上篇讲到我们投稿遇上认真的审稿人但编辑却一时糊涂，我们用事实让编辑改判使得文章顺利发表。这回要说更不幸的是碰上了一个不负责任的编辑，他／她压根没告诉我们审稿人的意见是什么，一人大包大揽，以Editorial Board comments名义把我们的文章草草毙了。大家本不想浪费时间准备改投其它杂志，可偏碰上了我们一个爱较真的MD（第一作者），她忍受不了review中错误百出的评议，一通毫不留情反驳email直接送到主编手里，她的email火药味很浓但每条理由充分，让主编不得不认真检讨他们的review，主编为他们编辑和审稿人的水平汗颜，于是越过原审稿人和编辑亲自审阅原稿，修改稿以及终稿。在我写这个故事的今天，该文已发表在Am J Ophthalmol (Internet Advance) 上了。全文请查： http://www.ajo.com/inpress

现在想把重点放在申述信上。本人欣赏这封信，自惭英文和魄力有限写不出这样有理有力的申述信，介绍给中国有兴趣同行们是希望它山之石，可以攻玉。

先介绍一点有关研究背景：白内障是眼科发病率最高的眼疾，在发展中国家是致盲首因，在发达国家虽可用现代手术方法治愈，但费用昂贵占所有眼病中首位。到目前为止我们对其发病机理知之甚少，预防更是一句空话。我们小组经过近十年的系列基础和临床实验研究，提出了眼内分子氧的内环境改变与常见的核性白内障发病有密切关系。然而证实这个理论有难以想象困难，其原因有三：

1)    此类研究只能在活体(in vivo)上进行，体外实验只能作为辅助研究；

2)    动物眼的解剖生理生化无法与人眼相拟，如玻璃体切除术后核性白内障只发生在人类，迄今为止尚无成功的动物模型；

3)   人的活体研究有非常严格的限制，只能利用某些特定疾病治疗时并在病人同意下做些观察研究。

幸运的是我们有一个包含MD和PhD在内的有共同研究志向团结一心的team，有良好的基础和临床相结合的研究经验，有广泛支持我们并志愿参加研究的病人群体（美国的病人大多乐意为科研作贡献）。具体到本次论文课题，我们认为人眼的水晶体是一个特殊器官，无血管无神经，它生存在一个低氧环境（<1%)所以其特有的代谢功能使其生长缓慢，能长期保持透明和弹性。一旦低氧环境被破坏如玻璃体视网膜手术或玻璃体液化（通常表现为飞蚊症），从视网膜血管网来的高浓度分子氧会长驱直入水晶体，其oxidativestress导致了水晶体核逐渐变硬变混形成白内障。以上这都是纸上谈兵的理论，要证实这个理论是否正确却不简单：即设法证实眼内低氧环境能保护水晶体；而高氧环境会导致核性白内障。我们文章的题目是：Ischemic Diabetic Retinopathy May Protect Against Nuclear Sclerotic Cataract。此研究利用缺血性糖尿病视网膜病变作为典型低氧模型，用玻璃体切除术后眼内形成较高氧浓度情况为对照，定量追踪观察两组病人水晶体变化一年左右，结果证实了低氧环境确实可以保护水晶体。这是一个全新的发现。此发现的意义不是为了就事论事说缺血糖尿病不太会发展为核性白内障，而是证明了低氧环境对人水晶体保持正常的重要性以及更为重要的是为预防核性白内障提出了一条可能的方向。

好了，言归正传，该说到伸述信了。英文部分是来自原文节选，中文是本人加入的少许解释。

......I am writing to you about my concerns regarding the quality of reviewers for a paper rejected by the AJO, but in this situation I am the author.  I do not wish to appear as a "disgruntled author" as my manuscripts have been rejected many times before without formal complaint.  On this occasion I merely wish to express my concern that the reviewers did not carefully read nor have the necessary background to judge the manuscript.  Allow me to explain.  ( 开场白，此信主要目的是针对编辑的审稿水平)。

1. "A Case-Control study design seems to be more appropriate to prove their hypothesis". （蓝色斜体字是编辑的意见，下同）

Prior to submission, all of the authors debated this subject at length and unanimously agreed that a prospective cohort study better described our 2 years of prospectively accumulating quantitative data.  We came to that conclusion after studying the following definitions: Cohort study and Case-control study...... (名词解释见后). In light of these definitions, I would like to suggest to the reviewer that a case-control study would not be any better than the prospective cohort study in proving the hypothesis presented in the manuscript. （我们确实email来往不下几十次讨论直到大家都弄明白为止，此编辑在这个基本概念上不清楚，有点自以为是了。）

2. "Diabetic patients usually have higher incidence of cortical lens opacity, and cortical opacity also influences visual function such as nuclear cataract. If they had provided a more detailed description of cataract progression according to cortical opacity, posterior capsular opacity and nuclear opacity, this may have more clinical significance."

The Scheimpflug camera that we used to objectively grade the progression of nuclear opacities also provides retroillumination images that can be used to quantify the extent of cortical and posterior subcapsular cataracts. Any changes in these opacities would have been evident. Only nuclear opacities progress after vitrectomy. A knowledgeable reviewer would have known this basic information. （白内障有三种类型，每种的发病机理各不同，糖尿病常引起皮质性和后囊下白内障，而玻璃体切除术术后主要引起核性白内障。编辑在这个问题上混淆不清，缺乏应有的专业知识。）

3. "The authors had previously reported in the 2006 AJO that diabetic eyes have lower intraocular oxygen tension compared with non-diabetic eyes, thus, have lesser nuclear sclerosis cataract. Given such, it is questionable that this article really presents any additional findings or stronger evidences compared to their previous report."

We are pleased that the reviewer is aware of our 2006 AJO paper showing that diabetic eyes have a lower intraocular oxygen tension compared with non-diabetic eyes.  However, in our previous study, we proposed that diabetics would have slower progression of nuclear cataract after vitrectomy. The present study was the test of this hypothesis. It would be scientifically inappropriate to assume that having lower oxygen would protect against nuclear cataract without testing this theory.  The present manuscript, for the first time, prospectively gathers quantitative data on nuclear cataract and demonstrates that ischemic diabetic eyes have less nuclear sclerotic cataract. （编辑把理论的假设和科学的求实混为一谈，这个错犯的太低级了。）

4.  "This study lacks sufficient evidence that the presence of ischemia than diabetes itself was more associated with delayed nuclear opacity because they did not directly compared ischemic diabetic retinopathy eyes with background diabetic retinopathy eyes."

This reviewer simply did not read the manuscript carefully. The Results section states, "Table 3 shows the average nuclear light scattering units as measured by Scheimpflug photography before and after vitrectomy in the non-diabetic eyes and the non-ischemic diabetic eyes undergoing surgery for non-diabetes related conditions such as macular hole and macular pucker. There was no statistically significant difference between these two groups. Therefore, for the purpose of the analysis, these non-diabetic and non-ischemic diabetic eyes were collectively grouped as "non-ischemic" eyes for comparison to eyes with ischemic diabetic retinopathy."  The non-ischemic diabetic eyes either had no retinopathy or background diabetic retinopathy, but they behaved post-vitrectomy just like non-diabetic eyes.  Therefore, this paper showed that it was not the presence of diabetes that protected against post-vitrectomy nuclear cataract but rather the presence of ischemic diabetic retinopathy. （任何研究人的疾病都是复杂的，不能如动物实验设定相同条件，我们必须根据病人患的疾病以及程度细细区别。编辑提的问题我们有详细回答，可惜他／她没有耐心读完就下了结论，自然被拍砖了。）

5.  "Age is the strongest factor which influences the development of postoperative nuclear sclerosis formation even in diabetic patients. Even though authors adjusted age factor using statistical analysis (multiple regression analysis), their very limited number of cases (at 12 months, n=5 vs. n=10) brings to question the reliability of their statistical results."

We agree that age is an important factor influencing the development of post-vitrectomy nuclear sclerotic cataract.  That is why we performed a multiple regression analysis.  We acknowledge that we had a small number of cases. That is why we used prospectively obtained Scheimpflug photographs.  Scheimpflug photography allows the researcher to objectively quantify NS cataract so that meaningful comparisons can be made with only small numbers of patients.  We have fulfilled our scientific obligations.  It is not appropriate to question the reliability of the result based only on the number of subjects. One uses statistics to demonstrate that, given the number of subjects enrolled, the differences in the groups are or are not significantly different. In this study, the differences between ischemic and non-ischemic eyes at 12 months post vitrectomy were large and highly significant (p=0.001). Finally, it should also be recognized that an important reason for the smaller number of cases in which opacity could be quantified at 12 months was that half of the non-ischemic cases had already had cataract surgery (as compared to only one of the ischemic subjects), thereby precluding analysis by Scheimpflug photography. This result further demonstrates the protective effect of ischemia.（补充，编辑说我们例数少了没错，但为什么少了是部分病人因为白内障发展太快不得不做了手术，这从另方面证实了结果的一致性。在修改本中，我们增加了后来半年的例数重新分析了结果。）

6.  "Gas tamponade is one of the known cataract aggravating factors. There were 17 cases of macular hole surgeries and 4 cases of retinal detachment surgeries included in the non-ischemia group. Was gas tamponade used in these cases?"

Again, the reviewer did not carefully read the manuscript.  The last sentence of the Results sections states, "Gender, race, surgical eye, gauge of surgery (i.e. 20, 23, 25 gauge vitrectomy), or use of intraocular gas tamponade were not significantly associated with nuclear opacity after vitrectomy (not shown)."   In addition, we are about to submit for publication a manuscript that proves (again via prospectively obtained Scheimpflug data) that gas tamponade does not aggravate post-vitrectomy NS cataract.  Thus, the reviewer has an incorrect, unproven bias on this topic. (编辑显然是一个懂眼科手术内行，但是不仔细读完全文就下结论不挨砖才怪。）

7. "There are issues concerning the novelty of the observations, and ability of the small sample size to answer the scientific question of whether it is ischemic retinopathy or diabetes itself that protects against nuclear cataract."

A careful reading of our manuscript would indicate that, in fact, this is new information collected prospectively using Scheimpflug technology to compensate for the small sample size.  Our statistical results are significant across the board (and not marginally so).  Finally, it is quite clear from the data presented that it is the presence of ischemic retinopathy alone and not merely the presence of diabetes that protects against post-vitrectomy NS cataract.  This is a novel finding.  It is an important finding.  It corroborates the growing hypothesis that the oxygen source for nuclear sclerotic cataract in all persons is the retina and perhaps the other vascularized tissues of the eye. （做临床研究，样本数永远是一个issue，这点我同意编辑的意见，但实际操作要看具体情况和方法。）

8. "Lower priority score."

The reviewers have failed to recognize one of the most important insights arising from this manuscript. By studying and understanding the lack of progression of post-vitrectomy nuclear sclerotic cataract in eyes with ischemic diabetic retinopathy, a novel strategy for preventing nuclear sclerotic cataract in eye becomes apparent: simply reduce the amount of molecular oxygen reaching the crystalline lens. Thus, we now have, for the first time, a rational approach for preventing the leading cause of blindness in the world. This merits a high priority score. (尽管我对本课题的研究结果和意义非常有信心，要这么毫不客气高度赞扬自己的文章，我还真做不到。可我们这位MD自信满满地做到了，这是我深为感慨和佩服的地方。）

收到此信后AJO主编很快回复，下面是主编的第一次回信内容：“Yes, the reviewers did see somewhat misguided. I have granted you a rebuttal for this manuscript and then you can do some revision and resubmission. You should have received that notice. Please include the comments below in the cover letter.”

后来呢？读者可以自己推理了。