The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction(PPI) has become an important drug target to upregul...The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction(PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1–Nrf2PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1's cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1–Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1–Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions.展开更多
Varicocelectomy is the most commonly performed surgical procedure for the treatment of male infertility. Although several different techniques for varicocele repair have been described in the literature, microsurgical...Varicocelectomy is the most commonly performed surgical procedure for the treatment of male infertility. Although several different techniques for varicocele repair have been described in the literature, microsurgical varicocelectomy performed through a subinguinal or inguinal incision is recognized as the gold-standard approach for varicocelectomy, due to high success rates with minimal complications. Standard indications for varicocelectomy include palpable varicocele（s）, with one or more abnormal semen parameters, and, for the couple trying to conceive, in the setting of normal or correctable female infertility. However, varicocele repair is often recommended and undertaken for reasons other than infertility, including low serum testosterone, testicular pain, testicular hypotrophy and poor sperm DNA quality. This article reviews the technical aspects of microsurgical varicocelectomy, and its indications in adults and adolescents.展开更多
加拿大心境障碍与焦虑障碍治疗协作组(Canadian Network for Mood and Anxiety Treatments,CANMAT)曾于2005年发布了第1版双相障碍管理指南,并分别于2007、2009和2013年对该指南进行了更新,其中最近的2次更新是与国际双相障碍学会(Inter...加拿大心境障碍与焦虑障碍治疗协作组(Canadian Network for Mood and Anxiety Treatments,CANMAT)曾于2005年发布了第1版双相障碍管理指南,并分别于2007、2009和2013年对该指南进行了更新,其中最近的2次更新是与国际双相障碍学会(International Society for Bipolar Disorders,ISBD)合作完成。2018版CANMAT/ISBD双相障碍治疗指南(以下简称指南)反映了自2005年首版指南发表以来本领域取得的重大进展,包括疾病诊断与疾病管理的更新以及药物治疗与心理治疗的近期研究进展。这些前沿进展中综合考虑了循证证据的级别,并基于治疗疗效、临床实践经验、安全性、耐受性和药物导致的转相风险等,对一线、二线及三线治疗方案进行了简明而清晰的推荐。本指南中新增内容涵盖了双相Ⅰ型障碍(BD-Ⅰ)的躁狂发作急性期、抑郁发作急性期和双相障碍维持期的一线及二线治疗推荐等级划分。这种对治疗推荐等级的划分综合考虑了治疗方法对双相障碍不同时相的影响,将进一步帮助临床医生做出基于循证证据的治疗决策。锂盐、喹硫平、双丙戊酸盐、阿塞那平、阿立哌唑、帕利哌酮、利培酮和卡利拉嗪单药或联合使用被推荐为躁狂发作急性期的一线治疗选择。BD-Ⅰ抑郁期的一线治疗选择包括喹硫平、鲁拉西酮、锂盐、拉莫三嗪单药,鲁拉西酮联合锂盐或双丙戊酸盐或拉莫三嗪辅助治疗。尽管急性期治疗有效的药物通常应继续用于BD-Ⅰ的维持期治疗,但也存在一些特殊情况(例如抗抑郁药)。现有数据表明,锂盐、喹硫平、双丙戊酸盐、拉莫三嗪、阿塞那平和阿立哌唑单药或联合治疗应被视为维持治疗的初始或更换治疗方案时的一线选择。除了探讨BD-Ⅰ的相关问题外,本指南中还对双相Ⅱ型障碍(BD-Ⅱ)的临床管理进行了系统回顾并给予治疗推荐,同时针对特殊人群也有相关推荐,如处于各个生殖展开更多
AIM: To assess the failure and bone-to-implant contact rate of dental implants placed on osteoporotic subjects. METHODS: Extensive examination strategies were created to classify studies for this systematic review. ME...AIM: To assess the failure and bone-to-implant contact rate of dental implants placed on osteoporotic subjects. METHODS: Extensive examination strategies were created to classify studies for this systematic review. MEDLINE(via Pub Med) and EMBASE database were examined for studies in English up to and including May 2014. The examination presented a combination of the MeS H words described as follow: "osteoporosis" or "osteopenia" or "estrogen deficiency" AND "implant" or "dental implant" or "osseointegration". Assessment of clinical and/or histological peri-implant conditions in osteoporosis subjects treated with titanium dental implants. The examination included a combination of the MeS H terms described as follow: "osteoporosis" or "osteopenia" or "estrogen deficiency" AND "implant" or "dental implant" or "osseointegration".RESULTS: Of 943 potentially eligible articles, 12 were included in the study. A total of 133 subjects with osteoporosis, 73 subjects diagnosed with osteopenia and 708 healthy subjects were assessed in this systematic review. In these subjects were installed 367, 205, 2981 dental implants in osteoporotic, osteopenic and healthy subjects, respectively. The failure rate of dental implant was 10.9% in osteoporotic subjects, 8.29% in osteopenic and 11.43% in healthy ones. Bone-to-implant contact obtained from retrieved implants ranged between 49.96% to 47.84%, for osteoporosis and non-osteoporotic subjects. CONCLUSION: Osteoporotic subjects presented higher rates of implant loss, however, there is a lower evidence to strengthen or refute the hypothesis that osteoporosis may have detrimental effects on bone healing. Consequently, final conclusions regarding the effect of osteoporosis in dental implant therapy cannot be made at this time. There are no randomized clinical trial accessible for evaluation and the retrospectivenature of the evaluated studies shall be taken in account when interpreting this study.展开更多
社会心理因素和癫痫治疗可能对癫痫患者及其家庭的健康相关生活质量(Health-related quality of life,HRQOL)产生显著影响,临床上广泛关注心理评估和治疗在改善HRQOL和癫痫共病中的作用。因此,国际抗癫痫联盟(ILAE)委托心理工作组,基于...社会心理因素和癫痫治疗可能对癫痫患者及其家庭的健康相关生活质量(Health-related quality of life,HRQOL)产生显著影响,临床上广泛关注心理评估和治疗在改善HRQOL和癫痫共病中的作用。因此,国际抗癫痫联盟(ILAE)委托心理工作组,基于其最近对癫痫患者心理治疗的Cochrane回顾证据的评估,制定了相关临床建议。近期关于癫痫患者心理治疗随机对照试验的Cochrane回顾是本文的主要证据来源。为提供具有实用意义的指导,我们根据美国神经病学学会证据水平系统以及推荐分级、评估、开发和评价系统对研究设计进行评级。本文是儿童和成人心理学家、神经病学家、精神病学家和神经精神病学家进行国际合作的顶点。ILAE执行委员会审查并批准了这一进程和结论。心理干预的最强证据被确定为最常见的心理健康问题,包括抑郁症、神经认知障碍和药物依从性。针对提高HRQOL和依从性以及减少共病症状(焦虑、抑郁)的心理干预应纳入癫痫综合护理中。一系列的心理策略(如认知行为疗法和正念疗法)为提升癫痫患者生活质量带来希望,也给癫痫临床工作者提供了治疗癫痫共病、应对挑战的临床建议。展开更多
To the Editor:In sepsis,bacterial endotoxins play a central role by inducing a dysregulated and exaggerated release of inflammatory mediators and cytokines,often described as the“cytokine storm”or“cytokinemia.”[1]...To the Editor:In sepsis,bacterial endotoxins play a central role by inducing a dysregulated and exaggerated release of inflammatory mediators and cytokines,often described as the“cytokine storm”or“cytokinemia.”[1]Both endotoxins and cytokines have been implicated in the development of organ dysfunction,including acute kidney injury(AKI).[2]Removing circulating endotoxins and excess cytokines from the circulation restores chemotactic gradients,localizing the immune response to the principal site of infection and re-establishing a regulated immune response.[1,3]Therefore,using hemofilters with enhanced endotoxin and cytokine adsorptive properties may bring about additional therapeutic benefits compared with conventional continuous renal replacement therapy(CRRT)filters.展开更多
基金the financial support of Grants CA133791, CA125868, and MH093197 from the National Institutes of Health, United States
文摘The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction(PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1–Nrf2PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1's cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1–Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1–Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions.
文摘Varicocelectomy is the most commonly performed surgical procedure for the treatment of male infertility. Although several different techniques for varicocele repair have been described in the literature, microsurgical varicocelectomy performed through a subinguinal or inguinal incision is recognized as the gold-standard approach for varicocelectomy, due to high success rates with minimal complications. Standard indications for varicocelectomy include palpable varicocele（s）, with one or more abnormal semen parameters, and, for the couple trying to conceive, in the setting of normal or correctable female infertility. However, varicocele repair is often recommended and undertaken for reasons other than infertility, including low serum testosterone, testicular pain, testicular hypotrophy and poor sperm DNA quality. This article reviews the technical aspects of microsurgical varicocelectomy, and its indications in adults and adolescents.
文摘加拿大心境障碍与焦虑障碍治疗协作组(Canadian Network for Mood and Anxiety Treatments,CANMAT)曾于2005年发布了第1版双相障碍管理指南,并分别于2007、2009和2013年对该指南进行了更新,其中最近的2次更新是与国际双相障碍学会(International Society for Bipolar Disorders,ISBD)合作完成。2018版CANMAT/ISBD双相障碍治疗指南(以下简称指南)反映了自2005年首版指南发表以来本领域取得的重大进展,包括疾病诊断与疾病管理的更新以及药物治疗与心理治疗的近期研究进展。这些前沿进展中综合考虑了循证证据的级别,并基于治疗疗效、临床实践经验、安全性、耐受性和药物导致的转相风险等,对一线、二线及三线治疗方案进行了简明而清晰的推荐。本指南中新增内容涵盖了双相Ⅰ型障碍(BD-Ⅰ)的躁狂发作急性期、抑郁发作急性期和双相障碍维持期的一线及二线治疗推荐等级划分。这种对治疗推荐等级的划分综合考虑了治疗方法对双相障碍不同时相的影响,将进一步帮助临床医生做出基于循证证据的治疗决策。锂盐、喹硫平、双丙戊酸盐、阿塞那平、阿立哌唑、帕利哌酮、利培酮和卡利拉嗪单药或联合使用被推荐为躁狂发作急性期的一线治疗选择。BD-Ⅰ抑郁期的一线治疗选择包括喹硫平、鲁拉西酮、锂盐、拉莫三嗪单药,鲁拉西酮联合锂盐或双丙戊酸盐或拉莫三嗪辅助治疗。尽管急性期治疗有效的药物通常应继续用于BD-Ⅰ的维持期治疗,但也存在一些特殊情况(例如抗抑郁药)。现有数据表明,锂盐、喹硫平、双丙戊酸盐、拉莫三嗪、阿塞那平和阿立哌唑单药或联合治疗应被视为维持治疗的初始或更换治疗方案时的一线选择。除了探讨BD-Ⅰ的相关问题外,本指南中还对双相Ⅱ型障碍(BD-Ⅱ)的临床管理进行了系统回顾并给予治疗推荐,同时针对特殊人群也有相关推荐,如处于各个生殖
基金Supported by Sao Paulo Research Foundation,FAPESP,No.2008/06972-6The National Council for Scientific and Technological Development,CNPq Nos.579157/2008-3,302768/2009-2 and 473282/2007-0+1 种基金Pesq-Doc scholarship to Dr.Shibli from University of GuaruhosScholarship to Dr.Giro from University of Guarulhos
文摘AIM: To assess the failure and bone-to-implant contact rate of dental implants placed on osteoporotic subjects. METHODS: Extensive examination strategies were created to classify studies for this systematic review. MEDLINE(via Pub Med) and EMBASE database were examined for studies in English up to and including May 2014. The examination presented a combination of the MeS H words described as follow: "osteoporosis" or "osteopenia" or "estrogen deficiency" AND "implant" or "dental implant" or "osseointegration". Assessment of clinical and/or histological peri-implant conditions in osteoporosis subjects treated with titanium dental implants. The examination included a combination of the MeS H terms described as follow: "osteoporosis" or "osteopenia" or "estrogen deficiency" AND "implant" or "dental implant" or "osseointegration".RESULTS: Of 943 potentially eligible articles, 12 were included in the study. A total of 133 subjects with osteoporosis, 73 subjects diagnosed with osteopenia and 708 healthy subjects were assessed in this systematic review. In these subjects were installed 367, 205, 2981 dental implants in osteoporotic, osteopenic and healthy subjects, respectively. The failure rate of dental implant was 10.9% in osteoporotic subjects, 8.29% in osteopenic and 11.43% in healthy ones. Bone-to-implant contact obtained from retrieved implants ranged between 49.96% to 47.84%, for osteoporosis and non-osteoporotic subjects. CONCLUSION: Osteoporotic subjects presented higher rates of implant loss, however, there is a lower evidence to strengthen or refute the hypothesis that osteoporosis may have detrimental effects on bone healing. Consequently, final conclusions regarding the effect of osteoporosis in dental implant therapy cannot be made at this time. There are no randomized clinical trial accessible for evaluation and the retrospectivenature of the evaluated studies shall be taken in account when interpreting this study.
文摘社会心理因素和癫痫治疗可能对癫痫患者及其家庭的健康相关生活质量(Health-related quality of life,HRQOL)产生显著影响,临床上广泛关注心理评估和治疗在改善HRQOL和癫痫共病中的作用。因此,国际抗癫痫联盟(ILAE)委托心理工作组,基于其最近对癫痫患者心理治疗的Cochrane回顾证据的评估,制定了相关临床建议。近期关于癫痫患者心理治疗随机对照试验的Cochrane回顾是本文的主要证据来源。为提供具有实用意义的指导,我们根据美国神经病学学会证据水平系统以及推荐分级、评估、开发和评价系统对研究设计进行评级。本文是儿童和成人心理学家、神经病学家、精神病学家和神经精神病学家进行国际合作的顶点。ILAE执行委员会审查并批准了这一进程和结论。心理干预的最强证据被确定为最常见的心理健康问题,包括抑郁症、神经认知障碍和药物依从性。针对提高HRQOL和依从性以及减少共病症状(焦虑、抑郁)的心理干预应纳入癫痫综合护理中。一系列的心理策略(如认知行为疗法和正念疗法)为提升癫痫患者生活质量带来希望,也给癫痫临床工作者提供了治疗癫痫共病、应对挑战的临床建议。
文摘To the Editor:In sepsis,bacterial endotoxins play a central role by inducing a dysregulated and exaggerated release of inflammatory mediators and cytokines,often described as the“cytokine storm”or“cytokinemia.”[1]Both endotoxins and cytokines have been implicated in the development of organ dysfunction,including acute kidney injury(AKI).[2]Removing circulating endotoxins and excess cytokines from the circulation restores chemotactic gradients,localizing the immune response to the principal site of infection and re-establishing a regulated immune response.[1,3]Therefore,using hemofilters with enhanced endotoxin and cytokine adsorptive properties may bring about additional therapeutic benefits compared with conventional continuous renal replacement therapy(CRRT)filters.
