耐一线药物及注射药物对耐多药结核病治疗效果的影响

背景和目的:最近的研究结果表明,对其他一线药物和注射类药物(如卡那霉素、卷曲霉素)等耐药是影响耐多药结核病(MDR-TB)患者治疗效果的独立危险因素.本研究旨在明确耐其他一线药物和注射类药物对韩国不合并人免疫缺陷病毒(HIV)感染的MDR-TB患者临床疗效的影响.方法:采用回顾性队列研究分析1996年1月至2005年12月首尔国家大学附属医院治疗的211例MDR-TB患者治疗效果,排除7例丢失和7例迁出,对197例患者进行了最终分析.     

The role of nutricline depth in regulating the ocean carbon cycle

Carbon uptake by marine phytoplankton, and its export as organic matter to the ocean interior (i.e., the “biological pump”), lowers the partial pressure of carbon dioxide (pCO₂) in the upper ocean and facilitates the diffusive drawdown of atmospheric CO₂. Conversely, precipitation of calcium carbonate by marine planktonic calcifiers such as coccolithophorids increases pCO₂ and promotes its outgassing (i.e., the “alkalinity pump”). Over the past ≈100 million years, these two carbon fluxes have been modulated by the relative abundance of diatoms and coccolithophores, resulting in biological feedback on atmospheric CO₂ and Earth's climate; yet, the processes determining the relative distribution of these two phytoplankton taxa remain poorly understood. We analyzed phytoplankton community composition in the Atlantic Ocean and show that the distribution of diatoms and coccolithophorids is correlated with the nutricline depth, a proxy of nutrient supply to the upper mixed layer of the ocean. Using this analysis in conjunction with a coupled atmosphere–ocean intermediate complexity model, we predict a dramatic reduction in the nutrient supply to the euphotic layer in the coming century as a result of increased thermal stratification. Our findings indicate that, by altering phytoplankton community composition, this causal relationship may lead to a decreased efficiency of the biological pump in sequestering atmospheric CO₂, implying a positive feedback in the climate system. These results provide a mechanistic basis for understanding the connection between upper ocean dynamics, the calcium carbonate-to-organic C production ratio and atmospheric pCO₂ variations on time scales ranging from seasonal cycles to geological transitions.     

颈动脉狭窄的筛查美国预防服务特别工作组对证据的更新

背景 在美国,脑血管病是导致死亡的第3位原因.在所有卒中病例中,由既往无症状颈动脉狭窄(carotid artery stenosis,CAS)造成的比例并不高.1996年,美国预防服务特别工作组得出结论,没有充分的证据推荐或反对通过体格检查或颈动脉超声在无症状患者中对CAS进行筛查.目的 评估采用双功能超声对无症状患者进行筛查以及应用颈动脉内膜切除术(carotid endarterectomy,CEA)对CAS进行治疗的利弊.数据来源 Medline和Cochrane数据库(检索日期为1994年1月-2007年4月)、最近的系统评价、检索文章的参考文献以及专家的建议.研究选择 选择对CAS进行筛查的英文随机对照试验(randomized controlled trial,RCT)、对CEA与药物治疗进行比较的RCT、筛查试验的系统评价以及对CEA害处的观察性研究,以回答下列问题:是否有直接证据表明使用超声筛查无症状CAS能降低卒中风险? 超声检测CAS的准确性如何? CEA治疗能否降低卒中残疾率或病死率? CAS筛查或CEA治疗是否会给患者带来伤害? 数据提取 使用预先确定的特殊工作组标准,对所有研究进行评估、提炼和质量评定.数据综合 至今尚未进行过CAS筛查的RCT.根据系统评价,超声检测CAS的敏感性约为94%,特异性约为92%.在经过选择的患者中由选定的外科医生进行手术治疗可使5年卒中风险降低约5%.在RCT中,CEA的30 d卒中和死亡发生率为2.7%～4.7%,而在观察性研究中的发生率更高(高达6.7%).局限性 证据不足以对有临床意义的CAS进行风险分层.对患者行CEA与药物治疗相比较的RCT是在经过选择的人群中由特定的外科医生实施的.结论 对无症状患者进行CAS筛查以及进行CEA治疗造成的实际卒中风险降低率尚不清楚;由于整个无症状人群中可治疗疾病的总体患病率不高且治疗会造成一定的害处,因此筛查的益处受到限制.     

Six-year clinical and immunologic follow-up of workers exposed to trimellitic anhydride

We report a 6-year study from 1979 through 1985 of workers exposed to trimellitic anhydride (TMA) in three groups of volunteers. Twenty-nine percent of workers (5/17) originally studied had immunologically induced respiratory disease. Subsequent to this evaluation, increased environmental control of TMA exposure was instituted. Since that time, there have been decreasing clinical symptoms and decreasing levels of antibody against TMA conjugated to human serum albumin. These long-term studies originally used radioimmunoassays, but enzyme-linked immunoassays against TMA-conjugated proteins are now demonstrated to be equally appropriate and are more cost-effective. With appropriate clinical and immunologic studies, immunologic airway reactions to TMA may be identified and then prevented by environmental control to decrease inhalation exposure to TMA. This is likely applicable to certain other chemical antigens that immunize by inhalation.     

Trisomy 18/trisomy 13 mosaicism in an adult with profound mental retardation and multiple malformations

We report on an adult woman with profound mental retardation and multiple anomalies who consists of 3 cell lines: one with trisomy 18, one with trisomy 13, and a normal cell line. Her phenotype includes manifestations of both trisomy syndromes. The origin of these cell lines could have been a doubly aneuploid (48,XX+ 13, + 18) or singly aneuploid (47,XX + 18 or 47,XX, + 13) zygote with subsequent mitotic nondisjunctions, or a normal zygote with multiple mitotic nondisjunctions. There have been four previous reports of mosaicism involving both trisomy D and trisomy E; all died in the first six months of life. Two of these cases had a doubly aneuploid (48,XX, + D + E) cell line. Our patient illustrates the need for study of several tissues in patients with complex aneuploidy syndromes or atypical manifestations of a given syndrome (such as prolonged survival), as well as the need for caution in counseling families about prognosis for survival in autosomal trisomies which usually are lethal.     

Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.Subject terms: Genetics research, Polycystic kidney disease, Genetic testing     

Aven‐mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma

Conventional high‐grade osteosarcoma is the most common primary bone sarcoma, with relatively high incidence in young people. In this study we found that expression of Aven correlates inversely with metastasis‐free survival in osteosarcoma patients and is increased in metastases compared to primary tumours. Aven is an adaptor protein that has been implicated in anti‐apoptotic signalling and serves as an oncoprotein in acute lymphoblastic leukaemia. In osteosarcoma cells, silencing Aven triggered G₂ cell‐cycle arrest; Chk1 protein levels were attenuated and ATR–Chk1 DNA damage response signalling in response to chemotherapy was abolished in Aven‐depleted osteosarcoma cells, while ATM, Chk2 and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven‐controlled ATR–Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix‐embedded cultures, Chk1 inhibition led to effective sensitization to chemotherapy. Together, these findings implicate Aven in ATR–Chk1 signalling and point towards Chk1 inhibition as a strategy to sensitize human osteosarcomas to chemotherapy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Calcium and neuronal cytoskeletal proteins: alterations with aging

Calcium plays a major role in regulating cellular function. Alterations in calcium systems may underlie some of the physiological changes associated with aging. Calcium activates calmodulin-dependent protein kinase, and this enzyme mediates some effects of calcium on cellular function. Calcium/calmodulin-dependent kinase II may play a significant role in specific cytoskeletal abnormalities of normal aging and selected neurodegenerative diseases.     

Mouse model of oral infection with virulent type A Francisella tularensis

Francisella tularensis is a gram-negative facultative intracellular pathogen and the causative agent of tularemia. Little is known about the immunopathogenesis of oral infection with this pathogen. Here, for the first time, we examined the susceptibility of mice to intragastric inoculation with virulent type A F. tularensis and characterized the course of infection and the associated host responses. Both immunocompetent and immunodeficient mice were relatively susceptible to intragastric inoculation of type A F. tularensis with a 50% lethal dose (LD(50)) of 10(6) organisms, which was 100,000-fold higher than the LD(100) for intradermal or respiratory routes of infection. Mice deficient in gamma interferon or tumor necrosis factor receptors 1 and 2 were more susceptible than wild-type controls to oral infection with a high dose of the pathogen. After oral inoculation, F. tularensis appeared first in the mesenteric lymph nodes (MLN) and then rapidly spread to the livers and spleens, where the organism multiplied to high numbers and induced marked neutrophilic infiltration and severe tissue necrosis. Infected mice showed rapid increases in tissue cytokine mRNA expression, which peaked in the MLN at 2 days postinfection (dpi) and in the liver and spleen at 3 dpi. The levels of gamma interferon, interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha, macrophage inflammatory protein 1alpha, KC, interferon-inducible protein 10, and monocyte chemotactic protein 1 were elevated from day 2 postinoculation onward. Moreover, mice intradermally immunized with the live vaccine strain of F. tularensis showed little survival advantage over naive mice after oral challenge with type A F. tularensis. These results suggest that type A F. tularensis is an effective oral pathogen that can cause fatal systemic infection and could pose a public health concern, particularly to immunocompromised individuals, if ingested in contaminated water and food.