BACKGROUND & AIMS: BACKGROUND:During the years preceding this study, we noticed a relatively unusual high number of individuals with elevated alanine aminotransferase (ALT) levels in O'Brien, a small rural town in Argentina. Moreover, four individuals from this town underwent liver transplantation owing to hepatitis C virus (HCV)-induced liver cirrhosis. These findings prompted us to conduct a large population-based survey to evaluate the prevalence of HCV in this community. METHODS AND RESULTS:A total of 1637 individuals were studied. The overall HCV-seroprevalence was 5.7% (93/1637), being slightly higher in men (45/769; 5.9%) than in women (48/868; 5.5%). HCV seroprevalence increased with age, reaching a peak rate of 23.9% among individuals between 61 and 70 years of age. HCV RNA was present in 82.7% of all HCV seropositive individuals identified and 100% of them were infected with genotype 1b. ALT elevations were detected in 44% of HCV+ patients and were only observed among viremic individuals. Hepatitis B virus infection was also prevalent (52%) among HCV-seropositive patients. The most common risk factor associated with HCV transmission identified was the apparent use of inadequately sterilized glass syringes by a health care provider serving the community; however, other risk factors may have also played a role in the dissemination of HCV. CONCLUSIONS:Our findings provide an explanation for the relative high number of individuals with elevated ALT levels observed in this community and form the basis of future prospective studies on the natural history of genotype 1b infection.

背景与目标：

BACKGROUND & AIMS: :Mevalonate kinase deficiency (MKD) is an autosomal recessive autoinflammatory disorder caused by mutations in the MVK gene resulting in deficient activity of mevalonate kinase (MK). Depending on the clinical severity, MKD may present as hyper-IgD and periodic fever syndrome (HIDS) or the more severe mevalonic aciduria (MA). We analyzed the MVK gene in 57 patients with MKD and found 39 different mutations including 15 novel mutations, expanding the total mutational spectrum of MKD to 63 mutations. To get more insight into the genotype-phenotype correlation in MKD, we studied the effect of selected missense mutations on MK protein stability and activity in various patient fibroblast cell lines. All MKD cell lines showed markedly decreased MK activities that correlated well with the clinical severity and, for most of the cell lines, with the amount of MK protein. When fibroblasts of MKD patients were cultured under conditions known to promote a more controlled protein folding, all cell lines of patients with the HIDS phenotype and few cell lines of patients with the MA phenotype showed an increase in the residual MK activity. This increase in enzyme activity correlates well with an increase in the MK protein levels in these cell lines, indicating that most of the mutations in MKD affect stability and/or folding of the MK protein rather than affecting the catalytic properties of the enzyme. The finding that the residual activity in MKD can be manipulated by environmental conditions may offer therapeutic options to alleviate or prevent the clinical symptoms associated with MKD.

背景与目标： : 甲羟戊酸激酶缺乏症 (MKD) 是由MVK基因突变引起的常染色体隐性自身炎症性疾病，导致甲羟戊酸激酶 (MK) 活性不足。根据临床严重程度，MKD可能表现为高IgD和周期性发热综合征 (HIDS) 或更严重的甲valonic酸尿症 (MA)。我们分析了57例MKD患者的MVK基因，发现了39个不同的突变，包括15个新突变，将MKD的总突变谱扩展到63个突变。为了更深入地了解MKD中的基因型-表型相关性，我们研究了选定的错义突变对各种患者成纤维细胞系中MK蛋白稳定性和活性的影响。所有MKD细胞系均显示出显着降低的MK活性，这与临床严重程度以及大多数细胞系与MK蛋白的含量密切相关。当在已知促进蛋白质折叠的条件下培养MKD患者的成纤维细胞时，具有HIDS表型的患者的所有细胞系和具有MA表型的患者的少数细胞系均显示出残留的MK活性增加。酶活性的增加与这些细胞系中MK蛋白水平的增加非常相关，这表明MKD中的大多数突变会影响MK蛋白的稳定性和/或折叠，而不是影响酶的催化特性。MKD中残留活性可以通过环境条件控制的发现可能为减轻或预防与MKD相关的临床症状提供治疗选择。

BACKGROUND & AIMS: :A previous study revealed that antibodies to hepatitis E virus (HEV) (anti-HEV) are highly prevalent among healthy individuals and farm pigs in Bali, Indonesia, and suggested that HEV infection may occur via zoonosis among Balinese people. However, there were no reports of acute hepatitis E in Bali. To elucidate whether Balinese HEV strains recovered from infected humans and pigs have significant sequence similarity, serum samples obtained from 57 patients (age, mean +/- standard deviation, 31.1 +/- 11.9 years) with sporadic acute hepatitis and from one hundred and one 2- or 3-month-old farm pigs in Bali were tested for anti-HEV and HEV RNA. Among the 57 patients, 2 (3.5%) had high-titer IgM/IgA class anti-HEV antibodies and one of them had detectable HEV RNA (BaliE03-46). Overall, 58 pigs (57.4%) tested positive for anti-HEV, while 5 pigs (5.0%) had detectable HEV RNA. Based on the 412-nucleotide sequence within open reading frame 2, the BaliE03-46 isolate and the 5 swine HEV isolates recovered from the viremic pigs were phylogenetically classified in genotype 4, but were only 77.3-90.8% identical to the genotype 4 HEV isolates reported thus far in China, India, Japan, Taiwan, and Vietnam. The BaliE03-46 isolate of human origin shared high identities of 97.3-98.3% with 4 of the 5 Balinese swine isolates, but differed by 16.1% from the remaining swine isolate. These results suggest that indigenous HEV strains of genotype 4 with marked heterogeneity are circulating in Bali, Indonesia, and that pigs are reservoirs of HEV for Balinese people who have a habit of ingesting uncooked pigs.

背景与目标： : 先前的一项研究表明，在印度尼西亚巴厘岛的健康个体和农场猪中，戊型肝炎病毒 (HEV) 抗体 (抗HEV) 非常普遍，并表明HEV感染可能是通过人畜共患病在巴厘岛人中发生的。然而，巴厘岛没有急性戊型肝炎的报道。为了阐明从受感染的人和猪中回收的巴厘岛HEV菌株是否具有显着的序列相似性，从57名患者中获得的血清样本 (年龄，平均值/标准差，31.1 +/- 11.9岁) 的散发性急性肝炎和巴厘岛101 2或3个月大的农场猪的抗HEV和HEV RNA测试。在57例患者中，2例 (3.5% 例) 具有高滴度的IgM/IgA类抗HEV抗体，其中1例具有可检测的HEV RNA (BaliE03-46)。总体而言，58头猪 (57.4%) 的抗HEV测试为阳性，而5头猪 (5.0%) 的HEV RNA可检测。根据开放阅读框2中的412核苷酸序列，从病毒血症猪中回收的BaliE03-46分离株和5株猪HEV分离株在系统发育上分为4型，但与迄今报道的4型HEV分离株仅77.3-90.8% 相同在中国、印度、日本、台湾，和越南。人类来源的BaliE03-46分离株与5个巴厘岛猪分离株中的4个具有97.3-98.3% 的高度同一性，但与其余的猪分离株相差16.1%。这些结果表明，具有明显异质性的基因型4的本土HEV菌株正在印度尼西亚巴厘岛传播，并且猪是巴厘岛人的HEV储存库，这些人习惯于摄取未煮熟的猪。

BACKGROUND & AIMS: :Seventy-two adult Chinese HIV-positive treatment-naïve patients were recruited in a study to evaluate prospectively the associations between CYP2B6 516 G/T polymorphisms and sleep quality following treatment with an efavirenz-based regimen. Overall, the patients gave an allelic frequency of 0.3 for CYP2B6 516 T, and a genotype frequency of 9.4% for TT. Compared to GG, GT gave a higher median value of plasma efavirenz level at four weeks (3.77 mg/L vs 2.59 mg/L, p < 0.001) and 12 months (3.57 mg/L vs 2.97 mg/L, p = 0.026). Using generalised estimating equations analysis to track the variance over time, there was poorer Pittsburgh Sleep Quality Index in GT compared to GG, while GT was associated with a higher efavirenz level of >4 mg/L. There was however no difference in the component sleep scores nor was there direct association between sleep quality and plasma efavirenz levels. The results suggested that CYP2B6 genotype was associated with different patterns of sleep problems, further investigation of which is warranted with the objective of optimizing therapy with efavirenz-based regimens.

背景与目标： : 在一项研究中招募了72名成年中国HIV阳性治疗初治患者，以前瞻性评估CYP2B6 516G/T多态性与基于依非韦伦的方案治疗后睡眠质量之间的关联。总体而言，患者516 T给予CYP2B6的等位基因频率为0.3，而TT的基因型频率为9.4%。与GG相比，GT在4周 (3.77 mg/L vs 2.59 mg/L，p <0.001) 和12个月 (3.57 mg/L vs 2.97 mg/L，p = 0.026) 时的血浆依非韦伦水平中位数更高。使用广义估计方程分析来跟踪随时间的变化，与GG相比，GT的匹兹堡睡眠质量指数较差，而GT与较高的efavirenz水平> 4 mg/L相关。然而，睡眠评分的组成部分没有差异，睡眠质量与血浆依非韦伦水平之间也没有直接关联。结果表明，CYP2B6基因型与不同模式的睡眠问题有关，有必要对其进行进一步研究，以优化基于依非韦伦的治疗方案。

BACKGROUND & AIMS: :Functional diversity of the highly polymorphic human leukocyte antigen class I (HLA-I) genes underlies successful immunologic control of both infectious disease and cancer. The divergent allele advantage hypothesis dictates that an HLA-I genotype with two alleles with sequences that are more divergent enables presentation of more diverse immunopeptidomes1-3. However, the effect of sequence divergence between HLA-I alleles-a quantifiable measure of HLA-I evolution-on the efficacy of immune checkpoint inhibitor (ICI) treatment for cancer remains unknown. In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient's genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at HLA-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex-peptide complex, which dictates ICI efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity.

背景与目标： : 高度多态性的人类白细胞抗原I类 (hla-i) 基因的功能多样性是对传染病和癌症的成功免疫控制的基础。分歧等位基因优势假说规定，具有两个等位基因的hla-i基因型具有更分歧的序列，能够呈现更多样的immunopeptidomes1-3。然而，hla-i等位基因之间的序列差异 (hla-i进化的可量化量度) 对免疫检查点抑制剂 (ICI) 治疗癌症疗效的影响仍然未知。在本研究中，通过量化每个患者基因型的hla-i等位基因之间的理化序列差异，确定了用ICIs治疗的癌症患者的种系hla-i进化差异 (HED)。HED是ICIs治疗后生存的重要决定因素。即使在hla-i完全杂合的患者中，上四分位HED的患者对ICIs的反应也比低HED的患者更好。此外，HED强烈影响肿瘤，病毒和自身免疫肽的多样性以及肿瘤内T细胞受体克隆性。与肿瘤突变负荷相似，HED是主要组织相容性复合物-肽复合物的多样性的基本指标，它决定了ICI的功效。该数据将不同的HLA等位基因优势与免疫治疗功效联系起来，并揭示了ICI反应如何依赖于HLA介导的免疫的进化效率。

BACKGROUND & AIMS: :Aromatic and heterocyclic amine carcinogens present in the diet and in cigarette smoke induce breast tumors in rats. N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) enzymes have important roles in their metabolic activation and deactivation. Human epidemiological studies suggest that genetic polymorphisms in NAT1 and/or NAT2 modify breast cancer risk in women exposed to these carcinogens. p-Aminobenzoic acid (selective for rat NAT2) and sulfamethazine (SMZ; selective for rat NAT1) N-acetyltransferase catalytic activities were both expressed in primary cultures of rat mammary epithelial cells. PABA, 2-aminofluorene, and 4-aminobiphenyl N-acetyltransferase and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine and N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline O-acetyltransferase activities were two- to threefold higher in mammary epithelial cell cultures from rapid than slow acetylator rats. In contrast, SMZ (a rat NAT1-selective substrate) N-acetyltransferase activity did not differ between rapid and slow acetylators. Rat mammary cells cultured in the medium supplemented 24 h with 10muM ABP showed downregulation in the N-and O-acetylation of all substrates tested except for the NAT1-selective substrate SMZ. This downregulation was comparable in rapid and slow NAT2 acetylators. These studies clearly show NAT2 acetylator genotype-dependent N- and O-acetylation of aromatic and heterocyclic amine carcinogens in rat mammary epithelial cell cultures to be subject to downregulation by the arylamine carcinogen ABP.

背景与目标： : 饮食和香烟烟雾中存在的芳香和杂环胺致癌物会诱发大鼠乳腺肿瘤。N-乙酰基转移酶1 (NAT1) 和N-乙酰基转移酶2 (NAT2) 在其代谢激活和失活中起重要作用。人类流行病学研究表明，NAT1和/或NAT2的遗传多态性改变了暴露于这些致癌物的女性的乳腺癌风险。对氨基苯甲酸 (对大鼠NAT2选择性) 和磺胺二甲嘧啶 (SMZ; 对大鼠NAT1选择性) N-乙酰转移酶催化活性均在大鼠乳腺上皮细胞的原代培养物中表达。PABA，2-氨基芴和4-氨基联苯N-乙酰基转移酶和N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] 吡啶和N-hydroxy-2-amino-3，8-二甲基咪唑并 [4,5-f] 喹喔啉O-乙酰基转移酶活性在快速乙酰化大鼠乳腺上皮细胞培养中高2至3倍。相反，SMZ (一种大鼠NAT1-selective底物) N-乙酰基转移酶活性在快速和慢速乙酰化剂之间没有差异。在补充10muM ABP的培养基中培养的大鼠乳腺细胞显示，除NAT1-selective底物SMZ外，所有测试底物的N-和O-乙酰化均下调。这种下调在快速和慢NAT2乙酰化剂。这些研究清楚地表明，在大鼠乳腺上皮细胞培养物中，芳香族和杂环胺致癌物的NAT2乙酰化剂基因型依赖性N-和O-乙酰化会受到芳基胺致癌物ABP的下调。

BACKGROUND & AIMS: :Circumvention of the p53 checkpoint in neuroblastoma (NB) might arise from increased expression of its main negative regulator MDM2. The SNP309, a T-to-G substitution in the MDM2 promoter, was associated with higher levels of MDM2 mRNA and protein, with consequent attenuation of the p53 pathway. The association between MDM2 SNP309 and disease progression and survival was evaluated in a cohort of 142 children with stage 4 NB. The SNP309 GG patients had a worse overall survival and a worse survival after relapse than the TT ones, whereas the heterozygotes showed an intermediate behaviour (p=0.043 and p=0.049, respectively, log-rank test for trend). No evident association between SNP309 and event free survival was found. The lack of association between SNP309 and MYCN status indicates that MDM2 SNP309 may be a new independent prognostic factor for stage 4 NB.

背景与目标： : 神经母细胞瘤 (NB) 中p53检查点的规避可能是由于其主要负调节因子mdm2的表达增加所致。SNP309是MDM2启动子中的T到G取代，与MDM2 mRNA和蛋白质的较高水平相关，因此p53途径减弱。在142名4期NB儿童的队列中评估了MDM2 SNP309与疾病进展和生存率之间的关联。与TT相比，SNP309 GG患者的总生存率和复发后的生存率更差，而杂合子表现出中等行为 (分别为p = 0.043和p = 0.049，趋势log-rank检验)。SNP309与无事件生存率之间没有明显的关联。SNP309与MYCN状态之间缺乏关联，表明MDM2 SNP309可能是4期NB的新的独立预后因素。

BACKGROUND & AIMS: :Phasing is the process of inferring haplotypes from genotype data. Efficient algorithms and associated software for accurate phasing in pedigrees are needed, especially for populations lacking reference panels of sequenced individuals. We present a novel method for phasing genotypes from whole-genome sequence data in pedigrees, called PULSAR (Phasing Using Lineage Specific Alleles/Rare variants). The method is based on the property that alleles specific to a single founding chromosome within a pedigree are highly informative for identifying haplotypes that are shared identical by descent. Simulation studies are used to assess the performance of PULSAR with various pedigree sizes and structures, and the effect of genotyping errors and the presence of nonsequenced individuals is investigated. In pedigrees with complete sequencing and realistic genotyping error rates, PULSAR correctly phases >99.9% of heterozygous genotypes, excluding sites at which all individuals are heterozygous, and does so with a switch error rate frequently below 10-4. PULSAR is highly accurate, capable of genotype error correction and imputation, and computationally competitive with alternative phasing software applicable to pedigrees. Our method has the significant advantage of not requiring reference panels that are essential for other population-based phasing algorithms. A software implementation of PULSAR is freely available.

背景与目标： : 定相是从基因型数据推断单倍型的过程。需要有效的算法和相关软件来对谱系进行精确定相，尤其是对于缺乏测序个体参考面板的人群。我们提出了一种新的方法，用于从谱系中的全基因组序列数据中定相基因型，称为脉冲星 (使用谱系特异性等位基因/稀有变体进行定相)。该方法基于以下特性: 谱系中特定于单个创始染色体的等位基因对于鉴定通过血统共享相同的单倍型具有高度的信息。模拟研究用于评估具有各种谱系大小和结构的脉冲星的性能，并研究了基因分型错误和非测序个体的影响。在具有完整测序和实际基因分型错误率的谱系中，脉冲星正确地阶段> 杂合基因型的99.9%，不包括所有个体都是杂合的位点，并且切换错误率通常低于10-4。PULSAR具有很高的准确性，能够进行基因型纠错和归因，并且与适用于谱系的替代定相软件在计算上具有竞争力。我们的方法具有不需要其他基于种群的定相算法必不可少的参考面板的显着优势。可以免费获得PULSAR的软件实现。

BACKGROUND & AIMS: BACKGROUND:The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)6/(TA)6 and (TA)6/(TA)7 genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai. METHODS:One hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine-adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)6/(TA)6 and (TA)6/(TA)7 genotypes were analyzed statistically. RESULTS:One hundred and fourteen patients (69.51 %) were identified with the (TA)6/(TA)6 genotype, forty-eight patients (29.27 %) with the (TA)6/(TA)7 genotype, and two patients (1.22 %) with the (TA)7/(TA)7 genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)6/(TA)7 genotype group were all higher than those in (TA)6/(TA)6 group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley concentration was correlated with PFS in the (TA)6/(TA)6 genotype. In the (TA)6/(TA)7 group, SN-38 peak concentration was correlated with CPT-11 starting dose and OS, valley concentration correlated with plasma bilirubin levels before CPT-11 treatment, delayed diarrhea, and OS. For the (TA)6/(TA)6 genotype, mPFS of the SN-38 peak concentration >43.2 ng/ml subgroup was significantly longer than that of ≤43.2 ng/ml subgroup (8.0 ± 0.35 vs. 6.5 ± 0.79 months, χ (2) = 17.18, p = 0.00) with a relatively high incidence of Grade I/II° myelosuppression; for the (TA)6/(TA)7 genotype, there was no significant difference in mOS between the SN-38 valley concentration >16.83 ng/ml and ≤16.83 subgroups (17.3 ± 0.45 vs. 18.8 ± 0.50 months, χ (2) = 1.38, p = 0.24), but the former had a higher incidence of Grade III/IV° mucositis and delayed diarrhea. For 2 (TA)7/(TA)7 cases, although 25 % dose reduction of CPT-11, which is calculated according to body surface area, Grade IV° bone marrow suppression and Grade III° delayed diarrhea still occurred after CPT-11 treatment, though both adverse effects resolved and did not recur again after a 50 % dose reduction. CONCLUSION:The (TA)6/(TA)6 genotype and (TA)6/(TA)7 genotype accounted for the most, and (TA)7/(TA)7 genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the (TA)6/(TA)6 genotype, CPT-11 dosage can be increased gradually to improve efficacy for patients with SN-38 peak concentration ≤43.2 ng/ml after CPT-11 infusion; and for (TA)6/(TA)7 genotype patients, CPT-11 dosage may be lowered appropriately to reduce serious adverse effects such as bone marrow suppression and delayed diarrhea without affecting the efficacy for those with SN-38 valley concentration >16.83 ng/ml. For (TA)7/(TA)7 genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.

背景与目标：

BACKGROUND & AIMS: BACKGROUND & AIMS:We investigated whether HBV genotype influences on-treatment HBsAg kinetics and/or the end-of-treatment HBsAg levels associated with long-term virological response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a±lamivudine in the Phase III trial. METHODS:All patients (n=230) who participated in long-term follow-up were included according to the availability of HBsAg level measurements. Long-term virological response was defined as HBV DNA ≤ 10,000cp/ml (1786IU/ml) at 5 years post-treatment. Genotype-specific end-of-treatment HBsAg levels associated with long-term virological response (identified by ROC analysis) were assessed in 199 patients with HBsAg measurements available at baseline and end-of-treatment. HBsAg kinetics according to genotype and long-term virological response were investigated in the 117 patients with additional samples available at weeks 12, 24, and 72. RESULTS:Baseline HBsAg levels were significantly higher for A than B, C, and D genotypes (p<0.05). On-treatment HBsAg kinetics varied according to HBV genotype. The difference between responders and non-responders was greatest for genotype A from weeks 12-24; for genotypes B and D from baseline to week 12; there was no significant difference over any timeframe for genotype C. High positive predictive values for long-term virological response could be obtained by applying end-of-treatment genotype-specific cut-offs: 75%, 47%, 71%, and 75% for genotypes A (<400IU/ml), B (<50IU/ml), C (<75IU/ml), and D (<1000IU/ml), respectively. CONCLUSIONS:On-treatment HBsAg kinetics vary between HBV genotypes. Genotype-specific monitoring timeframes and end-of-treatment thresholds could ameliorate response-guided treatment of HBeAg-negative chronic hepatitis B.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD. METHODS:Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8-26 years, and NOS1-ex1f VNTR genotype was determined. Whole-brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis. RESULTS:Consistent with previous literature, NOS1-ex1f was associated with total ADHD and hyperactivity-impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1-ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD. CONCLUSIONS:NOS1-ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies.

背景与目标：

BACKGROUND & AIMS: :Relevant resistance-associated substitutions (RASs) to elbasvir, the new HCV NS5A inhibitor, may limit its efficacy and lead to virological failure in HCV-GT1a-infected patients. There are few data outside clinical trials evaluating their prevalence and impact of elbasvir/grazoprevir. A multicenter cross-sectional study of 617 HCV-GT1a-infected individuals attended in 84 Spanish hospitals from the 17 Autonomous Communities and two Autonomous cities was performed. HCV population sequencing was used to identify RASs to elbasvir and the mutational pattern and drug sensitivity were confirmed by geno2pheno[HCV]. Viruses bearing RASs to elbasvir were present in 6.2% of HCV-GT1a infected patients. The most common RASs were the Y93C/H/N and Q30E/H/R (2.4% and 2.3%; respectively). Only 3.4% of patients had viruses with RASs that confer reduced susceptibility to elbasvir by geno2pheno[HCV] that identified exclusively the positions Q30H/R (n = 7) and Y93C/H/N (n = 8) as single mutations and Q30H + Y93H (n = 4) and Q30R + Y93H (n = 2) as double mutations considered as RASs to elbasvir. Lower prevalence of RASs to elbasvir in our HCV-GT1a-Spanish cohort was observed than reported previously in clinical trials. This information may be essential to guiding the implementation of elbasvir/grazoprevir in Spain, expected at the beginning of 2017 and the management of GT1a-infected patients.

背景与目标： : 新的HCV NS5A抑制剂elbasvir的相关耐药相关替代 (RASs) 可能会限制其功效并导致HCV-GT1a-infected患者的病毒学失败。在临床试验之外，很少有数据评估其对elbasvir/grazoprevir的患病率和影响。对来自17个自治社区和两个自治城市的84家西班牙医院的617名HCV-GT1a-infected进行了多中心横断面研究。HCV群体测序用于鉴定RASs至elbasvir，并通过geno2pheno[HCV] 确认突变模式和药物敏感性。在HCV-GT1a感染的患者中有6.2% 例存在带有RASs至elbasvir的病毒。最常见的RASs是Y93C/H/N和Q30E/H/R (分别为2.4% 和2.3%)。只有3.4% 的患者患有RASs病毒，该病毒通过geno2pheno[HCV] 降低了对elbasvir的敏感性，该病毒仅将Q30H/R (N   =   7) 和Y93C/H/N (N   =   8) 定位为单个突变和Q30H   Y93H (N   =   4) 和Q30R   +   Y93H (n   =   2) 作为双突变被认为是对elbasvir的RASs。在我们的HCV-GT1a-Spanish队列中观察到的RASs与elbasvir的患病率比以前在临床试验中报道的要低。这些信息对于指导在西班牙实施elbasvir/grazoprevir可能是必不可少的，预计在开始2017年和GT1a-infected患者的管理。

BACKGROUND & AIMS: :Alterations caused by a genotype III strain of Toxoplasma gondii were assessed with respect to the number and the morphometry of the myenteric neurons in the terminal ileum and the descending colon. Eighteen rats were divided into four groups: Acute Control Group (ACG, n=4); Acute Experimental Group (AEG, n=4); Chronic Control Group (CCG, n=5) and Chronic Experimental Group (CEG, n=5). NaCl solution was administered through gavage to the animals in the ACG and CCG. Toxoplasma gondii tachyzoites (10(4)) from a genotype III strain were orally administered to the AEG and CEG. Acute Groups were died after 24 hours, and the Chronic Groups after 30 days. Neuronal loss was not observed in both organs. The neurons atrophied in the terminal ileum as the opposite occurred with the neurons at the descending colon during the chronic phase of infection. In the terminal ileum, the neurons atrophied during the chronic phase of the infection as no alteration was found during the acute phase. For the descending colon, the neurons became hypertrophic during the chronic infection in opposition to the atrophy found during the acute phase.

背景与目标： : 根据回肠末端和降结肠中肌间神经元的数量和形态，评估了弓形虫III型菌株引起的改变。将18只大鼠分为四组: 急性对照组 (ACG，n = 4); 急性实验组 (AEG，n = 4); 慢性对照组 (CCG，n = 5) 和慢性实验组 (CEG，n = 5)。通过灌胃将NaCl溶液施用于ACG和CCG中的动物。将来自基因型III菌株的弓形虫速殖子 (10(4)) 口服给AEG和CEG。急性组在24小时后死亡，慢性组在30天后死亡。两个器官均未观察到神经元丢失。在感染的慢性阶段，降结肠的神经元在回肠末端萎缩，相反。在回肠末端，由于在急性期未发现任何改变，因此在感染的慢性期神经元萎缩。对于降结肠，神经元在慢性感染期间变得肥厚，与急性期发现的萎缩相反。

BACKGROUND & AIMS: :Hemochromatosis is predominantly associated with the HFE p.C282Y homozygous genotype, which is carried by approximately 1 person in 200 in Northern European populations. However, p.C282Y homozygosity is often characterized by incomplete penetrance. Here, we describe the case of a woman who had a major structural alteration in the HFE gene. Molecular characterization revealed an Alu-mediated recombination leading to the loss of the entire HFE gene sequence. Although homozygous for the HFE deleted allele, the woman had a phenotype similar to that seen in most women homozygous for the common p.C282Y mutation. Contrasting with previously reported results in Hfe knockout and Hfe knockin mice, our report gives further evidence that progression of the disease depends on modifying factors.

背景与目标： : 血色病主要与HFE p.C282Y纯合基因型有关，在北欧人群中，200年约有1人携带。然而，p.C282Y纯合性通常以不完全外显率为特征。在这里，我们描述了一名女性的情况，该女性的HFE基因发生了重大结构改变。分子表征揭示了Alu介导的重组导致整个HFE基因序列的丢失。尽管HFE缺失等位基因是纯合的，但该妇女的表型与大多数常见p.C282Y突变纯合的女性相似。与先前报道的Hfe基因敲除和Hfe基因敲除小鼠的结果相比，我们的报告提供了进一步的证据，表明疾病的进展取决于修饰因子。

BACKGROUND & AIMS: :The Genotype MTBDR assay was tested for its capability to detect rifampicin (RMP) and isoniazid (INH) resistance (r) and susceptibility (s) directly from 42 smear-positive sputum specimens (15 RMPr/INHr, 2 RMPs/INHr and 25 RMPs/INHs Mycobacterium tuberculosis complex strains). The concordance between the MTBDR assay and conventional drug susceptibility testing was 100%.

背景与目标： : 测试了基因型MTBDR测定的能力，以直接从42个涂片阳性痰标本 (15个RMPr/INHr，2个RMPs/INHr) 中检测利福平 (RMP) 和异烟肼 (INH) 的耐药性 (r) 和易感性 (s)/INHr和25个RMPs/INHs结核分枝杆菌复合菌株)。100% 了MTBDR测定与常规药物敏感性试验之间的一致性。