We were interested to see the paper by Langlands et al, in
which
‘prebiotic’ carbohydrates altered the mucosal flora,[1] but apparently had
no
effect on cell proliferation. The matter is of some importance as the
products
of in vivo fermentation (short chain fatty acids) may increase epithelial
cell
proliferation, leading to the possibility that such supplements could
actually
enhance t...
We were interested to see the paper by Langlands et al, in
which
‘prebiotic’ carbohydrates altered the mucosal flora,[1] but apparently had
no
effect on cell proliferation. The matter is of some importance as the
products
of in vivo fermentation (short chain fatty acids) may increase epithelial
cell
proliferation, leading to the possibility that such supplements could
actually
enhance the risk of colo-rectal cancer.[2,3]
The authors state that methodology (of gut microflora study) is
always an
important issue and we argue that this also applies to cell proliferation
studies, as the results of present work may be misleading on two counts.
Firstly we would never recommend the use of PCNA as a marker of cell
proliferation as:
1] the method is difficult to standardise;
2] the antigen has a long half-life; and
3] anomalous expression has been demonstrated in non-cycling near
tumours and after administration of growth factors.[4]
For sections Ki67 is far better, however even using this antibody the
results
of the present study are unlikely to be conclusive as only 2-4 crypts
could be
scored; for most studies we would recommend scoring 30 hemi crypts.
The second point is that reliance on labelling indices can be
misleading, as
lack of difference does not necessarily mean no proliferative change as
both
sides of the ratio (labelled cells divided by number of cells) could have
altered. This was demonstrated in our studies of EGF in parenterally fed
rats,
where no differences in labelling index between orally fed and
parenterally
fed rats could be seen despite halving tissue weight and crypt cell
production.
When the data was re-expressed as labelling per crypt, the effects of
treatment became apparent;[5] a similar effect was seen in the stomach
following misoprostol treatment.[6,7]
There is however, a far easier and well validated method available
for the
study of human tissue. This is the so-called microdissection technique in
which small pieces of stained material are teased apart and mitotic
figures
scored.[8] This literally allows one to score over a hundred crypts (if so
wished) and as the results are expressed per crypt the effects of changes
in
denominator are automatically accounted for.
References
1. Langlands, SJ, Hopkins, MJ, Coleman, N, et al. Prebiotic
carbohydrates
modify the mucosa associated microflora of the human large bowel. Gut,
(2004) 53, 1610-6.
2. Wasan, HS and Goodlad, RA Fibre-supplemented foods may damage
your health. Lancet, (1996) 348, 319-20.
3. Goodlad, RA Dietary fibre and the risk of colorectal cancer. Gut,
(2001) 48, 587-9.
4. Hall, PA, Coates, PJ, Goodlad, RA, et al. Proliferating cell nuclear
antigen
expression in non-cycling cells may be induced by growth factors in vivo.
Br J
Cancer, (1994) 70, 244-7.
5. Goodlad, RA, Lee, CY and Wright, NA Cell proliferation in the small
intestine and colon of intravenously fed rats: effects of urogastrone-
epidermal growth factor. Cell Prolif, (1992) 25, 393-404.
6. Goodlad, RA, Madgwick, AJ, Moffatt, MR, et al. Prostaglandins and the
gastric epithelium: effects of misoprostol on gastric epithelial cell
proliferation in the dog. Gut, (1989) 30, 316-21.
7. Goodlad, RA Defective denominators, or will people never learn?
Gastroenterology, (1995) 108, 1963.
8. Goodlad, RA, Levi, S, Lee, CY, et al. Morphometry and cell
proliferation
in endoscopic biopsies: evaluation of a technique. Gastroenterology,
(1991) 101, 1235-41.
The recent study by Noble and colleagues[1] did not find an
association of the DLG5 G113A polymorphism with either inflammatory bowel
disease (IBD) or Crohn’s disease (CD). Previous studies in other European
populations had reported an increase in 113A allele frequency in IBD and
CD patients [2,3], but, in striking contrast, Noble et al.[1] reported a
trend toward decreased carrier frequency for the 1...
The recent study by Noble and colleagues[1] did not find an
association of the DLG5 G113A polymorphism with either inflammatory bowel
disease (IBD) or Crohn’s disease (CD). Previous studies in other European
populations had reported an increase in 113A allele frequency in IBD and
CD patients [2,3], but, in striking contrast, Noble et al.[1] reported a
trend toward decreased carrier frequency for the 113A allele in the IBD
patients (p=0.069) and in the CD patients (p=0.057).
We believe there is reason to re-examine the genotype data used in
the Noble et al. report.
First, there are significant differences in the proportion of missing
genotypes between the IBD patients and the controls (p<0.00001,
Fisher’s exact test). Using the data in Table 1 and Table 3[1], the missing
genotype rate is 13% in controls and 4% in IBD patients. This difference
strongly suggests differences in DNA quality or genotyping process between
the IBD and control samples.
Second, using the data in Table 3[1], the G113A polymorphism is not
in Hardy-Weinberg equilibrium (HWE) in the IBD patients (HWE p-value=0.0056, likelihood ratio test). Hardy-Weinberg equilibrium describes the
relationship of allele and genotype frequencies in a randomly mating
population, and departure from HWE in controls is commonly used to test
for genotyping error.[4] If the G113A polymorphism is independent of
IBD disease status, then we expect the G113A polymorphism to be in HWE in
IBD patients. There are fewer heterozygote IBD patients than expected
under Hardy-Weinberg equilibrium, and this may be related to the
differences in heterozygote frequencies between IBD patients and controls
(p=0.033) and between CD patients and controls (p=0.029) reported by
Noble et al.[1] One possible explanation for this difference in
heterozygote frequencies is genotyping error in IBD patients caused by
allelic dropout of the 113A allele.
The differences in missing genotype rates and the departure from HWE
in IBD patients suggest that the quality of the genotype data that
underlie the conclusions of this study should be investigated.
References
1. Noble CL, Nimmo ER, Drummond H, et al. (2005) DLG5 variants do not
influence susceptibility to inflammatory bowel disease in the Scottish
population. Gut 2005;54:1416-20.
2. Stoll M, Corneliussen B, Costello CM, et al.(2004) Genetic
variation in DLG5 is associated with inflammatory bowel disease. Nat Genet
2005;36:476-80.
3. Daly MJ, Pearce AV, Farwell L, et al. (2005) Association of DLG5
R30Q variant with inflammatory bowel disease. Eur J Hum Genet 2005;13:835-
9.
4. Leal SM. Detection of genotyping errors and pseudo-SNPs via
deviations from Hardy-Weinberg equilibrium. Genet Epi 2005;29:204-14.
We read with a great interest the article by Giannini et al. in a recent
issue of Gut.[1]
Since the incidence of chronic liver diseases is growing,
we are convinced that the development of non-invasive predictive tools to
identify cirrhotic patients with oesophageal varices is of major interest.
Several markers have been studied, and among them platelet count is
commonly reported to be a go...
We read with a great interest the article by Giannini et al. in a recent
issue of Gut.[1]
Since the incidence of chronic liver diseases is growing,
we are convinced that the development of non-invasive predictive tools to
identify cirrhotic patients with oesophageal varices is of major interest.
Several markers have been studied, and among them platelet count is
commonly reported to be a good predictor of oesophageal varices. However,
in the eight studies already published,[2-9] their discriminative power
was moderate, with areas under the ROC curve of 0.70 or less, and this for
platelets alone [5] and for indexes combinating platelets to other markers.[2,5,6] Most of these studies have included heterogeneous group of
patients, with compensated and decompensated cirrhosis. In our unit, we
performed prospectively platelet count and screening upper
oesogastroduodenoscopy the same day to 41 patients with compensated
cirrhosis and confirmed the moderate value of platelet count alone
(AUROC=0.70 +/- 0.07) (Thabut, data not shown).
The major drawback of platelet count is that it can depend on other
factors than portal hypertension in cirrhotic patients. To avoid this
bias, Giannini developed an index based on platelet count/spleen
diameter ratio and found far better results than previous studies,[1]
with a c index (equivalent to the area under ROC curve) of 0.92 for
patients with compensated liver cirrhosis. However, we were surprised to
see that the use of platelets/spleen diameter ratio does not add
significant discrimination to platelet count alone (c index of 0.92 vs
0.88) in their population. Considering this point, their excellent results
would not be explained by the discriminative power of their index but by
the excellent diagnostic power carried by platelet count itself in their
series. Several explanations can be raised, and one of them is the high
rate of viral-related cirrhosis in their patients, where platelet count is
less exposed to variations than in alcoholic patients for example. This
point is of major concern for the further validation of their index,
recommended by the authors themselves, in other populations.
In conclusion, Giannini et al. have found a very performing index to
predict the presence of oesophageal varices in cirrhotic patients. We
think that the excellent performance they obtained was not due to their
index but to the surprisingly good performance of platelet count alone in
their patients. Considering the results carried by platelet count for the
prediction of oesophageal varices in the already published studies, we
fear that the warranted validation studies of this index show less
exciting results.
References
(1) Giannini E, Botta F, Borro P, Risso D, Romagnoli P, Fasoli A, et al. Platelet count/spleen diameter ratio: proposal and validation of a non
-invasive parameter to predict the presence of oesophageal varices in
patients with liver cirrhosis. Gut 2003;52(8):1200-5.
(2) Chalasani N, Imperiale TF, Ismail A, Sood G, Carey M, Wilcox CM, et al.
Predictors of large esophageal varices in patients with cirrhosis. Am J
Gastroenterol 1999;94(11):3285-91.
(3) Madhotra R, Mulcahy HE, Willner I, Reuben A. Prediction of esophageal
varices in patients with cirrhosis. J Clin Gastroenterol 2002;34(1):81-5.
(4) Ng FH, Wong SY, Loo CK, Lam KM, Lai CW, Cheng CS. Prediction of
oesophagogastric varices in patients with liver cirrhosis. J Gastroenterol
Hepatol 1999;14(8):785-90.
(5) Pilette C, Oberti F, Aube C, Rousselet MC, Bedossa P, Gallois Y, et al.
Non-invasive diagnosis of esophageal varices in chronic liver diseases. J
Hepatol 1999;31(5):867-73.
(6) Schepis F, Camma C, Niceforo D, Magnano A, Pallio S, Cinquegrani M, et al. Which patients with cirrhosis should undergo endoscopic screening for
esophageal varices detection? Hepatology 2001;33(2):333-8.
(7) Thomopoulos KC, Labropoulou-Karatza C, Mimidis KP, Katsakoulis EC,
Iconomou G, Nikolopoulou VN. Non-invasive predictors of the presence of
large oesophageal varices in patients with cirrhosis. Dig Liver Dis
2003;35(7):473-8.
(8) Zaman A, Hapke R, Flora K, Rosen HR, Benner K. Factors predicting the
presence of esophageal or gastric varices in patients with advanced liver
disease. Am J Gastroenterol 1999;94(11):3292-6.
(9) Zaman A, Becker T, Lapidus J, Benner K. Risk factors for the presence
of varices in cirrhotic patients without a history of variceal hemorrhage.
Arch Intern Med 2001;161(21):2564-70.
I agree that designing an RCT for a dietary treatment is difficult,
but some of the factors that have led to this trial being criticised could
have been avoided, even within the existing design of the trial.[1] For
example, if all those on the 'sham diet' who did not have high levels of
IgG to wheat had been asked to avoid wheat, that would have given roughly
equal numbers avoiding wheat in both groups...
I agree that designing an RCT for a dietary treatment is difficult,
but some of the factors that have led to this trial being criticised could
have been avoided, even within the existing design of the trial.[1] For
example, if all those on the 'sham diet' who did not have high levels of
IgG to wheat had been asked to avoid wheat, that would have given roughly
equal numbers avoiding wheat in both groups, and would have provided a
more stringent test of the hypothesis, at least in relation to this key
foodstuff.
It is indeed possible that a small sub-group of IBS patients exists
for whom an inflammatory response involving IgG antibodies is part of the
mechanism. Unfortunately, the design of the trial does not allow one to
distinguish between this possibility as an explanation for the results,
and the alternative explanation: that diets avoiding wheat and dairy
products, randomly distributed, will help some IBS patients. If there is
indeed a sub-group of IBS sufferers for whom IgG testing is relevant, the
way to identify them is by a qualitative rather than a quantitative study.
For example, one might take blood samples from a group of IBS patients,
then put them through a rigorous diagnostic elimination diet using an
established protocol. After double-blind placebo-controlled challenges to
confirm the foods identified, the results could be compared with IgG
levels before the diet. If there is a resaonably good match between the
two for some patients, and if those patients remain well while avoiding
those foods, it could be concluded that IgG testing had potential
predictive value in this sub-group. The inclusion of additional tests and
a very detailed history, at the outset of such a trial, might reveal
markers that could identify this sub-group in advance.
The problem with the current trial is that its ambiguities allow it
to be used to promote IgG testing to the general public, who are being
informed that these results provide unequivocal support for such testing
procedures in all IBS patients.[2]
The letter from Caroccio et al,[3] regarding infants with cow's-milk
sensitivity is interesting, especially the finding that the nature of the
IgG response varies from one food antigen to another. Their data on IgG
against milk antigens need to be viewed in the context of work by other
groups, who have not found any consistent pattern of IgG levels to milk
proteins in infants with confirmed clinical reactions to milk (whether IgE
-mediated or not).[4,5] It is also well known that the IgG response to food
in infants is very different from that of older children and adults, as
Caroccio et al have confirmed, and the relevance of findings in infants to
the screening of adults with IBS is therefore limited.
References
1. Whorwell P J, Atkinson W, Sheldon T A. Author's reply [electronic response to Hunter J O. Food elimination in IBS: the case for IgG testing remains doubtful] gutjnl.com 2004 URl direct link to eLetter
2. See, for example, http://www.allergy-testing.com/index2.html
3. Carroccio A, Scalici C. Di Prima L, Iacono G. IgG anti-betalactoglobulin in children with IBS symptoms: a valid aid to decide for the elimination [electronic response to Atkinson W, Sheldon T A, Shaath N, Whorwell P J. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial] gutjnl 2004 URL direct link to eLetter
4. Host A, Husby S, Gjesing B, Larsen J N, Lowenstein H. Prospective
estimation of IgG, IgG subclass and IgE antibodies to dietary proteins in
infants with cow milk allergy. Levels of antibodies to whole milk protein,
BLG and ovalbumin in relation to repeated milk challenge and clinical
course of cow milk allergy. Allergy 1992;47:218-229.
5. Hidvegi E, Cserhati E, Kereki E, Savilahti E, Arato A. Serum
immunoglobulin E, IgA, and IgG antibodies to different cow's milk proteins
in children with cow's milk allergy: association with prognosis and
clinical manifestations. Pediatr Allergy Immunol 2002;13:255-261.
we read with great interest the review by Asselah et al. (1), about
the relevance of steatosis in chronic hepatitis C. They properly report
that steatosis occurs more frequently in patients with chronic hepatitis C
(55%) than in the general population (20-30%) of adults in the Western
world (2), and that it is associated with various factors, including
obesity, high alcohol consumption, diabetes melli...
we read with great interest the review by Asselah et al. (1), about
the relevance of steatosis in chronic hepatitis C. They properly report
that steatosis occurs more frequently in patients with chronic hepatitis C
(55%) than in the general population (20-30%) of adults in the Western
world (2), and that it is associated with various factors, including
obesity, high alcohol consumption, diabetes mellitus, and hyperlipidaemia.
They also discuss experimental models demonstrating that hepatitis C virus
(HCV) proteins derived from genotype 1 isolates can induce steatosis (3-6). Among the conclusions, they claim the need for larger studies which
take into account confounding factors for steatosis.
We have recently published our experience in assessing the impact of
steatosis on antiviral treatment in a group of 102 naive patients with
chronic hepatitis C of different genotypes (7). We excluded subjects with
at least one of these features: present or past alcohol consumption, body
mass index of 30 or more (indicating obesity), hyperglicaemia,
hypercholesterolaemia and hypertriglyceridaemia. This was done to rule out
possible concomitant metabolic disorders, namely alcoholic hepatitis and
non alcoholic fatty liver disease. However, we observed that hepatic
steatosis was present histologically in 51% of cases; we then hypothesized
a potential direct pathogenic role of the virus in the induction of liver
steatosis, not limited to HCV genotype 3.
We also observed a significantly higher necroinflammatory activity
and a greater prevalence of an advanced stage of fibrosis in HCV patients
with steatosis.
Interestingly, the presence of steatosis was not associated with a
lower sustained virological response. To our knowledge, no previous work
reported a selected population like ours, and 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.
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.
3 Barba G, Harper F, Harada T, et al. Hepatitis C virus core protein
shows a cytoplasmic localization and associates to cellular lipid storage
droplets. Proc Natl Acad Sci USA 1997;94:1200–5.
4 Shi ST, Polyak SJ, Tu H, et al. Hepatitis C virus NS5A colocalizes
with the core protein on lipid droplets and interacts with
apolipoproteins. Virology 2002;292:198–210.
5 Perlemuter G, Sabile A, Letteron P, et al. Hepatitis C virus core
protein inhibits microsomal triglyceride transfer protein activity and
very low density lipoprotein secretion: a model of viral-related
steatosis. FASEB J 2002;16:185–94.
6 Okuda M, Li K, Beard MR, et al. Mitochondrial injury, oxidative
stress, and antioxidant gene expression are induced by hepatitis C virus
core protein. Gastroenterology 2002;122:366–75.
7 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.
We read the study by Prantera and colleagues, with great interest.
As the authors assert, there have been few good quality and well designed
clinical trials, with sufficient power, to examine the effects of
probiotics on inflammatory bowel disease.
This trial unfortunately also has a number of weaknesses both in its
reporting and methodology.
We read the study by Prantera and colleagues, with great interest.
As the authors assert, there have been few good quality and well designed
clinical trials, with sufficient power, to examine the effects of
probiotics on inflammatory bowel disease.
This trial unfortunately also has a number of weaknesses both in its
reporting and methodology.
The report does not make clear the exact time point at which patients
were recruited to the trial and randomized. As such recruitment bias may
be introduced. The issue of allocation concealment is also ignored in the
paper. Furthermore, at no point do the authors fully address the difficult
issue of standardisation, be it regarding the patient's disease, the
surgeon, the endoscopist or the assessors of clinical outcome.
The authors do not report any attempt to estimate the necessary
sample size for the study. The absence of a power calculation or
confidence intervals leaves the authors open to the same criticism that
they have levelled at other studies. The statistical analysis used is not
an intention to treat analysis. We also question whether a chi-squared
test was used to compare differences in proportions rather than a z test
as stated in the paper.
The study concludes that probiotics are ineffective in preventing
recurrence after curative resection. Indeed endoscopic recurrence was 25%
greater in the probiotic group, although this was not statistically
significant. However this conclusion is based on the analysis of just 37
patients. Clearly, the possibility of a type II error must be acknowledged.
The authors do accept that this must be considered a pilot study.
Given the possible biases and lack of power in this study, it should
not be considered to be Class Ib evidence. We feel this study re-inforces
the fact that a well designed, multi-centre randomised controlled trial is
needed to test the hypothesis of the whether probiotics are of any benefit
in Crohn's Disease.
Sood et al[1] are to be congratulated on their
prospective study to determine the incidence and prevalence of ulcerative
colitis in the Punjab region of India. Their study shows that ulcerative
colitis may not be as rare in the Asian sub-continent as was once
believed.
We have previously reported ethnic IBD incidence data from a
prospective study of over 13 million children, aged less...
Sood et al[1] are to be congratulated on their
prospective study to determine the incidence and prevalence of ulcerative
colitis in the Punjab region of India. Their study shows that ulcerative
colitis may not be as rare in the Asian sub-continent as was once
believed.
We have previously reported ethnic IBD incidence data from a
prospective study of over 13 million children, aged less than 16 years,
encompassing the entire population of the United Kingdom and Republic of
Ireland.[2] Children of South Asian [Indian,
Pakistani and Bangladeshi] origin had a higher incidence rate of IBD
compared to children of other ethnic groups [relative risk 1.5 (95% CI 1.1
-2.1, p = 0.01)], and that this was specifically because of a higher
incidence of ulcerative colitis [relative risk 1.5 (95% CI 1.1-2.2, p =
0.03)]. In the original retrospective regional study from Leicester [3] cited by Sood et al,[1] undertaken a decade
earlier, no significant difference in incidence of ulcerative colitis was
found between European and Asian children, although the absolute number of
cases were very small. However, Asian adults did have a higher incidence of
ulcerative colitis than non-Asians. A recent report has suggested that
there may be an increasing incidence of both ulcerative colitis and
Crohn’s disease amongst the adult Bangladeshi population of East London.[4] We were interested that Sood et al.[1] did not
report data on the incidence of Crohn’s disease, presumably because of the
difficulty in determining the diagnosis but also perhaps because of the
lower incidence and prevalence. In the United Kingdom national paediatric
study, Asians, compared to other ethnic groups, did not have a lower
incidence of Crohn’s disease and the incidence of ulcerative colitis was
higher.
With the rapid emergence of a large middle class in the Asian sub-
continent we suspect that in some ‘westernised’ populations the incidence
and prevalence of IBD, and specifically that of ulcerative colitis, may
over-take that recorded in populations of North European descent. Studies
amongst those in the paediatric age group in the Indian sub-continent
might be the first to detect such temporal changes.
References
(1) A Sood, V Midha, N Sood, A S Bhatia, and G Avasthi
Incidence and prevalence of ulcerative colitis in Punjab, North India. Gut 2003; 52: 1587-1590.
(2) Sawczenko A, BK Sandhu, et al. (2001). "Prospective survey of
childhood
Inflammatory Bowel Disease in the British Isles." Lancet 357: 1093-4.
(3) Probert CS, V Jayanthi et al. (1993). "Prevalence and family
risk of ulcerative colitis
and Crohn's disease: an epidemiological study among Europeans and south
Asians in
Leicestershire." Gut 34(11): 1547-51.
(4) Tsironi E, RM Feakins et al. (2002). "Incidence of inflammatory
bowel disease is
rising but of abdominal TB is falling in Bangladeshis in East London."
Gastroenterol
124(4): A212.
We thank Goodlad for his interest in our article.[1]
In our study[2] we assessed the expression of the three
markers most commonly used to indicate cell cycle
entry in tissue sections. Importantly, there was no
difference in the data obtained for all three. We agree
that PCNA is of limited value, for the reasons
mentioned by Goodlad and also the fact that the
protein has a role in DNA repa...
We thank Goodlad for his interest in our article.[1]
In our study[2] we assessed the expression of the three
markers most commonly used to indicate cell cycle
entry in tissue sections. Importantly, there was no
difference in the data obtained for all three. We agree
that PCNA is of limited value, for the reasons
mentioned by Goodlad and also the fact that the
protein has a role in DNA repair, which reduces its
specificity as a cell cycle marker. Similarly, Ki67 is not
expressed by all cycling cells, may be down-regulated
by nutritional deprivation and may also be involved in
non cell cycle-related processes, such as ribosomal
biosynthesis.[3]
We consider that the most useful markers of cycling
cells are the minichromosome maintenance (MCM)
proteins, which are abundant at all phases of the cell
cycle and are down-regulated following exit into
quiescence, differentiation or senescence.[3,4] MCMs
therefore provide a sensitive and specific indication of
cell cycle entry. In our opinion these markers are
preferable to counting mitotic figures, which is a
subjective and error-prone exercise that by definition
provides a limited, phase-specific indication of cell
cycle state in histological sections.
We agree that proliferation indices can be misleading
and that when assessing large bowel crypts it is
important to determine the number of labelled cells per
crypt.[5] We confirm that the mucosa in all subjects in
our study was microscopically normal, as well as
macroscopically normal, as stated. In particular, there
was no difference in crypt length and number of cells
per crypt between the study groups. The labelling
indices determined were therefore valid indicators of
cell cycle entry in the samples investigated.
Prebiotic carbohydrates, such as those used in our
study, are completely fermented in the large bowel and
none is excreted in faeces. The principal products of
this fermentation are short chain fatty acids (SCFA).
Whilst SCFA have been associated with increased cell
proliferation in some animal models, it is hard to
believe that what are the major anions in the colon of all
mammalian species should enhance the risk of
cancer, particularly since one of these fatty acids,
butyrate, is thought to be a differentiating agent.
Fermented carbohydrates, such as dietary fibre, when
measured properly in the diet, appear to protect against
colorectal cancer in observational studies.[6] The
observed lack of effect of prebiotic carbohydrates on
colonocyte proliferation in our study suggests that a
substantial increase in fermentable carbohydrate
intake, as provided by these prebiotics, does not
enhance proliferation as shown in some animal
models, and thus might be regarded as adding to the
protective role of the fermentable non-starch
polysaccharides (fibre).
References
1. Goodlad R A. Defective denominators [electronic response to Langlands S J, Hopkins M J, Coleman N, Cummings J H. Prebiotic carbohydrates modify the mucosa associated microflora of the human large bowel] gutjnl 2004 URL direct link to eLetter .
2. Langlands S J, Hopkins M J, Coleman N, Cummings J H. Prebiotic carbohydrates modify the mucosa associated microflora of the human large bowel. Gut 2004; 53: 1610-1616.
3. Gonzalez M A, Tachibana K K, Laskey R A, Coleman N.
Control of eukaryotic DNA replication by MCMs and
geminin: potential clinical exploitation. Nature Reviews
Cancer, Feb 2005, in press.
4. Musahl C, Holthoff H P, Lesch R, Knippers R.
Stability of the replicative Mcm3 protein in proliferating
and differentiating human cells. Exp Cell Res 1998: 241: 260-4.
5. Scott I S, Morris L S, Bird K, Davies R J, Vowler S L,
Rushbrook S M, Marshall A E, Laskey R A, Miller R,
Arends M J, Coleman N. A novel
immunohistochemical method to estimate cell cycle
state and phase in archival tissue: implications for
estimation of outcome in colorectal cancer. J Pathol 2003:
201:187-97.
6. Bingham S A 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: 1496-501.
We read this article with great interest. Treatment of anal fissure is
really troublesome. Here the author puts emphasis on the Neuromyogenic properties of anal sphincter and treatment by topical glyceryl trinitrate,
a nitric oxide donor, which decreases anal sphincter tone and improves
anal mucosal blood flow and promotes the healing of anal fissures. Because
of the easy application process glyceryl tri...
We read this article with great interest. Treatment of anal fissure is
really troublesome. Here the author puts emphasis on the Neuromyogenic properties of anal sphincter and treatment by topical glyceryl trinitrate,
a nitric oxide donor, which decreases anal sphincter tone and improves
anal mucosal blood flow and promotes the healing of anal fissures. Because
of the easy application process glyceryl trinitrate becomes popular.
In a study[1] published in NEJM showe that treatment with either topical nitroglycerin or botulinum toxin is as effective as an alternative to surgery for patients with chronic anal fissure, botulinum toxin is the
more effective nonsurgical treatment. Botulism toxin has proved its superiority than nitrates in many clinical trials.Despite the reported success[2] of botulinum toxin, its use has not been widely adopted, possibly due to the need for injection into the sphincter complex and
because it is expensive. The optimal dose and method of administration require validation.
Patients on nitroglycerin at some time in the course of treatment, reported moderate-to-severe headaches after application of the ointment. These headaches were transient (30 to 40 minutes) and were relieved with oral analgesia. some patients may stop applying the ointment because of
severe headache. Some patients in the nitroglycerin group reported moderate anal burning. A second potential difficulty is the development of drug tolerance, a problem well documented with nitrate therapy for cardiovascular disease and now also reported during treatment for anal
fissure.[3]
Yet a number of practical and theoretical questions remain unanswered about therapy with nitrates or botulinum toxin. For nitrates: Which preparation should be used, at what concentration, and how often should it be applied? For botulinum toxin: What dose should be used, and where
should it be injected — the internal or external sphincter? For both agents: Which works faster and with fewer adverse effects? How substantial is the problem of incontinence, and is it ever more than temporary? What are the relative costs? Finally, what are the long-term relapse rates? If
the beauty of chemical sphincterotomy lies in its transience, how often
will elevated sphincter pressures lead to recurrence months or years down
the road?
References
1.A Comparison of Injections of Botulinum Toxin and Topical Nitroglycerin
Ointment for the Treatment of Chronic Anal Fissure.Brisinda G., Maria G.,
Bentivoglio A. R., Cassetta E., Gui D., Albanese A.N Engl J Med 1999;
341:65-69, Jul 8, 1999.
2. A Comparison of Botulinum Toxin and Saline for the Treatment of Chronic
Anal Fissure.Maria G., Cassetta E., Gui D., Brisinda G., Bentivoglio A.
R., Albanese A.
N Engl J Med 1998; 338:217-220, Jan 22, 1998.
3.Watson SJ, Kamm MA, Nicholls RJ, Phillips RK. Topical glyceryl
trinitrate in the treatment of chronic anal fissure. Br J Surg 1996;83:771
-775.
The management of refractory, severe inflammatory bowel disease (IBD)
is yet an unsolved problem. We read with interest the article by
Stallmach and colleagues reporting safety and efficacy of intravenous
pulse cyclophosphamide in acute steroid refractory IBD.[1]
In common with other disease, the aims of therapy in IBD fall into
three categories:
The management of refractory, severe inflammatory bowel disease (IBD)
is yet an unsolved problem. We read with interest the article by
Stallmach and colleagues reporting safety and efficacy of intravenous
pulse cyclophosphamide in acute steroid refractory IBD.[1]
In common with other disease, the aims of therapy in IBD fall into
three categories:
(i) induction of remission;
(ii) maintenance of remission; and
(iii) prevention of relapse, all of which should be
undertaken with minimal mortality and morbidity either from the disease
itself or the therapy.
Based on the previous observations of improvement
in autoimmune diseases (i.e. vasculitides) Cyclophosphamide can be the
primary cytotoxic drug: pulse intravenous cyclophosphamide is probably
equally effective as oral cyclophosphamide at inducing remission and this
remission is usually maintained by continuing cyclophosphamide for 3–6
months before changing to a combination of other per os therapy. Therapy
must be continued to prevent relapse and for maintenance.[2]
We would like to report some other cases to enrich the experiences.
In our cohort we included patients with Crohn’s disease (CD) and
ulcerative colitis (UC). Four patients with CD and four with UC: all were
diagnosed according to the standard criteria. They did not respond to
conventional therapy so we treated them with pulse cyclophosphamide
therapy monthly (for 6 months, 800mg each time). Most patients entered
into remission after the second/third cyclophosphamide pulse. Disease
activity decreased, there was no side effects, no toxicity, and all the
patients went into long lasting remission. For the maintenance, patients
with CD were treated with methotrexate (10mg/week) and patients with UC
were treated with azathioprine (100mg/day). Remission seems to be stable.
These findings suggest that aggressive immunosuppressive therapy may
be useful in some refractory patients and further controlled study should
be considered in order to full evaluate this type of treatment as a
potential therapy in IBD.
IBD continue to pose a challenge to clinicians. Over the past few
years there have been significant advances in our understanding of
pathogenesis and treatment. These advances will hopefully in the next few
years lead to more specific and targeted treatments, with consequent
improvements in clinical outcomes. Intravenous pulse cyclophosphamide may
be a safe and effective treatment in patients with severe IBD unresponsive
to "conventional" treatment. It is also recommended as a first-line
adjunct to or replacement of systemic corticosteroids in the treatment of
IBD.
References
(1) Stallmach A, Wittig BM, Moser C et al. Safety and efficacy of
intravenous pulse cyclophosphamide in acute steroid refractory
inflammatory bowel disease. Gut 2003;52(3):377-82.
(2) Watts RA, Scott DG, Pusey CD et al. Vasculitis-aims of therapy. An overview. Rheumatology (Oxford) 2000;39(3):229-32.
Dear Editor
We were interested to see the paper by Langlands et al, in which ‘prebiotic’ carbohydrates altered the mucosal flora,[1] but apparently had no effect on cell proliferation. The matter is of some importance as the products of in vivo fermentation (short chain fatty acids) may increase epithelial cell proliferation, leading to the possibility that such supplements could actually enhance t...
Dear Editor,
The recent study by Noble and colleagues[1] did not find an association of the DLG5 G113A polymorphism with either inflammatory bowel disease (IBD) or Crohn’s disease (CD). Previous studies in other European populations had reported an increase in 113A allele frequency in IBD and CD patients [2,3], but, in striking contrast, Noble et al.[1] reported a trend toward decreased carrier frequency for the 1...
Dear Editor
We read with a great interest the article by Giannini et al. in a recent issue of Gut.[1]
Since the incidence of chronic liver diseases is growing, we are convinced that the development of non-invasive predictive tools to identify cirrhotic patients with oesophageal varices is of major interest. Several markers have been studied, and among them platelet count is commonly reported to be a go...
Dear Editor
I agree that designing an RCT for a dietary treatment is difficult, but some of the factors that have led to this trial being criticised could have been avoided, even within the existing design of the trial.[1] For example, if all those on the 'sham diet' who did not have high levels of IgG to wheat had been asked to avoid wheat, that would have given roughly equal numbers avoiding wheat in both groups...
Dear Editor,
we read with great interest the review by Asselah et al. (1), about the relevance of steatosis in chronic hepatitis C. They properly report that steatosis occurs more frequently in patients with chronic hepatitis C (55%) than in the general population (20-30%) of adults in the Western world (2), and that it is associated with various factors, including obesity, high alcohol consumption, diabetes melli...
Dear Editor
We read the study by Prantera and colleagues, with great interest. As the authors assert, there have been few good quality and well designed clinical trials, with sufficient power, to examine the effects of probiotics on inflammatory bowel disease.
This trial unfortunately also has a number of weaknesses both in its reporting and methodology.
The report does not make clear the exact...
Dear Editor
Sood et al[1] are to be congratulated on their prospective study to determine the incidence and prevalence of ulcerative colitis in the Punjab region of India. Their study shows that ulcerative colitis may not be as rare in the Asian sub-continent as was once believed.
We have previously reported ethnic IBD incidence data from a prospective study of over 13 million children, aged less...
Dear Editor
We thank Goodlad for his interest in our article.[1]
In our study[2] we assessed the expression of the three markers most commonly used to indicate cell cycle entry in tissue sections. Importantly, there was no difference in the data obtained for all three. We agree that PCNA is of limited value, for the reasons mentioned by Goodlad and also the fact that the protein has a role in DNA repa...
Dear Editor,
We read this article with great interest. Treatment of anal fissure is really troublesome. Here the author puts emphasis on the Neuromyogenic properties of anal sphincter and treatment by topical glyceryl trinitrate, a nitric oxide donor, which decreases anal sphincter tone and improves anal mucosal blood flow and promotes the healing of anal fissures. Because of the easy application process glyceryl tri...
Dear Editor
The management of refractory, severe inflammatory bowel disease (IBD) is yet an unsolved problem. We read with interest the article by Stallmach and colleagues reporting safety and efficacy of intravenous pulse cyclophosphamide in acute steroid refractory IBD.[1]
In common with other disease, the aims of therapy in IBD fall into three categories:
(i) induction of remission;...
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