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《科学》2010年11月5日本周新闻、科研道德规范
         
中国一个持续5年的医学争议波及到美国密歇根州，推迟了那里即将招募患者的临床试验。这个在密歇根州Royal Oak市的威廉·博蒙特医院的临床试验的目的是用手术改变脊柱裂患者的神经路经，使他们能够控制他们的膀胱。项目主持人Kenneth Peters上周确认资助试验的美国国立卫生研究院(NIH)要求复查。

发明神经改路手术的泌尿医生肖传国宣称在中国获得了惊人的结果，包括110位脊柱裂患者术后一年随访时的成功率为87%. 但围绕其工作的争议也是惊人的。前不久，警方指控武汉华中科技大学附属协和医院泌尿科主任肖传国指使人在街上打了他的两位批评者。被打伤的是方是民，他用方舟子的笔名运作新语丝网站，还有记者方玄昌，他曾编辑杂志报道，说中国患者未能从肖氏手术受益。

肖被以“寻衅滋事”判了5个半月的拘役。 他提出上诉。《科学》给肖的律师发了电子信，请求评论，但在付印前没得到答复。

对密歇根州基于肖氏手术的临床试验的质疑今年3月送达美国卫生与公众服务部(HHS)。一个号称“新语丝志愿者”的小组跟踪肖研究多年，他们发信到HHS下属的科研诚信办公室(ORI)和人类研究保护办公室(OHRP)。信中称“目前在美国展开的临床试验基于可疑数据”和存在其他问题。

科罗拉多州丹佛市的软件工程师、博客撰写人、志愿者之一的程鹗把信寄到ORI和OHRP。他说ORI在3月份回信表示不调查，因为他们的指控不够具体，而且肖在中国的工作超出ORI的管辖范围。但是，上周OHRP给程发了电子信，确认该办公室让资助机构重新考虑指控。

肖在科学界有不少朋友。博蒙特医院泌尿科主任Peters和30位研究者9月份曾签名一封公开信支持肖，信中敦促中国“保障他的人权”，赞扬肖是个“有同情心的人，他的诚实正直和给社会的创新科学贡献受到全世界的尊重”。

肖研究出来的神经改路手术原用来治疗脊髓损伤（SCI）患者并发的神经性膀胱症。神经跨接的想法最初由一位澳大利亚外科医生在1907年提出，医学文献中散落着一些部分成功的案例。不过肖在1980年代末提出的方法绕过中枢神经系统，把脊髓损伤病灶下的一根腰底部神经与一根或两根骶神经跨接起来，改变向膀胱和尿道肌肉输送信号的方式。肖宣称手术建立了一个新神经通路，病人可以通过挠或挤大腿皮肤启动自主排尿。

在大鼠和猫身上检验了这个想法后，肖在1994年申请并得到NIH资助在狗身上做试验，那时肖在美国纽约布鲁克林长岛学院医院工作。据他自己发表的描述，肖于1995年开始在河南省一个煤矿医院的中国SCI患者身上做临床试验，并最终把来自这些患者的结果发表在2003年的《泌尿学杂志(Journal of Urology)》上。这篇经过同行评议的文章报告了15位男性SCI患者接受手术的结果，这些患者都是反射亢进神经性膀胱（不自主地排尿），其中10人的获得令人满意的膀胱功能，2人部分恢复，2人失败，1人失去随访。

批评者指出肖的数据前后矛盾。比如在较早的报告中（有些是中文的），肖描述的患者手术后恢复时间是10到12个月，但2003年的最终报告说患者手术后12到18个月获得膀胱功能。还有，2003年报告中描述的15位患者都是反射亢进神经性膀胱，这似乎与肖早期的报告不符，早期报告中描述的既有反射亢进神经性膀胱患者，也有无反射膀胱（无法排尿）患者。

加利福尼亚州Sacramento 市加州大学戴维斯儿童医院儿童泌尿科主任Eric Kurzrock说，由于“病人选择偏见”，肖的研究存在“极大的缺陷”。Kurzrock特别批评其宣称的高成功率，指出没有随机可控的临床试验不可能有这样的数据。

治疗了SCI患者后，肖开始用神经改路手术来治疗脊柱裂儿童的膀胱功能失常，这类患者的脊髓通常不象脊髓损伤患者那样完全损坏。博蒙特医院首次在2006、2007年做的由私人资助的临床试验中招收了9位脊柱裂患者和2位SCI患者。Peters和共同作者报告了脊柱裂患者的初步结果，但是SCI患者的结果一直没有报告。目前NIH资助的临床试验目标是招募16位脊柱裂患者。最初的设计非盲、也没有对照组。Peters说NIH已经“成立一个关于我们研究的监督委员会。几星期前我们和他们碰了面，正在处理他们的评论。我们很快会提交修改过的临床试验方案，供他们复查”。

http://www.sciencemag.org/cgi/content/summary/330/6005/741
http://www.sciencenet.cn/m/user_content.aspx?id=380535

NEWS OF THE WEEK
RESEARCH ETHICS

Questions From China Snag U.S. Trial Of Nerve-Rerouting Procedure

(Photo) Under fire. Xiao Chuan-Guo’s reports of success in treating spina bifida patients have been challenged by Chinese critics.

A running 5-year medical brawl in China has spilled over into Michigan, where it has delayed a clinical trial about to enroll patients. The trial, based at the William Beaumont Hospital in Royal Oak, Michigan, aims to surgically reroute the nerves of spina bifida patients to give them control of their bladder. Principal investigator Kenneth Peters confirmed last week that the U.S. National Institutes of Health (NIH)—which is funding the work—has asked for a review.

The urologist who invented the nerve-rerouting procedure, Xiao Chuan-Guo, has claimed phenomenal results in China—including an 87% success rate for 110 spina bifida patients at their 1-year follow-up visits. But the controversy surrounding his work is phenomenal, too. Earlier this year police charged Xiao, head of urology at the Union Hospital affiliated with Huazhong University of Science and Technology in Wuhan, with organizing street attacks on two of his critics. Those injured were Fang Shimin, who under the pen name Fang Zhouzi operates the Xin Yu Si or New Threads Web site (www.xys.org), and journalist Fang Xuanchang (no relation to Fang Shimin), who has edited magazine articles about Chinese patients who failed to benefit from Xiao’s procedure.

Xiao was convicted of “causing disturbance” and sentenced to 5.5 months of detention (http://scim.ag/doctor-sentenced- Beijing). He has appealed the verdict. Science sent a request for comment to Xiao’s lawyer by e-mail but did not receive a response by presstime.

Questions about the clinical trial in Michigan based on Xiao’s procedure reached the U.S. Department of Health and Human Services in March, when the so-called New Threads Volunteers, a watchdog group that tracks Xiao’s research, sent a letter to the Office of Research Integrity (ORI) and the Office for Human Research Protections (OHRP). The letter alleged, among other things, that “the current clinical trials in the United States are based on dubious data.”

ORI declined to take action, according to Eddie Cheng, a blogger, software engineer, and member of the Volunteers, who mailed letters about Xiao’s study to ORI and OHRP. Cheng says ORI wrote back in March that the allegations weren’t specific and that Xiao’s work in China was out of its jurisdiction. Last week, however, OHRP confirmed in an e-mail to Cheng that it had asked the funding agency to evaluate the allegations.

Xiao has many friends in the scientific community. Peters, head of urology at the Beaumont Hospital, and 30 researchers signed an open letter in support of Xiao in September urging China to “protect his human rights” and praising Xiao as “a compassionate man who is respected worldwide for his integrity and his innovative scientific contributions to society.”

Xiao developed a nerve-rerouting procedure to treat neurogenic bladder disorder in patients with spinal cord injury (SCI). Nerve crossover was first proposed by an Australian surgeon in 1907; medical literature holds a scattering of partial success stories. But Xiao’s approach—which he proposed in the late 1980s—bypasses the central nervous system by grafting a lower lumbar nerve to one or two sacral nerves below the spinal cord lesion, rerouting signals to bladder and urinary muscles. Xiao claims to have established a new pathway that can be used to initiate voluntary urination by scratching or squeezing skin on the thigh.

After testing the idea on rats and cats, Xiao applied for and received an NIH grant in 1994 to study dogs at the Long Island College Hospital in Brooklyn, New York. According to his own published account, Xiao began a trial of the procedure with Chinese SCI patients at a hospital affiliated with a coal mine in Henan Province in 1995 and published final results from the SCI patients in 2003 in The Journal of Urology. This peer-reviewed article reported that of 15 male SCI patients—all with hyperreflexic neurogenic bladder (involuntary voiding)— who had the surgery, 10 gained satisfactory bladder function, two had partial recovery, two failed, and one was lost to follow-up.

Critics see inconsistencies in the data. For example, in early reports (some in Chinese), Xiao described patients’ recovery taking place between 10 and 12 months post-op, but the 2003 final report says that patients gained bladder function 12 to 18 months post-op. In addition, the depiction of all 15 patients as hyperreflexic in the 2003 report seems at odds with Xiao’s previous reports, which described treating a mix of patients with hyperreflexic bladder and areflexic bladder (failure to void).

Eric Kurzrock, chief of pediatric urology at the University of California, Davis, Children’s Hospital in Sacramento, California, says Xiao’s study is “extremely flawed” because of “patient selection bias.” Kurzrock is particularly critical of the claimed high success rate, because it is not based on data from a randomized, controlled trial.

After treating SCI patients, Xiao began using nerve rerouting to treat bladder malfunction in children with spina bifida, whose spinal cords are generally not as damaged as those of SCI patients. The first privately funded trial at Beaumont Hospital, which took place in 2006 and 2007, included nine spina bifida patients and two SCI patients; Peters and co-authors reported preliminary results from spina bifida patients, but results on SCI patients have not been reported. The current NIH-funded trial aims to enroll about 16 spina bifida patients; the original design was not blind and had no control group. Peters says NIH has “created an oversight committee for our study. We met with them a few weeks ago and are addressing their comments. We will be submitting a revised protocol soon for their review.”

–HAO XIN
www.sciencemag.org
SCIENCE VOL 330 5 NOVEMBER 2010 Published by AAAS