JerMa88/BMC_Gastroenterology_Peer_Reviews huggingface dataset:
Review for 10.1186/1471-230X-10-57 (2010)

Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 2Date:10 December 2009
Reviewer: Shinichi Ikushiro
Reviewer's report:
General comment
The authers described the combined effect of regulatory region polymorphisms of
Glibert syndrome on UGT1A1 promoter-dependent transcriptional activity. It is
important to estimate transcriptional activity of UGT1A1 gene in individual for
estimation of side effects of several drug treatment ( eg. irrinotecan toxicity). The
paper reported several haplotypes with different combinations of the 14 relavant
mutations of UGT1A1 expression regulatory region in Gilbert syndrome. Although
this article indicates the combine effects of polymorphisms in ( TATA box and
related regions), it is difficult to find the significant difference of expression
efficiency in those mutations.
Specific comments
1) To estimate the effect of CAR on the promoter –dependent expression in
reporter assay system, normalization of CAR expression is needed. . Did you
check the expression level of CAR in each experiments.
2) It is difficult to find the use of supplemental data in text. You should more
describe about the result of supplement data for multiple regression analysis.
3) Reference list contains some mistake. You should carefully check the
reference in Ref.23 and 30.
Level of interest: An article of insufficient interest to warrant publication in a
scientific/medical journal
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-57 (2010)

Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 2Date:11 January 2010
Reviewer: ElÃ-sio Costa
Reviewer's report:
I think this is a very interesting paper that, in my oppinion, can be accepetd for
publication in BMC Gastroenterology.
Review for 10.1186/1471-230X-10-57 (2010)

Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 2Date:5 February 2010
Reviewer: Rene HM te Morsche
Reviewer's report:
In the report by Katsuyuki Matsui and coworkers the promoter region of a number
of Japanese and Caucasian patients and controls were sequenced. Using the
most common haplotypes found they constructed luciferase containing plasmids
to reveal how much each haplotype contributes to the transcription of UGT1A1.
This report gives interesting information about what regions of the promoter are
important and how they influence the transcription of UGT1A1.
Minor Essential Revisions
Results:
Constructing diplotypes of the patients and controls would be really interesting.
Are patients always homozygous for certain polymorphisms in contrast to
controls?
And if the author have access to the bilirubin levels of the subjects used in this
report these would be very helpful in relating them to the diplotypes and the
transcription activity.
Discussion:
“Our result are also consistent…..Gilbert syndrome (5-10% of the population)”
This statement is not accurate since Gilbert syndrome is believed to be
associated with homozygous A(TA)7TAA. The prevalence of homozygous
subjects is about 12% in Caucasians and thus is not that different.
“Our result for A(TA)7TAA …..c.-3275T>G but without A(TA)7TAA”. However
also a haplotype with c.-3275G (typeII) was found in 23 controls in contrast to the
haplotypes with A(TA)7TAA which is less frequent found in controls. This
implicates that the c.3275T>G polymorphism is less important in Gilbert
syndrome patients than the A(TA)6/7TAA polymorphism although the reduction
in transcription is higher. Could the authors explain this.
Discretionary revisions
Background:
There are some articles like the one from Katrin Borucki et al. 2009 where
bilirubin levels are related to some polymorphisms also mentioned in this report.
To mention some of these findings would be of surplus value why the
researchers in this report constructed the plasmids in order to measure
transcription activity.
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
Review for 10.1186/1471-230X-10-57 (2010)

Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 2Date:5 February 2010
Reviewer: Libor Vítek
Reviewer's report:
The paper by Matsui et al. entitled ¨Combined effect of regulatory polymorphisms
on transcription of UGT1A1 as a cause of Gilbert syndrome¨ presents important
data on the role of various mutations in the regulatory region of UGT1A1 gene on
manifestation of Gilbert syndrome. This kind of information is very important to
account for the fact that only 50% A(TA)7TAA homozygotes manifest with
unconjugated hyperbilirubinemia. Nevertheless, there are several flaws, which
need to be clarified prior re-consideration of a paper for publication in BMC
Gastroenterology.
Major compulsory revisions:
1) The information on serum/plasma bilirubin levels in individual haplotypes is
completely lacking. This must be added to the Result section and Table 2, or
even depicted on the Figure, and discussed appropriately. In the Table 2,
information of numbers of subjects in individual haplotype groups should also be
added. This information seems to be essential to assess the clinical relevance of
studied haplotypes.
2) The authors state (page 5) that ¨the combined effect of homozygosity for both
A(TA)7TAA and c.-3275T>G is essential for manifestation of Gilbert syndrome¨
and that ¨Gilbert syndrome was observed only with homozygous c.-3275T>G at
gtPBREM¨ (page 14). The authors use references 22 and 25 as an evidence for
this statement. However, this statement not true, since there are at least two
reports demonstrating that homozygosity for c.-3275T>G is not always present in
Gilbert syndrome subjects (refs. 27,28, used by authors in different connotation).
This misstatement must be corrected.
Minor essential revisions:
Since CAR was convincingly shown to influence UGT1A1 transcription, the
authors should also comment, whether CAR mutations could explain some
variability in serum bilirubin levels common in Gilbert syndrome.
3) T-w/G-m/T-m/G-w depictions of expression vectors used in Figs 1 and 2
should be explained in the Figure legend to understand fully the Figs.
4) Supplementary data are not mentioned within the text. It is also not clear what
Study 1 and 2 really mean.
Discretionary comments
1) page 6: The term ¨50 Japanese population¨ looks weird and should be
substituted by a more appropriate term.
2) page 13: UGT1A1 gene should always be written in italics
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-57 (2010)

Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 2Date:10 February 2010
Reviewer: Ching-Shan Huang
Reviewer's report:
1. Are all the SNPs found in the subjects suffering from Gilbert syndrome also
observed in the normal controls? If the answer is yes, “mutation” should be
converted to “variation” at all.
2. Page 15: “Our results for A(TA)7TAA and c.-3275T>G are consistent with the
fact that some homozygotes with A(TA)7TAA do not suffer from Gilbert syndrome
[27,28], and that there are patients with homozygous c.-3275T>G but without
A(TA)7TAA [25].” The following article may be considered to be cited as an
additional reference: Huang YY, Huang MJ, Yang SS, Teng HC, Huang CS:
Variations in the UDP- glucuronosyltransferase 1A1 gene for the development of
unconjugated hyperbilirubinemia in Taiwanese. Pharmacogenomics 2008,
9:1229-1235.
3. Page 16: “Our study shows that -3275T>G and the ten polymorphisms
detected in the patients are not pppless important in their effect on transcription
than A(TA)7TAA, and that Gilbert syndrome is likely to be caused by the
combined effects of these polymorphisms.” Is “pppless” a mistake? Would it be
“less”?
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-57 (2010)

Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 3Date:7 April 2010
Reviewer: Shinichi Ikushiro
Reviewer's report:
The authers have improved the manuscript as suggested by referees' comments.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Review for 10.1186/1471-230X-10-57 (2010)

Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 3Date:14 April 2010
Reviewer: Rene HM te Morsche
Reviewer's report:
In the report by Katsuyuki Matsui and coworkers the promoter region of a number
of Japanese and Caucasian patients were sequenced. Using the most common
haplotypes they constructed luciferase containing plasmids to reveal how much
each haplotype contributes to the transcripion of UGT1A1. This report gives
interesting information about what regions of the promoter are important and how
they influence the transcription of UGT1A1.
The answers given by the authors on the previous report are satisfactory.
Discretionary revisions
Discussion:
"Our results also match......Gilbert syndrome (found in 3-10% of the population)"
The authors use alele frequencies in this sentence which makes the difference
between this frequency and the Gilbert syndrome frequency appear bigger than it
really is. It would be more appropriate to use the genotype frequency of the
homozygous A(TA)7TAA so these numbers can be seen a a better perspective.
Also lifestyle plays an important role whether patients phenotypically present with
Gilbert syndrome and thus patients having homozygous A(TA)7TAA do always
present the syndrome.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
Review for 10.1186/1471-230X-10-57 (2010)

Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 3Date:14 April 2010
Reviewer: Libor Vítek
Reviewer's report:
Minor comments:
The paper has improved substantially by addressing of all comments.
Nevertheless, since authors were not able to relate genotypes with serum
bilirubin levels, it should be steted at the end of paper taht further studies are
needed/planned to elucidate this relationship.
UG1A1 gene is not always written in italics (see e.g. p. 18)
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
'I declare that I have no competing interests
Review for 10.1186/1471-230X-10-58 (2010)

Reviewer's report
Title:Effects of mannoprotein E1 in liquid diet on inflammatory response and
TLR5 expression in the gut of rats infected by Salmonella typhimurium
Version: 1Date:12 January 2010
Reviewer: Shizuo Akira
Reviewer's report:
Several lines of evidence support a role for Toll-like receptor (TLR) signaling to
protect the intestine from pathogenic infection. TLR signaling at the level of the
intestinal epithelium is critical for mucosal immune responses. The intestine is
normally colonized by a large and diverse commensal microbiota and is
occasionally exposed to a variety of potential pathogens. One specific molecular
interaction that appears to play a key role in governing bacterial-intestinal
interactions is that of the bacterial protein flagellin with toll-like receptor 5. This
study investigates the effects of mannoprotein administration in a liquid diet on
inflammatory response and TLR5 expression changes during intestinal tissue
injury in a rat model of infection with Salmonella typhimurium. The study has
been well improved according to previous reviewer’s suggestions this time.
Major concerns:
1. Due to the change of their text, evaluation of bacterial translocation (BT) is
now appropriate.
2.After the paper has been reviewed by a gastroenterologist, the terminology
became correct.
3.The mechanisms of flagellin-TLR5 pathway (MYD 88) as well as mechanisms
of proliferatin (ERK) and apoptosis (bax,bcl2, FAS etc) were well-discussed in
the revised manuscript.
Minor concerns:
The authors changed all the points according to the reviewer’s suggestion
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Declaration of competing interests:
I declare that I have no competing interests' below.
Review for 10.1186/1471-230X-10-34 (2010)

Reviewer's report
Title:Development of an invasively monitored porcine model of
acetaminophen-induced acute liver failure
Version: 1Date:3 February 2010
Reviewer: Humphrey Hodgson
Reviewer's report:
This study contains worthwhile data, which should help other researchers
intending to develop a large animal model for acute liver failure. It has some
important messages, but there are also some significant omissions and areas of
discussion need attention.
A key approach in this porcine model was to monitor acetaminophen levels and
thus (more-or-less) avoid methaemoglobinaemia (an event which if it occurs
confounds comparison with human acetaminophen toxicity acute liver failure
problem).
An important omission in the clinical detail is an account of the anaesthetic
strategy used to maintain the animals. In particular what fluids were infused? The
increased pulmonary resistance and dyspnoea observed in many of the pigs
would be unsurprising if these hypoproteinaemic animals received large volumes
of saline and died of pulmonary oedema. (Incidentally fig 4 appears to be
mislabelled as the rising pulmonary pressure terminally is seen in the control
group). The authors speculate on the nature of the lung pathophysiology, but
provide no histological evidence.
The authors maintain that these animals developed encephalopathy on the basis
of a reversal of Fisher’s ratio. Whiles this ratio is correlated with the development
of encephalopathy in some studies, it is certainly not evidence of
encephalopathy. This short-coming should be at least discussed.
There was a failure to develop increased intracranial pressure in this model
which is a significant deviation from human analogue. Many other models of
acute liver failure in pigs e.g. ischaemic, do achieve this within this time frame.
This discrepancy should be discussed further.
The authors state that this model would be useful for the assessment of artificial
liver devices, but they should discuss this further. Although ‘reproducible’ the
survival of the animals varied enormously from 8 - >28hrs, and a significant
number of animals with euthanased. The criteria for ‘death under anaesthesia’
are not defined. In view of this group’s experience it would be very helpful for
them to address this issue – would they aim to improve survival – and if so how
would they measure survival – or do they have another criterion for failure or for
parameters to be improved.
These are immensely complicated as well as costly experiments to do; although
there are obvious short-comings as outlined, it would be unreasonable to ask the
group to reassemble (many of them no longer work in the initial centre) to do
further experimental work, however, the discussion could usefully address the
issues raised.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
'I declare that I have no competing interests'
Review for 10.1186/1471-230X-10-34 (2010)

Reviewer's report
Title:Development of an invasively monitored porcine model of
acetaminophen-induced acute liver failure
Version: 2Date:2 March 2010
Reviewer: Humphrey Hodgson
Reviewer's report:
I think the MS has been satisfactorily revised
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
declare that I have no competing interests' b
Review for 10.1186/1471-230X-10-34 (2010)

Reviewer's report
Title:Development of an invasively monitored porcine model of
acetaminophen-induced acute liver failure
Version: 2Date:3 March 2010
Reviewer: Amedeo Carraro
Reviewer's report:
Reviewer's report
Title: Development of an invasively monitored porcine model of
acetaminophen-induced acute liver failure
Version: 2 Date: 3 March 2010
Reviewer's report:
The study contains very interesting data and the clinical application is easily
conceivable.
The chances incorporated make the areas of discussion clearer. Even though the
need of further experiments in large population, in consideration of the difficulties
of such studies, this work can give many suggestions and input for further
investigations.
I have no more comments on the manuscript.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-55 (2010)

Reviewer's report
Title:Analysis of cell cycle-related proteins in gastric intramucosal
differentiated-type cancers based on mucin phenotypes: a new concept of
molecular carcinogenesis for early differentiated-type gastric cancers
Version: 1Date:15 November 2009
Reviewer: Masashi Fukayama
Reviewer's report:
Major revisions
1. The authors should tone down the title, since their results are not decisive
enough to propose the new concept of molecular carcinogenesis.
2. As the authors themselves admitted, it is more meaningful to use an absolute
rate (i.e., the actual %), rather than this internal relative value.
3. The CDX2 immunohistochemistry is not necessary in this study. The results
were not helpful, or even confusing, for the understanding the mucin phenotypes,
which the authors proposed as the classification of intramucosal differentiated
gastric carcinoma.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
I declare that I have no competing interests.
Review for 10.1186/1471-230X-10-55 (2010)

Reviewer's report
Title:Analysis of cell cycle-related proteins in gastric intramucosal
differentiated-type cancers based on mucin phenotypes: a new concept of
molecular carcinogenesis for early differentiated-type gastric cancers
Version: 1Date:17 November 2009
Reviewer: Yusuke Tajima
Reviewer's report:
The authors examined the relations between abnormalities of cell cycle-related
proteins and mucin phenotype in the early phase of differentiated-type gastric
cancers. From the findings of the study, the authors concluded that the cellular
mucin phenotypes of intramucosal differentiated-type adenocarcinomas of the
stomach are dependent on distinct cell cycle-related alterations, and that the
clinicopathological findings result from different pathways based on mucin
expression. The authors analyzed the large amount of data using a lot of
immunohistochemical markers. Although this is an informative paper, there are
several shortcomings that should be revised.
Major comments
(1) Gastric phenotype cancers may include several types of cancers, such as
MUC5AC+ and MUC6+, MUC5AC+ and MUC6-, and MUC5AC- and MUC6+.
Intestinal phenotype cancers also include MUC2+ and CD10+, MUC2+ and
CD10-, and MUC2- and CD10+. In fact, the authors noted that intestinal
phenotype tumors were sub-classified into 2 groups: colonic type (positive for
MUC 2 only) and small intestinal type (positive for CD10) (page 7, line 7). The
authors should mention the differences in clinicopathological features and
immunohistochemical factors examined among these subgroups.
(2) Some findings on the relations between mucin phenotype and expressions of
the cell cycle-related proteins determined in this study seem to overlap with those
in the previous papers. As a result, it is difficult to understand the new findings by
this paper analyzing the large amount of data. The authors need to further
distinguish their results from previous studies by others, perhaps in a summary
matrix table that would simplify understanding by the reader.
Minor comments
(1) The authors used the word “mucin phenotype”. However, does CD10
immunoreaction mean “mucin” expression?
(2) This study showed that p53 expression was more frequently found in gastric
phenotype cancers. However, previous papers reported that p53 mutation was
rather the characteristic of intestinal phenotype cancers or cancers with CD10
expression (Endoh et al. J Pathol 2000;191:257-263, Tajima et al. Clin Cancer
Res 2006; 12: 6469-6479). It is necessary to discuss with these papers.
(3) Figures
The figures showing expressions of mucin markers are needed?
(4) Table 3, figure 2, and figure 4
Gastric (intestinal, mixed, or unclassified) “type”?
Is gastric (intestinal, mixed, or unclassified) “phenotype” correct?
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-55 (2010)

Reviewer's report
Title:Analysis of cell cycle-related proteins in gastric intramucosal
differentiated-type cancers based on mucin phenotypes: a new concept of
molecular carcinogenesis for early differentiated-type gastric cancers
Version: 1Date:22 November 2009
Reviewer: Byung Lee
Reviewer's report:
Major Compulsory Revisions
1. Results, page 9, paragraph 1: the explanation about male/female ratio is
reversed. The description is the opposite of the data in Figure 2.
2. Discussion, paragraph 3, line 4: Is “Fig 5” mentioned in line 4 missing or does
it mean “Fig 4”?
Minor Essential Revisions
1. Most pathologists understand the discrepancy of cancer criteria between
Japan and Western countries. The cases shown in figure 1 and in figure 3 could
be tubular adenomas in most of the Western pathologists. If those cases do not
have lymph node metastasis as the authors believe, why those cases should be
called “cancer” rather than “precancerous lesion” (especially those cases of low
nuclear grade)?
2. Results, page 9, paragraph 2: Authors need to mention Figure 2 for the results
of cdx2 immunohistochemistry.
3. Figure 2: Arrows pointing upward or downward needs to be explained.
In addition, authors need to add the unit of the numbers by the vertical axis of
Figure 2.
4. Figure legends, page 25; The explanation for figure 2 is unclear.
5. Figure 3: Authors are recommended to rearrange the labels (a-h) in the same
location in each figure.
Level of interest: An article of limited interest
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
Review for 10.1186/1471-230X-10-55 (2010)

Reviewer's report
Title:Analysis of cell cycle-related proteins in gastric intramucosal
differentiated-type cancers based on mucin phenotypes: a new concept of
molecular carcinogenesis for early differentiated-type gastric cancers
Version: 1Date:30 November 2009
Reviewer: Shuho Semba
Reviewer's report:
The analysis of cell cycle-related proteins in gastric intramucosal
differentiated-type cancers based on mucin phenotypes: a new concept of
molecular carcinogenesis for early differentiated-type gastric cancers (Sugai et
al.) In this study, the authors investigated expression patterns of cell
cycle-related proteins in the early phase of differentiated-type gastric cancers
removed by ESD. The concept of this study seems good and the results are well
arranged. However, the reviewer recommends to re-prepare the manuscript
along with the points below.
1. The authors subclassified the gastric cancers analyzed according to the
expression patterns of the mucins. However, the Cdx2 status should be included
into the decision of these mucin phenotypes because Cdx2 plays an important
role for intestinal differentiation of gastric epithelia. For example, tumors showing
Cdx2+/CD10+/MUC2+ will be regarded as the intestinal-type gastric cancers and
tumors showing Cdx2-/MUC5AC+/MUC6+ will be included into the gastric-type
gastric cancers.
2. The figures need major modification. Prepare these figures in higher resolution
(figure 1 and 3) with the scale bars. And, in figure 2, the results are difficult to
understand. The results of up- and down-regulation of p27 protein are
overlapped? Figure 4 should be re-arranged for better understanding.
3. The descriptions in the results section are long and pointless. The percentages
of the immunohistochemistry are shown in figure 2.
4. The authors did not mention about the genetic background of these early
gastric cancers. Hasuo et al. examined the status of microsatellite instability to
assess the risk of recurrence of gastric cancer after initial ESD (Br J Cancer 96:
89-94, 2007). The authors need to discuss about this point.
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
I declare that I have no competing interests.
Review for 10.1186/1471-230X-10-55 (2010)

Reviewer's report
Title:Analysis of cell cycle-related proteins in gastric intramucosal
differentiated-type cancers based on mucin phenotypes: a new concept of
molecular carcinogenesis for early differentiated-type gastric cancers
Version: 3Date:18 January 2010
Reviewer: Shuho Semba
Reviewer's report:
In the revised version, the authors improved the manuscript and figures. They
responded to the reviewer's comments honestly.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Review for 10.1186/1471-230X-10-56 (2010)

Reviewer's report
Title:Nine-year incident diabetes is predicted by fatty liver indices: The French
D.E.S.I.R. study
Version: 1Date:15 February 2010
Reviewer: Melania Manco
Reviewer's report:
Balkau and Coll. aim to verify the effectiveness of 2 recently developed
mathematical indexes to predict incident T2DM, the FLI and the NAFLD-FLS.
Both indexes use surrogates of the MetS and liver enzymes.
To accomplish their aim, the researchers use data from a large cohort study, the
DESIR. Incident diabetes was estimated using as markers prescription of anti
diabetic drugs and values of fasting PG #7.0 mmol/l.
In this context, the manuscript may deserve publication as background for future
epidemiological studies. I think the manuscript can be improved by discussing
the high OR for T2DM which was observed in women with a FLI >70 and/or by
discussing the utility of such indexes as compared with traditional risk factors.
The authors present some of these results in the table but there is no discussion.
Major comment:
1. The risk for diabetes was particularly high in women with a FLI >70 (OR 37).
This gender related effect deserves additional analysis and discussion, i.e. in
relation to an effect of the menopause.
2. Please, make clear which is the plus value of the FLI index or of the
NAFLD-FLS respect to common predictors of T2DM such as familiarity for the
disease. Do the indexes identify different samples of high-risk individuals as
compared with traditional risk factors?
Minor comments:
1. Bedogni and not Bedogini (page 3)
2. BMI and not (BM)I (page 3)
3. In the introduction there is no need to talk about CRP or NEFA or TNF-alpha
as these measures do not enter the FLI or the NAFLD-FLS scores. May be the
authors want to highlight the concept that the NAFLD can be considered the
hepatic component of the MetS and that component of the syndrome enter both
the indexes.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-56 (2010)

Reviewer's report
Title:Nine-year incident diabetes is predicted by fatty liver indices: The French
D.E.S.I.R. study
Version: 1Date:21 February 2010
Reviewer: Jian-gao G Fan
Reviewer's report:
This is a large scaled prospective study on 9-year incidence of diabetes in a
French general population with fatty liver indices. Overall it is an interesting
finding that incident diabetes could be predicted by the Fatty Liver Index and the
NAFLD fatty liver score in both men and women. The question posed by the
authors is well defined. The methods are appropriate and well described. The
data are sound. The manuscript adheres to the relevant standards for reporting
and data deposition. The discussion and conclusions are well balanced and
adequately supported by the data. Limitations of the work are clearly stated. The
authors clearly acknowledge any work upon which they are building, both
published and unpublished. The title and abstract accurately convey what has
been found. Thus the writing is acceptable with minor essential revisions.
The authors should pay more attention to some figures in the Table 2 and Table
3, such as the number of men with fatty liver index #70 should be 277 instead of
270, and the number of women with Fatty Liver Index 20-69 where alcohol < 20
g/day should be 421 instead 481 in Table 2. The authors should give some
explanation if some data were missing in defining NAFLD fatty liver score. In
addition, ‘waist’ in table 1 should be changed into ‘waistline’ or ‘waist
circumference’.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
'I declare that I have no competing interests'
Review for 10.1186/1471-230X-10-56 (2010)

Reviewer's report
Title:Nine-year incident diabetes is predicted by fatty liver indices: The French
D.E.S.I.R. study
Version: 1Date:26 February 2010
Reviewer: Llorenç Caballeria
Reviewer's report:
Overall this is a good article especially because of the size of the sample studied,
the years of follow up and the invasive approach of predicting diabetes and the
progression of fatty liver used.
There are, however, several considerations which should be addressed.
Major Compulsory Revisions
The authors conclude that the two indexes studied predict the incidence of
diabetes. However, I have doubts with respect to the utility of the HAFLD-FLS
index. The authors should clarify this aspect since the utility of this index is
limited by the inclusion of diabetes and fasting insulin in its definition. I do not
understand how the presence of diabetes can be predicted if being diabetic is
included in the definition.
In the limitations the authors recognize the absence of imaging tests for the
follow up of fatty liver. The doubts presented are: Is the determination of these
indexes sufficient to suspect the progression of fatty liver?
Perhaps it would be interesting to at least do abdominal echogaphies to confirm
the progression of fatty liver at the same time as performing the indexes to
thereby support the importance of these indexes.
It is strange that the authors did not consider the use of abdominal echography
which is very usual, inexpensive and non invasive. The authors should address
these questions.
Discretionary Revisions
The authors show the incidence of diabetes at the end of the nine years of follow
up. Since the patients were examined every three years, I believe that it would
enrich the manuscript if the authors were to report the incidence of diabetes at
each visit.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Review for 10.1186/1471-230X-10-56 (2010)

Reviewer's report
Title:Nine-year incident diabetes is predicted by fatty liver indices: The French
D.E.S.I.R. study
Version: 1Date:14 March 2010
Reviewer: Janus Ong
Reviewer's report:
I. Major Compulsory Revisions
1. The indices used in this study still require validation in populations outside of
the populations that they were developed from. In addition, the performance
characteristics of the indices, the Fatty Liver Index in particular, leave room for
misclassification considering a positive likelihood ratio of only 4.2 for predicting
fatty liver.
2. The original reports for the two indices suggest cut-off scores for the diagnosis
of fatty liver disease - a FLI >/= 60 and a NAFLD-FLS > -0.640. It is thus the
understanding of this reviewer that the question the study wanted to answer was
whether NAFLD as diagnosed using the two indices would be predictive of
incident diabetes. An affirmative answer to this research question would be
clinically relevant as screening for diabetes might be advocated in patients
diagnosed with NAFLD. The analysis that would have been ideal would have
been to divide the patients into those with NAFLD and those without NAFLD
based on the cut-offs for both the FLI and the NAFLD-FLS. The two groups
would then be compared as to the development of incident diabetes. I would
submit that the results of the current analyses using quartiles are not at all
surprising as these indices contain known predictors of incident diabetes such as
triglycerides, BMI, and waist circumference for FLI and metabolic syndrome for
NAFLD-FLS. In fact, results to the contrary would be difficult to explain.
3. In the calculation of the odds ratios for incident diabetes, it would be expected
in the multivariate analysis that potential confounders of the association between
the indices and incident diabetes be adjusted for. Table 1 shows in addition to
the adjustment factors shown in Table 2, variables such as BMI, waist
circumference, cholesterol levels were correlated with the FLI and thus should be
included as adjustment factors.
II. Minor Essential Revisions
1. Biochemical measurements were conducted in several sites using different
equipment. Are the results from these different sites comparable?
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-56 (2010)

Reviewer's report
Title:Nine-year incident diabetes is predicted by fatty liver indices: The French
D.E.S.I.R. study
Version: 2Date:4 May 2010
Reviewer: Monica Nannipieri
Reviewer's report:
I reviewed the paper and I suggest that it could be accepted now without further
revisions
Level of interest: An article of limited interest
Quality of written English: Acceptable
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Review for 10.1186/1471-230X-10-56 (2010)

Reviewer's report
Title:Nine-year incident diabetes is predicted by fatty liver indices: The French
D.E.S.I.R. study
Version: 2Date:5 May 2010
Reviewer: Llorenç Caballeria
Reviewer's report:
Although the authors have not been able to clarify some of the issues raised due
to the limitations of their study appreciate the effort of the authors to clarify them.
Moreover, because of the importance of the study think that can be published
and hopefully in future studies take into account these limitations. This study
provides interesting data regarding diagnosis and possibility of progression and
opens many possibilities for research in this field.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-56 (2010)

Reviewer's report
Title:Nine-year incident diabetes is predicted by fatty liver indices: The French
D.E.S.I.R. study
Version: 2Date:11 May 2010
Reviewer: Janus Ong
Reviewer's report:
The manuscript is now acceptable in its current form.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-54 (2010)

Reviewer's report
Title:High prevalence of gastroesophageal reflux esophagitis in Chinese
patients with chronic liver diseases
Version: 1Date:21 January 2010
Reviewer: Daniel Jaspersen
Reviewer's report:
Major Compulsory Revisions:
Evaluation of Barrett`s esophagus is missing and should be added, if possible.
According to symptoms, the prevalence of NERD in the study patients should be
stated.
Which clinical conclusions should be drawn from the study? This should be
discussed.
Minor Essential Revisions:
Spelling mistakes: Abstract - Conclusions: "GE was more prevalent..." (instead of
"prevalence")
Figure 2: "The relationship..." (instead of "repationship")
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-54 (2010)

Reviewer's report
Title:High prevalence of gastroesophageal reflux esophagitis in Chinese
patients with chronic liver diseases
Version: 1Date:22 January 2010
Reviewer: Jan Hatlebakk
Reviewer's report:
- Major Compulsory Revisions
The manuscript is of interest, but raises some concerns which
1. I find the introduction and extensive discussion imprecise in wording and with
less focus on what the study is actually about. Both should be rewritten and the
extensive overlap should be corrected by taking out the first few sentences of the
introduction.
2. It is hard to accept that the symptoms of gERD were atypical, as is stated in
the discussion. Instead it is possible that the patients were asymptomatic from
GE, but suffered from other symptoms. What questionnaire was used to record
such atypical symptoms?
3. The classification of varices is uncommon, and no reference is given. I also
feel it is incorrect to change the exact wording of the LA classification of reflux
oesophagitis from what was originally published (even though it is likely to be a
correct interpretation).
4. I have problems adding up the number of patients in each subgroup. I am not
sure that using patients with acute hepatitis is an ideal control group, since their
digestive functions might be compromized. Can you have hepatitis E without
hepatitis B??
5. The detaiols of statistical analysis is not clear to me.
Level of interest: An article of limited interest
Quality of written English: Not suitable for publication unless extensively edited
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare I have no competing interests.
Review for 10.1186/1471-230X-10-54 (2010)

Reviewer's report
Title:High prevalence of gastroesophageal reflux esophagitis in Chinese
patients with chronic liver diseases
Version: 2Date:12 February 2010
Reviewer: Daniel Jaspersen
Reviewer's report:
In response to the points I raised, the authors have submitted a revised
manuscript. In addition, they have also provided a letter describing the changes
made.
My original criticisms have been answered.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Review for 10.1186/1471-230X-10-53 (2010)

Reviewer's report
Title:Non-Invasive Index of Liver Fibrosis induced by Alcohol, Thioacetamide
and Schistosomal Infection in Mice
Version: 4Date:6 March 2010
Reviewer: Emanuel Manesis
Reviewer's report:
Major Compulsory Revisions:
None.
Minor Essential Revisions:
1. The text needs extensive language and typing corrections. It must be reviewed
and corrected by a person proficient in English and medical terminology.
2. Changes in the text should have been highlighted.
3. Generic names of drugs are written with lower case letters (e.g. thioacetamide,
sylimarin) and their abbreviations in capitals.
4. (Page 5, 1st paragraph from top): “Sedico Co., ARE” & “Biltricide, Epico Co.,
ARE”: What “ARE” stands for? What is the country of company’s location?
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I have no competing interest
Review for 10.1186/1471-230X-10-53 (2010)

Reviewer's report
Title:Non-Invasive Index of Liver Fibrosis induced by Alcohol, Thioacetamide
and Schistosomal Infection in Mice
Version: 4Date:9 March 2010
Reviewer: giada Sebastiani
Reviewer's report:
The authors have now addressed the concerns that the reviewers have raised.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-53 (2010)

Reviewer's report
Title:Non-Invasive Index of Liver Fibrosis induced by Alcohol, Thioacetamide
and Schistosomal Infection in Mice
Version: 4Date:15 March 2010
Reviewer: James Fung
Reviewer's report:
The changes have been noted.
Major Comments:
1. Despite the re-submission and the initial concerns, there are still numerous
spelling and grammatical errors throughout the entire manuscript which needs to
be addressed
2. The abstract has been extensively re-written. In the results section - the
sentence 'highly (or moderately high)' needs to be changed. Also in the
conclusion it was stated that the index was 'liver-specific' - however this
conclusion cannot be drawn in the current study
3. The previous comments on using F0-F4 (rather than S1-S3) still stands.
Although the authors have changed one section, the remainder of the manuscript
remains unchanged
4. Under results section on Page 7 - there is a reference to Table 3 panel C
showing the correlation between the score and MDA/collagen/GSH. Panel C
cannot be found under table 3
5. The P values should be provided for the correlations in table 3
6. In table 5 I note that tha AUROC ranges for the training set all exceeded 1.0,
can the authors provide an explanation for this
7. The authors should provide the AUROC for the validation set for each of the
histological stages of fibrosis. In the discussion on page 12 it was stated that the
validation sets 'matched the pathological stages and grades, which was
independently assessed'
8. Under page 9 Validation Group, the figures provided for the correlation is from
the training set and not the validation set
9. Under discussion in page 11 - 'bilirubin and albumin are traditionally invested
to monitor liver histology' - is not true - we use the Child Pugh score and these
parameters to monitor the liver function and clinical status of the patient - not to
monitor liver histology.
10. The conclusion needs to be re-written
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-53 (2010)

Reviewer's report
Title:Non-Invasive Index of Liver Fibrosis induced by Alcohol, Thioacetamide
and Schistosomal Infection in Mice
Version: 5Date:12 May 2010
Reviewer: James Fung
Reviewer's report:
The manuscript now reads much better.
Minor comments:
Page 4 under 1-Test groups: please define "ip" in full
Page 6 under Statistical analysis: typos - "normality" & "histological"
Page 8 "To calculate the non-invasive score, both ....." - omit the word "both".
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Review for 10.1186/1471-230X-10-52 (2010)

Reviewer's report
Title:Toll-like receptor-2 deficiency enhances non-alcoholic steatohepatitis
Version: 1Date:15 December 2009
Reviewer: Jude Oben
Reviewer's report:
Given the importance of obesity induced liver disease as a major public health
threat in affluent nations, understanding the immunobiology of NAFLD/NASH is
clearly of importance as a prerequisite to devising preventative or curative
strategies. This mechanistic study by Rivera et al, is a welcomed addition in this
quest. The study concept is interesting, and the study designed and findings
interesting. That TLR 2 may confer some protection against NAFLD is novel and
should be on interest to your readers.
My comments are minor: the introduction has the potential to confuse:
the first paragraph refers to this type of liver disease being cryptogenic. Given
that many patients with NAFLD were previously classified as cryptogenic, the
sense of this pg should be altered to better reflect the fact that it is the
mechanism of NAFLD that is not fully elucidated, I would simply avoid
cryptogenic.
In the results section, Figure 1 is a little odd. There are no error bars for the
steatosis and necrosis. Was this an oversight or was the variability near minimal?
If these minor alterations could be made, I would be happier to recommend its
acceptance for publication
Review for 10.1186/1471-230X-10-52 (2010)

Reviewer's report
Title:Toll-like receptor-2 deficiency enhances non-alcoholic steatohepatitis
Version: 3Date:26 April 2010
Reviewer: Pranoti Mandrekar
Reviewer's report:
All previous comments made by this reviewer have been addressed.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare I have no competing interests