现在许多学科或方向的“不可信、不能重复”的SCI论文占了大多数 （1）孙学军，2015-10-14，临床前动物实验结果大多数不可靠 http://blog.sciencenet.cn/blog-41174-928004.html Poorly designed animal experiments in the spotlight. High-status journals or institutions no guarantees of carefully-reported trials. Daniel Cressey, 13 October 2015, Nature doi:10.1038/nature.2015.18559 http://www.nature.com/news/poorly-designed-animal-experiments-in-the-spotlight-1.18559 （2） 孙学军，2015-08-28，学术论文，让 我如何相信你！ 精选 http://blog.sciencenet.cn/blog-41174-916523.html Monya Baker, 27 August 2015, Over half of psychology studies fail reproducibility test Largest replication study to date casts doubt on many published positive results. http://www.nature.com/news/over-half-of-psychology-studies-fail-reproducibility-test-1.18248 （3） 孙学军，2015-06-10，美国无法重复生物医学研究年度费用高达280亿美元 精选 http://blog.sciencenet.cn/blog-41174-896872.html Monya Baker, 09 June 2015, Irreproducible biology research costs put at $28 billion per year Study calculates cost of flawed biomedical research in the United States. http://www.nature.com/news/irreproducible-biology-research-costs-put-at-28-billion-per-year-1.17711 （4） 许培扬，2014-07-10，CNPS顶级学术期刊论文的实验数据50%不能重现 http://blog.sciencenet.cn/blog-280034-810594.html Believe it or not: how much can we rely on published data on potential drug targets? 作者: Prinz, Florian; Schlange, Thomas; Asadullah, Khusru NATURE REVIEWS DRUG DISCOVERY 卷: 10 期: 9 页: 712-U81 出版年: SEP 2011 http://www.nature.com/nrd/journal/v10/n9/full/nrd3439-c1.html Phase II failures: 2008-2010 作者: Arrowsmith, John NATURE REVIEWS DRUG DISCOVERY 卷: 10 期: 5 页: 1-1 出版年: MAY 2011 http://www.nature.com/nrd/journal/v10/n5/full/nrd3439.html （5） 张九庆，2015-01-06，科学进步的未来：一个比喻性的总结 http://blog.sciencenet.cn/blog-542-856902.html 2013年7月31日英国《Nature》杂志上的一篇文章透露，在生物医学研究中，存在大量不具有可重复性的实验研究。例如，2011年，德国拜尔公司的一项内部调查发现，在67项内部临床前研究中，大约2/3无法验证。2012年，美国加州一家名为安进的制药公司对53项关于癌症的论文进行重复性检验，89%的研究结果无法重复。2013年5月，对美国德克萨斯州MD安德森肿瘤研究中心的一项调查研究发现，至少有50%的已发表数据无法进行重复。 NIH mulls rules for validating key results 作者: Wadman, Meredith NATURE 卷: 500 期: 7460 页: 14-16 出版年: AUG 1 2013 http://www.nature.com/news/nih-mulls-rules-for-validating-key-results-1.13469 感谢您指正以上任何错误！
关于在何种情况下才设立阳性对照药物组，我在查阅大量英文文献，许多基础药物实验研究并未设计这样的组。 但我最近在发表文章和申报课题时相继 被某某专家提出要加入阳性药物对照组。 我的理解，药理的研究，比如研究某某药是否通过某通路干预该疾病，不需要阳性药物对照组，但药效的实验应该需要。但国外的文献貌似真的甚至连药效的都没有这样的组。请看如下文献 Song X J, Yang C Y, Liu B, et al. Atorvastatin inhibits myocardial cell apoptosis in a rat model with post-myocardial infarction heart failure by downregulating ER stress response . International journal of medical sciences, 2011, 8(7): 564. Methods: Thirty-eight rats were randomly divided into three groups: a heart failure model group (model group), a heart failure plus atorvastatin treatment group (atorvastatin group) and a sham-surgery group (control group). Masao Tsujihata, Chikahiro Momohara, Iwao Yoshioka, Akira Tsujimura, Norio Nonomura, Akihiko Okuyama, Atorvastatin Inhibits Renal Crystal Retention in a Rat Stone Forming Model, The Journal of Urology, Volume 180, Issue 5, November 2008, Pages 2212-2217 Materials and Methods Ten-week-old specific pathogen-free male Sprague-Dawley rats were used. Atorvastatin (2 mg/kg) in 0.5% carboxymethyl cellulose was administered orally daily for 2 weeks. The rats were separated into 4 experimental groups, including group 1—water and 0.5% carboxymethyl cellulose daily, group 2—water and atorvastatin in 0.5% carboxymethyl cellulose daily, group 3—1% ethylene glycol dissolved in water, 0.5 μg vitamin D3 dissolved in 1 ml salad oil and 0.5% carboxymethyl cellulose daily, and group 4—1% ethylene glycol dissolved in water, 0.5 μg vitamin D3 dissolved in 1 ml salad oil and atorvastatin in 0.5% carboxymethyl cellulose daily.The ethylene glycol model of hyperoxaluria and the effect of atorvastatin treatment were analyzed in groups 1 to 4. van Vliet E A, Holtman L, Aronica E, et al. Atorvastatin treatment during epileptogenesis in a rat model for temporal lobe epilepsy . Epilepsia, 2011, 52(7): 1319-1330. Methods: Rats were orally treated with atorvastatin (once daily, 10 mg/kg) or vehicle for 14 days, starting 7 days before the induction of epilepsy (which was evoked by electrical stimulation of the angular bundle until rats developed status epilepticus). Seizure activity was monitored continuously until 6 weeks after status epilepticus using video-EEG (electroencephalography). 比如这最后这个癫痫的！！！很明显觉得该有阳性药物对照组！ 有没有专家给予解答？？？小弟不胜感激，什么时候才需要阳性药物对照组！是否有规范！
Animal Protectionists Call for Ending Cosmetics Animal Testing in China 2013-06-29 23:31:27 CRIENGLISH.com Web Editor: Liu Yuanhui Troy Seidle, director of Research Toxicology from Humane Society International, speaks at the 'Be Cruelty-Free', the world's largest campaign against cosmetics animal testing, in Beijing, China on Friday, June 28, 2013. 'Be Cruelty-Free', the world's largest campaign against cosmetics animal testing, was launched here in China on Friday to promote beauty without animal suffering. Animal protectionists are calling for industries to end mandatory testing of cosmetics on live animals. CRI's XYee has more. Humane Society International, or HSI, is a group that aims to protect all animals from suffering and prevent animal cruelty. In cooperation with domestic NGOs and the help of a Chinese pop singer, they have launched a Be Cruelty-free campaign in China in an effort to end cosmetics testing on animals. Peter Li, China Policies Specialist from HSI, explains the reasons behind the campaign. Today's campaign is about being cruelty-free. And this campaign is coming to China. China is the world's fourth largest market for beauty products, with the total volume being about 22 billion US dollars. And this number will grow even bigger in the future. China is also one of the few remaining nations still requiring animal testing in the cosmetics industry to legally verify products. As Peter Li mentioned, if the Chinese mainland continues to make it mandatory for cosmetics animal testing, then domestic consumers are not even left with the choice to opt for cosmetics that have not undergone animal testing. Equally important is the issue that China's domestically-produced cosmetics products will never enter international markets such as the EU. Earlier this year, bans on animal testing for cosmetic products in Europe came into full force. As of today, cosmetics tested on animals cannot be marketed any more in the EU. Andrew Rowan, the president of HSI explains. Animal testing is expensive, slow, and not terribly good at protecting human outcome. Currently, hundreds of cosmetics companies worldwide avoid animal testing by make use of the safe ingredients and non-animal tests available. However, most internationally recognized non-animal tests have not yet been officially accepted by Chinese regulators. The situation is beginning to change though. Troy Seidle is the director of Research Toxicology from HSI. So, about the 'Be Cruelty-Free Campaign' in China, there are a number of elements that ultimately were looking to see, such as to end animal testing requirements that the requirements come from the government. So, speaking with the regulatory agencies to discuss how can we move towards a similar approach to what Europe has done, because the EU and China are the largest trading partners. It is not as much a trade issue, as an animal welfare issue, moving them away from the unnecessary testing requirements. Doctor Blain Jones, from the Institute for In Vitro Sciences, a non-profit research and testing laboratory dedicated to the advancement of non-animal methods worldwide, says China is making efforts. China has been receptive to investigating the use of well-developed and validated non-animals methods such as the 3T3 Neutral Red Uptake test for phototoxicity. And this essay should be expected by the Food and Drug Administration, sometime later this year or next year. Blain says that the 3T3 Neutral Red Uptake test is the only non-animal test to achieve official acceptance in China. He also said China is the key to change, and they are looking forward to working with Chinese regulators, companies and scientists to see animal tests phased out.
June 29, 2013 Dear Dan, We did it! Our Be Cruelty-Free campaign has just scored another landmark victory for lab animals -- a ban on all animal testing for cosmetics in India! After more than a year of intensive campaigning and policy negotiations by HSI/India, the Drug Controller General has approved the complete removal of any mention of animal tests from India’s cosmetics standard. India now joins the ranks of Europe and Israel as subjecting rabbits, rats, and mice to painful or lethal testing becomes illegal and is replaced with modern non-animal alternatives. With your help, we can make the victory even sweeter! Urge India's Minister of Health and Family welfare to ban the import and sale of cruel cosmetics in India. HSI and our partners have been the driving force behind this testing ban, but we couldn’t have done it without the vital help of our supporters and so many elected representatives and celebrities. We thank the compassionate Members of Parliament--especially Smt Maneka Gandhi and Baijayant ‘Jay’ Panda--and other State Legislative Assemblies and Legislative Councils who took the time to press the government to take this step. And we're grateful to the long list of stars who shone for animals by signing our Be Cruelty-Free India pledge, raising public awareness of the unnecessary suffering endured by animals used for cosmetics testing. But our work isn’t done yet, and we're asking you to stand with us and take the next step -- act now to ban the import of any cosmetics tested on animals to India. If animal testing of cosmetics is illegal inside India’s labs, it also should be illegal on India’s shop shelves. As we did in Europe, HSI is leading the campaign in India for a ban on the import and sale of cosmetics that have been tested on animals anywhere in the world. Only then can India truly Be Cruelty-Free. We need your help, please take action today! A heartfelt thanks to all of you--without your support it would simply not be possible for our Be Cruelty-Free campaign to operate globally and achieve this kind of life-saving progress for animals. Sincerely, Andrew Rowan President and CEO Humane Society International
看 道听途说，段子一小筐 有关统计的论述，心理五味杂陈，如果科学计量学仅仅在统计学意义上进行，那么这么学科能走多远？ 电线杆与统计 做生物医学研究，统计分析必不可少，但统计分析究竟应该怎样做，其结果应该做何解释，却莫衷一是。有些杂志为此雇了专职的统计学家来把关，送出去的论文即使过了同行审议这一关，如果过不了统计学家这一关，还是要被打回来继续修改。写经费申请也一样，一定要说明计划做多少动物实验，统计的依据是什么（ power analysis ）。但评审人会不会仔细去读，则是另一回事了。我自己审基金的时候，对统计部分通常只是瞄一眼而已。问过几个同行，答案是： It's just an item on the checklist. 某日，听一个学术报告，报告人是做系统生物学的，讲着讲着就拐到了统计上，语惊四座：“统计对于生物学家，就像那醉汉见了电线杆子，可以用来做支撑（ for support ），但绝对不是用来照明的（ for illumination ）。”全场哄堂大笑。
空气中的PM2.5颗粒可增加心脏病发病风险 最近一些年来，中国城乡心脏病发病人口数量急剧增加，对此很多人认为与生活水平提高有关。但是，经过我过去八年的流行病学调查发现，这种所谓的“生活水平提高说”并不必然成立。从已有的数据表明，中国城乡中心脏病发病人群并不在“富裕”人群中呈现聚集现象，相对应的许多贫困人群的心血管发病率也并没有明显低于城市和乡村“富裕”人群的相应发病率，这种情况表明，无论贫富，心脏病患者均面对着同样的疾病诱发风险！ 最近（2012年6月），美国鲁斯韦尔大学糖尿病和肥胖中心的研究人员报道了他们对空气中PM2.5影响小鼠心血管系统疾病细胞与分子机制的研究结果 （Haberzettl P, Lee J, Duggineni D, McCracken J, Bolanowski D, O'Toole TE, Bhatnagar A, Conklin DJ.（2012）Exposure to ambient air fine particulate matter prevents VEGF-induced mobilization of endothelial progenitor cells from the bone marrow. Environ Health Perspect. 120(6):848-856.） 他们的研究结果直接表明，空气中的PM(2.5)颗粒可以通过阻止小鼠骨髓内的前体内皮细胞（Endothelial progenitor cell-EPC）向其周围血管内的移动而增加EPC细胞在小鼠骨髓内的水平。空气中的PM(2.5)颗粒抑制了该过程中由VEGF-受体激活而引发的信号传导路径，并因此影响到其下游的c-kit的激活。 空气中PM2.5颗粒阻滞骨髓内的前体内皮细胞向周围血管内的转移可以造成血管修复和再生能力的缺陷。 众所周知，血液中可循环的前体内皮细胞（Endothelial progenitor cell-EPC）是包括冠心病、糖尿病、高胆固醇血症、高血压的重要疾病风险因 子{参见] 。 相关文献 ：空气中的PM2.5颗粒
氢气生物学研究目前进展迅速，虽然有大量的动物实验证明对许多疾病具有治疗作用，但如果没有严格的随机对照临床试验的证据，则无法获得临床治疗特别是国家医药管理局等的最终许可，也就是说无法获得官方的正式批准用于临床的使用。开展严格对照的临床研究是氢气医学发展最重要的任务和手段。也是将来深入研究氢气生物学效应最重要的环境保障和研究目的。 但国际上在临床试验方面进展并不快，到目前为止，临床试验的报道基本都来自日本，这里是从世界卫生组织临床试验注册的信息中检索到的临床试验注册信息也说明这个问题，这些信息显示出日本在神经系统损伤治疗方面的关注度比较大，例如 6 项注册试验中有 3 项属于神经系统损伤治疗效果的研究，分别是中风、巴金森病和中度认知障碍的研究。比较有意思的是，最早报道氢气生物学效应的日本医科大学没有注册临床试验的信息，是他们没有信心，还是没有获得研究经费的资助。因为他们曾经获得来自商业公司的赞助，并成立氢气医学中心。从这一点上看，似乎没有这些问题。但内情不清楚。 第一项：氢气水治疗巴金森病 第二项：氢气水对正常人的抗氧化效果评价 第三项 氢气生理盐水注射对脑缺血的治疗效果评价 第四项 氢气水对中度认知障碍治疗效果的研究 第五项 氢气水治疗间质性膀胱炎 第六项 氢气水对糖尿病的治疗效果评价 所有信息可从世界卫生组织的临床试验注册网上免费检索，更详细的信息可从 http://apps.who.int/trialsearch/AdvSearch.aspx 检索。 建议检索词为 ： hydrogen 。 Recruitment status 选择 ALL 。否则无法获得全面的信息。 详细信息 第一项：氢气水治疗巴金森病 2012 年 3 月 14 日注册的用“氢气水治疗巴金森病”开始实验 2010 年 1 月 1 日顺天堂大学附属医院神经外科，联系人 Asako Yoritaka 。日本学者曾经报道使用氢气水治疗巴金森病的动物实验效果，发表论文 3 篇。全部使用自由饮用氢气水。治疗设计 The subjects should make 1000 ml of molecular hydrogen water which contains 1.6 ppm dissolved hydrogen by Aquerable, and consume for 48 weeks . Placebo water which is not contained molecular hydrogen water made from pseudo-machine. The subjects consume for48 weeks. 第二项：氢气水对正常人的抗氧化效果评价 Studies on in vivo effects of drinking a water product dissolving hydrogen gas as an in vitro antioxidant additive 杏林大学 Atsushi Hiraoka 自 2009 年 5 月 1 日开始的针对健康人的一项研究，排除肝脏肾脏功能异常和月经期女性。 Ingestion of 500ml per day of hydrogen gas-dissolving water for 1 week.Ingestion of 500ml per day of control water without hydrogen gas for 1 week.. 观察指标 the levels of serum LPO and urine 8-OHdG in subjects immediately before and after 1-week drinking period for 500ml per day of tap water with or without dissolved hydrogen gas at 0.34mg/l and 1-week before and after the drinking per day. 第三项 氢气生理盐水注射对脑缺血的治疗效果评价 日本国防医科大学神经外科 Hiroshi Nawashiro 于 2011/06/01 开始的 Molecular hydrogen for ischemic stroke 。选择诊断后症状发生 24 小时内脑缺血患者 Patients were eligible for enrollment if they were 18 years or older and had a clinical diagnosis of acute ischemic stroke within 24 hours of symptom onset. They had to score at least 6 on the National Institutes of Health Stroke Scale (NIHSS) with at least 2 points for limb weakness. All patients received appropriate routine stroke care as per local treatment practices, including alteplase for eligible patients presenting 3 hours from onset; patients receiving alteplase had to commence the study drug before the alteplase infusion.Exclusion criteria: Patients with acute ischemic stroke beyond 24 hours of symptom onset. 治疗方法为静脉点滴注射氢气生理盐水。效果评价 modified Rankin scale (mRS) (days 7, 30, and 90), the NIHSS (days 7 and 90), and the Barthel Index (days 7, 30, and 90) Safety Assessments Vital signs were recorded at enrollment and at specified times throughout the infusion and follow-up periods. Routine laboratory data and ECGs were performed at the time of enrollment, at 24 and 72 hours, and on day 7 and were analyzed centrally (ECGs at day 7 were performed only if abnormal at 72 hours). To assess any effect of hydrogen on hemorrhagic transformation after alteplase administration, brain imaging was repeated after 72 hours in patients who were receiving concomitant treatment with alteplase. Symptomatic hemorrhagic transformation was defined as an increase in the NIHSS score of at least 4 points within 36 hours, plus evidence of any blood on neuroimaging after treatment with alteplase. Patients meeting criteria for progressive stroke (NIHSS increase of 4 points within 72 hours) or new stroke in the first week were also reimaged. 第四项 氢气水对中度认知障碍治疗效果的研究 筑波医科大学临床医学研究所神经精神学系 Takashi Asada2009/07/01 开始的 A randomized trial to assess the effects of hydrogen-ride dissolution water for the patients with mild cognitive impairment (MCI). 中度认知障碍的研究。 招募对象： Inclusion criteria: 1) Participants of the Tone project. 2) Being able to give a written informed consent to the participation in the present study. 3) Having diagnosis of the mild cognitive impairment. 4) Being able to observe the following requirement: good compliance with the water; participation in the scheduled examinations for assessment; keeping a log-diary recording the consumption of the water. 5) Having a modified Hachinski Ischemic score of 4 or less. 6) Having the 15-item Geriatric Depression Scale score of 6 or less. Exclusion criteria: 1) Meeting DSM-IV TR criteria for dementing illnesses. 2) Having serious or unstable illnesses. 3) Having a history within past 5 years of serious infectious disease affecting the brain and/or malignant diseases. 4) Having a history of alcohol or drug abuse or dependence (on DSM-IV TR) within the past 5 years. 5) Receiving any types of anti-Alzheimer drugs. 6) Recent (within 4 weeks) initiation of medications that affect the central nervous system.Age minimum: 67years-old.Age maximum: Not applicable Gender: Male and Female 研究内容： mild cognitive impairment 治疗手段 The patients of hydrogen group will be intervened with 500ml hydrogen dissolution water every-day for 2 years. The patients of placebo group will be intervened with 500ml ordinary water every-day for 2 years. 效果评价 Score in Japanese version of ADAS-Cog and Mini Mental State Examination. Scores in Japanese version of ADCS-ADL, MRI and SPCET imaging, and Geriatric Depression Scale. 第五项 氢气水治疗间质性膀胱炎 Koushinkai Hospital 的 Comprehensive Support Project for Clinical Research Office 于 2008/07/01 开始的 A randomized trial to asses the effects of hydrogen-rich dissolution water in patients with interstitial cystitis 。至少现在没有氢气在间质性膀胱炎方面的研究报道，无论是动物实验还是临床报道。 研究对象标准： Inclusion criteria: 1) Patients who are able to give written informed consent 2) Patients who has the characteristic finding under hydraulic distension of the bladder in interstitial cystitis by cystoscope 3) It has taken more than 12 weeks after patients took the hydraulic distension of the bladder, and symptom of patients are in stable. 4) More than 7 marks in total of Interstitial Cystitis Score in registration 5) More than 4 marks in Q4 (degree of bladder pain) in Interstitial Symptom Score 6) Age is over 20 years and less than 80 years 7) Patients are able to do the following things in this trial; getting good compliance with intaking investigating food and coming to hospital, and writing the diary and the questionnaire accurately by themselvesExclusion criteria: 1) More than 200ml of an average voided volume at a time before the registration 2) Patients with active infection of urinary tract 3) Patients with bacterial cystitis within 12 weeks before registration 4) Patients with vaginosis 5) Patients with calculus of lower urinary tract or urethral diverticulum 6) Patients with nephrosis syndrome 7) Patients with active genital herpes 8) Patients who have operated the surgery in pelvis or its circumference and it has not taken more than 24 hours after the surgery 9) Patients with cerebrospinal disease 10) Patients with the follow disease or suspected disease; neurogenic bladder, cystitis radiation, tuberculous cystitis, cystitis with BCG, drug associated cystitis 11) Start, stop, or change of the dose of the following drugs within 4 weeks after the registration; (a) Antiphlogistic analgetic (b) Antidepressant (c) Anticholinergic drug (d) Antihistamine drug (e) Ataractic drug (f) Drug treatment for frequent urination and acraturesis (g) Steroid drug 12) Start or stop new bladder training or diet therapy within 4 weeks befor registration 13) Patients who has received bladder instillation therapy, electrical stimulation therapy, or acupuncture and moxibustion within 12 weeks before registration 14) Patients with serious hepatic or kidney damage 15) Patients with serious heart disease 16) Patients with malignant tumors which effect their general status or survival time 17) Patients with the history of serious drug-induced adverse effect 18) Patients who are in pregnancy, while breast-feeding, or have possibilities of them, or desire pregnancy in test period 19) Patients who have taken part in the her clinical research within 12 weeks 20) Patients who have taken part in the her clinical research within 12 weeks 21) Patients who are inadequate, which their physicians assessed itAge minimum: 20years-old Age maximum: 80years-oldGender: Male and Female 治疗方法 The patients will be intervened with hydrogen dissolution water group (hydrogen group) 200ml every three times in a day in 2 months (56days) . After that, the patients in hydrogen dissolution water group will be transferred to the additional intervention term after the end of intervention.And after that, the patients will be randomized to withdrawal terms for more 1 month with hydrogen dissolution water or with placebo water. The proportion of the patients who has been assessed "success" at the end of the intervention Secondary Outcome(s) 1) Changes of the Symptom Score in Interstitial Cystitis Symptom Index(ICSI) 2) Changes of the Problem Score in Interstitial Cystitis Problem Index(ICPI) 3) An Average frequency of urination per day 4) An Average voided volume at a time 5) Degree of urge to urinate; PUF symptom score 6) Degree of bladder pain 7) Impression by patients with GRA (Global Response Assessment) 8) Urine Test; 8-OHdG in urine 9) Adverse Events (we cannot deny the association between the food and the event) 第六项 氢气水对糖尿病的治疗效果评价 研究京都大学医学院 Comprehensive Support Project for Clinical Research Office 于 21/08/2008 开始的 A Randomized trial to assess the effects of hydrogen-rich dissolution water for patients with impaired glucose tolerance or impaired fasting glucose 。该研究已经发表论文。 研究对象标准： Inclusion criteria: 1) Patients who are abele to give written informed consent 2) FBS is over 100mg/dl and under 126mg/dl in registration 3) Age is over 20 years and less than 80 years 4) Type of practice: outpatient department 5) Patients are able to do the following things in this trial - getting good compliance with consuming investigational food and coming to hospital, and writing the diary and the questionnaire accurately by themselvesExclusion criteria: 1) Patients who have receive drug treatment for diabetes 2) Patients with the diseases which have possibility with impaired glucose tolerance 3) Patients with serious liver or kidney damage 4) Patients with serious heart disease or cerebrovascular disorders 5) Patients with serious disease in pancreas or blood disease 6) Patients with malignant tumors which effect their general status or survival time 7) Patients who are in pregnancy, while breast-feeding, have possibilities of them, or desire pregnancy in test period 8) Patients with alcohol abuse 9) Patients who have taken part in the her clinical research within 12 weeks 10) Patients who have taken part in the her clinical research within 12 weeks 11) Patients who are inadequate, which their physicians assessed it Age minimum: 20years-oldAge maximum: 70years-oldGender: Male and Female 研究内容 Impaired glucose tolerance or impaired fasting glucose 治疗手段 The patients will be intervened with hydrogen dissolution water group (hydrogen group) 200ml every three times in a day in 3 months (84days) . The patients will be intervened with normal water group (placebo group) 200ml every three times in a day in 3 months (84days) 效果评价方法 1)75gOGTT(glucose);0 minute (in the fasting state),30,60,90 minutes later after loading2)Delta AUC(0-120min);The difference of the area under the plasma glucose concentration before and after administration
据CEN周刊2012年4月23日报道的最新消息 ［1］ ，研究人员将半导体粒子的电气性能和引起发炎能力链接在一起。因为纳米粒子越来越多地融入到人们的生活，但是对于其毒理作用的关注不仅仅是消费者，环境科学家对于纳米微粒对人体健康的影响更是在不断进行深入研究。最为理想的情况就是开发一种以纳米粒子的化学性质为基础的毒性预测模型。已经有一个研究小组报告称，现在第一个这样的预测模型是采用金属氧化物纳米材料的电气性能和溶解性来预测纳米粒子的毒性，这项研究成果2012年4月15日在ACS Nano杂志网站发表 ［2］ 。 金属氧化物纳米粒子是属于半导体材料之列，在燃料电池和电子产品中推动氧化还原反应的发生。在此之前，纳米氧化物对于健康问题的影响已有研究，如电焊工的肺炎就是因为吸入了含有纳米金属氧化物粒子的烟雾所致 ［3］ 。 美国加利福尼亚大学洛杉矶分校（University of California, Los Angeles）的Andre Nel想知道纳米粒子的电气性能是否与他们的毒性有关联。每一种金属氧化物的反应活性都取决于其带隙,即从另外一种化合物或者材料获得一个电子所需要的能量，或者使自身失去一个电子给其他化合物或者材料所需要的能量。如果电子被一个细胞吸收,实际上就是纳米微粒与分子发生氧化还原反应。Andre Nel和他的研究小组其他成员认为,如果一个纳米粒子的能带隙的要求，与驱动这些细胞发生化学反应的能量相匹配，那么这种材料就可以破坏细胞的特有的良好调节以及严格遵循的氧化还原反应。生物化学家已经知道，如此的扰乱会导致细胞损伤，出现炎症。 为了验证他们的设想,研究人员研究了24种金属氧化物纳米材料。基于材料的带隙和已知的细胞氧化还原能量，研究团队预测,可能会有6种氧化物纳米粒子具有毒性，他们分别是TiO 2 、Ni 2 O 3 、CoO、Cr 2 O 3 、Co 3 O 4 以及Mn 2 O 3 。然后，将24种纳米粒子分别与人类支气管细胞和鼠血细胞接触。观测纳米金属氧化物粒子对于细胞的影响。实验结果发现，除了TiO2之外，另外预言的5种金属氧化物纳米粒子均可以引起细胞毒性反应，与对照（尚未与纳米微粒接触的）细胞相比较，细胞存活减少高达80%。就连未预言的2种金属氧化物（CuO和ZnO）也有毒性作用，但是与其他测试的金属氧化物纳米颗粒不同，这两种金属氧化物纳米粒子在水中溶解会释放有毒金属离子。基于这些结果,Andre Nel认为毒性模型不仅包括有关物质的能带隙,而且也与其溶解性有关。 然后,研究小组测试纳米粒子对活体动物健康的影响，迫使老鼠吸入纳米金属氧化物微粒悬浮剂，其中含有引起细胞毒性、最终导致动物肺炎的5种金属氧化物纳米微粒。实验结果发现,白细胞数量和细胞因子水平至少是暴露在5种金属氧化物纳米微粒中老鼠或者与其他纳米金属氧化物微粒接触的老鼠的5倍，而白细胞数量和细胞因子水平正是确诊炎症的2个指标。德国慕尼黑亥姆霍兹中心（Helmholtz Center Munich）的Wolfgang Kreyling认为该研究无愧是预测纳米粒子毒性的“一个真正优秀的首次尝试（a really good first attempt）”，其优势就是将细胞毒性与动物数据链接在一起。但该模型未必对于所有金属氧化物纳米微粒都适用，因为纳米粒子的制备很独特，其大小、形状和纯度各异，可能对其毒性产生戏剧性的影响。 ［1］Jeffrey M. Perkel. A Model To Predict Nanoparticle Toxicity［J/OL］. CEN, (April 23, 2012). http://cen.acs.org/articles/90/web/2012/04/Model-Predict-Nanoparticle-Toxicity.html . ［2］ZHANG Hai-yuan, JI Zhao-xia, XIA Tian, et al. Use of Metal Oxide Nanoparticle Band Gap to Develop a Predictive Paradigm for Oxidative Stress and Acute Pulmonary Inflammation ［J］. ACS Nano, ［April 15, 2012］. DOI: 10.1021/nn3010087, http://pubs.acs.org/doi/abs/10.1021/nn3010087 . ［3］Jane D McNeilly, Mathew R Heal, Iain J Beverland, et al. Soluble transition metals cause the pro-inflammatory effects of welding fumes in vitro［J］. Toxicology and Applied Pharmacology, 2004, 196(1): 95-107. DOI: 10.1016/j.taap.2003.11.021, http://dx.doi.org/10.1016/j.taap.2003.11.021 .
美国提出转化医学研究项目的本意很清楚，而中国对转化医学研究的认识偏大了，什么都搞转化，谁都可以搞转化。争抢炒作，一哄而上，必成灾难。 美国转化医学项目获得白宫支持 转化医学的概念是美国国立卫生研究院（NIH）于上世纪末提出的。当时NIH每年投入的医学研究经费高达200多亿美元，产生了大量的发明、技术、知识和论文，但美国人觉得他们的医疗状况并没有得到显著改善。究其原因，问题出在临床前试验到临床运用之间的巨大鸿沟。在美国，临床前作用良好的新药只有约30%能通过III期临床试验，大部分新药由于其毒性、体内分布等种种原因没有体现出比现有药物更好的疗效而遭淘汰。转化医学的研究就是为了比较动物实验与人体临床之间的差异，加快新药的研发速度并降低新药开发的风险。 http://news.sciencenet.cn/htmlnews/2011/10/253594.shtm 参考文献： White House Boosts Translational Medicine, Drug Chip Project http://news.sciencemag.org/scienceinsider/2011/09/white-house-boosts-translational.html Proposed National Center for Advancing Translational Sciences http://feedback.nih.gov/index.php/faq-ncats/ NIH Proposes New Center to Accelerate Drug Development http://blogs.wsj.com/health/2010/12/08/nih-proposes-new-center-to-accelerate-drug-development/ NCRR and the National Center for Advancing Translational Sciences http://ncrr.nih.gov/about_us/national_center_for_advancing_translational_sciences/
只要稍微有点免疫学常识的人，一看到魏于全院士Nature Medicine论文中的免疫印迹插图，都会不假思索的得出结论说，那是一个绝对的拙劣的造假。对于初学者或者不大熟悉现代免疫学的人来说，当然一下子可能上当受骗。我这就来说说，我认定他的这个实验结果是绝对胡编乱造的，不可能的，违背免疫学基本规律的根据。人体（也包括其它哺乳动物）的特异性免疫应答主要是由淋巴细胞，主要是T细胞和B细胞介导的。人体的淋巴细胞，无论是B细胞，还是T细胞，都是极不均一的群体。淋巴细胞通过其抗原受体识别抗原进行免疫应答的，一个淋巴细胞具有一种抗原受体，严格地说，一个特异的抗原表位的受体，也就是说，一个淋巴细胞只能识别一个特异性科研表位，与特定的抗原表位结合以后，活化，分裂增生，即克隆性增生。B细胞活化后产生抗体，T细胞活化后，产生细胞因子和细胞毒性T细胞，实现对带有相应抗原的分子和细胞的清除。因为人体内有一大群B细胞和T细胞，所以可以识别自然界存在的各种各样的，成千上万的抗原，在一个正常个体，凡是通过注射途径进入的任何外来的抗原性物质，都可被识别，并对之发生免疫应答。而且与自体抗原差异越大的蛋白一般会引起越强的反应，也就是说抗原性越强，引起的免疫反应越强。种属特异性抗原肯定是强抗原。进化中比较保守的蛋白分子，如粘附分子，内皮生长因子的受体的抗原性肯定要比种属特异性抗原要弱。魏于全院士免疫动物用的是异种内皮细胞。一个细胞的结构自然要比一个病毒，一个细菌复杂得多。一个细胞所含有的蛋白和其它的具有抗原性的物质有多少，没有人统计过，现在也无法统计。因为B细胞识别的是抗原表位，一个比较大的蛋白分子就可能有多个表位，一个细胞有许多蛋白分子，每个蛋白分子又有多个抗原表位，所以可以想像把一个异种内皮细胞注射入小鼠体内以后，必定会引起许多不同的B细胞活化，即许多克隆的B细胞活化，产生许多不同的抗体。我们举个例子，乙型肝炎病毒，结构比一个细胞简单多了，进入人体后都会产生不同的抗体，如抗表面抗原的抗体，抗核心抗原的抗体，e抗体，和前s抗体，而且每个抗体都会存在不同的克隆。另外，淋巴细胞对抗原的识别能力很强，即使是只有一个氨基酸序列的差异都可能被淋巴细胞识别，引起其产生不同的抗体。人的白细胞抗原是一类很多形性的抗原，人的每个有核细胞都带有白细胞抗原，正是由于它的多形性，夫妻两个人的白细胞抗原可能是不同的，多孕多产的妇女就可能因为性生活，怀孕而产生抗其丈夫的白细胞抗原的抗体。可以想像，淋巴细胞识别外来抗原的能力是多麽强大。魏于全院士的免疫印迹图片显示，用全细胞免疫的动物的血清和全细胞匀質做抗原所做的免疫印迹居然只得到了那么6条反应条带，这简直是免疫学的奇迹。他认为两个主要条带是VEGFRII和一个整合素分子，对于其它几个条带他也认为可能是他们新发现的与血管生长有关的因子。在他的整个文章里都没有描述，也没有怀疑过这些条带的蛋白分子是否有内皮细胞的其它与血管增生无关的，即其它功能结构蛋白分子的可能。一口笃定的说，他的小鼠所产生的抗体都是与血管生长有关的抗体，是介导他的小鼠肿瘤血管消失，肿瘤退化的分子。魏于全院士的实验结果简直要改写免疫学的基本原理了。他向小鼠注射的是人或牛的内皮细胞，他的小鼠的免疫系统竟然只识别人或牛内皮细胞的内皮细胞生长因子受体和整合素中的一个分子以及其它的可能与血管生长有关的分子，只产生与之反应的抗体，而对人和牛的内皮细胞的其它功能结构蛋白分子，甚至抗原性更强的种属特异性抗原一概不能识别，不予反应，不产生抗体。魏于全院士的这一实践成果说明，曾经把诺贝尔奖金授予建立单克隆抗体技术的Kohlor和Milstone是完全错误的。用魏于全院士在这一论文中所建立的技术免疫动物就可以得到所需要的近乎单克隆的目标抗体。单是拥有这么一种小鼠，这样一个技术就是超国际水平的，就应当申请国家专利，深入研究一下，再多写几篇有关论文，就可以稳拿诺贝尔生理医学奖了。怪不得中国政府机构，中国科学院直到今天还不惜巨资，不惜成本大力支持魏于全院士，原来就是等待着这一天呢？还有一个重要的，魏于全院士忘记了的重要问题，就是，B细胞识别的抗原表位主要的是构象依赖性表位。而魏于全用以免疫小鼠的内皮细胞都是经过戊二醛固定了的，戊二醛固定引起蛋白变性，蛋白变性以后，其抗原表位和天然状态下绝对不同。用这种固定了的抗原所产生的抗体往往不会结合天然状态下即生理状态下的抗原表位。魏于全院士用固定的血管内皮细胞免疫小鼠所产生的抗体竟然和小鼠内皮细胞有那么好的结合特性，这不能不说是又一个免疫学理论与实践的奇迹。魏于全院士还忘记了一个最重要的问题，肿瘤免疫有其自身的特点，不同于一般的感染免疫，移植免疫。用通俗的讲笑话的比喻来说，肿瘤细胞和免疫系统似乎在玩警察与小偷，猫与老鼠的游戏。肿瘤细胞与免疫活性细胞总是在藏猫猫，肿瘤细胞已经在进化中获得了逃逸免疫监视的能力，而免疫活性细胞也还有帮助肿瘤细胞逃逸免疫监视，助纣为虐的一面。这正是当前肿瘤免疫治疗难于突破的一个重要障碍。魏于全院士，坐在自己的书斋里，只凭自己的空想，让自己的免疫小鼠产生自己预想的结果，按自己的预想结果编制谎言，绘制图表，把文章写的天衣无缝，只能唬住一些没有做过类似实验，对免疫学只有肤浅了解的年轻学子和他自己的学生。我个人的圈子很小，国内外的学者认识的也不止数百，包括四川大学的在内，我和他们也多次交换过意见，他们都没有一个人相信魏于全院士的论文是真的。他们许多人都是不屑一顾的说，it is too good to believe.当然，魏于全院士生活在这样一个特殊的国度，特殊的时代，也可谓之的确是生逢其时，才会如此飞黄腾达。
1. 内皮细胞疫苗治疗肿瘤，能行吗？ 请看魏于全的试验结果。 对内皮细胞疫苗治疗组小鼠，魏于全院士明确指出是在肿瘤接种后一周开始治疗的，每周两次，连续 4 周。在结果中，魏于全院士说道，经内皮细胞疫苗治疗的荷瘤小鼠，肿瘤进展延缓，最终退化。用 GEN-T 或 HUVECs （即内皮细胞疫苗）处理的小鼠较未治疗或用 SVEC4-10 治疗的小鼠存活时间明显延长。 但是，魏于全却一时犯了糊涂，编谎时犯了一个严重的错误，给出了这样一个肿瘤生长曲线图，和 肿瘤组织中的血管定量直方图。这一下子捅了个大漏子。魏于全论文的图 2 提供的肿瘤生长曲线。可以明显看到，在肿瘤接种后的第 14 天左右，治疗组小鼠的肿瘤已经开始停止生长，此后肿瘤呈进行性缩小，直至完全消失。这就是说，魏于全院士的荷瘤小鼠，仅仅接受疫苗注射一次，经过一周，即刚刚建立原发性免疫，尚未或刚刚开始加强注射，继发性免疫尚未建立时，肿瘤已经开始停止生长 , 更不用说，在加强免疫时一般都会引起抗体水平的暂时性减低。仅仅一次免疫接种就能引起如此有效的免疫效果，即使在传染病的疫苗预防中也不多见，对于肿瘤免疫更不可思议。如果真是像魏于全说的这样的话，的确是个奇迹，只可惜魏于全的这一结果发表后，至今已经有近十个年头，却不再见到魏于全在这一方面的任何类似追踪研究，这一事实已经再清楚不过的证明了，他的文章中的结果连他自己也不相信了。然而中科院和科技部，教育部还要对之一再包庇，还要给予那样大的经费资助，这难道是对人民负责的麽。 Figure2 Nature Medicine 6 , 1160 - 1166 (2000) doi:10.1038/80506 Immunotherapy of tumors with xenogeneic endothelial cells as a vaccine Yu-quan Wei, Qing-ru Wang, Xia Zhao, Li Yang, Ling Tian, You Lu, Bin Kang, Chong-jiu Lu, Mei-juan Huang, Yan-yan Lou, Fei Xiao, Qiu-ming He, Jing-mei Shu, Xing-jiang Xie, Yun-qiu Mao, Shong Lei, Feng Luo, Li-qun Zhou, Chong-en Liu, Hao Zhou, Yu Jiang, Feng Peng, Liang-ping Yuan, Qiu Li, Yang Wu Ji-yan Liu Figure2. Induction of the therapeutic anti-tumor immunity. Meth A fibrosarcoma cells ( a and e ), H22 hepatoma cells ( b and f ) and MA782/5S mammary carcinoma cells ( c , d , g and h ) were introduced subcutaneously into mice, and then the mice were treated with fixed SVEC4-10 cells ( ), HUVECs or GEN-T cells ( ) or PBS alone ( ). a , b and d , Tumor sizes in mice treated with HUVECs ( ). e , f and h , Survival of mice treated with HUVECs ( ). c and g , Tumor sizes and survival of mice treated with GEN-T cells ( ). Previous | Next 但是，必须注意的是，魏于全院士论文的核心，他的整个肿瘤治疗理论的核心是使用异种内皮细胞疫苗免疫小鼠后，小鼠体内产生了抗血管内皮细胞的抗体和免疫活性细胞，由此引起小鼠肿瘤的血管闭塞和消失，导致肿瘤缩小和退化，这就是说，血管数量减少，血管消失在先，而肿瘤缩小退化在后。然而魏于全在其论文中提供了图 5 以做为支持他的这一理论的支柱。但是，这个直方图恰好又一次证明魏于全在实验和论文组织中撒了弥天大谎。魏于全论文的图 2 显示，肿瘤在接种后的第 14 天开始停止生长，然而在图 5e 中显示，在肿瘤注射后 14 天，内皮细胞疫苗组和对照组肿瘤组织中的血管定量并无差别，到第 21 天时才显示疫苗注射组肿瘤组织中血管数量才稍有减少，第 28 天和第 35 天更形减少。这张图表的数据不是和他的理论显著矛盾吗？即在肿瘤停止生长时，肿瘤组织中的血管并未减少，这不是自打嘴巴麽？从这两张图表中，魏于全院士在组织这一实验和论文过程中撒谎，编造结果的行为不是铁证如山了吗。 2. 内皮细胞疫苗能预防肿瘤吗？ 魏于全院士说，小鼠经内皮细胞疫苗免疫 4 周后，给其接种肿瘤细胞 1 10 5 1 10 7 细胞 / 小鼠。他的内皮细胞疫苗免疫预防效果很好，这些小鼠完全得到了免疫保护，而且是持久的。不过，他提供的图 1 显示，疫苗预防组的小鼠大约在肿瘤接种后，肿瘤均已长出，大概在第 3 ， 4 天时，达最大体积，直径约 2-3mm 大小，约第 7-8 天时消失（ b,c, 和 e ）而 d 显示约在 12-13 天消失。这里的问题是，既然用了不同数量级的内皮细胞疫苗接种，又用了 3 个不同数量级和不同种类的瘤细胞接种，为什么在这里只给出了一个结果，尤其是无论在正文内和图注中都没有写明注射的做为疫苗的内皮细胞的数量，也没有写明接种的瘤细胞的准确数量，这绝对不是诚实的表现。魏于全自称是肿瘤生物治疗专家，自然懂得疫苗的预防效果和免疫方案（包括疫苗的量和注射的时间，次数等）有关，接种 1X10 2 和 1X10 7 的疫苗免疫效果绝不相同。既然花钱花时间花人力做了那么多的实验，为什么不提供这一方面的结果呢？另外，在他的免疫预防组，使用了 3 个不同的数量级肿瘤细胞给小鼠接种，为什么在结果中不明确告诉读者他的这个试验所接种的瘤细胞的具体数量。做过这种实验的人都知道，接种 1 10 5 瘤细胞时，即使未受过免疫的正常小鼠，往往也会有一部分甚至大部分小鼠长不出肿瘤，或长出肿瘤后发生自发退化。 既然魏于全院士实验的目的是要证实其疫苗预防的效果，就应当在论文中将上述问题交代得清清楚楚，是绝对不能马虎 的。魏于全既然是专家，他知道在组织这样的论文时，该强调什么，什么是重点。在论文中他为什么不叙述清楚，不能不让人怀疑他自己心里有鬼。另外一个无法解释的问题是，既然注射的疫苗是有效的，那么，为什么对刚刚接种的瘤细胞没有杀伤作用，而要等到瘤细胞倍增几次以后都长到直径 2-3mm 时才开始杀伤。我不知道，魏于全院士又该如何解释。 总之，撒谎很难不露出马脚的，编谎总是很难编得园的。只要在阅读论文时，把作者的结论，材料与方法和结果反复核对，尤其是所附图表与结果认真核对，那些喜欢弄虚作假的学术骗子总会不经意间露出马脚的。对于稿件中含糊不清的内容一定要让作者阐述清楚，必要时，要求作者提供原始数据，这样严格把关，才有可能从源头上预防和根治学术腐败，为净化我国的学术空气做出贡献，也才能提高自己刊物的信誉。
标签: 动物实验
