The preoccupation with the question of whether or not MAP is the
cause of CD has split the gastroenterological world into ‘believers’ and
‘non believers’ with much fervour and polarity such that a likely middle-
ground could be neglected. The current argument is simplistic and fails
to consider the complexity of the many environmental and genetically
determined defects of immune regulation and barrier...
The preoccupation with the question of whether or not MAP is the
cause of CD has split the gastroenterological world into ‘believers’ and
‘non believers’ with much fervour and polarity such that a likely middle-
ground could be neglected. The current argument is simplistic and fails
to consider the complexity of the many environmental and genetically
determined defects of immune regulation and barrier protection that
combine to produce a gut mucosal disease of considerable heterogeneity.
Perhaps a useful parallel that may help put MAP infection in CD into
perspective is the equally vigorous debate current among cardiologists
regarding the controversial role of Chlamydia pneumoniae in the
pathogenesis of atherosclerosis – arterial inflammation is present,
bacteria are regularly found (albeit with difficulty) in plaque, animal
models show acute progressive atheroma-like lesions, and the outcome of
clinical trials using antibiotics is not encouraging due to poorly
designed studies with inadequate antibiotic regimens. In understanding
the putative roles of both bacteria in terms of their respective putative
disorders, it is important to recognise that infection with these bacteria
appears not to be essential for disease, and that the classical principles
of a host/parasite relationship where the dominant determinant of outcome
is the parasite, do not apply. In CD any chronic infection is imposed
upon a complicated network of pro-inflammatory events with their checks
and balances. In these circumstances, Dr Sartor’s ‘cons’ (transmissible
infection, similarities between CD and Johne’s disease in ruminants,
effect of immune suppression and ambiguous therapeutic response to
antibiotics) are not persuasive arguments against a role of MAP in the
promotion of disease, as they do not address circumstances where host
factors are important determinants of outcome. In practice, Koch’s
postulates are of limited value, but there is overwhelming agreement that
intra-mucosal infection drives inflammation in CD.
With respect to MAP the questions are :-
(i) When present, to what extent does MAP contribute to this
‘bacterial drive’’?
(ii) In what proportion of subjects with CD is MAP present?
The answer to the second question is “variable, perhaps ranging from
20-30% in some areas, to 70-90% in others”. It is dismissive to suggest
that ‘technical’ factors account for the low prevalence reported by a
number of experienced scientists. The answer to the first question is more
difficult, and is currently unknown. The selective removal of MAP and
identification of a MAP-specific pathogenic host response is yet to be
achieved.
An observation of importance is that it is only since the
introduction of antibiotic strategies designed specifically for the
eradication of MAP infection has encouraging long term clinical
improvement been reported. The outcome of a recent controlled antibiotic
trial has been awaited.[1] This study, despite its poor design and use of
sub-therapeutic dosages for treatment of atypical mycobacteria[2], showed
significant improvement in the treated group over the placebo at 16 weeks
(p<_0.02 with="with" maintenance="maintenance" of="of" subsequent="subsequent" remission="remission" at="at" a="a" level="level" similar="similar" to="to" that="that" observed="observed" in="in" conventionally="conventionally" treated="treated" controls.="controls." need="need" for="for" properly="properly" designed="designed" studies="studies" appropriate="appropriate" dosage="dosage" selected="selected" antibiotics="antibiotics" duration="duration" therapy="therapy" and="and" monitoring="monitoring" map="map" status="status" is="is" the="the" greatest="greatest" importance="importance" clearly="clearly" establish="establish" role="role" anti-map="anti-map" management="management" cd.="cd." danger="danger" such="such" critical="critical" may="may" be="be" neglected="neglected" as="as" result="result" confusion="confusion" surrounds="surrounds" polarized="polarized" debate="debate" on="on" whether="whether" or="or" not="not" cause="cause" cd="cd" because="because" wrong="wrong" question="question" being="being" asked.="asked." p="p"/>References
1. Selby W et al. Antibiotic Therapy for Crohn’s Disease. Proceeding in the
Gastroenterology Society of Queensland Update, June 2005:5.
2. Wallace RJ et al, Diagnosis and Treatment of Disease Caused by
Nontuberculous Mycobacteria, Am J Respir Crit Care Med 1997; 156:S1-S25.
We read with interest the findings of Forrest et al ; Gut 2005; 54: 1174-1179, regarding their prognostic algorithm for alcoholic hepatitis;
Glasgow alcoholic hepatitis score (GAHS). The study uses robust clinical
end-points to develop an algorithm that has diagnostic advantages over the
modified discriminant function score (DFS). We would like to discuss some
of the future implications of this importa...
We read with interest the findings of Forrest et al ; Gut 2005; 54: 1174-1179, regarding their prognostic algorithm for alcoholic hepatitis;
Glasgow alcoholic hepatitis score (GAHS). The study uses robust clinical
end-points to develop an algorithm that has diagnostic advantages over the
modified discriminant function score (DFS). We would like to discuss some
of the future implications of this important study.
The overall death rate in the study was 23% at 28 days and the death
rate of patients with a DFS >32 was 29% at 28 days in the derivation
population. The latter figure is lower than the placebo arms of many of
the RCTs of alcoholic hepatitis that range between 35 to 50%.[1-3] This
difference compared to the published literature may be attributable to
case definition. It is possible that there were a fewer number of patients
in the derivation cohort for GAHS with true alcoholic hepatitis. Some of
the previous studies of alcoholic hepatitis have required liver biopsy
evidence of alcoholic hepatitis as part of the case definition. This was
not the case for entry into the derivation cohort for the GAHS study and
the case definition was based solely on clinical and biochemical evidence
of liver dysfunction in patients with heavy alcohol consumption. In the
validation population there was biopsy evidence of alcoholic hepatitis in
only 33%.
While this may invalidate the GAHS as a means for identifying cases
of alcoholic hepatitis it does not invalidate its use in identifying
patients at risk of death when admitted to hospital with liver dysfunction
on a background of heavy alcohol use. This makes it far more pragmatic
than tests based on biopsies as many hospitals do not have access to
specialised services to perform transjugular liver biopsies in the acute
setting. Furthermore, there are published RCTs which have not required
histological evidence of alcoholic hepatitis before allocating treatment.[1,4] The corollary to this is that although alcoholic hepatitis often
presents with clinical features of fever, leucocytosis and
hyperbilirubinaemia, there remains a differential diagnosis which may
require a biopsy to resolve.[5]
It is important to differentiate between true alcoholic hepatitis and
severe liver dysfunction in patients with heavy alcohol consumption
because it will influence the choice of intervention. Randomised
controlled trials that use GAHS to identify patients with alcoholic
hepatitis might be greatly underpowered if the therapy, e.g. steroids, is
effective in alcoholic hepatitis but ineffective or harmful in other
clinical conditions where abnormal clinical parameters might be associated
with heavy alcohol consumption. The selection of risk stratification
models should be determined by the severity of the adverse effects of the
therapy under trial. Those with more severe adverse effects will warrant
models with high specificity whereas drugs with minimal side effects will
benefit from a model with a high sensitivity. Compared to the DFS, the
GAHS has an increased specificity, decreased sensitivity and improved
accuracy making it suited to the selection of subjects in studies using
more toxic therapies.
The utility of the GAHS will depend upon the effect of its use in the
care of patients. We suggest that the next step in the evaluation of GAHS
should be a clinical trial to see if patients randomised to risk
stratification with GAHS followed by appropriate interventions have a
better outcome than those managed conventionally.
We think this is an excellent study using robust clinical end points.
It is a practical model which can be used easily at the bed side, to give
valuable prognostic information. Success of future therapeutic trials in
alcoholic hepatitis will not only depend on the efficacy of the drug but
also the appropriate selection of patients by models and their respective
cut-off points.
Yours sincerely,
I N Guha
WM Rosenberg
University of Southampton Liver Unit
Mail point 811
Level D
Southampton General Hospital
Trenoma Road
S016 6YD
References
1. Carithers RL, Jr., Herlong HF, Diehl AM, Shaw EW, Combes B, Fallon
HJ, Maddrey WC. Methylprednisolone therapy in patients with severe
alcoholic hepatitis. A randomized multicenter trial. Ann Intern Med
1989;110:685-690.
2. Mathurin P, Mendenhall CL, Carithers RL, Jr., Ramond MJ, Maddrey
WC, Garstide P, Rueff B, Naveau S, Chaput JC, Poynard T. Corticosteroids
improve short-term survival in patients with severe alcoholic hepatitis
(AH): individual data analysis of the last three randomized placebo
controlled double blind trials of corticosteroids in severe AH. J Hepatol
2002;36:480-487.
3. Ramond MJ, Poynard T, Rueff B, Mathurin P, Theodore C, Chaput JC,
Benhamou JP. A randomized trial of prednisolone in patients with severe
alcoholic hepatitis. N Engl J Med 1992;326:507-512.
4. Mendenhall CL, Anderson S, Garcia-Pont P, Goldberg S, Kiernan T,
Seeff LB, Sorrell M, Tamburro C, Weesner R, Zetterman R. Short-term and
long-term survival in patients with alcoholic hepatitis treated with
oxandrolone and prednisolone. N Engl J Med 1984;311:1464-1470.
5. Oxford Textbook of Clinical Hepatology 2nd Edition. Edited by
Bircher J, Benhamou J, Mcintyre N, Rizetto M and Rodes J. Volume 2,
Chapter 15.3; 1185-1238.
Mueller-Koch et al. in Gut 2005 June 14th (Epub) describe clinical and molecular evidence for a 'new entity' of hereditary colorectal cancer. Clustering of colorectal cancer (CRC) within families has been known for
some time [1] and it is not surprising that some such families will meet the Amsterdam Criteria (AC) even though they do not carry a germline mutation in a DNA mismatch repair gene. It has bee...
Mueller-Koch et al. in Gut 2005 June 14th (Epub) describe clinical and molecular evidence for a 'new entity' of hereditary colorectal cancer. Clustering of colorectal cancer (CRC) within families has been known for
some time [1] and it is not surprising that some such families will meet the Amsterdam Criteria (AC) even though they do not carry a germline mutation in a DNA mismatch repair gene. It has been demonstrated previously that AC-positive families without evidence of a DNA mismatch
repair defect do not show either the clinical or pathological features of HNPCC/Lynch syndrome.[2] With respect to CRC the differences extend to multiplicity, anatomical site, histopathology, and DNA ploidy status.[2]
With respect to colorectal adenomas, these are more frequent but less advanced in AC-positive families in which there is no evidence of a DNA mismatch repair defect.[3] More recently it has been shown that the differences extend to the risks of developing both CRC and extra-colonic cancer.[4] The fundamental issue is whether it is reasonable to continue to use the limited set of clinical features that comprise the AC as a diagnostic label when there is clear evidence that families that meet the AC are clinically heterogeneous.[5]
References
1. Vasen HFA, Taal BG, Griffioen G, Nagengast FM, Cats A, Menko F, et al. Clinical heterogeneity of familial colorectal cancer and its influence on screening protocols. Gut 1994;35:1262-6.
2. Jass JR, Cottier DS, Jeevaratnam P, Pokos V, Holdaway KM, Bowden ML, et al. Diagnostic use of microsatellite instability in hereditary non-polyposis colorectal cancer. Lancet 1995;346:1200-1.
3. Jass JR, Pokos V, Arnold JL, Cottier DS, Jeevaratnam P, Van de Water NS, et al. Colorectal neoplasms detected colonoscopically in at-risk members of colorectal cancer families stratified by the demonstration of DNA microsatellite instability. J Mol Med 1996;74:547-51.
4. Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, et al. Lower cancer incidence in Amsterdam-1 criteria families without mismatch repair deficiency. Familial colorectal cancer type X. JAMA 2005;293:1979-85.
5. Jass JR. Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC). Gut 2004;53:1055.
We have been following the case of a 41 year old male with
spontaneous and recurrent episodes of vomiting occurring regularly in a cycle every 4-6 months, separated by symptom-free intervals, which started 5 years ago. Endoscopy and imaging studies were negative for disease. He is healthy and does not have any other active medical problems. He
admitted to be a daily marijuana user for the past 20 years....
We have been following the case of a 41 year old male with
spontaneous and recurrent episodes of vomiting occurring regularly in a cycle every 4-6 months, separated by symptom-free intervals, which started 5 years ago. Endoscopy and imaging studies were negative for disease. He is healthy and does not have any other active medical problems. He
admitted to be a daily marijuana user for the past 20 years. A scintigraphic gastric emptying study performed last November 2004 revealed delayed emptying at the 2nd and 4th hour (39% [40-78%] and 64% [84-98%] respectively [normal range in brackets]).
Allen et al.[1] suggested the association of cannabis use and hyperemesis. We advised our patient to cease from marijuana use. After 2 weeks of abstention, a repeat gastric emptying study was performed, and showed normal 2nd and 4th hour emptying (58% and 94% respectively). Clinically, it is still too premature at this point to make a statement
whether he will be free from his cyclic vomiting episodes.
The mechanism of cannabinoid hyperemesis and cyclic vomiting syndrome is unknown. To date, cyclic vomiting has not been shown to be associated with any GI functional testing abnormality. Clinical studies on the effect of cannabis showed delayed gastric emptying in healthy volunteers.[2] The case series of Allen et al. suggested the association
of chronic cannabis use and hyperemesis but the physiologic explanation of the phenomena was not fully elucidated.
The presentation of this case was not an attempt to explain the neuropharmacology of chronic marijuana use and its role in cyclic vomiting syndrome. Rather, we are more intrigued by the observation that chronic marijuana use may lead to gastric dysmotility resulting in hyperemesis, and that the dysmotility may normalize after a period of cessation. It is
apparent that further studies are needed to determine marijuana-associated toxicity. Also, the association between marijuana use and cyclic vomiting syndrome should further be explored with longitudinal, population based
studies.
We do, however, reiterate the views of Allen et al. that in the management of patients presenting with hyperemesis, marijuana use should be ascertained, and its cessation should be recommended.
References:
1.Allen, J.H., G.M. de Moore, R. Heddle, et al., Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut, 2004. 53(11): p. 1566-70.
2.McCallum, R.W., I. Soykan, K.R. Sridhar, et al., Delta-9-
tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study. Alimentary Pharmacology & Therapeutics, 1999. 13(1): p. 77-80.
With great interest we read the tutorial by Forbes. We would like to
stress that the count of CD4 lymphocytes (and possibly immunoglobulines)
might be quite helpful in the differential diagnosis of chronic
inflammatory bowel disease and tuberculosis as evidenced by the following
case report:
A 35-year-old Iranian patient presented to our clinic with chronic
diarrhea, intermittent abdominal pa...
With great interest we read the tutorial by Forbes. We would like to
stress that the count of CD4 lymphocytes (and possibly immunoglobulines)
might be quite helpful in the differential diagnosis of chronic
inflammatory bowel disease and tuberculosis as evidenced by the following
case report:
A 35-year-old Iranian patient presented to our clinic with chronic
diarrhea, intermittent abdominal pain and a 10 kg weight loss over the
last four months. The right lower abdomen was slightly tender at the
physical examination. Routine laboratory tests revealed hypochromic
microcytic anemia, an elevated ESR (88 mm in the first hour) and a low
serum albumin of 25 g/l (normal range 35-50 g/l). Multiple ulcers with
signs of scarring were detected by colonoscopy in the distal ascending
colon (Fig. 1a).
Figure 1a
The histological examination of biopsy specimens
disclosed granulomatous disease of the ascending colon (Fig. 1b) but
normal mucosa in the more distal colon and the rectum.
Despite a normal peripheral leukocyte count, the peripheral CD4
lymphocytes had decreased to 17/µl (normal range 400-1800/µl).
Figure 1b
HIV infection was excluded. However, the tuberculin test was positive, and
Ziehl-Neelsen staining demonstrated acid-fast bacilli in the colonic
biopsies (Fig. 1c). The left lung showed some pleural scarring on the
chest x-ray. Ultrasound revealed slight pericardial effusion as well as
some ascites. Antituberculotic chemotherapy was initiated, and
nonresistant Mycobacterium tuberculosis was finally cultured from the
colonic biopsies. Now, five years later, the patient is well, and the
peripheral CD4 lymphocyte count has normalized.
Figure 1c
Hans Scherübl, MD
Charité-Universitätsmedizin Berlin, Germany
Martin Zeitz, MD
Campus Benjamin Franklin, Berlin, Germany
Corresponding address:
Hans Scherübl, MD,
Gastroenterologie, Infektiologie, Rheumatologie
Charité-Universitätsmedizin Berlin,
Campus Benjamin Franklin
Hindenburgdamm 30, 12200 Berlin, Germany
hans.scherubl@charite.de
Phone: 0049 30 84453534
John MRyan, Alistair Murray, Sarah O Connell, Tulo Alugo
20 July, 2005
Dear Editor,
We read with interest the latest guidelines for the management of
acute pancreatitis. We noted no mention of emergency medicine in the
guidelines and in particular we did not identify any emergency physician
in the working party. Was the British Association for Emergency Medicine
consulted during the production of the guidelines?
Patients with acute pancreatitis most frequently present to emer...
We read with interest the latest guidelines for the management of
acute pancreatitis. We noted no mention of emergency medicine in the
guidelines and in particular we did not identify any emergency physician
in the working party. Was the British Association for Emergency Medicine
consulted during the production of the guidelines?
Patients with acute pancreatitis most frequently present to emergency
departments with undifferentiated abdominal pain and in late presentations
where the patient may present in shock the diagnosis is not always
immediately evident.
We note section 9.0 which pertains to the initial management and
prevention of complications. However, the reality persists in 2005 that the
majority of patients presenting to emergency departments in the UK with
undifferentiated abdominal pain will first be seen by relatively junior
Senior House Officers.
We believe that an algorithm which includes the important early
investigations and specific treatments would be helpful. In particular
specific mention of the value of early arterial blood gas analysis and
lactate measurement as early markers of organ failure should be specified.
These tests are readily available in most emergency departments as a near
patient test and their value should be clearly specified.
In summary, while these guidelines are undoubtedly helpful we are
disappointed that there is no clear evidence of involvement with emergency
medicine in their production when the specialty of emergency medicine has
such important relevance to the disorder. Perhaps the next revision might
include representation in the working party.
We thank Dr. Jolobe very much for his letter which mentions the difficulty of
establishing the diagnosis of acute pancreatitis in patients with diabetic
ketoacidosis.
We did not address diagnostic tests and medical intensive care
treatment of acute pancreatitis in the present article, but reviewed the
interventional and surgical treatment strategies in acute pancreatitis.
There is no doubt...
We thank Dr. Jolobe very much for his letter which mentions the difficulty of
establishing the diagnosis of acute pancreatitis in patients with diabetic
ketoacidosis.
We did not address diagnostic tests and medical intensive care
treatment of acute pancreatitis in the present article, but reviewed the
interventional and surgical treatment strategies in acute pancreatitis.
There is no doubt that treatment of acute pancreatitis including organ
failure in its early phase is solely supportive.[1] Due to improvements
of intensive care medicine, the mortality of severe disease has been
decreased dramatically over the past decades.
However, to treat the
patient adequately, the correct diagnosis has to be made. Therefore, the
first step in the diagnostic process of acute pancreatitis is to think of
this disease. According to the last classification of Atlanta [2], acute
pancreatitis is an acute inflammatory process of the pancreas with
variable involvement of other regional tissues or remote organ systems.
From the clinical point of view, acute upper abdominal pain and elevated
pancreatic enzyme levels are needed to diagnose acute pancreatitis.
As
pointed out by Dr Jolobe, acute pancreatitis is still underdiagnosed
under certain clinical conditions including diabetic ketoacidosis, but
also in other clinical situations such as shock of unknown origin,
patients under intensive care treatment, as well as rare causes of the
disease. Since acute pancreatitis can be associated with diabetic
ketoacidosis and the association between these two is of a two-way cause
and effect relationship, early imaging of the pancreas is recommended in
these patients to establish the correct diagnosis.
Our article "Management of acute pancreatitis: from surgery to
interventional intensive care." focused only on the surgical and
interventional treatment of severe acute pancreatitis.[3]
Yours sincerely,
Jens Werner, MD
Markus Büchler, MD
References
1. UK guidelines for the management of acute pancreatitis. Gut. 2005
May;54 Suppl 3:iii1-9.
2. Bradley ELd. A clinically based classification system for acute
pancreatitis. Summary of the International Symposium on Acute
Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993;
128(5):586-90.
3. Werner J, Feuerbach S, Uhl W, Büchler M. Management of acute
pancreatitis: from surgery to interventional intensive care. Gut 2005;
54:426-436.
Tateishi et al. in a recently publication in Gut (2005;54:419-425)
proposed the “Tokyo score”, a new prognostic model for hepatocellular
carcinoma (HCC). This score consists of four factors: serum albumin,
bilirubin, size and number of tumours. This model was established by
analysing survival time among HCC patients treated with medical ablation.
HCC was detected with ultrasound and/or computed tomo...
Tateishi et al. in a recently publication in Gut (2005;54:419-425)
proposed the “Tokyo score”, a new prognostic model for hepatocellular
carcinoma (HCC). This score consists of four factors: serum albumin,
bilirubin, size and number of tumours. This model was established by
analysing survival time among HCC patients treated with medical ablation.
HCC was detected with ultrasound and/or computed tomography (CT). In the
external validation the predictive ability of Tokyo score was equal to
CLIP score. It is in the conclusions of the authors, that “the Tokyo score
may be useful in predicting the prognosis of HCC patients who are
candidates for these curative treatments” and that “the Tokyo score may
not be predictive for advanced disease”.
The Tokyo score is coming to be added in a total of over 20
classification-scoring systems for HCC, which were evaluated and proposed
during the last 15 years. One of the recent developments in the field is
the radical revision of the Tumour-Node-Metastasis System of the
International Union against Cancer considering primary liver tumours.[1]
This 6th edition of TNM system is not taking under consideration in the
above mentioned publication.
A consensus conference about staging systems for HCC organized by the
American Hepato-Pancreato-Biliary Assosiation and the American Joint
Commission on Cancer declared that there is no “ideal” system, but pointed
out that the CLIP system has the advantage of using readily available
clinical, radiological, and laboratory data to stage patients.[2] It was
one of the purposes of this consensus conference to impede the continuous
proposal of new staging systems for HCC and to find a solution for
international comparison of the HCC data. Predictive ability of Tokyo
score is not found to be better as the wide accepted CLIP score.
Liver cirrhosis in Child-Pugh B/C class was present in 45% of the
training sample. Furthermore, it is not clear in how many of the patients
in this study a CT was performed as the diagnosis was established. The
identification of the number of HCC lesions in the cirrhotic liver remains
a difficult task. In a retrospective study of 70 patients with HCC in
cirrhosis undergoing liver transplantation, correct identification of the
number of tumours was only 34%. Sensitivity of radiological imaging was
especially poor for tumours between 1-2cm and <_1cm _21="_21" and="and" _0="_0" respectively.3="respectively.3" krinsky="krinsky" et="et" al.="al." showed="showed" that="that" magnetic="magnetic" resonance="resonance" imaging="imaging" depicted="depicted" only="only" _39="_39" of="of" _118="_118" hcc="hcc" in="in" cirrhosis="cirrhosis" for="for" an="an" overall="overall" sensitivity="sensitivity" _33.="_33." detection="detection" small="small" tumours="tumours" was="was" inadequate="inadequate" with="with" _11="_11" _52="_52" lesion="lesion" between="between" _1="_1" _2cm="_2cm" three="three" _4="_4" _72="_72" lesions1cm="lesions1cm" correctly="correctly" classified.4="classified.4" lopez="lopez" hanninen="hanninen" evaluating="evaluating" the="the" ct="ct" reported="reported" a="a" _20="_20" _5.="_5." same="same" findings="findings" were="were" by="by" bhartia="bhartia" concluding="concluding" identification="identification" tumors="tumors" smaller="smaller" than="than" _1cm="_1cm" is="is" still="still" limited.6="limited.6" furthermore="furthermore" klintmalm="klintmalm" prospective="prospective" randomized="randomized" multicentre="multicentre" trial="trial" multifocal="multifocal" incidentally="incidentally" found="found" _48="_48" _169="_169" patients="patients" analyzed7="analyzed7" p="p"/> Besides, ablative methods for HCC are nowadays considered as
palliative and not as “curative treatments”. Mazzaferro et al. in a
prospective study of the histologic response-rate of radiofrequency
ablation (RFA) in 60 cirrhotic patients with small HCCs awaiting liver
transplantation found a complete response rate of 55%. According to the
authors, RFA “should not be considered an independent therapy for HCC”.[8]
The prospective validation of the new TNM system and the wide
application of the CLIP system could contribute to an international
stratification of a treatment strategy for HCC. New scoring proposals are
always interesting, especially these with easily application, as the
"Tokyo score". However, the risk of application of different systems in
different countries could lead to further confusion and remind us the
biblical “tower of Babel”.
References
1. Sobin LH, Wittekind CH. TNM Classification of malignant tumours.
Sixth edition. West Sussex: John Wiley & Sons Ltd.; 2002.
2. Di Bisceglie AM, Strasberg S. A common staging system for
hepatocellular carcinoma. Hepatology 2004;39: 550-1.
3. Sotiropoulos GC, Malagó M, Molmenti E, et al. Liver Transplantation
for hepatocellular carcinoma in cirrhosis: Is clinical tumor
classification prior to transplantation realistic? Transplantation
2005;79:483-7.
4. Krinsky GA, Lee VS, Theise ND, et al. Transplantation for
hepatocellular carcinoma and cirrhosis: Sensitivity of magnetic resonance
imaging. Liver Transpl 2002;8:1156-64.
5. Lopez Hanninen E, Vogl TJ, Bechstein WO, et al. Biphasic spiral
computed tomography for detection of hepatocellular carcinoma before
resection or orthotopic liver transplantation. Invest Radiol 1998;33:216-
21.
6. Bhartia B, Ward J, Guthrie JA, Robinson PJ. Hepatocellular
carcinoma in cirrhotic livers: Double-contrast thin-section MR imaging
with pathologic correlation of explanted tissue. AJR Am J Roentgenol
2003;180:577-84.
7. Klintmalm GB. Liver transplantation for hepatocellular carcinoma: a
registry report of the impact of tumor characteristics on outcome. Ann
Surg 1998;228:479-90.
8. Mazzaferro V, Battiston C, Perrone S, et al. Radiofrequency
ablation of small hepatocellular carcinoma in cirrhotic patients awaiting
liver transplantation: a prospective study. Ann Surg 2004;240: 900-9.
I write as the statistician on the paper by Mulcare and collaborators
[1] which was criticised by Drs Kolho and Järvelä in their "Author's
Reply" eLetter to Gut Online. I wish to correct two assertions made by
Drs Kolho and Järvelä. The first is their claim that our statistical
procedure “contains a risk for wrong conclusions” because “adult-type
hypolactasia is difficult to assess due to inaccurate d...
I write as the statistician on the paper by Mulcare and collaborators
[1] which was criticised by Drs Kolho and Järvelä in their "Author's
Reply" eLetter to Gut Online. I wish to correct two assertions made by
Drs Kolho and Järvelä. The first is their claim that our statistical
procedure “contains a risk for wrong conclusions” because “adult-type
hypolactasia is difficult to assess due to inaccurate diagnostic tests”.
This would indeed be true had we applied a ‘naïve’ test (for example, a
chi-squared test) in which we had assumed the diagnoses of hypolactasia to
be without error. In fact, not only did we assume that diagnoses occurred
with error, but we did not even presume to know exactly what that level of
error was. Instead, our uncertainty about the true level of error was
modelled in a Bayesian framework and trained using available published
data on comparisons of ‘true’ diagnoses (e.g. based on biopsy results) and
‘indirect’ diagnoses (e.g. based on breath hydrogen).
To accomplish this,
a novel statistical method was developed, and described in [1]. The fact
that we incorporated these additional sources of error into our method
means that the p-values we obtained were not as low as they would have
been had we applied a naïve test such as a chi-squared test. Our
remarkable finding was that, despite this, we still found significant
departures in multiple sub-Saharan African populations. This led us to
reject the Null Hypothesis that the presence of the C/T-13910 variant
alone, even with diagnostic error, could explain the published data on
lactase persistence in Africa. Other reasons must be sought to explain
our results, one of which is the possibility that additional genetic
variants influence lactase persistence.
The second assertion by Drs Kolho and Järvelä was that there were “no
statistics shown against the C/T-13910–variant but only speculation
presented in the paper by Mulcare et al.” The meaning is unclear here.
Certainly, statistics both in the sense of ‘data’ and in the sense of
‘inference’ were presented in our paper (see above). Our conclusions
regarding the C/T-13910 variant were derived from carefully-constructed
statistical inference, and not mere ‘speculation’.
Reference
1. Mulcare CA et al. The T allele of a single-nucleotide polymorphism
13.9 kb upstream of the lactase gene (LCT) (C-13.9kbT) does not predict or
cause the lactase-persistence phenotype in Africans. Am J Hum Genet 2004;
74:1102 -10.
We were interested to read the article of Asakawa et al. Gut
2005;54:18-24 which reported that ICV and peripheral administration of des
-acylated ghrelin inhibited food intake in mice in the fasted state.
Acylated ghrelin (AG) has a unique biological structure with an acyl side
chain on the 3rd amino acid residue. AG is an endogenous ligand for the
growth hormone secretagogue receptor (GHS-R1a) [1] and...
We were interested to read the article of Asakawa et al. Gut
2005;54:18-24 which reported that ICV and peripheral administration of des
-acylated ghrelin inhibited food intake in mice in the fasted state.
Acylated ghrelin (AG) has a unique biological structure with an acyl side
chain on the 3rd amino acid residue. AG is an endogenous ligand for the
growth hormone secretagogue receptor (GHS-R1a) [1] and stimulates feeding
and growth hormone release. In contrast, des-acylated ghrelin (DAG),
which does not have the acyl side chain, has no affinity for the GHS-R1a.[1] As the authors suggest, their results might indicate the presence of
an alternative receptor through which des-acylated ghrelin acts.
We were interested to investigate whether DAG would modulate feeding.
We injected saline, 0.3nmol/g AG and 0.3nmol/g DAG to C57Bl6 male mice
intraperitoneally on two occasions, firstly in the fed state and secondly
following a 20 hour fast and measured food intake at 1, 2, 4, 6 and 24
hours post injection (Figure 1). In the fasting experiment, we also
injected 0.03nmol/g PYY3-36 as a positive control. All animal procedures
were approved by the British Home Office Animals (Scientific Procedures)
Act 1986 (Project License number 70/5281). Results were analyzed using a
one-way repeated measures ANOVA.
As previously reported [2], AG
stimulated feeding in the fed state. However, DAG had no significant
effect on food intake in the fed state. In the fasting study, PYY3-36
significantly inhibited feeding. AG stimulated cumulative food intake in
the fasted mice for up to 6 hours post injection, although the percentage
increase compared with saline was less than in the fed state (% increase 2
hours following ghrelin injection: fed state 320%, fasted state 30%). In
contrast with the findings of Asakawa et al., DAG had no effect on food
intake at any time point examined. We used a higher dose of DAG than that
administered by Asakawa et al. (approximately 7.5nmol vs. 3nmol per mouse)
and therefore the absence of a feeding effect associated with DAG is
unlikely to be explained by differences in doses.
In conclusion, we have observed that acylated ghrelin stimulated food
intake in the fasting as well as the fed state. In contrast with the
findings of Asakawa et al., there was no alteration in feeding in either
the fed or fasting state following des-acylated ghrelin. Our results
suggest that circulating acylated ghrelin stimulates feeding independently
of des-acyl ghrelin.
References
1. Kojima M, Hosoda H, Date Y et al. Ghrelin is a growth-hormone-
releasing acylated peptide from stomach. Nature 1999;402(6762):656-60.
2. Wren AM, Small CJ, Ward HL et al. The novel hypothalamic peptide
ghrelin stimulates food intake and growth hormone secretion. Endocrinology
2000;141(11):4325-8.
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Dear Editor,
We were interested to read the article of Asakawa et al. Gut 2005;54:18-24 which reported that ICV and peripheral administration of des -acylated ghrelin inhibited food intake in mice in the fasted state. Acylated ghrelin (AG) has a unique biological structure with an acyl side chain on the 3rd amino acid residue. AG is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a) [1] and...
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