Fluoroquinolones-Associated Disability: It Is Not All in Your Head

Round 1

Reviewer 1 Report

Review
Fluoroquinolones-associated disability: it is not all in your head

The paper presents interesting view to new aspects of fluoroquinolone toxicity.
However, a few issues require to be improved.

1. Lack of figures /schemes of presented anatomical and biochemical relations.
The details of vagus nerve regulatory loops represent a relative narrow aspect of neurology and biochemistry.  
These details should be presented in the introduction in a form of a detailed scheme. Then, it will be easy to follow the desceription of these relations in the text. 
The only figure in 475 line is not sufficient and it is to simple.  
This (or separete) figure should contain the afferent regulatory loops, as well. The detailed view to all the regulatory loops is the necessery introduction for further discussion. Also, the final effects of stimulation of Ach/NANC part of vagus nerve on the intestine /stomach/pancreas should be presented rather in the introduction to follow the influence of FQ on this regulation.
It was difficult to follow for me while reading the text if the stimulation of gabaa receptors generates the increase or decrease in the activity of vagus nerve (its  Ach/NANC part). I should be more clearly written the introducion if GABA pathway increases od decreases the number of action potentials in vagus nerve and if it increases or decreases the activity of the intestine/ stomach/ pancreas (with clear distinguishing the Ach and NANC axis).
The effect of  vagus nerve resection and the relation to Parkinson D could be also presented in some figure (lines 306-314)

2. There is generally not recommended to use such words as "regulate" "dysregulate" "influence"  "modulate" "dysfunction" which do not show the direction of reulation. Such sentences do not introduce information for the reader. Use instead "activate", "stimulate", "inhibit", "decrease" to show direction of regulation if possible. Manuscript should be evaluated carefully with respect of this criterion.

3. the latin sentence "et cetera" should not be written together , etc. is recommended rather.

4. line 289: however, several other neurotransmitters can be released including glutamate, catecholamines, glycine 
it is not clear where they are released...

5. line 158: Very important trace element is Mn which is crucial for mitochondrial work (e.g.SOD2) and it is not presented in the list.
 The short review concerning the role of this element and connection with FQs is recommended. At least - add it to the list.

6. line 559: insulin resistance may occur as a result of increased circulating insulin levels
It is not true. Increased insulin levels are the effect and not the reason of insuline resistance.
The defect of the insulin receptor and the increase in glucose levels in the blood causes the increase in insulin production and level in the blood.

 

Author Response

To the attention of Reviewer #1,
We are sincerely grateful for your insightful comments. We believe that with your help our manuscript entitled "Fluoroquinolones-associated disability: it is not all in your head" has since improved significantly. We are providing a point-by-point response to your comments and highlighted the changes in the amended manuscript in yellow.

“1. Lack of figures /schemes of presented anatomical and biochemical relations.

The details of vagus nerve regulatory loops represent a relative narrow aspect of neurology and biochemistry.  

These details should be presented in the introduction in a form of a detailed scheme. Then, it will be easy to follow the desceription of these relations in the text. 

The only figure in 475 line is not sufficient and it is to simple.  

This (or separete) figure should contain the afferent regulatory loops, as well. The detailed view to all the regulatory loops is the necessery introduction for further discussion. Also, the final effects of stimulation of Ach/NANC part of vagus nerve on the intestine /stomach/pancreas should be presented rather in the introduction to follow the influence of FQ on this regulation.”

We thank you for your suggestion, and we agree with this comment. Therefore, we have created a new Figure 1 showing a diagram of the vagal regulatory loops including the afferent branch of the vagus nerve, as well as more details describing the effects of glutamate and GABA at the NTS to DMV synapse, and the effects of the cholinergic and NANC pathways on the gastrointestinal tract (line 315). The paragraph “A vulnerable target: the vagus nerve” has been edited to reflect these changes (lines 287, 288, 291-296). Figure 2 (former figure 1) has been edited to better explain the two possible mechanisms of fluoroquinolones toxicity on the vagus nerve and includes the details that were missing in the first submission according to your suggestions (line 534).

It was difficult to follow for me while reading the text if the stimulation of gabaa receptors generates the increase or decrease in the activity of vagus nerve (its  Ach/NANC part). I should be more clearly written the introducion if GABA pathway increases od decreases the number of action potentials in vagus nerve and if it increases or decreases the activity of the intestine/ stomach/ pancreas (with clear distinguishing the Ach and NANC axis).

We agree with this suggestion. We have, accordingly, revised the paragraph “A vulnerable target: the vagus nerve” to emphasize this point (please, see the previous comment for the lines).

The effect of  vagus nerve resection and the relation to Parkinson D could be also presented in some figure (lines 306-314)

Thank you for this suggestion. This is certainly an interesting aspect of vagal pathophysiology. However, in the case of this review, the addition of a third figure relating solely to Parkinson’s Disease seems slightly out of scope, since we want to emphasize the possible neurotoxic effect of Fluoroquinolones on this cranial nerve.

“2. There is generally not recommended to use such words as "regulate" "dysregulate" "influence"  "modulate" "dysfunction" which do not show the direction of reulation. Such sentences do not introduce information for the reader. Use instead "activate", "stimulate", "inhibit", "decrease" to show direction of regulation if possible. Manuscript should be evaluated carefully with respect of this criterion.”

Thank you for the suggestion. We agree with this point and have edited the manuscript accordingly when appropriate.

“3. the latin sentence "et cetera" should not be written together , etc. is recommended rather.”

Thank you for the suggestion. We have edited the resubmitted manuscript accordingly.

“4. line 289: however, several other neurotransmitters can be released including glutamate, catecholamines, glycine it is not clear where they are released…”

We are grateful for pointing out that this sentence was not as clear as we intended it to be. We have clarified that these neurotransmitters are released by the NTS (line 291).

“5. line 158: Very important trace element is Mn which is crucial for mitochondrial work (e.g.SOD2) and it is not presented in the list. The short review concerning the role of this element and connection with FQs is recommended. At least - add it to the list.”

Thank you for sharing this important pathophysiological mechanism with us. We have since then incorporated the role of Mn2+ and SOD2 in the “Overview of Fluoroquinolones toxicity” paragraph (lines 195-200).

“6. line 559: insulin resistance may occur as a result of increased circulating insulin levels It is not true. Increased insulin levels are the effect and not the reason of insuline resistance. The defect of the insulin receptor and the increase in glucose levels in the blood causes the increase in insulin production and level in the blood.”

We are very grateful for your comment. We have corrected our mistake and added more information regarding insulin and the vagus nerve (lines 594-617).

Reviewer 2 Report

The manuscript entitled Fluoroquinolones-associated disability: it is not all in your head by Maya Z Freeman et al., is highly interesting, it is well presented and structured.  - As minor point I would suggest the authors to include a table to summarize all drug-drug interactions (in determining FQs toxicity). 

Author Response

To the attention of Editor #2, 
We want to thank you for your time and effort put in reviewing our manuscript entitled "Fluoroquinolones-associated Disability: it is not all in your head" submitted for publication in NeuroSci. 

“As minor point I would suggest the authors to include a table to summarize all drug-drug interactions (in determining FQs toxicity). “

We thank you for your suggestion, and we agree. We have since added a table to summarize the known drug-drug interactions and the resulting effects (line 154).

Round 2

Reviewer 1 Report

All my suggestions have been introduced into manuscript.

I accept it for publicaction.