基因治疗杜氏肌营养不良的研究进展

进行性肌营养不良(progressive muscular dystrophy,PMD)是一种X连锁隐性遗传病,由于抗肌萎缩蛋白基因的开放阅读框(Open reading frame,ORF)突变引起,使该蛋白在肌肉收缩和舒张过程中失去了维持细胞稳定性的关键作用。目前没有从根本上治疗该病的方法,随着分子生物学的发展,进行性肌营养不良的基因治疗出现新的突破,本综述旨在介绍进行性肌营养不良的最常见的类型—杜氏肌营养不良(Duchenne muscular dystrophy,DMD)的基因治疗方法,着重介绍最近取得的进展—新兴CRISPR/Cas9技术和诱导多能干细胞技术结合治疗DMD。     

Duchenne肌营养不良的基因治疗研究进展

Duchenne肌营养不良（DMD）为X连锁常见的神经肌肉遗传病之一，由于骨骼肌肌膜上的抗肌萎缩蛋白完全或部分缺失引起。不幸的是，从发现这种疾病以来已经历经大约150年，但是还是不可治愈。然而，20年前DMD基因的发现却大大地改变了这种疾病的发展状况。最近，基因治疗的研究取得了较大的进展。本文就DMD的基因治疗的进展加以综述。     

Mdx小鼠细胞治疗的种子细胞及移植途径研究现状

Duchenne型肌营养不良(简称DMD)是最常见的X连锁隐性遗传性肌病,患病率在男性活产婴儿中约为1/3 500,DMD主要的发病机制是由于抗肌萎缩蛋白(dystrophin)基因突变,导致其基因产物缺失,引起骨骼肌坏死以及功能严重受损.依据DMD的发病机制,有效的治疗途径不外乎改变突变的基因以表达功能正常的蛋白,或者直接将正常的细胞移植发病部位替换病变的细胞.理想的细胞移植治疗就是将具有较好增殖和分化能力的细胞,高效移植入宿主病变器官并发挥治疗作用,但目前细胞移植治疗还处于动物实验研究阶段.Mdx小鼠是DMD最为常见的动物模型,目前对其研究面临的最大问题是选择怎样的种子细胞及移植途径才能达到最理想的治疗效果,国内外许多研究者就此问题进行了探索.本文就近年来的研究成果作一综述.     

Mdx鼠细胞治疗的种子细胞及移植途径研究现状

Duchenne型肌营养不良（简称DMD）是最常见的X连锁隐性遗传性肌病，患病率在男性活产婴儿约为1/3500，其主要的发病机制是由于dystrophin（抗肌萎缩蛋白）基因突变，导致其基因产物（dystrophin蛋白）缺失，引起骨骼肌坏死以及功能严重受损，目前尚无有效的治疗方法，。依据DMD的发病机制，有效的治疗途径不外乎改变突变的基因以表达功能正常的蛋白，或者直接将正常的细胞移植发病部位替换病变的细胞。理想的细胞移植治疗就是将具有较好增殖和分化能力的细胞，高效移植入宿主病变器官并在其发挥治疗作用，但主要还处于动物实验研究阶段。Mdx[1]鼠是DMD最为常见的动物模型，目前对其实验研究的细胞治疗途径，面临的最大问题是选择哪类种子细胞及怎样的移植途径才能达到最理想的治疗效果？国内外许多研究者就此问题进行了探索。本文就近年来的一些研究成果做一综述。     

Duchenne肌营养不良的基因治疗进展

Duchenne肌营养不良(DMD)基因治疗的目的是补充骨骼肌和心肌内已经缺失的抗肌萎缩蛋白。本文对DMD基因治疗中目的基因的选择,基因靶向,载体的选择,目的基因的运送途径等方面作一综述。     

Duchenne肌营养不良基因缺陷及基因治疗

Duchenne肌营养不良(DMD)是常见的神经肌肉遗传病之一,由于骨胳肌肌膜上的抗肌萎缩蛋白(dystrophin)完全或部分缺失引起.本文介绍了dystrophin的结构和功能,对DMD基因治疗的目的基因,基因治疗方式(包括病毒载体和非病毒载体),基因转染途径作了较为全面的介绍,指出腺相关病毒载体介导的基因治疗及干细胞移植是有希望的治疗方向,经全身途径使目的基因广泛转染骨胳肌并实现心肌和膈肌的转染,是基因治疗研究的难点.     

应用间期细胞原位PCR检测基因缺失型杜氏肌营养不良

目的：建立原位PCR技术，用于检测遗传性疾病。方法：应用抗肌萎缩蛋白（dystrophin)的基因48及51号外显子的引物，使用直接法原位PCR，检测正常人及Duchenne型肌营养不良症（DMD）患者。结果：正常男性96％间期淋巴细胞出现信号斑点，而DMD缺失型患者间期淋巴细胞均未出现信号斑点。结论：原位PCR技术不破坏细胞形态结构，能精确定位靶基因，兼有PCR及原位杂交技术两者优点。可作为检测缺失型DMD患者及产前诊断的手段。     

造血干细胞治疗假肥大型肌营养不良的抗肌萎缩蛋白的改变

目的探讨假肥大性肌营养不良(Duchenne muscular dystrophy,DMD)患者经造血干细胞移植前后其肌肉形态及抗肌萎缩蛋白的表达的改变。方法对8例DMD患者进行造血干细胞移植前后应用肌肉活检及抗肌萎缩蛋白进行检测。结果患儿在移植后180天的肌肉活检可见新生肌细胞形成,抗肌萎缩蛋白免疫组化呈弱阳性,少数为强阳性反应。结果表明造血干细胞移植治疗DMD,可在移植后促进肌肉新生,肌肉抗肌萎缩蛋白表达,提示造血干细胞移植将有益于DMD的治疗。     

外显子跳跃治疗Duchenne型肌营养不良症的研究进展

Duchenne型肌营养不良症是一种致死性肌肉疾病,抗肌萎缩蛋白基因缺陷是导致本病的原因,目前本病尚无特效的疗法.反义寡核苷酸(antisense oligonucleotides,AOs)诱导的外显子跳跃作为一种新的治疗手段具有良好的应用前景.本文主要从外显子跳跃治疗的原理、基础研究及临床研究进行综述.     

骨髓移植治疗Duchenne型肌营养不良模型鼠的实验研究

目的：观察骨髓移植治疗Duchenne型肌营养不良（DMD）模型鼠（mdx鼠）后,骨骼肌中抗肌萎缩蛋白的表达，以及病理、生理和运动功能的变化情况，从而正确评价骨髓移植治疗DMD的疗效。 方法： 以正常C57鼠作为供者，以致死剂量放疗后的mdx鼠作为受者进行骨髓移植，在移植后4个月和6个月分别用荧光免疫组化法观察抗肌萎缩蛋白表达情况，用HE染色观察并计算骨骼肌细胞核中心移位纤维比例（CNF），同时进行mdx鼠腓肠肌电生理检查和运动功能检测。 结果： 骨髓移植后的mdx鼠骨骼肌细胞膜上有部分抗肌萎缩蛋白表达，CNF比例和肌肉湿重下降，mdx鼠的被动运动功能增强。 结论： 骨髓移植后，骨髓干细胞在mdx鼠体内的骨骼肌和骨髓中定居，并分化成可以表达抗肌萎缩蛋白的骨骼肌细胞，使mdx鼠病理、生理得到部分改善，最终导致了肌肉的运动功能的增强。说明骨髓移植治疗DMD是有一定价值的，为临床应用提供实验基础。     

Brief Therapy and Family/Couple Therapy: An Essential Redundancy

"Brief" therapy and "family/couple" therapy are largely overlapping and redundant. Although there are almost no family/couple therapies that explicitly set time limits on treatment as a matter of course, the four central technical factors of brief therapy almost inevitably lead to therapeutic brevity in systems-oriented treatment. In this paper I emphasize that family/couple therapists tend to adhere to the dominant treatment values of brief individual therapists and set out the therapeutic values among family/couple therapists that increase the likelihood of most family/couple therapy being brief. Finally, I propose that families' and therapists' expectations about the length of treatment serve an important role in establishing the therapeutic alliance. The empirical study of the components of such expectations, and discrepancies in such expectations between therapists and families, may provide a fruitful approach for optimizing the therapeutic alliance and thus positively influencing treatment outcomes.     

How Far Have We Come in Teletherapy? Comment on “Telephone‐Administered Psychotherapy”

Telecommunication allows for therapy to be done in many formats, including telephone, computer teleconferencing, and e-mail. My comments are directed broadly at how telecommunications can be used to provide psychological services. My comments include observations on the review article, impressions following a computer search on the topic of electronic therapy, thoughts on other uses of electronic psychological services, and caveats regarding ethical and legal issues.     

Lessons Offered,Lessons Learned: Reflections on How Doing Family Therapy Can Affect Therapists

Only in working conjointly with couples and families do therapists literally witness clients struggling to improve their most intimate relationships. In writing this article, we realized that, in true systemic fashion, not only have many of our clients benefited from working with us, but also we have learned some invaluable lessons from them. Indeed, practicing couple and family therapy gives therapists many opportunities to learn about themselves, especially when it is done thoughtfully. In this article, we reflect on myriad ways in which couples and family therapy has affected each of us personally—as individuals, as partners, as parents, as adult children in our families of origin, and as educators.     

What Allows Therapy to Be Brief? Introduction to the Special Series

This article introduces the field of brief therapy and the special series on six varieties of it. The orientations covered are psychodynamic, behavioral, experiential, family/couples systems, strategic, and integrative. Most therapy conducted in the United States always has been and continues to be brief despite many clinicians' perceptions to the contrary. What allows a therapy to be time efficient, however, differs as a function of each therapy's theoretical orientation. The articles in this series focus on what features allow each therapeutic model to be short term, the techniques and theory of change it encompasses, relevant research, and likely future trends.     

In vivo molecular targeted radiotherapy

Unsealed radionuclides have been in clinical therapeutic use for well over half a century. Following the early inappropriate clinical administrations of radium salts in the early 20th century, the first real clinical benefits became evident with the use of (131)I-sodium iodide for the treatment of hypothyroidism and differentiated thyroid carcinoma and (32)P-sodium phosphate for the treatment of polycythaemia vera. In recent years the use of bone seeking agents (89)Sr, (153)Sm and (186)Re for the palliation of bone pain have become widespread and considerable progress has been evident with the use of (131)I-MIBG and (90)Y-somatostatin receptor binding agents. Although the use of monoclonal antibody based therapeutic products has been slow to evolve, the start of the 21st century has witnessed the first licensed therapeutic antibody conjugates based on (90)Y and (131)I for the treatment of non-Hodgkin's lymphoma. The future clinical utility of this form of therapy will depend upon the development of radiopharmaceutical conjugates capable of selective binding to molecular targets. The availability of some therapeutic radionuclides such as (188)Re produced from the tungsten generator system which can produce activity as required over many months, may make this type of therapy more widely available in some remote and developing countries.Future products will involve cytotoxic radionuclides with appropriate potency, but with physical characteristics that will enable the administration of therapeutic doses with the minimal need for patient isolation. Further developments are likely to involve molecular constructs such as aptamers arising from new developments in biotechnology.Patient trials are still underway and are now examining new methods of administration, dose fractionation and the clinical introduction of alpha emitting radiopharmaceutical conjugates. This review outlines the history, development and future potential of these forms of therapy.     

What Makes Brief Psychodynamic Therapy Time Efficient

To be brief and effective, psychodynamic therapy relies on six features or techniques of practice. These include (a) patient selection, especially maturity of interpersonal or object relations, (b) formulation of an individualized clinical focus stated as intrapsychic conflict, maladaptive interpersonal patterns, or negative feelings about the self, (c) a deliberate time limit that adds a sense of intensity and urgency and sets in motion therapist and patient expectancies as to when change will occur, (d) active techniques of detailed inquiry, focusing, interpretation, and, in some models, confrontation, (e) emphasis on the termination stage, especially issues of separation, loss and limitations in life, and (f) goal setting, which requires setting priorities so that time is used most efficiently. This paper reviews and evaluates relevant research and presents emerging trends for future practice of brief psychodynamic therapy.     

病毒介导的免疫治疗癌症进展

病毒主要作为基因转染载体在免疫治疗中发挥重要作用.本文详细地介绍了病毒载体类型,病毒介导的对肿瘤细胞、宿主细胞的调节,病毒疫苗等免疫治疗癌症的研究进展,可为癌症免疫治疗的基础和临床研究提供参考.     

质子治疗设备的现状和发展

为了实现质子治疗,必须有一套比常规电子直线加速器更复杂,规模更大的质子治疗设备与系统。本文首先简要地介绍质子治疗装置的系统原理,基本结构和当前国际上的质子治疗装备的商品供应概况。在此基础上进一步论述国际质子治疗装置的现状和当前的质子治疗装置研制发展。在文的最后再简要地介绍当前国际上的已有的专用质子治疗中心近况。     

Is cognitive–behavioral therapy more effective than other therapies?: A meta-analytic review

Cognitive–behavioral therapy (CBT) is effective for a range of psychiatric disorders. However, it remains unclear whether CBT is superior to other forms of psychotherapy, and previous quantitative reviews on this topic are difficult to interpret. The aim of the present quantitative review was to determine whether CBT yields superior outcomes to alternative forms of psychotherapy, and to examine the relationship between differential outcome and study-specific variables. From a computerized literature search through September 2007 and references from previous reviews, English-language articles were selected that described randomized controlled trials of CBT vs. another form of psychotherapy. Of these, only those in which the CBT and alternative therapy condition were judged to be bona fide treatments, rather than “intent-to-fail” conditions, were retained for analysis (28 articles representing 26 studies, N = 1981). Four raters identified post-treatment and follow-up effect size estimates, as well as study-specific variables including (but not limited to) type of CBT and other psychotherapy, sample diagnosis, type of outcome measure used, and age group. Studies were rated for methodological adequacy including (but not limited to) the use of reliable and valid measures and independent evaluators. Researcher allegiance was determined by contacting the principal investigators of the source articles. CBT was superior to psychodynamic therapy, although not interpersonal or supportive therapies, at post-treatment and at follow-up. Methodological strength of studies was not associated with larger or smaller differences between CBT and other therapies. Researchers' self-reported allegiance was positively correlated with the strength of CBT's superiority; however, when controlling for allegiance ratings, CBT was still associated with a significant advantage. The superiority of CBT over alternative therapies was evident only among patients with anxiety or depressive disorders. These results argue against previous claims of treatment equivalence and suggest that CBT should be considered a first-line psychosocial treatment of choice, at least for patients with anxiety and depressive disorders.     

A review of technology-assisted self-help and minimal contact therapies for drug and alcohol abuse and smoking addiction: is human contact necessary for therapeutic efficacy?

Technology-based self-help and minimal contact therapies have been proposed as effective and low-cost interventions for addictive disorders, such as nicotine, alcohol, and drug abuse and addiction. The present article reviews the literature published before 2010 on computerized treatments for drug and alcohol abuse and dependence and smoking addiction. Treatment studies are examined by disorder as well as amount of therapist contact, ranging from self-administered therapy and predominantly self-help interventions to minimal contact therapy where the therapist is actively involved in treatment but to a lesser degree than traditional therapy and predominantly therapist-administered treatments involving regular contact with a therapist for a typical number of sessions. In the treatment of substance use and abuse it is concluded that self-administered and predominantly self-help computer-based cognitive and behavioral interventions are efficacious, but some therapist contact is important for greater and more sustained reductions in addictive behavior.