PGD to reduce reproductive risk: the case of mitochondrial DNA disorders

This paper discusses the pros and cons of introducing PGD for mitochondrial DNA (mtDNA) disorders such as NARP (Neurogenic muscle weakness, Ataxia, Retinis Pigmentosa)/Leigh, MELAS (Mitochondrial myopathy, Encephalopathy, Lactic acidosis, and Stroke-like episodes), private mtDNA mutations and LHON (Leber Hereditary Optic Neuropathy). Although there is little experience with PGD for mtDNA disorders, it is reasonable to assume that in many cases, the best one can achieve is the selection of the 'least' affected embryos for transfer. So instead of 'promising' parents a healthy child, PGD in these cases can only aim at reducing reproductive risk. From an ethical point of view, this raises challenging questions about parental and medical responsibilities. The main argument in favour of PGD is that it offers couples at risk the opportunity of reducing their chances of having a severely affected child. Potential objections are manifold, but we conclude that none of them supplies convincing moral arguments to regard risk-reducing PGD as unacceptable. Nevertheless, introducing this new application of PGD in clinical practice will raise further complex issues of determining conditions for its responsible use.     

消化不良症状量表和生活质量量表评价功能性消化不良的研究进展

功能性消化不良(FD)是常见的胃肠道疾病,消化不良症状量表和生活质量量表是目前评价FD干预措施疗效较为客观的手段。本文就消化不良症状量表和生活质量量表评价FD的研究进展作一综述。     

The Wee1 kinase inhibitor MK1775 suppresses cell growth,attenuates stemness and synergises with bortezomib in multiple myeloma

Multiple myeloma stem-like cells (MMSCs) are responsible for initiation and relapse, though novel treatment paradigms that effectively eradicate MMSCs are yet to be developed. Selective inhibition of the cell cycle regulatory kinase Wee1 by MK1775 is being explored as a potential anti-cancer therapeutic. We report that higher expression of Wee1 is correlated with poor survival in multiple myeloma (MM). The MM models and patient-derived CD138⁺ plasma cells are particularly sensitive to the growth-inhibitory effects of the Wee1 inhibitor MK1775. MK1775 induces Mus81-Eme1 endonuclease-mediated DNA damage in S-phase cell cycle that results in a blockade of replication and then apoptosis. Furthermore, MK1775 strongly suppresses the features of stemness in vitro, in vivo and in primary CD138⁺ cells by decreasing ALDH1⁺ cell fraction and the expression of ALDH1. In addition, co-treatment of MK1775 with bortezomib is synergistic in vitro and in vivo. Bortezomib, although it enhances ALDH1⁺ cells, when combined with MK1775 abrogates this stimulatory effect on stemness. Considering MM as an invariably incurable malignancy due to the presence of heterogenic myeloma stem-like cells, our study presents inhibition of Wee1 as a promising targeted therapy for MM and provides a compelling rationale to further investigate the activity of MK1775 against myeloma in clinical settings.     

The chronic cerebral effects of cannabis use. II. Psychological findings and conclusions

This paper examines the research evidence on the question of whether sustained use of marijuana may produce chronic cerebral impairment as measured by neuropsychological measures. Evidence from both American and cross-cultural studies suggests that marijuana probably does not produce chronic cerebral impairment, although subtle impairment cannot be ruled out. Several suggestions for new lines of research are discussed including prospective studies, effects of cannabis use on later aging processes, and true experimental studies.     

CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials

Small molecule pharmacological inhibition of dominant human genetic disease is a feasible treatment that does not rely on the development of individual, patient‐specific gene therapy vectors. However, the consequences of protein inhibition as a clinical therapeutic are not well‐studied. In advance of human therapeutic trials for CAPN5 vitreoretinopathy, genetic inactivation can be used to infer the effect of protein inhibition in vivo. We created a photoreceptor‐specific knockout (KO) mouse for Capn5 and compared the retinal phenotype to both wild‐type and an existing Capn5 KO mouse model. In humans, CAPN5 loss‐of‐function (LOF) gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes. Ocular examination of the retina of Capn5 KO mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 LOF CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these LOF variants were nearby known disease‐causing variants within the proteolytic core and in regions of high homology between human CAPN5 and 150 homologs, yet the LOF of CAPN5 was tolerated as opposed to gain‐of‐function disease‐causing variants. These results indicate that localized inhibition of CAPN5 is a viable strategy for hyperactivating disease alleles.     

小儿肠套叠超声与X线平片诊断的对比研究

目的:探讨超声与X线平片在诊断小儿肠套叠中的价值.方法:总结分析行超声及X线平片检查并经手术或X线下空气灌肠确诊的肠套叠患儿63例,以及均行超声及X线检查其他原因的腹痛患儿40例,分析其超声及X线报告结果.结果:63例肠套叠中,B超确诊肠套叠61例,X线平片确诊小儿肠套叠38例,超声灵敏度、特异度均较高.结论:小儿肠套叠应首选B超检查.     

138例儿童颅外恶性生殖细胞肿瘤临床研究

目的:研究儿童恶性生殖细胞瘤（malignant germ cell tumor，MGCT）的临床及预后特征。方法:回顾性分析1998年1月至2016年1月上海儿童医学中心收治的初发颅外MGCT患儿138例。对患儿的临床特点、疗效及预后做综合分析。结果:按病理分期，Ⅰ期患儿5年总生存期（overall survival，OS）OS为100.00%，Ⅱ期患儿5年为94.44%，Ⅲ期5年OS为96.43%，Ⅳ期5年OS为88.73%。多因素分析显示，病理分期对生存率的影响有统计学差异（P<0.01），年龄、性别及部位对于生存率的影响无显著统计学差异。本研究中共有13例Ⅰ/Ⅱ期患儿接受手术后临床观察，有5例（38.5%）在2年内出现疾病复发进展的情况并接受化疗，目前均达到临床缓解。结论:通过以手术联合含铂类药物化疗并根据临床危险度的不同分层治疗MGCT瘤患儿，可得到较好的临床疗效。     

利福喷丁的临床药物动力学研究

本文报道利福喷丁正常人药物动力学研究结果，健康志愿者１０人单剂口服利福喷丁粉剂及胶囊６００ｍｇ后的体内过程均符合血管外一室模型，其血药峰浓度分别为１７．４３ｍｇ／Ｌ（粉剂）和１８．３８ｍｇ／Ｌ（胶囊），达峰时间为９，７０ｈ（粉剂和）和８．２１ｈ（胶囊），消除半衰期（ｔ１／２ｋｅ）为１９．９０ｈ（粉剂）和１９．４２ｈ（胶囊），以上各项参数经统计学处理均无明显意义，胶囊的相对生物利用度为１０４．７２％，口服该药后有少量自尿中以原形排出体外，给药后２ｈ内分别排出给药量的１１．３０％（粉剂）和１１，２９％（胶囊）。