Background A subarachnoid hemorrhage (SAH) is a debilitating stroke. Activation of the lectin pathway (LP) of the complement system in SAH patients could worsen the prognosis; however, conflicting results have been reported. This potentially reflects that pathological changes at the site of injury are not reflected in peripheral blood. Aims of the study To measure the concentration of LP proteins in blood from the site of brain injury compared with peripheral blood in SAH patients, and to determine the concentration of LP proteins in cerebrospinal fluid (CSF). Methods We included 11 SAH patients undergoing aneurysm clipping or external ventricular drainage. Blood was collected from the site of injury and from a peripheral artery and/or CSF simultaneously. LP proteins were measured using time-resolved immunofluorometric assays. Results In all patients, the cerebral blood concentration of mannan-binding lectin, collectin liver-1 and collectin kidney-1, and mannan-associated serine proteases 1 and 2 were lower than in peripheral blood. The LP proteins were almost undetectable in CSF. Conclusion Lectin pathway protein concentrations measured in peripheral blood do not always reflect changes at the site of injury. For some proteins, more information could be obtained in blood from the site of injury when investigating pathogenic mechanisms.
Proteins of the Lectin Pathway of complement activation at the site of injury in subarachnoid hemorrhage compared with peripheral blood
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Decision Letter
2020/05/2222-May-2020
Dear Dr. Anker-Møller:
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Author Response
2020/05/16Reviewer comment 1:
The new title is better than the first draft, but it is still not precise and concise enough to summarize your findings
Our answer:
We thank the reviewer for this comment. And we agree this title should be more precise. We have thus changed the title to:
“Proteins of the Lectin Pathway of complement activation at the site of injury in subarachnoid hemorrhage compared with peripheral blood”
Reviewer comment 2:
In the results section, perhaps you can further modify the statement to explain more clearly the patient sample collection information shown in table 1 to avoid misunderstandings.
Our answer:
We agree, this could be explained more clearly, and we have this changes the test to:
"Eleven patients were included; nine women and two men with a median age of 51 years (range 39 to 73). We obtained peripheral and cerebral blood samples from four patients. From six patients we obtained samples from peripheral blood and CSF, and from one patient we managed to get both peripheral blood, cerebral blood and a CFS sample (table 1)."
Reviewer comment 3:
I still think the findings are based on a small sample , but are acceptable as exploratory findings.
We thank the reviewer for his/hers decision.
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Decision Letter
2020/05/1111-May-2020
We recognise that the impact of the COVID-19 pandemic may affect your ability to return your revised manuscript to us within the requested timeframe. If this is the case, please let us know.
Dear Dr. Anker-Møller:
Manuscript ID BRB3-2019-10-0670.R1 entitled "Inflammation at the site of injury in subarachnoid hemorrhage" which you submitted to Brain and Behavior, has been reviewed very favorably and minor revisions have been requested. I invite you to respond to the comments appended below and revise your manuscript.
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Once again, thank you for submitting your manuscript to Brain and Behavior and I look forward to receiving your revision.
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Editor in Chief, Brain and Behavior
nsharma@partners.orgAssociate Editor Comments to Author:
Reviewer(s)' Comments to Author:
Reviewer: 2
Comments to the Author
The new title is better than the first draft, but it is still not precise and concise enough to summarize your findings. In the results section, perhaps you can further modify the statement to explain more clearly the patient sample collection information shown in table 1 to avoid misunderstandings. I still think the findings are based on a small sample , but are acceptable as exploratory findings.Decision letter by
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Reviewer report
2020/05/09The new title is better than the first draft, but it is still not precise and concise enough to summarize your findings. In the results section, perhaps you can further modify the statement to explain more clearly the patient sample collection information shown in table 1 to avoid misunderstandings. I still think the findings are based on a small sample , but are acceptable as exploratory findings.
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Author Response
2020/02/28Reply to reviewers
Manuscript ID BRB3-2019-10-0670
(Black: reviewer, Red Italics: reply/comment to reviewer)We value and thank the reviewer for his/hers insightful and constructive feedback.
Below, we provide a point-by-point response to the comments.Reviewer: 1
1. The title and the findings in the text is not matching. The authors should analyzed few inflammatory markers in the blood sample.
We thank the reviewer for this comment. And we agree this title could be more precise. We have thus changed the title to:
“Proteins of the Lectin Pathway of complement activation at the site of injury in subarachnoid hemorrhage compared with peripheral blood”Introduction part: third paragraph, first sentence needs references.
References have been added.The number of patients included in this study is very low.
We agree, that this is a clear limitation of the study, which we also address in the discussion. It was unfortunately what was doable within the project period. What limited our patient inclusion was mainly the fact, that most of the SAH-patients admitted to our ward was treated with endovascular coils, and could therefore not be part of the study.It is unclear why the authors did not used heparinized tube for blood collection, in order to avoid coagulation.
We did contemplate using both heparinized and EDTA tubes. However, in the open brain procedures, where blood was “taken” directly from the site of injury, some degree of coagulation had already taken place, and thus, we decided after discussing this with our coagulation experts, that it would be more correct (for comparison with peripheral blood) to use serum.The authors stated that they used the blood from 5 patients and the CSF from the five patients. Are they same patients?
Yes. All samples that are compared are paired samples. We’ve added a table, see the newly added table 1 in the main document.The authors succeeded to collect all desire samples (bloods can CSF) from only one patient making the study too preliminary and conclusion based on this study might be biased.
We thank the reviewer for this point of view. However, we must beg to differ. Our intention with the study from the start was to compare protein concentrations at the site of injury compared to peripheral measurements. Our hypothesis from the beginning was, that very likely there are things we measure differently in the blood than when we work with what is actually going on at the site of injury. We believe, that we actually give an indication of just that with our study, and highlight a potential problem in many studies where biomarkers are measured in peripheral blood.In the results section, the author mentioned that they obtained peripheral blood sample and CSF samples, but in table 1, they mentioned n=7.
Thank you for the observation, we have revised the results section and added a new table to make the number of included patients clearer. Please see table 1 in the main document.No control data is provided in the study.
Reference intervals for proteins measured in peripheral blood (serum) of healthy individuals are given in figure 1 (the punctuated horizontal lines). These are all results obtained in our own laboratory (ref 9). For ethical reasons we could not sample blood from the cerebrum of healthy individuals.
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- pre-publication peer review (ROUND 1)
Decision Letter
2020/01/2020-Jan-2020
Dear Dr. Anker-Møller:
Manuscript ID BRB3-2019-10-0670 entitled "Inflammation at the site of injury in subarachnoid hemorrhage" which you submitted to Brain and Behavior, has been reviewed. Some revisions to your manuscript have been recommended. Therefore, I invite you to respond to the comments appended below and revise your manuscript.
Before submitting your revisions:
Prepare a response to the reviewer comments appended below in point-by-point fashion. In order to expedite the processing of the revised manuscript, please be as specific as possible in your response and indicate the page numbers in the manuscript where you have addressed each comment.
Prepare a revised manuscript (word document), highlighting the changes you’ve made. Save this new document on your computer as you will be asked to upload it during the revision submission process. NOTE: Please be sure to keep in mind reviewer comments and incorporate your responses within the manuscript. There may well be areas where you disagree; for example, you may want to write, "A reviewer suggests that... However, I disagree because...". In any case, please try to address all of the concerns that are raised within the manuscript.
In addition to your revised manuscript with changes highlighted, please also save a “clean” copy where the changes are not marked.
To submit your revised manuscript:
- Log in by clicking on the link below
*** PLEASE NOTE: This is a two-step process. After clicking on the link, you will be directed to a webpage to confirm. ***
https://mc.manuscriptcentral.com/brainandbehavior?URL_MASK=1cae8c676b8649dda573cd39c268f3c8
OR
Log into https://mc.manuscriptcentral.com/brainandbehavior and click on Author Center. Under author resources, use the button “Click here to submit a revision”. PLEASE DO NOT SUBMIT YOUR REVISIONS AS A NEW MANUSCRIPT.
Follow the on-screen instructions. First you will be asked to provide your “Response to Decision Letter”—this is the response to reviewer comments that you prepared earlier.
Click through the next few screens to verify that all previously provided information is correct.
File Upload: Delete any files that you will be replacing (this includes your old manuscript). Upload your new revised manuscript file with changes highlighted, a “clean” copy of your revised manuscript file, any replacement figures/tables, or any new files. Once this is complete, the list of files in the “My Files” section should ONLY contain the final versions of everything. REMEMBER: figures/tables should be in jpeg, tiff, or eps format. We hope that you will designate one of the figures in your paper to be considered for our online covers and potential publication on our blog.
Review and submit: please be sure to double-check everything carefully so that your manuscript can be processed as quickly as possible.
Deadlines:
Because we are trying to facilitate timely publication of manuscripts submitted to Brain and Behavior,your revised manuscript should be uploaded as soon as possible. If it is not possible for you to submit your revision in 2 months, we may have to consider your paper as a new submission. If you feel that you will be unable to submit your revision within the time allowed please contact me to discuss the possibility of extending the revision time.If you would like help with English language editing, or other article preparation support, Wiley Editing Services offers expert help with English Language Editing, as well as translation, manuscript formatting, and figure formatting at www.wileyauthors.com/eeo/preparation. You can also check out our resources for Preparing Your Article for general guidance about writing and preparing your manuscript at www.wileyauthors.com/eeo/prepresources.
Once again, thank you for submitting your manuscript to Brain and Behavior and I look forward to receiving your revision.
Sincerely,
Dr. Nutan Sharma
Editor in Chief, Brain and Behavior
nsharma@partners.orgAssociate Editor Comments to Author:
Reviewer(s)' Comments to Author:
Reviewer: 1
Comments to the Author
1. The title and the findings in the text is not matching. The authors should analyzed few inflammatory markers in the blood sample.
2. Introduction part: third paragraph, first sentence needs references.
3. The number of patients included in this study is very low.
4. It is unclear why the authors did not used heparinized tube for blood collection, in order to avoid coagulation.
5. The authors stated that they used the blood from 5 patients and the CSF from the five patients. Are they same patients?
6. The authors succeeded to collect all desire samples (bloods can CSF) from only one patient making the study too preliminary and conclusion based on this study might be biased.
7. In the results section, the author mentioned that they obtained peripheral blood sample and CSF samples, but in table 1, they mentioned n=7.
8. No control data is provided in the study.Decision letter by
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Reviewer report
2019/12/21- The title and the findings in the text is not matching. The authors should analyzed few inflammatory markers in the blood sample.
- Introduction part: third paragraph, first sentence needs references.
- The number of patients included in this study is very low.
- It is unclear why the authors did not used heparinized tube for blood collection, in order to avoid coagulation.
- The authors stated that they used the blood from 5 patients and the CSF from the five patients. Are they same patients?
- The authors succeeded to collect all desire samples (bloods can CSF) from only one patient making the study too preliminary and conclusion based on this study might be biased.
- In the results section, the author mentioned that they obtained peripheral blood sample and CSF samples, but in table 1, they mentioned n=7.
- No control data is provided in the study.
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