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1、Dear Dr. XXX, Thank you for arranging a timely review for our manuscript. We are pleased to know that our study is of general interest for the readers of NUTRITION. We have carefully evaluated the reviewers critical comments and thoughtful suggestions, responded to these suggestions point-by-point,
2、and revised the manuscript accordingly. All changes made to the text are in red so that they may be easily identified. With regard to the reviewers comments and suggestions, we wish to reply as follows:Enclosures:(1) Correspondences to your reviewers;(2) One copy of the revised manuscript;(3) A flop
3、py disk containing the revised manuscript.(4) Copyright assignmentTo reviewer#11. The author should add a few review articles on ghrelin for readers in the Introduction.We added two reviews in our revised manuscript.2. The increase in ghrelin levels do not necessary indicate that weight loss in dise
4、ase is well compensated (Introduction and Discussion). This may be interpreted to be insufficient to recover to the previous body weight.There is possibility that the increase in ghrelin levels may result from the insufficient to recover to the previous body weight, but it is more likely that the in
5、crease in ghrelin level indicate that weight loss in disease is well compensated. Shimizu et al1 reported that baseline plasma ghrelin level was significantly higher in cachectic patients with lung cancer than in noncachectic patients and control subjects. As weight loss is a chronic process and ghr
6、elin levels may change more rapid than weight loss, the increase in ghrelin in those chronic diseases is unlikely result from the insufficient to recover to the previous body weight. Moreover, this author also reported that follow-up plasma ghrelin level increased in the presence of anorexia after c
7、hemotherapy, which further suggests that the increase ghrelin level may represent a compensatory mechanism under catabolicanabolic imbalance in cachectic patients with lung cancer1.3. The authors should refer to the original report that IL-1b decrease plasma ghrelin levels(Gastroentelorogy 120:337-3
8、45,2001) We referred this article as the reviewer suggested. In fact, this is a mistake of us. Many thanks for the reviewers suggestion.4. Ref. 13 dose not include data on ghrelin.We are so sorry to make this mistake for citing the Ref.13. We replaced the reference in the paper.5. There is no report
9、 that desacyl ghrelin stimulates food intake. It is the consensus at present acyl ghrelin is involved in feeding response to starvation. Therefore, the authors should be careful about their interpretation described in the last paragraph in page 10. We made it clear in the paper that ghrelin has two
10、isoforms (“active” and “inactive”). Only the “active” isoform is involved in feeding response to starvation. But the “inactive” isoform has other activities like anti-proliferative activity on tumor cell lines as described in the manuscript.To reviewer#2Major comments1. Earlier studies have shown th
11、at circulating ghrelin level is increased in underweight patients with CHF, lung cancer, and liver cirrhosis. In the present study, however, plasma ghrelin level was decreased despite a significant weight loss in COPD. In addition, earlier studies have reported that circulating ghrelin correlated po
12、sitively with BMI in patients with CHF and lung cancer. However, the present study demonstrated that plasma ghrelin level correlated positively with BMI in COPD patients. Thus, there are considerable discrepancies between the present study and earlier studies. These discrepancies should be discussed
13、 in detail. The author also stated the regulation of ghrelin secretion was disturbed in COPD patients. However, they did not clarify this mechanism.We stated that the role of ghrelin in patients with COPD may be different from its role in CHF, cancer and liver cirrhosis and discussed this difference
14、 in the last paragraph of page 9. Following the reviewers suggestion, we added that “plasma ghrelin correlated positively with percent predicted residual volume and residual volume/total lung capacity ratio” as the evidence for further supporting that respiratory abnormalities may take part in the r
15、egulation of plasma ghrelin levels.2. The authors demonstrated that plasma ghrelin level correlated negatively with plasma TND-a and CRP in COPD patients. However, Nagaya et al. have shown that plasma ghrelin level correlates positively with plasma TNF-a level in patients with CHF. This discrepancy
16、should be discussed. According to the reviewer indicated, we discussed this discrepancy in the second paragraph of page 9.3. The author stated that respiratory abnormalities may take part in the regulation of plasma ghrelin level in COPD. The authors should describle the relationship between plasma
17、ghrelin level and pulmonary function in COPD. There are evidences that respiratory abnormalities may take part in the regulation of plasma ghrelin level in lung diseases with respiratory abnormalities2,3. As our study was designed to investigate whether the plasma ghrelin levels are increased or dec
18、reased in COPD and whether the plasma ghrelin levels relates to the increased systemic inflammation in those patients, so we didnt analysis the relationship between plasma ghrelin level and pulmonary function. Minor comments1. Circulating ghrelin level exhibits a circadian rhythm. Therefore, the aut
19、hors should describle the limitation of their measurement of ghrelin in single samples. Its true that circulating ghrelin level exhibits a circadian rhythm and to monitor the ghrelin levels in different time points is better than just measured a single sample. However, we collected the samples at th
20、e fasting state (from 9:00 p.m. on the previous night.) by venipuncture at 7:00 a.m. as most studies did2,4. So our results can exclude the possibility that the difference between groups was result from the circadian rhythm of ghrelin and are well compared with other studies. 2. In the Results secti
21、on, plasma ghrelin level in healthy controls was different with that in 0.25+0.22ng/ml, whereas, in Figure 1A, it was approximately 1.8ng/ml. We fixed this in our revised manuscript. We are so sorry to make this mistake.To reviewer#31. About the paper of Itoh et al in AJRCC. As the reviewer said, th
22、e study by Itoh et al was not published when the current manuscript were submitted. We discussed the difference between the findings of their study and our study in revised manuscript.2. Abstract Conclusion: “plasma ghrelin decreased in COPD”. This sounds like the authors have followed subjects for
23、a long time and that the diagnosis COPD was conformed, the plasma ghrelin decreased. This was however not the aim nor the case-a reformulation is necessary.We fixed this as the reviewer suggested in our revised manuscript.3. Introduction(1) Page 2. Ref.1. is a letter to the editor in Br J Nutr and i
24、s a comment concering an earlier published paper. It is not a reference that support the statement. Several other references exist in the literature to be used instead.Thanks for the reviewers suggestion. We replaced this reference by other one.(2) Page 2, line 5. “To understand weight loss mechanis
25、ms in this disease may be helpful to improve quality of life in these patients”. Do you really think that if we researchers understand the mechanisms that automatically would make the patients happier? We replaced this sentence with “To understand weight loss mechanisms in this disease may be helpfu
26、l to combat weight loss in these patients”4. Methods(1) Patients: How were the patient and control subjects selected?The authors state that none of the control subjects was taking and medications-was that also the case for the patients?That was also the case for the patients. In fact, most of the CO
27、PD patients in China do not take any medications when the disease is clinically stable because of economic reason.Page 4, line 2. A short description of ATS criteria would be helpful for readers who are not familiar with those criteria.As those criteria are widely used by researcher and physicians,
28、we did not describe them in our paper as some paper did. If you think it is necessary to do so, we may add a short description.Page4, line3, what do you mean by “other diseases”? COPD patients most often have a lot of other diseases.We are so sorry to mis-express this - we just means that those pati
29、ents did not have the disease that known to affect the plasma ghrelin level. We fixed it in our revised manuscript. Page 4, line 5. If I understand it correctly, none of the COPD patients were smokers or ex-smokers, i.e. another reason exists for their COPD. Cigarette smoking is the main cause of CO
30、PD, but here you have studied patients having other reasons for the disease. What dose this mean regarding the representativity of the study group?Could it affect the results in some way? Smoking increases the plasma ghrelin level5. It is difficult for us to define “ex-smokers” because there is no s
31、tudy about that whether the ex-smoking will affect the plasma ghrelin level or not. This may lead to the representativity problem. However, those patients in our study still lost the weight and had system inflammation as most COPD patients did. Further study should be designed to investigate the eff
32、ect of ex-smoking on plasma ghrelin level.Page 4, line 6.Why do the authors refer to Whatmore et al? That study investigated ghrelin in healthy adolescents and has nothing to do with factor known to affect serum ghrelin level.We are sorry to make this mistake. We replaced this reference. (2) Body co
33、mpositionPage 4, last line page 5, line1. The deuterium dilution study performed by Baarends et al was using arm to foot bioelectrical impedance spectroscopy. In the current manuscript the foot to foot bioelectrical impedance assessment is used. The readers are lead to believe that the foot to foot
34、BIA is also validated with deuterium dilution in COPD patients, which I think is not the case.Thanks for the carefulness of the reviewer. However, there are still evidences that our method is well correlated with DEXA6 and arm to foot bioelectrical impedance7, so it is appropriate to use this method
35、 in our study. However, because those sentences will lead to the confusion, we deleted them in revised manuscript according to suggestion of the reviewer. Page 5, line 4. The %fat was calculated by the machine. It should be stated on which material these calculations are based on healthy subject? yo
36、ung or old? How many.According to the instruction of the manufactory, we selected the standard model for this calculation (the other model was athletic). We stated this in the revised manuscript.(3) StatisticalA reference by Scols et al is used to strengthen the use of values below the detection lim
37、it and the use of log. Other reasons need to be provided. What if Schols et al did a statistical error using values that were below the detection limit? There do exist statistical reasonsfor log the values do they exist in this manuscript?Its very important to select a suitable statistical method fo
38、r process the data. There are 6 data below the detection limit in ghrelin and 1 data in leptin. If these data were discarded, it may increase the possibility of type two error as lower ghrelin levels were exclude. However, if the data were analyzed originally, it may increase the possibility of type
39、 one error as they below the detection limit. So it is reasonable to adopt the method used by Schols et al. As to log transformation, we added the necessary information in the text according to the opinion of the reviewer. 5. DiscussionPage 8. line 2-3. COPD patients had lower ghrelin levels compare
40、d to the control subjects. Did the control subjects have “normal” ghrelin values?We selected seventeen age-matched healthy males as control subjects. Those subjects were healthy. So we can take their ghrelin levels as “normal” ghrelin values. However, we think true “normal ghrelin values” should be
41、based on large population study. Page9. line 18. Following “CHF, cancer and liver cirrhosis” a reference is needed here.We added references as the reviewer suggested.Page9. last line.ghrelin instead of gherlin.We fixed it.Page 11. Delete the summary, it is the same as the conclusion in the abstract.
42、We wrote the summary according to the guideline for author of the journal. If you think the summary should be cut, we may delete it.6. Reference As mentioned above, some of the references are not appropriate. They should be replaced by more appropriate and explanatory references.Many thanks for the
43、reviewers suggestion. We replaced those references in the revised manuscript.References:1.Shimizu, Y., Nagaya, N., Isobe, T., et al. Increased plasma ghrelin level in lung cancer cachexia. Clin Cancer Res 2003; 9: 7742.Itoh, T., Nagaya, N., Yoshikawa, M., et al. Elevated Plasma Ghrelin Level in Unde
44、rweight Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2004; 3.Haqq, A. M., Stadler, D. D., Jackson, R. H., et al. Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in
45、 Prader-Willi syndrome. J Clin Endocrinol Metab 2003; 88: 22064.Nagaya, N., Uematsu, M., Kojima, M., et al. Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors. Circulation 2001; 104: 20345.Fagerberg, B
46、., Hulten, L. M.,Hulthe, J. Plasma ghrelin, body fat, insulin resistance, and smoking in clinically healthy men: the atherosclerosis and insulin resistance study. Metabolism 2003; 52: 14606.Tyrrell, V. J., Richards, G., Hofman, P., et al. Foot-to-foot bioelectrical impedance analysis: a valuable too
47、l for the measurement of body composition in children. Int J Obes Relat Metab Disord 2001; 25: 2737.Nunez, C., Gallagher, D., Visser, M., et al. Bioimpedance analysis: evaluation of leg-to-leg system based on pressure contact footpad electrodes. Med Sci Sports Exerc 1997; 29: 524一篇稿子从酝酿到成型历经艰辛，投出去之后
48、又是漫长的等待，好容易收到编辑的回信，得到的往往又是审稿人不留情面的一顿狂批。这时候，如何有策略有技巧的回复审稿人就显得尤为重要。好的回复是文章被接收的重要砝码，而不恰当的回复轻则导致再次修改从而拖延发稿时间，重则导致文章被拒，前功尽弃。下面把我平时总结的一些答复审稿人的策略和写回复信的格式和技巧跟大家交流一下。首先，绝对服从编辑的意见。在审稿人给出各自的意见之后，编辑一般不会再提出自己的意见。但是，编辑一旦提出某些意见，就意味着他认为这是文章里的重大缺陷，至少是不合他的口味。这时，我们唯一能够做的只能是服从。因为毕竟是人家掌握着生杀予夺的大权。第二，永远不要跟审稿人争执。跟审稿人起争执是非常
49、不明智的一件事情。审稿人意见如果正确那就不用说了，直接照办就是。如果不正确的话，也大可不必在回复中冷嘲热讽，心平气和的说明白就是了。大家都是青年人，血气方刚，被人拍了当然不爽，被人错拍了就更不爽了。尤其是一些名门正派里的弟子，看到一审结果是major而不是minor本来就已经很不爽了，难得抓住审稿人的尾巴，恨不得拖出来打死。有次审稿，一个审稿人给的意见是增加两篇参考文献（估计也就是审稿人自己的文章啦），结果作者在回复中写到，making a reference is not charity！看到之后我当时就笑喷了，可以想象审稿人得被噎成什么样。正如大家所想的那样，这篇稿子理所当然的被拒了，虽然后
