肯尼迪病的临床分析及分子遗传学诊断

目的 本文通过5例经基因检测明确诊断的肯尼迪病（Kennedy＇s disease,KD）患者,探讨KD的临床表现和辅助检查特点及诊断.方法 收集5例疑似KD患者的详细病史、体格检查、血液生化、肌电图和肌肉病理等资料,用PCR扩增并测序方法测定雄性激素受体（AR）基因1号外显子CAG的重复序列拷贝数.结果 KD主要临床表现是四肢肌肉萎缩、无力和肢体震颤,舌肌萎缩和构音障碍；部分患者出现内分泌症状和肌酸激酶（CK）增高.肌电图可见广泛神经源性损害和感觉神经传导速度下降.肌肉病理为神经性损害.患者AR基因CAG重复序列的重复次数为48 ～ 58次.结论 KD有相对独特的临床、电生理及病理特征,确诊有赖于AR基因的（CAG）n拷贝数的检测.     

Enhancing viral vaccine production using engineered knockout vero cell lines – A second look

The global adoption of vaccines to combat disease is hampered by the high cost of vaccine manufacturing. The work described herein follows two previous publications (van der Sanden et al., 2016; Wu et al., 2017) that report a strategy to enhance poliovirus and rotavirus vaccine production through genetic modification of the Vero cell lines used in large-scale vaccine manufacturing. CRISPR/Cas9 gene editing tools were used to knockout Vero target genes previously shown to play a role in polio- and rotavirus production. Subsequently, small-scale models of current industry manufacturing systems were developed and adopted to assess the increases in polio- and rotavirus output by multiple stable knockout cell lines. Unlike previous studies, the Vero knockout cell lines failed to achieve desired target yield increases. These findings suggest that additional research will be required before implementing the genetically engineered Vero cell lines in the manufacturing process for polio- and rotavirus vaccines to be able to supply vaccines at reduced prices.     

Decrease in neuroimmune activation by HSV-mediated gene transfer of TNFα soluble receptor alleviates pain in rats with diabetic neuropathy

The mechanisms of diabetic painful neuropathy are complicated and comprise of peripheral and central pathophysiological phenomena. A number of proinflammatory cytokines are involved in this process. Tumor necrosis factor α (TNF-α) is considered to be one of the major contributors of neuropathic pain. In order to explore the potential role of inflammation in the peripheral nervous system of Type 1 diabetic animals with painful neuropathy, we investigated whether TNF-α is a key inflammatory mediator to the diabetic neuropathic pain and whether continuous delivery of TNFα soluble receptor from damaged axons achieved by HSV vector mediated transduction of DRG would block or alter the pain perception in animals with diabetic neuropathy. Diabetic animals exhibited changes in threshold of mechanical and thermal pain perception compared to control rats and also demonstrated increases in TNFα in the DRG, spinal cord dorsal horn, sciatic nerve and in the foot skin, 6 weeks after the onset of diabetes. Therapeutic approaches by HSV mediated expression of p55 TNF soluble receptor significantly attenuated the diabetes-induced hyperalgesia and decreased the expression of TNFα with reduction in the phosphorylation of p38MAPK in the spinal cord dorsal horn and DRG. The overall outcome of this study suggests that neuroinflammatory activation in the peripheral nervous system may be involved in the pathogenesis of painful neuropathy in Type 1 diabetes which can be alleviated by local expression of HSV vector expressing p55 TNF soluble receptor.     

Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development

A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene–brain–behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ∼6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development.     

Association between peroxisome proliferator-activated receptor-γ gene polymorphism (Pro12Ala) and Helicobacter pylori infection in gastric carcinogenesis

Abstract

Objective. Helicobacter pylori infection is accompanied by inflammatory processes leading to peptic ulcer and gastric cancer in the minority of infected individuals. The interaction between H. pylori virulence factors, host defense mechanisms and environmental factors determine the outcome of clinical manifestations. One of the host factors involved in the processes of inflammation and carcinogenesis is the peroxisome proliferator-activated receptor-γ (PPAR-γ) molecule. The present case–control study aimed to determine polymorphism of PPAR-γ gene and its association with H. pylori infection and gastrointestinal diseases (peptic ulcer and non-cardia gastric cancer) in Iranian patients. Materials and methods. One hundred and fifty-five patients with upper gastrointestinal diseases (76 peptic ulcer and 79 non-cardia gastric cancer) and 152 matched controls were genotyped for PPAR-γ gene polymorphism (Pro12Ala) by the PCR–RFLP method. Infection with H. pylori was confirmed by histology, the rapid urease test (RUT) and ELISA assay (IgG anti-H. pylori). Results. The frequency of PPAR-γ G (Ala 12) allele was significantly higher in H. pylori positive patients with non-cardia gastric cancer than in controls (22.8% vs. 3.9%, p = 0.027; OR = 3.28; 95% CI = 1.21–8.89), But there was no significant difference without infection (p = 0.7). Moreover, the PPAR-γ polymorphism was not associated with peptic ulcer in the presence or absence of H. pylori infection. Conclusion. Our results indicated PPAR-γ G allele may be an important contributor to non-cardia gastric cancer in Iranian H. pylori infected patients.     

Mercury,APOE, and children's neurodevelopment

The benefit of the nutritious elements in fish is insufficient for explaining the controversial finding regarding prenatal mercury (Hg) exposure and neurodevelopment; the varying frequency of susceptible genes among these populations may shed light on these observations. However, limited studies have been reported on the association between genetic susceptibility of prenatal Hg exposure and child development. Apolipoprotein E (APOE, protein; Apoe, gene) is a major protein transporter expressed in the brain. The Apoe epsilon 4 (ɛ4) allele is associated with poor neural repair function and is a risk factor associated with Alzheimer disease. We conducted a prospective cohort study in 2004 and 2005. In this study, 168 subjects were recruited at delivery and followed up at two years of age, and genetic polymorphisms of Apoe were included to assess genetic susceptibility and to determine the relationship between Hg concentrations in cord blood and neurodevelopment. The results showed that adverse effects on neurodevelopment were consistently associated with prenatal Hg exposure in all subtests of Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT) among ɛ4 carriers as assessed by both simple linear and multiple linear regression models. After controlling for confounding factors, statistical significance was found in the subtests of cognition tests (β = −8.47, 95% confidence interval (CI) = −16.10 to −0.84), social tests (β = −11.02, 95% CI = −20.85 to −1.19) and the whole test of CDIIT (β = −10.45, 95% CI = −17.36 to −3.54) in a multiple linear regression model. Additionally, the interaction effect between gene polymorphisms of Apoe and Hg levels was significant in the whole test CDIIT and subtests of cognition, language and fine motor tests. In conclusion, Apoe modifies the adverse effects of cord blood Hg on neurodevelopment at the age of two years.     

Genetics of inflammation and atopy

Multiple chromosomal regions and polymorphisms of several candidate genes have been linked to or associated with atopic diseases (hayfever, asthma, allergic eczema and rhinitis). In this mini-review, we present data demonstrating that the genetic regulation of the inflammatory response makes a major contribution to the risk of atopy. These data also suggest that the quantity (or quality) of the inflammation affects the priming phase of atopy, i.e., that induced by allergens or infectious agents in early childhood.