Reviewer's report
Title:Paneth cell metaplasia in newly diagnosed inflammatory bowel disease in
children
Version:2Date:24 December 2013
Reviewer: Ilyssa Gordon
Reviewer's report:
Major compulsory revisions
Methods paragraph 1:
General:
1. I see that you were able to review clinical and radiological findings to select
your patients for inclusion in your review. Also in the discussion paragraph 4 you
state that “…many of the patients had been symptomatic for months….” Please
include a description of pertinent endoscopic findings, disease duration, and
symptoms, to complete the clinical picture and to possibly draw additional
statistical comparisons (see for example your reference 15).
Methods paragraph 2:
General:
2. I understand this study was of a review of slides prepared for diagnostic
interpretation. However, as your review included cell counts (i.e. Paneth cells and
eosinophils) the thickness of the section and type of stain is pertinent information
which must be included.
3. Did all patients have all colon sites biopsied? Please state yes or no, and if no,
please give the breakdown and include in your figure 1 legend. This pertains also
to Results paragraph 2 sentence 3: why did one UC patient have no Paneth
cells? Was there no proximal colon to evaluate? Otherwise please comment on
possible reasons for someone having no Paneth cells at all (i.e. even in the
proximal colon) - has this been reported before?
Fourth sentence:
4. Your choice of methodology for counting Paneth cells appears to be adequate,
however, is there a reference or precedent for using this methodology? Also, I
believe it is more or less standard to include the initials of the co-author who is
the “experienced histopathologist” in parentheses following that statement (I see
in the authors contribution section you state two people performed the histologic
examination - did they each perform the evaluation separately on all of the
biopsies or split them up? Was there interobserver variability?).
Final sentence:
5. Please clarify your specific histologic criteria to interpret “architectural
distortion”, see methods from your reference 15 for an example of this. Also
should include your grading/score used for this parameter in the statistical
calculation.
Results paragraph 3:
First sentence:
6. What about UC vs control for sigmoid and rectum? Was this not significant? If
not please discuss why in discussion.
Second sentence:
7. What about CD vs control for rectum? Was this not significant? If not please
discuss why in discussion.
Discussion paragraph 1:
Third sentence:
8. “…which suggests that metaplasia occurs here also.” This should be deleted
or revised as this does not fit with your previously stated definition of metaplasia
in background paragraph 2. This phenomenon would correctly be termed
hyperplasia, and has been described as such in the previous literature.
Final sentence:
9. I’m not sure what your intention is by this statement. Do you mean these would
be atypical histologic findings in and of themselves in an otherwise completely
normal biopsy? Or do you mean they are diagnostic of IBD when present in the
absence of any other histologic or endoscopic features of IBD? Or that when
found in IBD they are atypical? Please clarify or delete the sentence.
Discussion paragraph 2:
Fourth sentence:
10. I think this is a serious conclusion without statistical analysis to back it up and
would recommend determining whether PCM is an independent diagnostic
feature of pediatric IBD by statistical analysis before making this statement. Also,
please discuss how this conclusion relates with the prevailing notion (see (Bevins
and Salzman, 2011; Gersemann et al., 2012) that an abnormal mucus layer in
UC leads to a secondary hyperplasia/metaplasia of Paneth cells to secrete
antimicrobial alpha defensins. Also please discuss how this conclusion might
relate to CD patients with NOD2 mutations who have alpha defensin deficiency.
Discussion paragraph 3:
Final sentence:
11. I respectfully disagree with your interpretation of Glickman et al’s findings in
your reference 15. While I agree with your statement that “it is not clear the PCM
is a feature of chronicity in children”, the study by Glickman et al found that there
was patchiness of chronic features as well as some degree of rectal sparing.
Unfortunately, beyond stating that they assessed PCM as a non-architectural
feature of chronicity, they do not clarify their specific results or conclusions
pertaining to PCM in their study. Please review this reference and clarify your
comparison of your findings to their findings.
Minor essential revisions
Background paragraph 1:
First sentence:
1. “secreting the” (needs a space)
2. “the antimicrobial peptide alpha defensin” revise to a plural form as there are
two known human alpha defensins, e.g. “the antimicrobial alpha defensin
peptides”
3. Please include Bevins & Salzman 2011(Bevins and Salzman, 2011) with
references 2-5 as this is a pertinent reference to your readers and contains a
complete and more recent list of the antimicrobials secreted by Paneth cells.
Third sentence:
4. Please state a reference for the Paneth cell physiology stated in the sentence.
For example, Mathan 1987(Mathan et al., 1987). I see that your overall statement
is likely derived from uncited elements of your reference 9, nonetheless, I do feel
this type of statement requires a reference and would recommend to cite the
primary source and your reference 9 as well.
Final sentence:
5. Reference 8 is fine, but I do not see this information in your reference 9.
Background paragraph 2:
Third sentence:
6. Please spell out Paneth cell metaplasia (PCM) at first use in main text.
Final sentence:
7. “been found” (needs a space)
Results paragraph 1:
8. Demographic information should be placed in a Table 1 and details need not
be delineated in the text. The whole first paragraph can be replaced with a
sentence referring the reader to demographic details in Table 1.
Results paragraph 2:
Second sentence:
9. Please define “distal colon” for clarity.
Results paragraph 3:
Second sentence:
10. Please add to the end of the sentence “compared with controls” for clarity.
Bevins, C. L., Salzman, N. H., 2011. Paneth cells, antimicrobial peptides and
maintenance of intestinal homeostasis. Nat Rev Micro. 9, 356-368.
Gersemann, M., et al., 2012. Innate immune dysfunction in inflammatory bowel
disease. Journal of Internal Medicine. 271, 421-428.
Mathan, M., et al., 1987. The morphogenesis of the human Paneth cell.
Histochemistry. 87, 91-96.
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.
Reviewer's report
Title:Paneth cell metaplasia in newly diagnosed inflammatory bowel disease in
children
Version:2Date:24 December 2013
Reviewer: Ilyssa Gordon
Reviewer's report:
Major compulsory revisions
Methods paragraph 1:
General:
1. I see that you were able to review clinical and radiological findings to select
your patients for inclusion in your review. Also in the discussion paragraph 4 you
state that “…many of the patients had been symptomatic for months….” Please
include a description of pertinent endoscopic findings, disease duration, and
symptoms, to complete the clinical picture and to possibly draw additional
statistical comparisons (see for example your reference 15).
Methods paragraph 2:
General:
2. I understand this study was of a review of slides prepared for diagnostic
interpretation. However, as your review included cell counts (i.e. Paneth cells and
eosinophils) the thickness of the section and type of stain is pertinent information
which must be included.
3. Did all patients have all colon sites biopsied? Please state yes or no, and if no,
please give the breakdown and include in your figure 1 legend. This pertains also
to Results paragraph 2 sentence 3: why did one UC patient have no Paneth
cells? Was there no proximal colon to evaluate? Otherwise please comment on
possible reasons for someone having no Paneth cells at all (i.e. even in the
proximal colon) - has this been reported before?
Fourth sentence:
4. Your choice of methodology for counting Paneth cells appears to be adequate,
however, is there a reference or precedent for using this methodology? Also, I
believe it is more or less standard to include the initials of the co-author who is
the “experienced histopathologist” in parentheses following that statement (I see
in the authors contribution section you state two people performed the histologic
examination - did they each perform the evaluation separately on all of the
biopsies or split them up? Was there interobserver variability?).
Final sentence:
5. Please clarify your specific histologic criteria to interpret “architectural
distortion”, see methods from your reference 15 for an example of this. Also
should include your grading/score used for this parameter in the statistical
calculation.
Results paragraph 3:
First sentence:
6. What about UC vs control for sigmoid and rectum? Was this not significant? If
not please discuss why in discussion.
Second sentence:
7. What about CD vs control for rectum? Was this not significant? If not please
discuss why in discussion.
Discussion paragraph 1:
Third sentence:
8. “…which suggests that metaplasia occurs here also.” This should be deleted
or revised as this does not fit with your previously stated definition of metaplasia
in background paragraph 2. This phenomenon would correctly be termed
hyperplasia, and has been described as such in the previous literature.
Final sentence:
9. I’m not sure what your intention is by this statement. Do you mean these would
be atypical histologic findings in and of themselves in an otherwise completely
normal biopsy? Or do you mean they are diagnostic of IBD when present in the
absence of any other histologic or endoscopic features of IBD? Or that when
found in IBD they are atypical? Please clarify or delete the sentence.
Discussion paragraph 2:
Fourth sentence:
10. I think this is a serious conclusion without statistical analysis to back it up and
would recommend determining whether PCM is an independent diagnostic
feature of pediatric IBD by statistical analysis before making this statement. Also,
please discuss how this conclusion relates with the prevailing notion (see (Bevins
and Salzman, 2011; Gersemann et al., 2012) that an abnormal mucus layer in
UC leads to a secondary hyperplasia/metaplasia of Paneth cells to secrete
antimicrobial alpha defensins. Also please discuss how this conclusion might
relate to CD patients with NOD2 mutations who have alpha defensin deficiency.
Discussion paragraph 3:
Final sentence:
11. I respectfully disagree with your interpretation of Glickman et al’s findings in
your reference 15. While I agree with your statement that “it is not clear the PCM
is a feature of chronicity in children”, the study by Glickman et al found that there
was patchiness of chronic features as well as some degree of rectal sparing.
Unfortunately, beyond stating that they assessed PCM as a non-architectural
feature of chronicity, they do not clarify their specific results or conclusions
pertaining to PCM in their study. Please review this reference and clarify your
comparison of your findings to their findings.
Minor essential revisions
Background paragraph 1:
First sentence:
1. “secreting the” (needs a space)
2. “the antimicrobial peptide alpha defensin” revise to a plural form as there are
two known human alpha defensins, e.g. “the antimicrobial alpha defensin
peptides”
3. Please include Bevins & Salzman 2011(Bevins and Salzman, 2011) with
references 2-5 as this is a pertinent reference to your readers and contains a
complete and more recent list of the antimicrobials secreted by Paneth cells.
Third sentence:
4. Please state a reference for the Paneth cell physiology stated in the sentence.
For example, Mathan 1987(Mathan et al., 1987). I see that your overall statement
is likely derived from uncited elements of your reference 9, nonetheless, I do feel
this type of statement requires a reference and would recommend to cite the
primary source and your reference 9 as well.
Final sentence:
5. Reference 8 is fine, but I do not see this information in your reference 9.
Background paragraph 2:
Third sentence:
6. Please spell out Paneth cell metaplasia (PCM) at first use in main text.
Final sentence:
7. “been found” (needs a space)
Results paragraph 1:
8. Demographic information should be placed in a Table 1 and details need not
be delineated in the text. The whole first paragraph can be replaced with a
sentence referring the reader to demographic details in Table 1.
Results paragraph 2:
Second sentence:
9. Please define “distal colon” for clarity.
Results paragraph 3:
Second sentence:
10. Please add to the end of the sentence “compared with controls” for clarity.
Bevins, C. L., Salzman, N. H., 2011. Paneth cells, antimicrobial peptides and
maintenance of intestinal homeostasis. Nat Rev Micro. 9, 356-368.
Gersemann, M., et al., 2012. Innate immune dysfunction in inflammatory bowel
disease. Journal of Internal Medicine. 271, 421-428.
Mathan, M., et al., 1987. The morphogenesis of the human Paneth cell.
Histochemistry. 87, 91-96.
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.
Please review this paper.
user
Reviewer's report
Title:Paneth cell metaplasia in newly diagnosed inflammatory bowel disease in
children
Version:2Date:24 December 2013
Reviewer: Ilyssa Gordon
Reviewer's report:
Major compulsory revisions
Methods paragraph 1:
General:
1. I see that you were able to review clinical and radiological findings to select
your patients for inclusion in your review. Also in the discussion paragraph 4 you
state that “…many of the patients had been symptomatic for months….” Please
include a description of pertinent endoscopic findings, disease duration, and
symptoms, to complete the clinical picture and to possibly draw additional
statistical comparisons (see for example your reference 15).
Methods paragraph 2:
General:
2. I understand this study was of a review of slides prepared for diagnostic
interpretation. However, as your review included cell counts (i.e. Paneth cells and
eosinophils) the thickness of the section and type of stain is pertinent information
which must be included.
3. Did all patients have all colon sites biopsied? Please state yes or no, and if no,
please give the breakdown and include in your figure 1 legend. This pertains also
to Results paragraph 2 sentence 3: why did one UC patient have no Paneth
cells? Was there no proximal colon to evaluate? Otherwise please comment on
possible reasons for someone having no Paneth cells at all (i.e. even in the
proximal colon) - has this been reported before?
Fourth sentence:
4. Your choice of methodology for counting Paneth cells appears to be adequate,
however, is there a reference or precedent for using this methodology? Also, I
believe it is more or less standard to include the initials of the co-author who is
the “experienced histopathologist” in parentheses following that statement (I see
in the authors contribution section you state two people performed the histologic
examination - did they each perform the evaluation separately on all of the
biopsies or split them up? Was there interobserver variability?).
Final sentence:
5. Please clarify your specific histologic criteria to interpret “architectural
distortion”, see methods from your reference 15 for an example of this. Also
should include your grading/score used for this parameter in the statistical
calculation.
Results paragraph 3:
First sentence:
6. What about UC vs control for sigmoid and rectum? Was this not significant? If
not please discuss why in discussion.
Second sentence:
7. What about CD vs control for rectum? Was this not significant? If not please
discuss why in discussion.
Discussion paragraph 1:
Third sentence:
8. “…which suggests that metaplasia occurs here also.” This should be deleted
or revised as this does not fit with your previously stated definition of metaplasia
in background paragraph 2. This phenomenon would correctly be termed
hyperplasia, and has been described as such in the previous literature.
Final sentence:
9. I’m not sure what your intention is by this statement. Do you mean these would
be atypical histologic findings in and of themselves in an otherwise completely
normal biopsy? Or do you mean they are diagnostic of IBD when present in the
absence of any other histologic or endoscopic features of IBD? Or that when
found in IBD they are atypical? Please clarify or delete the sentence.
Discussion paragraph 2:
Fourth sentence:
10. I think this is a serious conclusion without statistical analysis to back it up and
would recommend determining whether PCM is an independent diagnostic
feature of pediatric IBD by statistical analysis before making this statement. Also,
please discuss how this conclusion relates with the prevailing notion (see (Bevins
and Salzman, 2011; Gersemann et al., 2012) that an abnormal mucus layer in
UC leads to a secondary hyperplasia/metaplasia of Paneth cells to secrete
antimicrobial alpha defensins. Also please discuss how this conclusion might
relate to CD patients with NOD2 mutations who have alpha defensin deficiency.
Discussion paragraph 3:
Final sentence:
11. I respectfully disagree with your interpretation of Glickman et al’s findings in
your reference 15. While I agree with your statement that “it is not clear the PCM
is a feature of chronicity in children”, the study by Glickman et al found that there
was patchiness of chronic features as well as some degree of rectal sparing.
Unfortunately, beyond stating that they assessed PCM as a non-architectural
feature of chronicity, they do not clarify their specific results or conclusions
pertaining to PCM in their study. Please review this reference and clarify your
comparison of your findings to their findings.
Minor essential revisions
Background paragraph 1:
First sentence:
1. “secreting the” (needs a space)
2. “the antimicrobial peptide alpha defensin” revise to a plural form as there are
two known human alpha defensins, e.g. “the antimicrobial alpha defensin
peptides”
3. Please include Bevins & Salzman 2011(Bevins and Salzman, 2011) with
references 2-5 as this is a pertinent reference to your readers and contains a
complete and more recent list of the antimicrobials secreted by Paneth cells.
Third sentence:
4. Please state a reference for the Paneth cell physiology stated in the sentence.
For example, Mathan 1987(Mathan et al., 1987). I see that your overall statement
is likely derived from uncited elements of your reference 9, nonetheless, I do feel
this type of statement requires a reference and would recommend to cite the
primary source and your reference 9 as well.
Final sentence:
5. Reference 8 is fine, but I do not see this information in your reference 9.
Background paragraph 2:
Third sentence:
6. Please spell out Paneth cell metaplasia (PCM) at first use in main text.
Final sentence:
7. “been found” (needs a space)
Results paragraph 1:
8. Demographic information should be placed in a Table 1 and details need not
be delineated in the text. The whole first paragraph can be replaced with a
sentence referring the reader to demographic details in Table 1.
Results paragraph 2:
Second sentence:
9. Please define “distal colon” for clarity.
Results paragraph 3:
Second sentence:
10. Please add to the end of the sentence “compared with controls” for clarity.
Bevins, C. L., Salzman, N. H., 2011. Paneth cells, antimicrobial peptides and
maintenance of intestinal homeostasis. Nat Rev Micro. 9, 356-368.
Gersemann, M., et al., 2012. Innate immune dysfunction in inflammatory bowel
disease. Journal of Internal Medicine. 271, 421-428.
Mathan, M., et al., 1987. The morphogenesis of the human Paneth cell.
Histochemistry. 87, 91-96.
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.
assistant