Disease susceptibility genes for autism

Autism is a complex neurodevelopmental disorder characterized by impairment in social interaction accompanied by a delay or lack of language, restricted interests, stereotyped behavior, and repetitive movement. Genetic predisposition to autism is evident from family and twin studies, and heritability in idiopathic autism is estimated at over 90%. Frequency of the disorder is approximately 1:2000 with a male to female ratio of 4:1. Affected individuals look normal at birth, and the symptoms manifest at the first 2-3 years of life. The spectrum of clinical symptoms and the severity of the disorder are variable even among siblings. Family studies and several genome-wide linkage analyses support the hypothesis of complex inheritance with involvement of as many as 10-100 genes of moderate effect. Identification of genes responsible for the phenotype would help to understand the molecular mechanisms of the disorder. Several genes have been proposed to play a role in susceptibility to autism, and this paper will overview those genes and their potential role in the disorder.     

Association study of COMT gene Val158Met polymorphism with auditory P300 and performance on neurocognitive tests in patients with schizophrenia and their relatives.

A number of studies have reported an association between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and neuropsychological traits in patients with schizophrenia, their relatives and healthy controls, with the Met allele carriers performing better on neurocognitive tasks than those with the Val allele. But the association was not confirmed in all studies. The present paper was aimed at further investigation of the COMT gene relationship with some neurocognitive traits, assessing mainly working and verbal memory, and to P300 event-related potentials (auditory oddball). A total sample of 319 individuals, including schizophrenic patients, their relatives and controls, was studied. No significant differences in performance of neurocognitive tasks were found by Val158Met genotypes. An association was observed between the Met/Met genotype and higher amplitude in centro-parietal area in relatives. Factors that could explain the non-replication of previous studies on the COMT gene polymorphism and neurocognitive traits are discussed. We suggest here that (1) Val158Met polymorphism rather exerts a modifying influence on brain activation in general than impacts directly on performance of the particular neurocognitive test, and (2) P300 amplitude seems to be a correlate of this activation reflecting, along with information processing, the subject's affective and personality features.     

Taurine reverses neurological and neurovascular deficits in Zucker diabetic fatty rats

Increased oxidative stress is implicated in the pathogenesis of diabetic peripheral neuropathy (DPN). However, the efficacy of antioxidant therapy on DPN complicating type 2 diabetes remains unexplored. We therefore determined the ability of the antioxidant taurine to reverse deficits of hind limb sciatic motor and digital sensory nerve conduction velocity (NCV), nerve blood flow (NBF), and sensory thresholds in hyperglycemic Zucker diabetic fatty (ZDF) rats. Experimental groups comprised lean nondiabetic (ND), ND treated with taurine (ND + T), untreated ZDF diabetic (D), and D rats treated with taurine (D + T). Compared to ND rats, 23%, 15% and 56% deficits of motor NCV, sensory NCV and NBF, respectively as well as thermal and mechanical hyperalgesia were reversed by taurine. An 84% deficit of dorsal root ganglion neuron calcitonin gene-related peptide in D rats was prevented by taurine. In summary, the antioxidant taurine reverses neurological and neurovascular deficits in experimental type 2 diabetes.     

Arteriovenous fistula for long-term venous access for boys with hemophilia

OBJECTIVES: Hemophilia is a sex-linked condition affecting about 1 of every 5000 males in the United States. The management of children with hemophilia can be improved with regular intravenous infusion of factor VIII or IX, thus preventing crippling and sometimes fatal hemorrhage. Maintaining this vital intravenous access is often hampered by gradual loss of superficial veins or repeated central catheter sepsis and thrombosis. This study reviewed an experience with arteriovenous fistula in selected hemophilia patients with limited venous access. METHODS: Consecutive patients operated on between October 2000 and July 2006 for venous access with the creation of an arteriovenous fistula were reviewed. They were selected because of repeated problems with other venous access. Patency, ease of use, duplex scan derived brachial artery diameter, and arm length were assessed. RESULTS: During a 69-month period, 10 arteriovenous fistulas (five brachial artery-basilic vein fistulas, 5 brachial artery-cephalic vein fistulas) were created for nine patients. The patients were a median age of 5.5 years (range, 1 to 27 years), and all were <13 except the 27-year-old patient. There were no postoperative hematomas requiring evacuation. One arteriovenous fistula failed to mature and was redone in the opposite arm, which subsequently occluded after 13 months. Of the mature fistulas, patency was 100% at 1 year, 80% (4/5) at 3 years, and 75% (3/4) at 4 years, with mean follow-up of 22 months. Brachial artery diameter increased in the involved arm by a ratio of 1.95 (range, 1.51 to 2.5) compared with the opposite arm. Arm length disparity was increased by 0.5 cm (range, 0.8 to 1.5 cm) in the involved arm. All fistulas allowed good access at home by a care provider. CONCLUSIONS: For hemophilia patients with compromised venous access, arteriovenous fistulas provide good early patency. Brachial artery diameter and arm length require continued follow-up.     

Aicardi syndrome: epilepsy surgery as a palliative treatment option for selected patients and pathological findings

The optimal treatment for medically refractory epilepsy in Aicardi syndrome (AS) is still unclear. Palliative surgical treatment, including vagus nerve stimulation and corpus callosotomy, has therefore been used. There is limited data on the role of resective epilepsy surgery as a treatment choice in patients with AS. Here, we describe the seizures, anatomo‐pathological findings, and neurodevelopmental outcome of palliative epilepsy surgery in two children with AS who had resective epilepsy surgery at the Cleveland Clinic. The related literature is also reviewed. Case 1 had a left functional hemispherectomy and was free of seizures and hypsarrhythmia for six months after surgery. Her gross motor skills improved after surgery. Outcome at 43 months was 1–3 isolated spasms per day. Case 2 had a right fronto‐parietal lobectomy. Her seizures improved in frequency and severity, but remained daily after epilepsy surgery. Neurodevelopment changes included improved alertness and recognition of caregivers. This patient died 21 months after epilepsy surgery of unclear causes. Surgical pathology in both cases showed focal cortical dysplasia associated with other findings, such as nodular heterotopia and polymicrogyria. Epilepsy surgery could be an alternative palliative treatment choice in selective cases of AS, but studies on a larger patient cohort are needed to identify the possible role of surgery in children with AS. The complexity of the pathological findings may offer an explanation for the severity of seizures in AS.     

Bone markers, calcium metabolism, and calcium kinetics during extended-duration space flight on the mir space station.

Bone loss is a current limitation for long-term space exploration. Bone markers, calcitropic hormones, and calcium kinetics of crew members on space missions of 4-6 months were evaluated. Spaceflight-induced bone loss was associated with increased bone resorption and decreased calcium absorption. INTRODUCTION: Bone loss is a significant concern for the health of astronauts on long-duration missions. Defining the time course and mechanism of these changes will aid in developing means to counteract these losses during space flight and will have relevance for other clinical situations that impair weight-bearing activity. MATERIALS AND METHODS: We report here results from two studies conducted during the Shuttle-Mir Science Program. Study 1 was an evaluation of bone and calcium biochemical markers of 13 subjects before and after long-duration (4-6 months) space missions. In study 2, stable calcium isotopes were used to evaluate calcium metabolism in six subjects before, during, and after flight. Relationships between measures of bone turnover, biochemical markers, and calcium kinetics were examined. RESULTS: Pre- and postflight study results confirmed that, after landing, bone resorption was increased, as indicated by increases in urinary calcium (p < 0.05) and collagen cross-links (N-telopeptide, pyridinoline, and deoxypyridinoline were all increased >55% above preflight levels, p < 0.001). Parathyroid hormone and vitamin D metabolites were unchanged at landing. Biochemical markers of bone formation were unchanged at landing, but 2-3 weeks later, both bone-specific alkaline phosphatase and osteocalcin were significantly (p < 0.01) increased above preflight levels. In studies conducted during flight, bone resorption markers were also significantly higher than before flight. The calcium kinetic data also validated that bone resorption was increased during flight compared with preflight values (668 +/- 130 versus 427 +/- 153 mg/day; p < 0.001) and clearly documented that true intestinal calcium absorption was significantly lower during flight compared with preflight values (233 +/- 87 versus 460 +/- 47 mg/day; p < 0.01). Weightlessness had a detrimental effect on the balance in bone turnover such that the daily difference in calcium retention during flight compared with preflight values approached 300 mg/day (-234 +/- 102 versus 63 +/- 75 mg/day; p < 0.01). CONCLUSIONS: These bone marker and calcium kinetic studies indicated that the bone loss that occurs during space flight is a consequence of increased bone resorption and decreased intestinal calcium absorption.     

CONUT评分对HER2阳性早期乳腺癌复发转移的预测作用

目的 探讨控制营养状态(CONUT)评分对人表皮生长因子受体2(HER2)阳性早期乳腺癌患者复发转移中的预测价值。方法 将2012年1月至2020年10月于新疆医科大学附属肿瘤医院行手术切除并接受曲妥珠单抗治疗的154例HER2阳性早期乳腺癌患者为研究对象进行回顾性分析。基于患者术前血清白蛋白、总胆固醇水平及外周血淋巴细胞计数,计算CONUT评分。通过受试者操作特征曲线(ROC曲线)对CONUT评分截止点进行分类:高CONUT与低CONUT组。组间基线特征分布的比较采用卡方χ2检验或Fisher确切概率法。绘制Kaplan-Meier曲线,并通过单因素和多因素Cox回归分析确定CONUT评分与乳腺癌患者复发转移的关系。结果 ROC曲线表明CONUT评分预测乳腺癌患者术后复发转移的最佳截止点为2.5,曲线下面积(AUC)为0.689 (95%CI=0.577～0.801)。基于此截止点,将所有患者分为高CONUT组(≥3分)与低CONUT组(<3分)。Kaplan-Meier曲线展示两组患者的5年无复发生存(RFS)率分别为69.7%和86.9%,差异具有统计学意义(χ2=8.00...     

Melatonin and Metformin Failed to Modify the Effect of Dacarbazine in Melanoma

Lessons Learned

• Melatonin did not increase the efficacy of systemic chemotherapy in melanoma.
• Metformin did not increase the efficacy of systemic chemotherapy in melanoma.