel T, Mori M, Wood K, Stokes KY, Russell J, Krieglstein
CF, Granger DN. Platelet-leukocyte (WBC) interactions in experimental
colitis are mediated by CD40L and ICAM-1. Gastroenterology 126 (Suppl 2):
A-21, 2004.
8. Danese S, de La Motte C, Sturm A, JD V, West GA, Strong SA, Katz J,
Fiocchi C. 2003. Platelets trigger a CD40-dependent inflammatory response
in the microvasculature of Inflammatory bowel disease patients.
Gastroenterology 124: 1249-64.
9. Danese S, Katz J, Saibeni S, Papa A, Gasbarrini A, Vecchi M, Fiocchi C.
2003. Activated platelets are the source of elevated levels of soluble
CD40 ligand in the circulation of Inflammatory bowel disease patients.
Gut: 1435-41.
10. Danese S, Scaldaferri F, Papa A, Pola R, Gasbarrini A, Sgambato A,
Cittadini A. 2004. CD40L-positive platelets induce CD40L expression de
novo in endothelial cells: adding a loop to microvascular inflammation.
Arterioscler Thromb Vasc Biol 24: e162.
We note Dr Browning's interest in our work. Unfortunately, we find
his letter
to be factually incorrect, and therefore scientifically misleading.
In attempting to analyse further our own data, he has made invalid
assumptions regarding our data set, which render his calculations
inaccurate,
and his conclusions inappropriate. Moreover, the selected literature
references which he quotes omit c...
We note Dr Browning's interest in our work. Unfortunately, we find
his letter
to be factually incorrect, and therefore scientifically misleading.
In attempting to analyse further our own data, he has made invalid
assumptions regarding our data set, which render his calculations
inaccurate,
and his conclusions inappropriate. Moreover, the selected literature
references which he quotes omit critical recent data and reviews of this
area,
and are not representative of the current state of knowledge.
In response to requests from the scientific referees of our paper, we
included
data on 294 controls, who had been typed for either the DLG variants, the
OCTN1/2 variants, or both OCTN1/2 and DLG5 variants. The OCTN1/2 data
(not the focus of this paper) were added, as a marker independent of the
DLG5 gene, in order to show that the two sets of controls were
homogeneous. Of these 294 controls, DLG5 genotyping was undertaken in
269 samples, and successful genotypes obtained in 256 (95.2%). Thus the
failure rate in controls (4.8%) was similar to that in IBD patients (4.4%,
p=0.78
by Chi squared analysis). The Hardy-Weinberg data which Dr Browning
derives are not attributable to genotyping failure.
The contribution of the DLG5 gene is clearly complex. Dr Browning
fails to
quote a series of large studies in adult European populations which are
directly pertinent to our work. In the same volume of Gut as our paper,
Torok
et al.[1] show no association of the DLG5 113A variant in the German
population, with a non-significant reduction in 113A allelic frequency in
Crohn's disease (625 CD patients, 1012 controls). Vermeire et al. performed
studies in 2032 Belgian individuals, using strategies of case-control
analysis,
as well as transmission disequilibrium testing, and noted significant
undertransmission of the DLG5 113A allele towards affected offspring
(p=0.01, by Chi squared analysis.[2] Data presented in abstract from
Cambridge[3], and Oxford[4] show no significant association - in the full
paper in press, the final analysis of the Cambridge data again
demonstrates
non-significant reduction in 113A allelic frequency in Crohn's disease
(personal communication, Miles Parkes).
It is noteworthy that unpublished data from our own Unit suggest
that in
childhood onset disease, the penetrance of the DLG5 113A allele may be
critically influenced by gender, and environmental influences (Russell et
al.,
submitted).
These issues have recently been the subject of thoughtful editorials,
and
correspondence both in Gastroenterology[5], and most recently in the
European Journal of Human Genetics[6,7] - again unfortunately these
manuscripts are not considered by Dr Browning. We of course feel strongly
that this area is clearly of great interest, but we regretfully find the
deficiencies in Dr Browning's letter to be potentially counter-productive.
References
1. Torok H, Glas J, Tonenchi L et al. Polymorphisms in the DLG5 and
OCTN
cation transporter genes in Crohn's disease. Gut 2005:54:1421-7.
2. Vermeire S, Pierik M, Hlavaty T et al. Association of Organic
Cation
Transporter Risk Haplotype with Perianal Penetrating Crohn's disease, but
not
with Susceptibility to IBD. Gastroenterology 2005:129:1845-53.
3. Waller S, Tremelling M, Bredin F, Greenfield S, Parkes M.
Replication of
association between IBD and TNF-857, but not DLG5,NFKB, Keratin 8, or
TUCAN/CARD8 Gut 2005:54;suppl2 A95.
4. Cummings JRF, Herrlinger KR, Ahmad T, Jewell DP. Genotype-
phenotype
analyses of the IBD susceptibility gene DLG5. Gut 2005:54: suppl 2 A95.
5. Trinh TT, Rioux JD. Understanding Association and Causality in the
Genetic
Studies of Inflammatory Bowel Disease. Gastroenterology 2005;129: 2106
-2109.
6. Tenesa A, Noble C, Satsangi J, Dunlop M. Association of DLG5 and
inflammatory bowel disease across populations. Eur Journal Hum Genet 2006
Jan 4 e-pub.
7. Daly MJ, Rioux JD. Reply to Tenesa et al Association of DLG5 and
inflammatory bowel disease across populations. Eur Journal Hum Genet 2006
Jan 4 e-pub.
I am not aware of any data that have shown beyond doubt that
therapeutic endoscopy improves outcome. This study showed that second
therapeutic endoscopy failed to improve outcome but reduced the number of
cases "requiring" surgery. This raises serious questions about the
validity of current indications for surgery for operative mortality is
high in these circumstances and has not improved in almost fiv...
I am not aware of any data that have shown beyond doubt that
therapeutic endoscopy improves outcome. This study showed that second
therapeutic endoscopy failed to improve outcome but reduced the number of
cases "requiring" surgery. This raises serious questions about the
validity of current indications for surgery for operative mortality is
high in these circumstances and has not improved in almost five decades.
The mortality m,ight even have increased because surgeons are less
experienced with ulcer surgery, those dealing with bleeding ulcers being
particularly challenging.
It is now known that the development of shock, defined as a gastric
intramucosal acidosis, is the best predictor of outcome in the critically
ill the likelihood of developing organs dysfunctions and dying increasing
as the degree and duration increases.[1] More importantly in this context
is that the presence of haemodynamically compensated shock before surgery
has an adverse effect upon outcome.[2] The goal should, therefore, be to
identify operative candidates within one hour of their development of a
gastric intramucosal acidosis and operate immediately on those who require
surgery. The question is how to do this without subjecting patients to
unnecessary operations.
One way of doing this might be to use sequential measurements of the
magnitude of blood loss on the assumption that those most likely to
benefit from surgery will be those se rate of blood loss is greatest. One
way of obtaining sequential measurements of the rate of blood loss would
be to use indium-111-labeled red blood cells or surrogate.[3]
The first step should be to perform a prospective observational study
with organ dysfunctions, thirty-day and possibly six-month mortalities as
end-points. Better citeria for selecting patients who require surgery
might be derived from the analysis of these data and tested in a
complementary rospective interventional study.
References
(1) Fiddian-Green RG, Haglund U, Gutierrez G, Shoemaker WC. Goals for
the resuscitation of shock.
Crit Care Med. 1993 Feb;21(2 Suppl):S25-31.
(2) Poeze M, Takala J, Greve JW, Ramsay G Pre-operative tonometry is
predictive for mortality and morbidity in high-risk surgical patients.
Intensive Care Med. 2000 Sep;26(9):1272-81.
(3) Beckman RL, Pittenger GL, Swanson DP, Thrall JH, Fiddian-Green RG.
Blood loss measured with indium-111-labeled red blood cells in dogs.
Radiology. 1983 Jul;148(1):243-5.
I read the report by Gaya et al on brown spots in the bowel with
interest.[1] Three patients who had been on oral
iron therapy were found to have brown pigment in the gastric, duodenal and
terminal ileal mucosa. This pigment stained with Perl’s Prussian Blue
thus indicating the presence of haemosiderin. Gaya et al commented that
this condition is poorly documented in the gastrointestina...
I read the report by Gaya et al on brown spots in the bowel with
interest.[1] Three patients who had been on oral
iron therapy were found to have brown pigment in the gastric, duodenal and
terminal ileal mucosa. This pigment stained with Perl’s Prussian Blue
thus indicating the presence of haemosiderin. Gaya et al commented that
this condition is poorly documented in the gastrointestinal literature.
Although most reports on duodenal pseudomelanosis consisted of single
case studies, nine patients, one of whom also had gastric involvement,
were described in this journal in 1987.[2] Seven had end-stage renal
failure while an eighth had undergone transplantation. Eight of the nine
had been on oral iron supplements. The pigment, found mainly within
macrophages in the lamina propria, stained positively with Perl’s stain in
five patients, positively with the Masson-Fontana stain normally used to
identify melanin in one, and positively with both methods in three. Two
kinds of electron-dense structures, either angular or rounded to
irregularly shaped, were demonstrable by electron microscopy. Electron-probe X-ray analysis of the pigment from six patients showed iron to be
present in all six, while sulphur was present in five. The iron:sulphur
ratios of the angular structures ranged from 1:0.41 to 1:1.17, while
those for the rounded structures ranged from 1:0.15 to no sulphur being
detectable at all. Iron was also shown in the duodenal biopsies of 34 of
48 uraemic patients on oral iron supplements compared to 22 of 120
patients with normal renal function endoscoped for miscellaneous
indications. Rex and Jersild subsequently reported a further three
patients with duodenal pseudomelanosis and also found iron and sulphur
within rounded and angular structures seen on electron microscopy.[3] Their patients were hypertensive but had not used oral iron supplements
and were not in renal failure.
It was postulated that duodenal pseudomelanosis resulted from iron
deposition, probably following luminal absorption, initially staining
positively with Perl’s stain, corresponding to rounded structures on
electron microscopy.[2] In some patients, sulphur is also incorporated
into the granules, which become angular in shape and then react positively
with the Masson-Fontana method.[2]
Duodenal pseudomelanosis regressed in some patients.[2] The staining
properties of the pigment has also been known to change, from being
positive with the Perl’s stain but negative for the Masson-Fontana stain,
to staining positively by both methods one year later.[2] Further
detailed and follow-up studies of patients with this rare condition may
help to elucidate its pathogenesis and significance.
References
1. Gayal D R, Stanley A J, Foulis A K. Brown spots in the bowel. Gut 2004; 53:1744, 1763.
2. Kang J Y, Wu A Y T, Chia J L S, Wee A, Sutherland I H, Hori R. Clinical
and ultrastructural studies in duodenal pseudomelanosis. Gut 1987; 28:
1673-81.
3. Rex D K, Jersild R A. Further characterization of the pigment in
pseudomelanosis duodenai in three patients. Gastroenterology 1988;95:177-
82.
We read with interest the article by Ehrer A J, et al.[1] the authors have conclusively proven the benefit of
sildenafil citrate in reducing the lower oesophageal sphincter pressure
and propulsive forces in the body of oesophagus in both healthy subjects
and patients with esophageal dysmotility disorders. The beneficial effect
was shown to last for upto 8 hours after a single, daily dose of 50...
We read with interest the article by Ehrer A J, et al.[1] the authors have conclusively proven the benefit of
sildenafil citrate in reducing the lower oesophageal sphincter pressure
and propulsive forces in the body of oesophagus in both healthy subjects
and patients with esophageal dysmotility disorders. The beneficial effect
was shown to last for upto 8 hours after a single, daily dose of 50 mg.
We have done a similar study in patients with irritable bowel
syndrome (IBS) and wish to share our results.
Irritable bowel syndrome is characterized by disturbances of
gastrointestinal functions that occur in everybody from time to time in
response to dietary indiscretions or psychological upheavals, but present
to a greater extent and with greater frequency in patients with IBS.[3] the
abnormal patterns of motor activity have been demonstrated in colon [4] but
also in jejunum, ileum [5] and esophagus.[6]
Nitric oxide (NO) is a major inhibitory neurotransmitter in
gastrointestinal tract.[2] NO activates soluble guanylate cyclase thereby
enhancing the production of guanosine 3’, 5’- cyclic mono phosphate
(cGMP). Sildenafil blocks the degradation of NO by blocking
phosphodiesterase type 5. This results in increased levels of NO, leading
to increased level of cGMP and cGMP dependent protein kinase. This
causes relaxation of smooth muscles in various organs. We thought of
utilizing this effect of sildenafil citrate and study its effects on IBS
patients having colonic dysmotility.
A prospective, open label, intention to treat study was planed. 58
married male, patients with irritable bowel disease, diagnosed on the
basis of Rome II criterion,[7] were screened. Out of these 18 reported
erectile dysfunction (ED) along with symptoms of IBS. These 18 patients
were enrolled for the study. They were aged between 20-40 years with mean
age of 29 ±9.54 years. After explaining the nature of the study 17 patients
consented for participation in the study. All the drugs were discontinued
for a period of 2 weeks run in period, except fiber supplements, which
were continued throughout the study period. Baseline characteristics were
recorded along with the symptoms. The patients were asked to score theirs
symptoms (IBS and ED symptoms) on a scale of 1 to 10 at the beginning of
the study and on every follow up, to compare the improvement after
treatment. The patients were started on 12.5 mg of sildenafil citrate once
daily at bed time. They were asked to note down improvement in their
symptoms and any untoward effects. The patients were followed up at 2
weekly intervals for 6 weeks and the drug dose was increased at every
follow up. The maximum dose given was 37.5 mg / day. Compliance was
measured by pill count. All the patients complied with the therapy. Only
2 patients reported minor side effects like headache and flushing with
37.5 mg dose. All the patients experienced significant improvement in
their ED but none of them reported any improvement in any IBS symptoms.
Though sildenafil citrate in known to relax smooth muscle cells in
various organs and has been found to be effective in improving esophageal
dysmotility1 patients of IBS with erectile dysfunction did not report any
improvement in their symptoms with 37.5 mg/day dose. The reason for this
lack of response could be the lower dose used by us in the study group.
Since there are no studies available till date regarding the use of
sildenafil in IBS and no guidelines are available regarding the minimum /
maximum dose of sildenafil to be used in gastrointestinal dysmotility, we
gradually hiked up the dose so as to avoid significant side effects.
References
(1) Ehrer AJ, Schwartz I, Hammer HF, Petnehazy T, Scheidl SJ, Weber K,
Krejs G. Effect of sildenafil on oesophageal motor function in healthy
subjects and patients with esophageal motor disorders. Gut 2002;50:758-64.
(2) Sanders KM, Ward SM. Nitric oxide as a mediator of non adrenergic, non
cholinergic neurotransmitter. Am J Physiol 1995;489: 735-43.
(3)Read NW. Irritable bowel syndrome, (Chapter 91). In Feldman M, Friedman LS,
Sleisenger (Eds) Gastrointestinal and liver disease, 7th edition. London: Saunders, 2002. Pp.1794-1806.
(4) McKee DP, Quigley EMM. Intestinal motility in irritable bowel syndrome:
Is IBS a motility disorder? Dig Dis Sci 1993;38:1761-82.
(5) Kellow JE, Gill RC, Wingate DL. Prolonged ambulant recording of small
bowel motility demonstrates abnormality in irritable bowel syndrome. Gastroenterology 1990;98:1208-18.
(6) Read NW. Visceral afferent information and functional bowel disease:
Evidence of dyssensation and altered reflux function. In Mayer EA,
Raybould NE (Eds) Basic and clinical aspects of chronic abdominal pain. Amstredum: Elsevier, 1993. Pp.87-96.
(7) Drossman DA. Rome II: The functional intestinal disorders. McLean, Va,
Degnan Associates, 2002.
We read with interest the article by Mawdsley and Rampton on the
relationship between psychological stress, increased disease activity in
inflammatory bowel diseases (IBD), and the role of...
We read with interest the article by Mawdsley and Rampton on the
relationship between psychological stress, increased disease activity in
inflammatory bowel diseases (IBD), and the role of alterations in the
hypothalamic-pituitary-adrenal (HPA) axis function (Gut 2005; 54:
1481-91). In IBD patients, chronic colonic inflammation induces a
downregulation of HPA axis responses, and animal studies have shown that
altered function of the HPA axis renders rodents susceptible to stress-induced
increases in gastrointestinal inflammation. Central receptors located in the
medial prefrontal cortex and hippocampus play a crucial role in glucocorticoid
(GC) mediatedcounterregulation of
stress-induced HPA axis activation [1].
Polymorphisms of the GC receptor (GR) gene may contribute
to the large interindividual variations in sensitivity to GCs and HPA axis
activity, that are frequently observed in healthy individuals. Several
polymorphisms of the GR gene have been described, and three of these are
relatively frequent; however, knowledge on the influence of these polymorphisms
on HPA axis response is very limited.
A genetic study was carried out in our laboratory to
evaluate the incidence of these polymorphisms in 57 young patients with IBD (34
with Crohn’s disease, CD and 23 with ulcerative colitis, UC, mean age 13.8
years, range 1-45 years, 41.4% males, 58.6% females). The study was approved by
the local ethics committee and written informed consent was obtained from all
patients or their relatives or guardians. The studied polymorphisms have been
the BclI, in intron 2, and the N363S polymorphism in exon 2, that have been
associated with an increased sensitivity to GCs in vivo [2][3] and the ER22/23EK polymorphism, in exon
2, associated with a partial form of GC resistance [4]. Genomic DNA was extracted from
peripheral leukocytes, amplified with specific primers and subsequently
digested with MnlI (ER22/23EK), Tsp509I (N363S) or BclI restriction enzymes
[5][6].
The results of the analysis are presented in table I;
we found a significantly higher frequency of the BclI mutated
genotype in patients with CD in comparison with healthy controls (p= 0.03,
Fisher test, OR 3.84; 95%CI 1.23-11.91), no difference was on the contrary
observed between UC patients and controls.
BclI
GENOTYPEn (%)
OR (95% CI)
p value
Wild type
Heterozygous
Mutated
Mutated vs not mutated
Controls
(n= 70)
30 (42.9%)
34 (48.5%)
6 (8.6%)
-
-
CD
(n=34)
9 (26.5%)
16 (47%)
9 (26.5%)
3.84
(1.23-11.91)
0.03
UC
(n=23)
10 (43.5%)
12 (52.2%)
1 (4.3%)
1.03 (0.39-
2.65)
1
ER22/23EK
Wild type
Heterozygous
Mutated
Heterozygous vs wild type
Controls
(n= 70)
67 (95.7%)
3 (4.3%)
0 (0%)
-
-
CD
(n=34)
32 (94.1%)
2 (5.9%)
0 (0%)
1.39
(0.22- 8.78)
0.6
UC
(n=23)
22 (95.7%)
1 (4.3%)
0 (0%)
1.01
(0.10- 10.27)
1
N363S
Wild type
Heterozygous
Mutated
Heterozygous vs wild type
Controls
(n= 70)
67 (95.7%)
3 (4.3%)
0 (0%)
-
-
CD
(n=34)
33 (97.1%)
1 (2.9%)
0 (0%)
0.68
(0.07- 6.76)
1
UC
(n=23)
21 (91.3%)
2 (8.7%)
0 (0%)
2.13(0.33-13.60)
0.6
Table I: BclI, ER22/23EK and N363S
genotype in patients with CD, UC and controls.
The BclI polymorphism has been associated
with high systolic pressure, insulin sensitivity, body mass index and abdominal
fat distribution [2][7]; carriers of the mutated
allele have increased GC sensitivity, and higher cortisol suppression after low
dose dexamethasone [8]. A higher frequency of the mutated genotype has been observed in this
study in patients with CD; this mutation could lead to an increased sensitivity
in peripheral and central GRs, determining a raised susceptibility to feedback
inhibition of GCs on the HPA axis. It is of interest that previous studies have
demonstrated [9], in a subgroup of patients
with Crohn’s disease, alterations of the HPA axis resulting in relative
hypocortisolism.
No difference was on the contrary observed for the
N363S polymorphism,associated with an
increased sensitivity to GCs [3][10], or the ER22/23EK polymorphism, that is,
on the contrary, associated with a partial form of GC resistance [4] (table I).
This is the first study examining the possibility that IBD may be
associated withGR polymorphisms; our
results support the hypothesis that common polymorphisms in the GR gene may
have modulating effects on the relation between psychological factors and HPA
axis regulation in patients with CD. These data however need to be confirmed in
a larger group of patients.
The Authors declare no competing interest.
Acknowledgements
This research was supported by grants from the
Italian Ministry of University and Scientific Research (PRIN projects 2004065777
and 2003053403) and the Italian Ministry
of Health. Dr. Sara De Iudicibus, Dr. Gabriele Stocco and Dr. Ilenia Drigo are
recipients of research felloships from IRCCS Burlo Garofolo, Trieste.
References
1.Sternberg
EM, Chrousos GP, Wilder RL, et al. The stress response and the regulation of
inflammatory disease. Ann Intern Med 1992;117:854-66.
2.Buemann B, Vohl MC,
Chagnon M, et al. Abdominal visceral fat is associated with a BclI
restriction fragment length polymorphism at the glucocorticoid receptor gene
locus. Obes Res 1997;5:186-92.
3.Lin
RC, Wang WY, Morris BJ. High penetrance, overweight, and glucocorticoid
receptor variant: case-control study. Bmj
1999;319:1337-8.
4.van
Rossum EF, Koper JW, Huizenga NA, et al. A polymorphism in the glucocorticoid
receptor gene, which decreases sensitivity to glucocorticoids in vivo, is
associated with low insulin and cholesterol levels. Diabetes 2002;51:3128-34.
5.Koper
JW, Stolk RP, de Lange P, et al. Lack of association between five polymorphisms
in the human glucocorticoid receptor gene and glucocorticoid resistance. Hum Genet 1997;99:663-8.
6.Bachmann
AW, Sedgley TL, Jackson RV, et al. Glucocorticoid receptor polymorphisms and
post-traumatic stress disorder. Psychoneuroendocrinology
2005;30:297-306.
7.Weaver
JU, Hitman GA, Kopelman PG. An association between a Bc1I restriction fragment
length polymorphism of the glucocorticoid receptor locus and hyperinsulinaemia
in obese women. J Mol Endocrinol 1992;9:295-300.
8.van Rossum EF, Koper JW,
van den Beld AW, et al. Identification of the BclI polymorphism in the
glucocorticoid receptor gene: association with sensitivity to glucocorticoids
in vivo and body mass index. Clin
Endocrinol 2003;59:585-92.
9.Reinshagen
M, Haefele T, Holicki S, et al. The ultra low dose ACTH-test identifies a
subgroup of patients with Crohns disease and an impaired hypothalamo-pituitary-adrenal
(HPA) axis. Gastroenterology 2002;122:S1384.
10.Huizenga NA, Koper JW, De
Lange P, et al. A polymorphism in the glucocorticoid receptor gene
may be associated with and increased sensitivity to glucocorticoids in vivo. J
Clin Endocrinol Metab 1998;83:144-51.
These well informed guidelines [1] are largely accurate, however,
section 3.3, dealing with resuscitation in the critically ill does need
some correction. The implication is that transfusion in critically ill
patients with evidence of gastrointestinal haemorrhage is indicated to
maintain Hb > 10 g/dl. This cannot be demonstrated by the quoted study.[2] In this randomised controlled study of alternati...
These well informed guidelines [1] are largely accurate, however,
section 3.3, dealing with resuscitation in the critically ill does need
some correction. The implication is that transfusion in critically ill
patients with evidence of gastrointestinal haemorrhage is indicated to
maintain Hb > 10 g/dl. This cannot be demonstrated by the quoted study.[2] In this randomised controlled study of alternative transfusion
strategies in 838 patients, not only were patients with active blood loss
excluded from study; but the main thrust of its conclusion was that there
was a mortality benefit in ITU patients if Hb was maintained between 7-9
g/dl rather than 10-12g/dl. Furthermore a prospective 50 patient study of
transfusion strategies in non variceal gastrointestinal haemorrhage
demonstrated no survival benefit with more liberal or expectant
transfusion strategies. Indeed it demonstrated increased rebleeding in the
transfused group [3] Clearly transfusion of blood products is required in
patients who are shocked (HR >100 bpm, systolic BP <100mmHg) with
evidence of active gastrointestinal bleeding, however, it is not clear
that patients, who are critically ill and with Hb <10g/dl benefit from
transfusion strategies to maintain Hb >10g/dl, and it has not been
demonstrated in this group that mortality is related to the severity of
the anaemia.
References
(1) Palmer KE. Non variceal upper gastro intestinal haemorrhage:
guideleines. Gut 2002, Suppl IV, 51
(2) Herbert PC, Wells G, Blajchman MA et al. A multicentre, randomised
controlled clinical trial of transfusion requirements in critical care.
New Eng J Med 1999, 340; 409-417
(3) Blair SD, Janvrin SB, McCollum CN et al. Effect of early blood
transfusion on gastrointestinal haemorrhage. Br J Surg 1986 73; 783-785.
Authors would like to reemphasize on the fact that haemodialysis (HD) patients and intravenous drug abusers (IVDAs) - are the two heterogeneous groups that have very little in common other than the modes of transmission of HCV infection, since both of them -
1. Form the high-risk groups for the parentrally acquired HCV
infection.
2. Survive in a high-risk environment amid rath...
Authors would like to reemphasize on the fact that haemodialysis (HD) patients and intravenous drug abusers (IVDAs) - are the two heterogeneous groups that have very little in common other than the modes of transmission of HCV infection, since both of them -
1. Form the high-risk groups for the parentrally acquired HCV
infection.
2. Survive in a high-risk environment amid rather suboptimal hygienic
conditions and HCV infected individuals in the vicinity.
3. May possibly share contaminated equipments and between the HCV
infected and noninfected individuals.
4. May reuse equipments (syringes, needles among IVDAs and dialyzers
among HD patients and contaminated vials among both).
5. Have an obligatory requirement for repetitive punctures and / or
cannulations of vascular (access) sites.
6. Are at an increased risk for the acquisition of multiple infections
with other blood borne viruses (including Hepatitis B virus and HIV) in
addition to HCV infection.[1]
Molecular studies have clearly implicated nosocomial route as the
principal mode of HCV transmission in the modern hospital based HD
settings [2,3] whereas repeated blood transfusions are no longer
considered a major risk factor since, with routine HCV screening through
highly sensitive tests (ELISA anti-HCV) for blood donors - the risk factor
of post-transfusion HCV infection is less than 1/100,000 blood units.[4,5] Moreover, persistently and significantly lower prevalence of anti-HCV
antibody positivity among blood donors in comparison to that of HD
cohorts, worldwide, is suggestive of transmission of HCV infection within
the dialysis unit through means other than blood transfusions. In
addition, the outbreaks of HCV transmission have been frequently reported
in HD units, due to failures to strictly adhere to the universal
precautions, for instance- failure to change gloves between the patients
while performing HD treatments.[6]
The contamination of vascular access sites requiring regular
punctures and cannulations to carry out HD is likely to take place at some
stage during the handling of these accesses via nosocomial pathway through
cross infection mechanism from the patients already infected being
dialyzed in physical proximity of the non-infected ones.
The anti-HCV positivity increases with time on dialysis (dialytic
age) in these patients, more than 50% of whom are elderly with
comorbidities such as malnutrition, diabetes mellitus and malignancies and
therefore immunocompromized.Dialytic age has been reported to be a potent
predictor of the risk of acquirement of HCV infection.[7] The chances of
acquiring HCV infection are significantly enhanced after a decade of HD
with the reported predictable risk of 10% per year.[8] Then again,
authors are in agreement with Alavian et al on the fact that nearly 80%
of IVDAs the majority of whom are otherwise healthy, fairly young and
immunocompetent individuals, develop anti-HCV antibodies during the very
first year of the beginning of drug abuse - truly makes a "remarkable
difference" as regards to HCV infection, between the two groups.
Evidently rigorous enforcement of standard infection control measures
in addition to possibly strict isolation of the HCV positive patients
might be of great help in reducing the new HCV seroconversions in high
prevalence HD units;[9,10] however, neither infection control measures
nor the isolation of HCV infected IVDAs, are likely to prove pragmatic for
this group with unusually altered attitude towards life.
References
(1) Hassan AA, Khalil RY. Prevalence of three blood borne viruses
(HBV, HCV, HIV-1) among hemodialysis patients in Cairo. Saudi Kidney Dis
Transplant Bull1993; 4:72
(2) Stuyver L, Claeys H, Wyseur A et al. Hepatitis C virus in
hemodialysis unit: Molecular evidence for nosocomial transmission. Kidney
Int1996; 49:889-895.
(3) MC Laughlin KJ, Cameron SO, Good T et al. Nosocomial transmission
of hepatitis C within a British dialysis center. Nephrol Dial Transplant
1997; 12:304-309.
(4) Van der Poel CL. Hepatitis C virus and blood transfusion: Past and
present risks. J Hepatol 1999; 31:101-106.
(5) Okuda K, Hayashi H, Kobayashi S, Irie Y. Mode of hepatitis C
infection transmission not associated with blood transfusion among
hemodialysis patients. J Hepatol 1995; 23:28-31.
(6) Alfurayah O, Sabeel A, Al Ahdal MN et al. Hand contamination with
hepatitis C virus in staff looking after hepatitis C positive hemodialysis
patients. Am J Nephrol 2000; 20:103-106
(7) Hardy NM, Sandroni R, Danielson S, Wilsom WJ. Antibody to hepatitis
C virus increases with time on hemodialysis. Clin Nephrol 1992; 38:44-48.
(8) Giammaria U, De Moe F, Acetelli S et al. HCV infection in
hemodialyzed patients: Incidence and correlation and Dialytic age. Nephron
1992; 61:335-336.
(9) Saxena AK, Panhotra BR. Nosocomial transmission of hepatitis C
virus: impact of strict isolation on annual seroconversion rate in
hemodialysis unit. Saudi J Kidney Dis Transplant. 2002; 13: 186-187
(10) Saxena AK, Panhotra BR, Sundaram DS et al. The impact of dedicated
space, dialysis equipment and nursing staff on the transmission of
hepatitis C in hemodialysis unit of the Middle East. Am J Infect Control.
2003; 31:26-33.
Further to Coleman et al’s reply to my letter,[1] I would like to question the
advocacy
of minichromosome maintenance (MCM) proteins as proliferative markers, as
the number MCM positive cells can greatly exceed other labels and they are
widely distributed on unreplicated chromatin.[2] They would appear to be
more of an indicator of replication potential and, as such, are likely to be
useful...
Further to Coleman et al’s reply to my letter,[1] I would like to question the
advocacy
of minichromosome maintenance (MCM) proteins as proliferative markers, as
the number MCM positive cells can greatly exceed other labels and they are
widely distributed on unreplicated chromatin.[2] They would appear to be
more of an indicator of replication potential and, as such, are likely to be
useful markers of dysplasia.[3] In addition, scoring immunohistochemical labelled cells is just as, if not
more, ‘subjective and error prone’ than scoring mitotic figures (which are far
easier
to score in ‘squash’ preparation than in sections).
My main concern still stands as scoring histological sections of human
biopsies, unlike squash preparations, leads to the sampling of a very
limited
number of crypts (2-4 in the present study), which prevents credence of
the
‘observed lack of effect’ of prebiotic carbohydrates.
Finally, I think that the jury is still out on the ‘protective role’
of fermentable
non-starch polysaccharides (fibre) as while the EPIC study showed a
dramatic
effect of intrinsically high fibre diets,[4] many other studies have shown
null
effects and some of these, especially the intervention ones, demonstrated
adverse effects. For example wheat bran supplementation increased polyp
recurrence in women[5] and ispaghula had a more general adverse effect on
polyps.[6]
References
1. Coleman N, Langlands S, Hopkins M, Cummings J. Authors' reply [electronic response to Goodlad R A. Defective denominators] gutjnl.com 2004 URL direct link to eLetter
3. Alison, MR, Hunt, T and Forbes, SJ Minichromosome maintenance (MCM)
proteins may be pre-cancer markers. Gut, (2002) 50, 290-1.
4. Bingham, SA, Day, NE, Luben, R, et al. Dietary fibre in food and
protection against colorectal cancer in the European Prospective
Investigation
into Cancer and Nutrition (EPIC): an observational study. Lancet, (2003)
361,
1496-1501.
5. Alberts, DS, Martinez, ME, Roe, DJ, et al. Lack of Effect of a High-
Fiber
Cereal Supplement on the Recurrence of Colorectal Adenomas. The New
England Journal of Medicine, (2000) 342, 1156-62.
6. Bonithon-Kopp, C, Kronborg, O, Giacosa, A, et al. Calcium and fibre
supplementation in prevention of colorectal adenoma recurrence: a
randomised intervention trial. Lancet, (2000) 356, 1300–06.
We appreciate the interest of Guidi et al. according our
review about the relevance of steatosis in chronic hepatitis C.[1] We
would like to outline three points according to their comments: the
prevalence of steatosis in regard to genotype; the role of
necroinflammation; the relationship between steatosis and treatment
outcome.
Firstly, several studies have observed a significant association...
We appreciate the interest of Guidi et al. according our
review about the relevance of steatosis in chronic hepatitis C.[1] We
would like to outline three points according to their comments: the
prevalence of steatosis in regard to genotype; the role of
necroinflammation; the relationship between steatosis and treatment
outcome.
Firstly, several studies have observed a significant association
between HCV genotype 3 infection and the presence of steatosis.[2,3]
Steatosis is present in 73% of HCV genotype 3 patients and in 50% of
patients infected with genotypes other than 3 (mainly genotype 1).[1] In
HCV genotype 1 patients, steatosis occurs more frequently than in the
general population of adults in the Western world (estimation of 20-30%).
So we do agree with the hypothesis of a potential direct pathogenic role
of the virus in the induction of liver steatosis, not limited to HCV
genotype 3.[1, 4-5] Furthermore, in a study from Abid et al., the HCV
core protein, from patients with severe (genotype 3a) or no (other
genotypes) liver steatosis, was expressed in Huh7 cells.[6]
Although
triglyceride accumulation occurred with genotypes 1b, 3a and 3h, the
genotype 3a core protein expression resulted in the highest level of
accumulation. In another recent study a positive correlation between
steatosis and the number of infected hepatocytes was observed only in
genotype 3 patients.[7] In most cases the number of cells with steatosis
greatly outnumbered that of HCV infected cells (HCV-antigens using
immunoperoxidase technique). The conclusion was that steatosis do not
appear to be directly related to the presence of HCV-antigens within
single hepatocytes, an indirect, possibly cytokine mediated, mechanism
might be operative.
Secondly, several studies have found a highly significant link
between steatosis and necroinflammation activity in one hand; and between
necroinflammation activity and fibrosis in another hand.[1, 2] Fatty
accumulation is not fibrogenic per se. Steatosis in presence of
necroinflammation could increase fibrosis progression rate. Furthermore,
we conducted a meta-analysis on individual patients' data of 3,068
patients with histologically confirmed chronic hepatitis C from several
centers.[8] Steatosis was independently associated with genotype 3, the
presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol
abuse, higher BMI and older age. Fibrosis was independently associated
with inflammatory activity, steatosis, male gender and older age, while
HCV genotype 2 was associated with reduced fibrosis. The association
between steatosis and fibrosis was invariably dependent on a simultaneous
association between steatosis and hepatic inflammation.
Thirdly, Guidi et al. reported in a selected population with chronic
hepatitis C, that the presence of steatosis was not associated with a
lower sustained virological response (SVR).[4] One main interest in their
study was that they rule out possible concomitant metabolic disorders,
namely alcoholic hepatitis and metabolic factors associated with non
alcoholic fatty liver disease. In a large study involving 1428 naïve
patients with chronic hepatitis C, the presence of steatosis was
associated with a lower SVR rate, even after taking into account other
factors (P <.001).[9] Absence of baseline steatosis, as well as end of
follow-up steatosis, was associated with higher SVR, except in patients
with genotype 3. In another retrospective analysis of 174 patients with
chronic hepatitis C, obesity (and not steatosis) was a negative predictor
of SVR.[10] It could be that obesity (with increased plasma free fatty
acid) higher causes steatosis, and then each independently diminishes
response to treatment. Obesity decreases interferon bioavailability and
impairs the immune response to HCV. The opposite was found in a study
involving nondiabetic European patients with HCV genotype 1 at low risk
for the metabolic syndrome, where the prevalence of steatosis was nearly
60%.[11] Insulin resistant was a risk factor for moderate/severe
steatosis, especially in men. Moderate/severe steatosis was found
associated with hyporesponsiveness to treatment.
We obviously agree on the need for larger works which could contribute to
explain the mechanisms that promote the occurrence of steatosis in chronic
hepatitis C, and the relationship with response to treatment.
References
1 - Asselah T, Rubbia-Brandt L, Marcellin P, et al. Steatosis in
chronic hepatitis C: why does it really matters? Gut 2006; 55 123-130.
2 - Asselah T, Boyer N, Guimont MC, et al. Liver fibrosis is not
associated with steatosis but with necroinflammation in French patients
with chronic hepatitis C. Gut. 2003;52(11):1638-43.
3 - Rubbia-Brandt L, Fabris P, Paganin S, et al. Steatosis affects
chronic hepatitis C progression in a genotype specific way. Gut.
2004;53(3):406-12.
4 - Guidi M, Muratori P, Granito A, et al. Hepatic steatosis in
chronic hepatitis C: impact on response to anti-viral treatment with peg-
interferon and ribavirin. Aliment Pharmacol Ther 2005; 22:943-9.
6 - Abid K, Pazienza V, de Gottardi A, et al. An in vitro model of
hepatitis C virus genotype 3a-associated triglycerides accumulation. J
Hepatol. 2005;42(5):744-51.
7 - Grassi A, Ballardini G, Susca M, et al. HCV liver infection and
liver steatosis: evidence for indirect mechanisms in genotype 3? Aliment
Pharmacol Ther. 2005;22 S 2:79-82.
8 - Leandro G, Mangia A, Hui J, et al. Relationship Between
Steatosis, Inflammation and Fibrosis in Chronic Hepatitis C: a Meta-
Analysis of Individual Patient Data. Gastroenterology, in press.
9 - Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment
with peginterferon or interferon alfa-2b and ribavirin on steatosis in
patients infected with hepatitis C.Hepatology. 2003;38(1):75-85.
10 - Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass
index is an independent risk factor for nonresponse to antiviral treatment
in chronic hepatitis C. Hepatology. 2003; 38: 639-44.
11 - Cammà C, Bruno S, Di Marco V, et al. Insulin resistance is
associated with steatosis in nondiabetic patients with genotype 1 chronic
hepatitis C. Hepatology 2006;43:64-71.
T Asselah1, L Rubbia-Brandt2, P Marcellin1 and F Negro2 & 3
1 Service d’Hépatologie and INSERM CRB3, Hôpital Beaujon, Clichy,
University of Paris VII, France.
2 Service de Pathologie Clinique, Hô ;pital Universitaire, Genève,
Switzerland.
3 Services de Gastroentérologie et d’Hépatologie, Hôpital
Universitaire, Genève, Switzerland
Correspondence to:
Dr T Asselah, MD, PhD, VDSM
Service d’Hépatologie and INSERM CRB3, Hô ;pital Beaujon, Clichy 92
110, France. E-mail: tarikasselah@hotmail.com.
Dear Editor,
We read with great interest the paper by Gao et al, where the authors elegantly prove the efficacy of a CD40 antisense oligonucleotide for the treatment of trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats.[1] Their results are in keeping with previous reports in which immunoblockade of CD40 ligand (L) was also able to ameliorate experimental colitis. The authors conclude that inte...
Dear Editor,
We note Dr Browning's interest in our work. Unfortunately, we find his letter to be factually incorrect, and therefore scientifically misleading.
In attempting to analyse further our own data, he has made invalid assumptions regarding our data set, which render his calculations inaccurate, and his conclusions inappropriate. Moreover, the selected literature references which he quotes omit c...
Dear Editor
I am not aware of any data that have shown beyond doubt that therapeutic endoscopy improves outcome. This study showed that second therapeutic endoscopy failed to improve outcome but reduced the number of cases "requiring" surgery. This raises serious questions about the validity of current indications for surgery for operative mortality is high in these circumstances and has not improved in almost fiv...
Dear Editor
I read the report by Gaya et al on brown spots in the bowel with interest.[1] Three patients who had been on oral iron therapy were found to have brown pigment in the gastric, duodenal and terminal ileal mucosa. This pigment stained with Perl’s Prussian Blue thus indicating the presence of haemosiderin. Gaya et al commented that this condition is poorly documented in the gastrointestina...
Dear Editor
We read with interest the article by Ehrer A J, et al.[1] the authors have conclusively proven the benefit of sildenafil citrate in reducing the lower oesophageal sphincter pressure and propulsive forces in the body of oesophagus in both healthy subjects and patients with esophageal dysmotility disorders. The beneficial effect was shown to last for upto 8 hours after a single, daily dose of 50...
Dear Editor.
We read with interest the article by Mawdsley and Rampton on the relationship between psychological stress, increased disease activity in inflammatory bowel diseases (IBD), and the role of...
Dear Editor
These well informed guidelines [1] are largely accurate, however, section 3.3, dealing with resuscitation in the critically ill does need some correction. The implication is that transfusion in critically ill patients with evidence of gastrointestinal haemorrhage is indicated to maintain Hb > 10 g/dl. This cannot be demonstrated by the quoted study.[2] In this randomised controlled study of alternati...
Dear Editor
Authors would like to reemphasize on the fact that haemodialysis (HD) patients and intravenous drug abusers (IVDAs) - are the two heterogeneous groups that have very little in common other than the modes of transmission of HCV infection, since both of them -
1. Form the high-risk groups for the parentrally acquired HCV infection.
2. Survive in a high-risk environment amid rath...
Dear Editor
Further to Coleman et al’s reply to my letter,[1] I would like to question the advocacy of minichromosome maintenance (MCM) proteins as proliferative markers, as the number MCM positive cells can greatly exceed other labels and they are widely distributed on unreplicated chromatin.[2] They would appear to be more of an indicator of replication potential and, as such, are likely to be useful...
Dear Editor,
We appreciate the interest of Guidi et al. according our review about the relevance of steatosis in chronic hepatitis C.[1] We would like to outline three points according to their comments: the prevalence of steatosis in regard to genotype; the role of necroinflammation; the relationship between steatosis and treatment outcome.
Firstly, several studies have observed a significant association...
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