BACKGROUND & AIMS: :The three opioid receptor genes, and in particular the mu and delta loci (OPRM1 and OPRD1, respectively), are compelling candidates to influence risk for substance dependence. Previous study of a variant at the OPRD1 locus, T921C, has shown association with opioid dependence. This variant does not alter protein sequence, and could not be directly responsible for a physiologic effect. We sequenced the OPRD1 coding region in six individuals with differing T921C alleles, to identify new common variants more likely to explain the association with phenotype. We identified one novel variant in exon 1, 80T-->G, which predicts a change in amino acid sequence from phenylalanine (80T) to cysteine (80G) (F27C). We present here basic population genetics of this variant, and population genetic data for the T921C variant. We found significant differences in allele frequency between populations, and a maximum frequency of the 80G allele of 9%, in each of two European populations. This variant could contribute to the previously reported association results.

背景与目标： ：三个阿片样物质受体基因，特别是mu和delta位点（分别为OPRM1和OPRD1），是影响物质依赖风险的诱人候选物。先前对OPRD1基因座的变体T921C的研究表明与阿片样物质依赖性有关。该变体不改变蛋白质序列，并且不能直接负责生理作用。我们在六个具有不同T921C等位基因的个体中对OPRD1编码区进行了测序，以鉴定出更可能解释与表型关联的新的常见变体。我们在第1外显子80T-> G中鉴定出一个新的变异体，该变异体预测了氨基酸序列从苯丙氨酸（80T）变为半胱氨酸（80G）（F27C）的变化。我们在这里介绍了该变种的基本种群遗传学，以及T921C变种的种群遗传数据。我们发现在两个欧洲人群中，人群之间的等位基因频率存在显着差异，而80G等位基因的最大频率为9％。此变体可能有助于先前报告的关联结果。

BACKGROUND & AIMS: :The delta-opioid receptor mediates rewarding effects of many substances of abuse. We reported an increased frequency of the minor G-allele of single-nucleotide polymorphism (SNP) rs569356 (the only variant identified so far in the promoter region of the delta-opioid receptor gene (OPRD1)) in subjects with opioid dependence. In this study, we examined the functional significance of this variant. OPRD1 promoter region harboring SNP rs569356 was amplified by PCR and inserted into a firefly luciferase reporter vector. HEK293 cells were co-transfected with these constructs and a renilla luciferase vector to control for transfection efficiency. Expression of firefly luciferase (driven by the OPRD1 promoter) was measured by a dual luciferase reporter assay and normalized by renilla luciferase expression. Moreover, alleles altering expression were further assessed for binding of human brain nuclear proteins by electrophoretic mobility shift assay (EMSA). The minor G-allele was associated with significantly greater expression levels of firefly luciferase than the major A-allele of SNP rs569356 (P=0.003). EMSA also showed specific gel shift bands, suggesting that SNP rs569356 is situated in the binding site of potential transcription factors. These results suggest that the minor G-allele of SNP rs569356 may enhance transcription factor binding and increase OPRD1 expression.

背景与目标： ：δ阿片样物质受体介导许多滥用物质的有益作用。我们报道了在阿片类药物依赖患者中，单核苷酸多态性（SNP）rs569356（迄今为止在δ-阿片受体基因（OPRD1）的启动子区域中鉴定出的唯一变异）的次要G-等位基因频率增加。在这项研究中，我们检查了此变体的功能意义。通过PCR扩增具有SNP rs569356的OPRD1启动子区域，并将其插入萤火虫荧光素酶报道载体中。将HEK293细胞与这些构建体和海肾荧光素酶载体共转染，以控制转染效率。萤火虫萤光素酶的表达（由OPRD1启动子驱动）通过双重萤光素酶报告基因测定进行测定，并通过海肾萤光素酶的表达进行归一化。此外，通过电泳迁移率变动分析（EMSA）进一步评估了改变表达的等位基因与人脑核蛋白的结合。与SNP rs569356的主要A等位基因相比，次要G等位基因与萤火虫荧光素酶的表达水平显着相关（P = 0.003）。 EMSA还显示出特定的凝胶移位带，表明SNP rs569356位于潜在转录因子的结合位点。这些结果表明，SNP rs569356的次要G等位基因可能增强转录因子结合并增加OPRD1表达。

BACKGROUND & AIMS: BACKGROUND:Pharmacotherapy of alcohol dependence (AD) is at an early stage of development; currently available medications have limited efficacy. It would be clinically valuable to identify, before initiation of a course of treatment, those patients who, based on genetic markers, are most likely to respond to a specific pharmacotherapy. A previous report suggested that a functional variant at the genetic locus encoding the mu opioid receptor (Asn40Asp) is such a marker, in short-term (3-month) treatment with the opioid-blocking drug naltrexone (NTX). METHODS:We studied polymorphic variants at each of the 3 opioid receptor genes--OPRM1, OPRD1, and OPRK1, which encode the mu, delta, and kappa opioid receptors, respectively--including the OPRM1 Asn40Asp variant--as predictors of response to NTX or placebo in 215 alcohol-dependent male subjects who participated in Veterans Affairs Cooperative Study 425, "Naltrexone in the Treatment of Alcohol Dependence." RESULTS:At the 3-month time point, treatment condition, age, and the pretreatment number of drinks per drinking day were all significant (p<0.05) predictors of the rate of relapse and time to relapse. Although NTX had no significant effect on relapse to heavy drinking in the overall sample in CSP 425, it significantly reduced relapse in the subgroup that provided DNA for analysis (i.e., the present study sample). There were no significant interactions between any individual single nucleotide polymorphisms studied and NTX treatment response. CONCLUSIONS:These results do not support association of the OPRM1 Asn40Asp polymorphism with NTX treatment response for AD.

背景与目标： 背景：酒精依赖（AD）的药物治疗尚处于发展初期。目前可用的药物疗效有限。在开始一个疗程之前，根据遗传标记确定最有可能对特定药物疗法产生反应的患者，在临床上具有重要的临床价值。先前的一份报告表明，在短期（3个月）使用阿片类药物阻断剂纳曲酮（NTX）治疗的情况下，编码mu阿片受体（Asn40Asp）的遗传基因座处的功能变异就是这样的标记。
方法：我们研究了3种阿片受体基因-OPRM1，OPRD1和OPRK1的多态变异体，它们分别编码mu，delta和kappa类阿片受体-包括OPRM1 Asn40Asp变异体-作为对反应的预测因子参加退伍军人事务合作研究425，“纳曲酮治疗酒精依赖性”的215名酒精依赖性男性受试者中的NTX或安慰剂。
结果：在三个月的时间点上，治疗条件，年龄和每个饮酒日的预处理次数均是复发率和复发时间的重要预测指标（p <0.05）。尽管NTX在CSP 425的整个样本中对重度饮酒的复发没有显着影响，但它显着降低了提供DNA进行分析的亚组（即本研究样本）的复发。在研究的任何单个单核苷酸多态性与NTX治疗反应之间没有显着的相互作用。
结论：这些结果不支持OPRM1 Asn40Asp多态性与AD的NTX治疗反应的关联。

BACKGROUND & AIMS: INTRODUCTION:We performed a retrospective study to evaluate demographics, clinical course, outcome, and radiological findings of children with respiratory syncytial virus (RSV) infection. METHODS:Four hundred patients admitted between October 2013 and May 2016 were enrolled. Clinical and radiographic trends were evaluated for association with severity of RSV presentation. Severity was defined as hospitalization >2 days, pediatric intensive care unit admission, or need for mechanical ventilation. RESULTS:Common clinical findings included fever (78.5%), coughing (97%), rhinorrhea/congestion (93%), and hypoxia (44.8%). Hypoxia was seen in 64.7% of the severe group compared with 32.0% in the nonsevere group ( P < .001). Airspace opacification was seen in 49.2% of chest X-rays of the severe group compared with 26.4% in the nonsevere group ( P < .001). CONCLUSION:Higher incidence of hypoxia or airspace opacification on chest X-ray may be predictors of poorer outcomes for patients with RSV infection.

背景与目标： 简介：我们进行了一项回顾性研究，以评估呼吸道合胞病毒（RSV）感染儿童的人口统计学，临床病程，结局和放射学表现。
方法：纳入2013年10月至2016年5月期间收治的400例患者。评估临床和放射学趋势与RSV表现的严重程度相关。严重程度定义为住院> 2天，小儿重症监护病房入院或需要机械通气。
结果：常见临床表现包括发烧（78.5％），咳嗽（97％），鼻漏/充血（93％）和缺氧（44.8％）。重症组低氧发生率为64.7％，非重度组为32.0％（P <.001）。严重组的胸部X线片中出现气管混浊的比例为49.2％，而非严重组的比例为26.4％（P <.001）。
结论：胸部X光片缺氧或空域浑浊的发生率较高可能是RSV感染患者预后较差的预示因素。

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BACKGROUND & AIMS: :Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative. We hypothesized that common variants in OPRD1 would be associated with differences in brain structure, particularly in regions relevant to addictive and neurodegenerative disorders. One very common variant (rs678849) predicted differences in regional brain volumes. We replicated the association of this single-nucleotide polymorphism with regional tissue volumes in a large sample of young participants in the Queensland Twin Imaging study. Although the same allele was associated with reduced volumes in both cohorts, the brain regions affected differed between the two samples. In healthy elderly, exploratory analyses suggested that the genotype associated with reduced brain volumes in both cohorts may also predict cerebrospinal fluid levels of neurodegenerative biomarkers, but this requires confirmation. If opiate receptor genetic variants are related to individual differences in brain structure, genotyping of these variants may be helpful when designing clinical trials targeting delta opioid receptors to treat neurological disorders.

背景与目标： ：δ阿片样物质受体与多种精神病和神经疾病有关。这些受体在滥用药物的增强特性中起关键作用，OPRD1（编码阿片类阿片受体的基因）中的多态性与成瘾有关。三角洲阿片受体也参与保护神经元免受缺氧和缺血性应激。在这里，我们首先检查了738名老年参与者的大量样本，这些样本来自阿尔茨海默氏病神经影像学倡议组织的神经影像学和遗传数据。我们假设OPRD1中的常见变异与大脑结构的差异有关，尤其是在与成瘾性和神经退行性疾病有关的区域。一种非常常见的变体（rs678849）预测了局部大脑体积的差异。我们在昆士兰双胞胎成像研究的大量年轻参与者中复制了这种单核苷酸多态性与区域组织体积的关联。尽管两个队列中相同的等位基因与体积减少相关，但两个样本之间受影响的大脑区域有所不同。在健康的老年人中，探索性分析表明，两个队列中与脑容量减少相关的基因型也可能预测神经退行性生物标志物的脑脊液水平，但这需要证实。如果阿片受体的遗传变异与脑结构的个体差异有关，那么在设计针对δ阿片受体的临床试验以治疗神经系统疾病时，这些变异的基因分型可能会有所帮助。

BACKGROUND & AIMS: BACKGROUND:A recent study reported strong evidence for the involvement of a region on human chromosome 1 and genetic susceptibility to anorexia nervosa (AN). A more detailed analysis of this region has suggested 2 genes that may account for this susceptibility. These data suggest that polymorphisms in both the serotonin 1D (HTR1D) and opioid delta 1 (OPRD1) receptor genes show a significant association with restricting AN (RAN). METHODS:In the current study, we have conducted an independent association study on 226 females meeting DSM-IV criteria for AN and 678 matched volunteers. RESULTS:We genotyped 4 SNPs in HTR1D and 6 SNPs in OPRD1. 3 SNPs were found to be associated with both RAN and binge-purge AN (BPAN) within the gene for OPRD1. We also found evidence of association between 2 polymorphisms within HTR1D and RAN. CONCLUSIONS:These data support the hypothesis that polymorphisms within this region form a component of the genetic basis to susceptibility to RAN. However, further work is required to understand the processes that may be mediated by these genes.

背景与目标： 摘要背景：最近的一项研究报道了有力的证据表明，人类第1号染色体上的一个区域参与了遗传性神经性厌食症（AN）的遗传易感性。对该区域进行的更详细分析表明，有2个基因可能解释了这种敏感性。这些数据表明，血清素1D（HTR1D）和阿片类药物δ1（OPRD1）受体基因的多态性均与限制性AN（RAN）密切相关。
方法：在本研究中，我们对226名符合DSM-IV标准的AN和678名匹配志愿者进行了独立的关联研究。
结果：我们对HTR1D中的4个SNP和OPRD1中的6个SNP进行了基因分型。发现3个SNP与OPRD1基因内的RAN和狂暴清除AN（BPAN）相关。我们还发现HTR1D和RAN中2个多态性之间存在关联的证据。
结论：这些数据支持以下假设：该区域内的多态性构成了对RAN易感性的遗传基础的组成部分。但是，需要进一步的工作来理解这些基因可能介导的过程。

BACKGROUND & AIMS: :Opioid receptors and their endogenous peptide ligands play important roles in neurotransmission and neuromodulation in response to addictive drugs such as heroin, cocaine, and alcohol. In an earlier study, we reported that variation in the genes encoding the kappa-opioid receptor (OPRK1) and its peptide ligand (PDYN) were associated with the risk for alcoholism. We continued our investigation of the role of the opioid system in alcohol dependence by analyzing the genes encoding the micro- and delta-opioid receptors and their peptide ligands. We analyzed 18 OPRM1 SNPs, 18 OPRD1 SNPs, 7 PENK SNPs, and 7 POMC SNPs in a sample of 1923 European Americans from 219 multiplex alcohol dependent families. Employing a family-based test of association, we found no evidence that these four genes were significantly associated with alcohol dependence. We also did not find association between these genes and illicit drug dependence. Secondary analyses employing the narrower phenotype of opioid dependence (83 affected individuals) demonstrated association with SNPs in PENK and POMC, but not in OPRM1 or OPRD1. Haplotype analyses provided further support for the association of PENK and POMC with opioid dependence. Therefore, our data provide no support for the idea that variations in OPRM1, OPRD1, PENK and POMC are associated with alcohol dependence or general illicit drug dependence, but variations in PENK and POMC appear to be associated with the narrower phenotype of opioid dependence in these families.

背景与目标： 阿片受体及其内源肽配体在对海洛因，可卡因和酒精等成瘾药物的反应中，在神经传递和神经调节中起重要作用。在较早的研究中，我们报道了编码κ阿片受体（OPRK1）及其肽配体（PDYN）的基因变异与酗酒风险有关。我们通过分析编码微阿片受体和δ阿片受体及其肽配体的基因，继续研究阿片样物质系统在酒精依赖中的作用。我们在来自219个多重酒精依赖家庭的1923个欧洲美国人的样本中分析了18个OPRM1 SNP，18个OPRD1 SNP，7个PENK SNP和7个POMC SNP。使用基于家庭的关联测试，我们没有发现这四个基因与酒精依赖显着相关的证据。我们还没有发现这些基因与非法药物依赖性之间的关联。使用较窄的阿片类药物依赖表型（83个受影响的个体）进行的次要分析表明，PENK和POMC中与SNP相关，而OPRM1或OPRD1中与SNP不相关。单倍型分析为将PENK和POMC与阿片类药物依赖性相关提供了进一步的支持。因此，我们的数据不支持以下观点：OPRM1，OPRD1，PENK和POMC的变异与酒精依赖或一般非法药物依赖有关，但PENK和POMC的变异似乎与这些患者中阿片样物质依赖的较窄表型有关。家庭。

BACKGROUND & AIMS: :The three opioid receptor genes, and in particular the mu and delta loci (OPRM1 and OPRD1, respectively), are compelling candidates to influence risk for substance dependence. Previous study of a variant at the OPRD1 locus, T921C, has shown association with opioid dependence. This variant does not alter protein sequence, and could not be directly responsible for a physiologic effect. We sequenced the OPRD1 coding region in six individuals with differing T921C alleles, to identify new common variants more likely to explain the association with phenotype. We identified one novel variant in exon 1, 80T-->G, which predicts a change in amino acid sequence from phenylalanine (80T) to cysteine (80G) (F27C). We present here basic population genetics of this variant, and population genetic data for the T921C variant. We found significant differences in allele frequency between populations, and a maximum frequency of the 80G allele of 9%, in each of two European populations. This variant could contribute to the previously reported association results.

背景与目标： ：三个阿片样物质受体基因，特别是mu和delta位点（分别为OPRM1和OPRD1），是影响物质依赖风险的诱人候选物。先前对OPRD1基因座的变体T921C的研究表明与阿片样物质依赖性有关。该变体不改变蛋白质序列，并且不能直接负责生理作用。我们在六个具有不同T921C等位基因的个体中对OPRD1编码区进行了测序，以鉴定出更可能解释与表型关联的新的常见变体。我们在第1外显子80T-> G中鉴定出一个新的变异体，该变异体预测了氨基酸序列从苯丙氨酸（80T）变为半胱氨酸（80G）（F27C）的变化。我们在这里介绍了该变种的基本种群遗传学，以及T921C变种的种群遗传数据。我们发现在两个欧洲人群中，人群之间的等位基因频率存在显着差异，而80G等位基因的最大频率为9％。此变体可能有助于先前报告的关联结果。

BACKGROUND & AIMS: BACKGROUND:Pain clinicians have always been challenged by the variability of response to pain treatment. Differences in the degree of pain stimulation and pain sensitivity, weight and age differences, prior opioid use and tolerance, as well as the differences in bioavailability of various opioid formulations have been cited as causes for the wide variability in analgesia seen with opioids. Genetics may explain the variability of responses and help to predict more effective (or less dangerous) medication choices and doses. Genetics may also help to predict the response to specific opioids and antidepressants. OBJECTIVES:In this review article, we discuss the genetic influence of nociception, analgesia, and hyoanalgesia. The CYP450 enzymes involved in the metabolism and activity of opioids and adjuvant analgesics are genetically controlled, as are the opioid receptors and a variety of brain chemistries. METHODS:This article discusses the specific pain implications of genetic variations in CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A7, OPRM1, OPRK1, OPRD1, COMT, GABA, UGT, MC1R, GCH1, ABCB1, P-glycoprotein, 5HTR1A, 5HTR2A, MTHFR, CACNA2D2, and 5-HTTLPR. RESULTS:Recent research findings suggest the relationship between genetic predisposition and clinical behavior, including the risk of opioid misuse and addiction. While urine drug testing may hint at genetic issues regarding opioid metabolism, cheek swab DNA testing has become economically viable, and we review the current and future genetic pain issues that may influence the decisions that pain clinicians make every day. CONCLUSION:Genetic testing may explain and predict many of the clinical responses seen with opioids and adjuvant medications, and may help the clinician identify those patients at genetic risk of opioid misuse and addiction.

背景与目标： 背景：疼痛临床医生一直受到对疼痛治疗反应的可变性的挑战。疼痛刺激和疼痛敏感性程度的差异，体重和年龄的差异，先前使用阿片类药物和耐受性的差异以及各种阿片类药物制剂的生物利用度差异被认为是阿片类药物镇痛广泛差异的原因。遗传学可以解释反应的变异性，并有助于预测更有效（或更危险）的药物选择和剂量。遗传学也可能有助于预测对特定阿片类药物和抗抑郁药的反应。
目的：在这篇综述文章中，我们讨论了伤害感受，镇痛和镇痛的遗传影响。涉及阿片类药物和辅助镇痛药的代谢和活性的CYP450酶，阿片受体和各种脑化学物质均受到基因控制。
方法：本文讨论CYP1A2，CYP2C8，CYP2C9，CYP2C19，CYP2D6，CYP2E1，CYP3A4，CYP3A7，OPRM1，OPRK1，OPRD1，COMT，GABA，UGT，MC1R，G1蛋白的遗传变异对特定疼痛的影响，5HTR1A，5HTR2A，MTHFR，CACNA2D2和5-HTTLPR。
结果：最近的研究结果表明遗传易感性与临床行为之间的关系，包括阿片类药物滥用和成瘾的风险。虽然尿液药物检测可能提示有关阿片类药物代谢的遗传问题，但颊拭子DNA检测已在经济上可行，我们将回顾当前和未来的遗传性疼痛问题，这些问题可能会影响临床医生每天做出的决定。
结论：基因检测可以解释和预测使用阿片类药物和辅助药物所见的许多临床反应，并可以帮助临床医生识别出有阿片类药物滥用和成瘾的遗传风险的患者。

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:Drug addiction is a serious illness with deleterious functional and social consequences for both the affected individuals, their families, and society at large. In spite of the abundant research on substance dependence, there are few effective treatments for this disease. Given the crucial role of the endogenous opioid system in the development and maintenance of substance abuse disorders, this review focuses on the opioidergic system and examines the role of opioidergic genes in the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addiction. METHODS:Scopus (all databases) and Pubmed were systematically searched with no language or year restrictions, up to July 2014, for studies that focused on the relationship between polymorphisms of opioidergic genes and the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addictions. Selected search terms were opioid, gene, polymorphism, drug therapy, substance abuse, and response. RESULTS AND CONCLUSIONS:The genetic variability of μ-, δ- and κ-opioid receptors genes OPRM1, OPRD1, and OPRK1 modulates the efficacy of opioid antagonist treatments such as naltrexone and methadone, as well as the cocaine vaccine. Despite the number of promising reports, data from additional cohorts are needed to substantiate these findings. SCIENTIFIC SIGNIFICANCE:Gene variant profiling could help predict treatment response and assist in developing effective treatments for alcohol, opioid, and cocaine addiction.

背景与目标： 背景与目的：药物成瘾是一种严重的疾病，对受影响的个人，他们的家庭和整个社会都具有有害的功能和社会后果。尽管对物质依赖性进行了大量研究，但是对于这种疾病几乎没有有效的治疗方法。鉴于内源性阿片类药物系统在滥用药物的发生和维持中的关键作用，本综述着重于阿片类药物系统，并研究了阿片类药物基因在酒精，阿片类药物和可卡因成瘾药物治疗中的作用。
方法：直到2014年7月，系统地搜索Scopus（所有数据库）和Pubmed，没有语言或年份限制，研究重点在于阿片类药物基因多态性与酒精，阿片类药物和可卡因成瘾药物治疗结果之间的关系。选择的搜索词是阿片类药物，基因，多态性，药物治疗，药物滥用和反应。
结果与结论：μ，δ和κ阿片受体基因OPRM1，OPRD1和OPRK1的遗传变异性可调节纳曲酮和美沙酮等阿片拮抗剂治疗以及可卡因疫苗的疗效。尽管有大量有希望的报告，但仍需要来自其他队列的数据来证实这些发现。
科学意义：基因变异分析可以帮助预测治疗反应，并帮助开发有效的治疗酒精，阿片类药物和可卡因成瘾的方法。