Reviewer's report
Title:Antibodies against gonadotropin-releasing hormone (GnRH) and
destruction of enteric neurons in 3 patients suffering from gastrointestinal
dysfunction
Version: 1Date:18 October 2009
Reviewer: Tamas Ordog
Reviewer's report:
GENERAL COMMENTS
This report of 3 cases investigates the interesting hypothesis that circulating
autoantibodies against gonadotropin-releasing hormone (GnRH) may lead to
neuron degeneration in the gut and consequent dysmotility in a subset of patients
with diverse forms of idiopathic gastrointestinal dysmotilities. The study builds on
a previous case study by the same group showing dysmotility and degeneration
of GnRH+ neurons in a patient who had developed anti-GnRH autoantibodies
from buserelin treatment. In this paper the authors also attempt to establish a
causal relationship between the autoantibodies and neuron loss by using a rat
enteric neuronal culture indicator system. Strengths of the paper are the
interesting hypothesis, the demonstration of anti-GnRH antibodies in the sera of
patients with dysmotilities and the inclusion of the mechanistic, in vitro studies.
However, the results from the latter do not support the main conclusion of the
paper and the mechanistic experiments are incomplete. The authors did not
attempt to discuss and interpret the intriguing findings that the majority of enteric
neurons express GnRH and about one-half express receptors for GnRH. Most
unfortunately, the authors also failed to ensure that their submission is complete
and Figure 2A and the entire Figure 3 are missing and could not be evaluated.
MAJOR COMPULSORY REVISIONS
1. The paper cannot be properly evaluated without the missing figures, which
must be replaced.
2. Only serum from Case 3 affected neuron survival in vitro and commercial
anti-GnRH sera were also ineffective. Despite these negative findings, the
authors claim that the anti-GnRH autoantibodies in Case 3 were the most likely
cause of neuron degeneration and symptoms. Based on the data, this claim is
not justified. It is equally or even more likely that inflammatory cytokines in the
serum of this diabetic patient with high degree of inflammation were responsible
for the described neurotoxicity. To positively link the neuron loss to the
anti-GnRH antibodies, the authors need to demonstrate that the neurotoxicity can
be eliminated or significantly reduced by pre-absorbing the patient’s serum with
GnRH or a suitable analog. The neuroprotective effect of buserelin (applied
alone) does not constitute sufficient evidence in this regard.
3. The authors should discuss their intriguing observation that a very high
percentage of enteric neurons express GnRH or GnRH receptors. How rigorously
has their immunostaining been evaluated? Have they performed pre-absorption
studies? Have they tested multiple antibodies? Is there evidence of GnRH
neurosecretion or neurotransmission in the enteric nervous system? What
function(s) do they think GnRH could perform in the ENS?
MINOR ESSENTIAL REVISIONS
1. There should be no spece between “gastro” and “paresis”.
2. Page 7: The authors probably meant “anti-LHRH receptor” in the 5th line from
the bottom.
DISCRETIONARY REVISION
1. The authors should consider including images of GnRH+ and GnRH receptor+
neurons in Figure 3.
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.
Reviewer's report
Title:Antibodies against gonadotropin-releasing hormone (GnRH) and
destruction of enteric neurons in 3 patients suffering from gastrointestinal
dysfunction
Version: 1Date:18 October 2009
Reviewer: Tamas Ordog
Reviewer's report:
GENERAL COMMENTS
This report of 3 cases investigates the interesting hypothesis that circulating
autoantibodies against gonadotropin-releasing hormone (GnRH) may lead to
neuron degeneration in the gut and consequent dysmotility in a subset of patients
with diverse forms of idiopathic gastrointestinal dysmotilities. The study builds on
a previous case study by the same group showing dysmotility and degeneration
of GnRH+ neurons in a patient who had developed anti-GnRH autoantibodies
from buserelin treatment. In this paper the authors also attempt to establish a
causal relationship between the autoantibodies and neuron loss by using a rat
enteric neuronal culture indicator system. Strengths of the paper are the
interesting hypothesis, the demonstration of anti-GnRH antibodies in the sera of
patients with dysmotilities and the inclusion of the mechanistic, in vitro studies.
However, the results from the latter do not support the main conclusion of the
paper and the mechanistic experiments are incomplete. The authors did not
attempt to discuss and interpret the intriguing findings that the majority of enteric
neurons express GnRH and about one-half express receptors for GnRH. Most
unfortunately, the authors also failed to ensure that their submission is complete
and Figure 2A and the entire Figure 3 are missing and could not be evaluated.
MAJOR COMPULSORY REVISIONS
1. The paper cannot be properly evaluated without the missing figures, which
must be replaced.
2. Only serum from Case 3 affected neuron survival in vitro and commercial
anti-GnRH sera were also ineffective. Despite these negative findings, the
authors claim that the anti-GnRH autoantibodies in Case 3 were the most likely
cause of neuron degeneration and symptoms. Based on the data, this claim is
not justified. It is equally or even more likely that inflammatory cytokines in the
serum of this diabetic patient with high degree of inflammation were responsible
for the described neurotoxicity. To positively link the neuron loss to the
anti-GnRH antibodies, the authors need to demonstrate that the neurotoxicity can
be eliminated or significantly reduced by pre-absorbing the patient’s serum with
GnRH or a suitable analog. The neuroprotective effect of buserelin (applied
alone) does not constitute sufficient evidence in this regard.
3. The authors should discuss their intriguing observation that a very high
percentage of enteric neurons express GnRH or GnRH receptors. How rigorously
has their immunostaining been evaluated? Have they performed pre-absorption
studies? Have they tested multiple antibodies? Is there evidence of GnRH
neurosecretion or neurotransmission in the enteric nervous system? What
function(s) do they think GnRH could perform in the ENS?
MINOR ESSENTIAL REVISIONS
1. There should be no spece between “gastro” and “paresis”.
2. Page 7: The authors probably meant “anti-LHRH receptor” in the 5th line from
the bottom.
DISCRETIONARY REVISION
1. The authors should consider including images of GnRH+ and GnRH receptor+
neurons in Figure 3.
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.
Please review this paper.
user
Reviewer's report
Title:Antibodies against gonadotropin-releasing hormone (GnRH) and
destruction of enteric neurons in 3 patients suffering from gastrointestinal
dysfunction
Version: 1Date:18 October 2009
Reviewer: Tamas Ordog
Reviewer's report:
GENERAL COMMENTS
This report of 3 cases investigates the interesting hypothesis that circulating
autoantibodies against gonadotropin-releasing hormone (GnRH) may lead to
neuron degeneration in the gut and consequent dysmotility in a subset of patients
with diverse forms of idiopathic gastrointestinal dysmotilities. The study builds on
a previous case study by the same group showing dysmotility and degeneration
of GnRH+ neurons in a patient who had developed anti-GnRH autoantibodies
from buserelin treatment. In this paper the authors also attempt to establish a
causal relationship between the autoantibodies and neuron loss by using a rat
enteric neuronal culture indicator system. Strengths of the paper are the
interesting hypothesis, the demonstration of anti-GnRH antibodies in the sera of
patients with dysmotilities and the inclusion of the mechanistic, in vitro studies.
However, the results from the latter do not support the main conclusion of the
paper and the mechanistic experiments are incomplete. The authors did not
attempt to discuss and interpret the intriguing findings that the majority of enteric
neurons express GnRH and about one-half express receptors for GnRH. Most
unfortunately, the authors also failed to ensure that their submission is complete
and Figure 2A and the entire Figure 3 are missing and could not be evaluated.
MAJOR COMPULSORY REVISIONS
1. The paper cannot be properly evaluated without the missing figures, which
must be replaced.
2. Only serum from Case 3 affected neuron survival in vitro and commercial
anti-GnRH sera were also ineffective. Despite these negative findings, the
authors claim that the anti-GnRH autoantibodies in Case 3 were the most likely
cause of neuron degeneration and symptoms. Based on the data, this claim is
not justified. It is equally or even more likely that inflammatory cytokines in the
serum of this diabetic patient with high degree of inflammation were responsible
for the described neurotoxicity. To positively link the neuron loss to the
anti-GnRH antibodies, the authors need to demonstrate that the neurotoxicity can
be eliminated or significantly reduced by pre-absorbing the patient’s serum with
GnRH or a suitable analog. The neuroprotective effect of buserelin (applied
alone) does not constitute sufficient evidence in this regard.
3. The authors should discuss their intriguing observation that a very high
percentage of enteric neurons express GnRH or GnRH receptors. How rigorously
has their immunostaining been evaluated? Have they performed pre-absorption
studies? Have they tested multiple antibodies? Is there evidence of GnRH
neurosecretion or neurotransmission in the enteric nervous system? What
function(s) do they think GnRH could perform in the ENS?
MINOR ESSENTIAL REVISIONS
1. There should be no spece between “gastro” and “paresis”.
2. Page 7: The authors probably meant “anti-LHRH receptor” in the 5th line from
the bottom.
DISCRETIONARY REVISION
1. The authors should consider including images of GnRH+ and GnRH receptor+
neurons in Figure 3.
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.
assistant