CD4~+CD25~+Treg细胞、TGF-β和IL-10在反复自然流产中的变化

目的探讨外周血CD4+CD25+Treg细胞数量和抑制性细胞因子TGF-βI、L-10含量变化在反复自然流产中的作用。方法采用ELISA法检测30例反复自然流产患者3、0例正常妊娠妇女和30例正常非孕妇女外周血抑制性细胞因子TGF-β和IL-10含量,三色流式细胞术检测上述研究对象外周血CD4+CD25+T细胞比例。结果反复自然流产组妇女外周血CD4+CD25+Treg细胞的百分率(6.66±1.30)%明显低于正常非孕组(10.99±2.64)%(P<0.05)和正常妊娠组(12.63±3.05)%(P<0.05)。反复自然流产组妇女外周血TGF-β(123.64±27.31)pg/L明显低于正常非孕组对照组TGF-β(179.25±24.67)pg/L(P<0.05)和正常妊娠组TGF-β(211.72±63.49)pg/L(P<0.05);反复自然流产组妇女外周血IL-10(145.37±42.45)pg/L明显低于正常非孕组对照组IL-10(203.47±42.56)pg/L(P<0.05)和正常妊娠组IL-10(234.45±51.21)pg/L(P<0.05)。结论外周血CD4+CD25+Treg细胞的比例低下以及抑制性细胞因子TGF-β和IL-10含量降低可能参与反复自然流产的发生。     

妊娠相关血浆蛋白A与血清新蝶呤在不稳定型心绞痛病变中的意义

目的探讨冠心病患者血清妊娠相关血浆蛋白A(PAPP-A)、血清新蝶呤(NPT)水平与冠状动脉不稳定斑块的相关性。方法应用ELISA方法检测正常对照(C组,31例)、稳定型心绞痛(SA组,41例)、不稳定型心绞痛(UA组,61例)患者血清PAPP-A、NPT水平。冠状动脉造影检测冠脉复杂狭窄数量。结果 UA组血清PAPP-A、NPT水平分别为(12.17±3.08)μg/L、(9.27±3.01)μg/L,明显高于SA组的(8.38±3.31)μg/L、(7.16±3.60)μg/L和对照组的(4.71±3.09)μg/L、(5.01±1.70)μg/L(P<0.01);UA组血清PAPP-A水平和NPT呈显著正相关(r=0.45,P<0.01);在SA组和C组血清PAPP-A水平和NPT无明显相关性(P>0.05)。UA组冠脉复杂狭窄数明显大于SA组和C组(P<0.01);UA组血清PAPP-A、NPT水平均与冠脉复杂狭窄数呈正相关(r1=0.51,r2=0.36,P<0.01)。结论冠心病患者血清PAPP-A与NPT水平升高提示冠脉斑块不稳定,可能是冠脉病变活动性的指标。     

萘醌老化黑碳对Treg分化的影响及机制研究

目的探讨萘醌老化黑碳(1,4NQ-BC)对Treg细胞分化的影响及其机制方法从6～8周龄C57BL/6小鼠的浅表淋巴结中用磁珠分选法提取幼稚CD4~+T细胞,分为对照组(Th0)、TGF-β诱导组(TGF-β)和在TGF-β基础上加入1,4NQ-BC的处理组(5 ng/ml的TGF-β+50μg/ml的1,4NQ-BC),于体外诱导分化,3 d后收集细胞,用Foxp3-PE染色后进行流式检测;取适量各组细胞提取蛋白,进行Western blot实验,检测Smad2蛋白量结果 TGF-β诱导组相对于对照组Treg细胞比例从0.75%增加到43.4%(P0.05),加入1,4NQ-BC的处理组相较于TGF-β诱导组,Treg细胞比例从43.4%下降至10.33%(P0.05);Western blot实验显示相对于TGF-β诱导组, 1,4NQ-BC处理组TGF-β通路上的Smad2蛋白量明显降低,差异有统计学意义(P0.05)。结论 1,4NQ-BC在体外抑制幼稚CD4+T细胞向Treg分化,其作用机制可能是通过抑制TGF-β通路上的Smad2蛋白达到抑制分化的作用。     

匹多莫德口服液对小儿支原体肺炎外周血辅助性T细胞/CD4+CD25+Treg的影响北大核心CSCD

目的研究匹多莫德对小儿支原体肺炎Th17/CD4+CD25+Treg的影响。方法用随机数表将65例患儿分为试验组33例和对照组32例。2组均采用阿奇霉素进行序贯治疗,试验组额外给予匹多莫德口服液0.4 g·d^(-1),共治疗2周。对比2组患儿的临床疗效和药物不良反应(ADR)。抽取患者肘静脉血,用流式细胞法测定Th17/CD4+CD25+Treg,用酶联免疫吸附实验测定血清白细胞介素-17A(IL-17A)、转化生长因子β1(TGF-β_1)水平,用荧光定量PCR实验测定单个核细胞的维A酸相关孤独受体γt(RORγt)与叉头蛋白3(Foxp3)的mRNA表达。结果治疗后,试验组的有效率为90.9%(30例/33例),高于对照组的62.5%(20例/32例),差异有统计学意义(P<0.05)。治疗后,试验组Th17/CD4+CD25+Treg、IL-17A/TGF-β1及RORγt/Foxp3分别为0.97±0.18,1.25±0.21,1.49±0.21,对照组分别为1.25±0.20,1.69±0.26,1.68±0.18,试验组均低于对照组,差异均有统计学意义(P<0.01,P<0.05)。试验组与对照组ADR发生率分别为21.2%(7例/33例)和18.8%(6例/32例),2组差异无统计学意义(P>0.05)。结论匹多莫德能够调节支原体肺炎患儿Th17/CD4+CD25+Treg平衡,是其免疫学机制的重要组成部分。     

免疫球蛋白对中晚期肝病并发感染患者炎症指标和T淋巴细胞亚群的影响

目的评估中晚期肝病并发感染患者经免疫球蛋白治疗后,其炎症指标与T淋巴细胞亚群的变化情况。方法86例中晚期肝病并发感染患者,依据治疗方法不同分为对照组和观察组,各43例。对照组采取常规治疗,观察组在对照组基础上给予免疫球蛋白治疗。比较两组患者临床疗效以及治疗前后的炎症指标、T淋巴细胞亚群水平。结果观察组患者治疗总有效率88.37%高于对照组的62.79%,差异具有统计学意义(P<0.05)。治疗后,两组患者C反应蛋白(CRP)、降钙素原(PCT)、白介素-6(IL-6)水平均有所改善,且观察组C-CRP(7.11±1.21)mg/L、PCT(0.44±0.11)μg/L、IL-6(69.43±1.21)pg/ml均优于对照组的(9.65±1.23)mg/L、(0.62±0.22)μg/L、(74.26±1.32)pg/ml,差异均具有统计学意义(P<0.05)。治疗后,两组患者CD4^+、CD8^+、CD4^+/CD8^+、调节性T(Treg)细胞水平均有所改善,且观察组患者CD4^+、CD8^+、CD4^+/CD8^+、Treg细胞水平分别为(34.26±2.64)%、(33.64±3.42)%、(0.84±0.12)、(7.65±0.33)%,均优于对照组的(37.69±2.65)%、(29.46±3.26)%、(1.12±0.23)、(6.54±0.63)%,差异均具有统计学意义(P>0.05)。结论经免疫球蛋白治疗,中晚期肝病并发感染患者病症显著改善,有效提高抗感染效果,抑制炎症反应,提高患者免疫功能,显著提高临床治疗效果,值得推广。     

甲泼尼龙对哮喘患者外周血CD4~+ CD25~+调节性T细胞影响的体外研究

目的观察哮喘患者外周血中CD4+ CD25+调节性T细胞(Treg)功能状态及甲泼尼龙对其的影响。方法清晨取静脉血5 mL,常规分离外周血单个核细胞,分为健康组、哮喘组及1×10-7 mol·L-1甲泼尼龙哮喘干预组,刺激培养48 h,用ELISA法测定IL-10及TGF-β1的浓度;流式细胞仪检测CD4+CD25+Treg的比例及细胞内Foxp3表达,用SPSS 17.0进行分析。结果哮喘组,外周血CD4+ CD25+ Treg细胞比例降低,CD4+ CD25+ Foxp3+ Treg细胞减少,TGF-β1分泌减少,IL-10分泌有增高趋势,但与健康组比较无统计学意义;甲泼尼龙可以明显增加哮喘急性发作期患者CD4+ CD25+ Treg比例,Foxp3表达明显增强;但未能增加TGF-β1及IL-10的分泌。结论哮喘患者CD4+ CD25+ Treg功能低下,可能是哮喘发病机制之一;甲泼尼龙可能通过上调CD4+ CD25+ Treg数量,起到控制哮喘急性发作的作用。     

西罗莫司体外选择性扩增人体天然CD4~+CD25~+调节性T细胞

目的探讨西罗莫司(SIR)对人类天然CD4+CD25+调节性T细胞(Treg)的存活及扩增的作用。方法初次亲属活体供肾移植受者8例,应用MACS免疫磁珠法分选CD4+CD25-和CD4+CD25+T细胞,流式细胞仪进行检验,体外培养两种细胞,并在后者中非别加入SIR与环孢素(CsA)。单向混合淋巴细胞培养验证培养前后调节性T细胞的免疫抑制功能。结果CsA组Treg占CD4+T细胞的(2.92±0.55)%,低于空白对照组(7.67±0.91)%(P<0.01);SIR组Treg占CD4+T细胞的(10.81±1.05)%,高于空白对照组和CsA组(P<0.01)。体外混合淋巴细胞培养结果表明体外SIR扩增前后的Treg加入CD4+CD25-细胞MLR培养体系中,其CPM值分别为8345±2079及9418±2274,两者间差异无显著性,但均低于CD4+CD25-细胞正常MLR培养(P<0.05)。结论SIR体外对人体天然CD4+CD25+T细胞亚群有促增殖效应,而CsA则具有抑制效应,扩增后的CD4+CD25+T细胞与天然CD4+CD25+T细胞有相同的免疫抑制作用。     

外周血T淋巴细胞对乙肝病毒相关慢加急性肝衰竭患者预后的影响

目的 探讨乙肝病毒相关慢加急性肝衰竭(HBV-ACLF)患者外周血T淋巴细胞亚群比例对其预后的影响.方法 选择HBV-ACLF患者43例,随访观察3个月后患者的存活率,应用流式细胞仪测定外周血CD3+、CD4+和CD8+T淋巴细胞及CD4+ CD25+ Treg细胞的百分比,并计算CD4+和CD8+T淋巴细胞比值,分析T淋巴细胞亚群对乙肝病毒相关慢加急性肝衰竭患者预后的影响,选择门诊同期健康体检者20例为健康对照组.结果 3个月后,43例HBV-ACLF患者存活26例,死亡17例.与肝衰竭存活组相比,肝衰竭死亡组CD3+细胞百分率(22.96±20.59)％、CD8+细胞百分率(31.63±12.69)％均低于存活组(37.89±17.36)％和(36.52±9.75)％,而CD4+细胞百分率(55.15±14.23)％、CD4+/CD8+(1.77±1.38)高于存活组(48.51±13.35)％、(1.32±0.68),均差异有统计学意义(P＜0.05),但两组之间CD4+ CD25+ Treg细胞比例差异无统计学意义.与健康对照组相比,肝衰竭死亡组患者外周血CD3+、CD8+T淋巴细胞及CD4+ CD25+ Treg细胞比例下降,CD4+T淋巴细胞、CD4+/CD8+升高,肝衰竭存活组患者CD3+T淋巴细胞及CD4+ CD25+ Treg细胞百分比下降,均差异有统计学意义(P＜0.05).结论 T淋巴细胞亚群比例的变化在一定程度上可以预测HBV-ACLF患者的预后,外周血T淋巴细胞CD3+、CD8+、CD4+ CD25+ Treg比例下降的程度越重,预后可能越差.     

CD4^＋CD25^＋Treg细胞、TGF-β和IL-10在反复自然流产中的变化

目的探讨外周血CD4＋CD25＋Treg细胞数量和抑制性细胞因子TGF-βI、L-10含量变化在反复自然流产中的作用。方法采用ELISA法检测30例反复自然流产患者3、0例正常妊娠妇女和30例正常非孕妇女外周血抑制性细胞因子TGF-β和IL-10含量,三色流式细胞术检测上述研究对象外周血CD4＋CD25＋T细胞比例。结果反复自然流产组妇女外周血CD4＋CD25＋Treg细胞的百分率（6.66±1.30）%明显低于正常非孕组（10.99±2.64）%（P〈0.05）和正常妊娠组（12.63±3.05）%（P〈0.05）。反复自然流产组妇女外周血TGF-β（123.64±27.31）pg/L明显低于正常非孕组对照组TGF-β（179.25±24.67）pg/L（P〈0.05）和正常妊娠组TGF-β（211.72±63.49）pg/L（P〈0.05）;反复自然流产组妇女外周血IL-10（145.37±42.45）pg/L明显低于正常非孕组对照组IL-10（203.47±42.56）pg/L（P〈0.05）和正常妊娠组IL-10（234.45±51.21）pg/L（P〈0.05）。结论外周血CD4＋CD25＋Treg细胞的比例低下以及抑制性细胞因子TGF-β和IL-10含量降低可能参与反复自然流产的发生。     

支原体肺炎儿童外周血CD4+CD25+调节性T细胞水平的变化及维生素A的调节作用

目的 探讨肺炎支原体肺炎(MPP)患儿外周血淋巴细胞中CD4+ CD25+调节性T细胞(Treg)、T细胞亚群CD3+、CD4+、CD4+/CDs水平的变化及临床意义;探讨体外实验时维生素A体内活性代谢产物视黄酸对MPP患儿外周血淋巴细胞CD4+ CD25+ Treg细胞、T细胞亚群CD3+、CD4+表达及CD4+/CD8+比率的调节干预作用.方法 选择2012年10-12月在空军总医院儿科确诊为MPP的20例住院患儿作为研究对象,其中10例患儿作为病例试验组,另10例患儿作为病例对照组(即未与视黄酸孵育),同期10例同龄健康儿童作为正常对照组.收集患儿及正常对照儿童外周血标本,分离单个核细胞,用流式细胞仪检测外周血淋巴细胞中CD4+ CD25+ Treg细胞、T细胞亚群CD3+、CD4+、CD4+/CD8+水平,病例试验组提取其淋巴细胞在体外培养基中加入一定量视黄酸共同培养孵育,再次测定CD4+ CD25+ Treg细胞、T细胞亚群CD3+、CD4+、CD4+/CD8+水平,将上述指标进行比较分析.结果 病例组患儿外周血淋巴细胞中CD4+ CD25+ Treg细胞、CD4+/CD8+、CD3+百分比分别为(4.5±1.9)％、(1.3±0.9)％、(38.9±11.4)％,正常对照组儿童分别为(13.2±2.5)％、(7.9±3.0)％、(65.1±8.8)％,病例对照组明显低于正常对照组,差异有统计学意义(P＜0.05),而与视黄酸共同孵育后病例试验组以上指标明显升高,分别上升至(9.2±3.8)％、(5.9±2.5)％、(81.3±11.6)％,与病例对照组比较差异有统计学意义(P＜0.05),与正常对照组比较差异无统计学意义(P＞0.05).结论 MPP患儿外周血淋巴细胞中CD4+ CD25+ Treg细胞、CD3+T细胞表达明显受抑,CD4+/CD8+亚群比例异常,T细胞亚群数量及功能明显紊乱,而体外试验时维生素A体内活性代谢产物视黄酸干预后能增强淋巴细胞CD4+ CD25+ Treg细胞、CD3+ T细胞表达,恢复CD4+/CD8+亚群比例,纠正T细胞亚群功能失衡,从而增强、协调机体免疫、抗感染能力,为维生素A辅助治疗MPP提高参考.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

---

Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.