Modeling Alzheimer's disease and other proteopathies in vivo: is seeding the key?

Summary.  Protein misfolding and aberrant polymerization are salient features of virtually all central neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, triplet repeat disorders, tauopathies, and prion diseases. In many instances, a single amino acid change can predispose to disease by increasing the production and/or changing the biophysical properties of a specific protein. Possible pathogenic similarities among the cerebral proteopathies suggest that therapeutic agents interfering with the proteopathic cascade might be effective against a wide range of diseases. However, testing compounds preclinically will require disease-relevant animal models. Numerous transgenic mouse models of β-amyloidosis, tauopathy, and other aspects of AD have now been produced, but none of the existing models fully recapitulates the pathology of AD. In an attempt to more faithfully replicate the human disease, we infused dilute AD-brain extracts into Tg2576 mice at 3-months of age (i.e. 5–6 months prior to the usual onset of β-amyloid deposition). We found that intracerebral infusion of AD brain extracts results in: 1) Premature deposition of β-amyloid in eight month-old, β-amyloid precursor protein (βAPP)-transgenic mice (Kane et al., 2000); 2) augmented amyloid load in the injected hemisphere of 15 month-old transgenic mice; 3) evidence for the spread of pathology to other brain areas, possibly by neuronal transport mechanisms; and 4) tau hyperphosphorylation (but not neurofibrillary pathology) in axons passing through the injection site. The seeding of β-amyloid in vivo by AD brain extracts suggests pathogenic similarities between β-amyloidoses such as AD and other cerebral proteopathies such as the prionoses, and could provide a new model for studying the proteopathic cascade and its neuronal consequences in neurodegenerative diseases. Received June 28, 2001 Accepted August 6, 2001 Published online June 26, 2002     

In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals

There is a great deal of evidence to support a pathogenic role of oxidative stress in Alzheimer's disease (AD), but the sources of reactive oxygen species have not been directly demonstrated. In this study, using a novel in situ detection system, we show that neurofibrillary tangles and senile plaques are major sites for catalytic redox reactivity. Pretreatment with deferoxamine or diethylenetriaminepentaacetic acid abolishes the ability of the lesions to catalyze the H2O2-dependent oxidation of 3,3'-diaminobenzidine (DAB), strongly suggesting the involvement of associated transition metal ions. Indeed, following chelated removal of metals, incubation with iron or copper salts reestablished lesion-dependent catalytic redox reactivity. Although DAB oxidation can also detect peroxidase activity, this was inactivated by H2O2 pretreatment before use of DAB, as shown by a specific peroxidase detection method. Model studies confirmed the ability of certain copper and iron coordination complexes to catalyze the H2O2-dependent oxidation of DAB. Also, the microtubule-associated protein tau, as an in vitro model for proteins relevant to AD pathology, was found capable of adventitious binding of copper and iron in a redox-competent manner. Our findings suggest that neurofibrillary tangles and senile plaques contain redox-active transition metals and may thereby exert prooxidant or possibly antioxidant activities, depending on the balance among cellular reductants and oxidants in the local microenvironment.     

Antifungal drug resistance pattern of Candida. spp isolated from vaginitis in Ilam-Iran during 2013-2014

Vaginal Candidiasis is the most common and important opportunistic fungal infection in women. By increasing use of antifungal drugs in recent years, it has caused drug resistance. This study aims to evaluate antifungal drugs susceptibility of Candida. spp isolated of women with vaginitis from Ilam-Iran during 2013-2014. samples were collected and cultured from 385 women with vaginitis, then Candida.spp was diagnosed by standard method. Antifungal drug susceptibility test for nystatin 100 unit/disk, fluconazole 10µg/disk, itraconazole 10µg/disk, ketoconazole 10µg/disk, amphotericinB 20µg/disk, clotrimazole 10µg/disk, posaconazole 5µg/disk, and voriconazole 1µg/disk were carried out by M44-A method(CLSI). From all culture positive samples, 150 isolates were Candida albicans and 89 isolates were non-albicans. The resistance to fluconazole, itraconazole, ketoconazole, clotrimazole, voriconazole, posaconazole, nystatin and amphotericin B was 76%, 62%, 72%, 55%, 6%, 7%, 1% and 0%. The highest resistance was seen for fluconazole , itraconazole, and the highest susceptible was seen for nystatin and amphotericin B. These results indicate nystatin and amphotericin B can be used as the first line for empirical therapy of vaginal candidiasis in the district.     

石杉碱甲联合注射用鼠神经生长因子对老年痴呆MMSE评分及日常生活能力的影响

目的:研究石杉碱甲联合注射用鼠神经生长因子对老年痴呆简易智力状态检查量表(MMSE)及日常生活能力量表(ADL)评分的影响。方法:选择2015年6月～2018年6月我院收治的98例老年痴呆患者,随机分为两组。对照组口服石杉碱甲,起始给药剂量为每次100μg,每天2次,第2周给药剂量调整为每次150μg,每天2次,维持用量。观察组联合静脉滴注鼠神经生长因子,每次20μg,每天1次。比较两组治疗前后ADL和MMSE评分、血清白细胞介素(IL)-1β、C-反应蛋白(CRP)、IL-6、肿瘤坏死因子-α(TNF-α)水平的变化。结果:治疗后,观察组的总有效率为87.75%(43/49),明显高于对照组[69.39%(34/49)](P0.05);两组治疗后的ADL和MMSE评分及血清IL-1β、CRP、IL-6和TNF-α水平均较治疗前明显降低(P0.05),且观察组以上指标均明显低于对照组(P0.05)。结论:与单用石杉碱甲相比,注射用鼠神经生长因子联合石杉碱甲可更有效改善其日常生活能力和认知功能,且能显著降低血清炎症因子水平。     

脑源性神经生长因子对老龄鼠智能影响的探讨

目的研究脑源性神经营养因子（bDNF）改善痴呆老龄鼠学习记忆的作用机制;胆碱乙酰转移酶活性（ChAT-IR）、胆碱酯酶（AchE）活性的影响。方法利用海马内注射bDNF及免疫组织化学技术,观察给药前后各组迷宫试验,胆碱乙酰转移酶（ChAT）、胆碱酯酶（AchE）活性的变化。结果治疗组学习记忆能力有明显改变（P〈0.05）。与对照组比较ChAT-IR表达明显增加（P〈0.01）,AchE活性明显增强（P〈0.01）。结论bDNF使胆碱乙酰转移酶活性（ChAT）、胆碱酯酶（AchE）活性增强;对老龄鼠的智能有改善作用。     

乳杆菌阴道泡腾片与甲硝唑治疗细菌性阴道炎的疗效比较

目的观察乳杆菌阴道泡腾片治疗细菌性阴道炎的疗效。方法采用双盲、随机对照的方法,在4家医院的妇产科门诊将232例患者分成试验组(n=116)和对照组(n=116)。试验组用药为乳杆菌阴道泡腾片、对照组用药为甲硝唑阴道泡腾片,阴道放置,每晚1片,疗程7 d。治疗前后分别进行临床症状评分、测阴道分泌物pH、做线索细胞和胺试验检查,进行总有效率评定。结果经2种药物治疗后所有患者临床症状均明显减轻,治疗前后自身比较差异有显著性(P<0.01);80%以上的患者呈现线索细胞转(-)、胺试验转(-),超过一半的患者阴道分泌物pH低于4.5;临床治疗总有效率分别为74.78%和83.33%。2种药物组间比较治疗效果差异无显著性(P>0.05)。结论阴道补充乳杆菌与使用甲硝唑治疗产生了相似的效果,有可能成为新的治疗细菌性阴道炎的方法。     

雌二醇联合乳酸菌阴道胶囊治疗老年性阴道炎的临床效果研究

目的:研究雌二醇联合乳酸菌阴道胶囊治疗老年性阴道炎的临床效果,为临床治疗老年性阴道炎提供参考依据。方法:选择2016年1月~2017年5月在我院进行诊治的老年性阴道炎患者94例,随机分为观察组与对照组,每组各47例。对照组给予阴道放置乳酸菌阴道胶囊治疗,每日睡前放置1粒,连续使用一周;观察组联合采用阴道放置戊酸雌二醇治疗,每日睡前放置1片(0.5 mg),连续使用一周。比较两组的临床治疗效果,检测两组患者治疗前后血清孕酮、雌二醇、促黄体生成激素以及促卵泡生成激素水平,并且于治疗后随访观察1年,观察两组的复发率。结果:治疗后,观察组的有效率为95.74%(45/47),明显高于对照组[82.98%(39/47)](P0.05)。两组治疗前后的血清孕酮、雌二醇、促黄体生成激素以及促卵泡生成激素水平比较差异均无统计学意义(P0.05)。治疗后6个月,观察组的复发率为4.25%(2/47),明显低于对照组[14.89%(7/47)](P0.05);观察组治疗后1年的复发率为8.51%(2/47),明显低于对照组[23.40%(11/47)](P0.05)。结论:雌二醇联合乳酸菌阴道胶囊治疗老年性阴道炎的临床效果明显优于单纯使用乳酸菌阴道胶囊治疗,且不会对机体内的激素水平造成影响,并可有效降低其复发率。     

阴道用乳杆菌活菌胶囊联合六味地黄汤治疗老年性阴道炎的临床效果和对血清性激素水平的影响

目的:研究阴道用乳杆菌活菌胶囊联合六味地黄汤治疗老年性阴道炎的临床效果和对血清激素水平的影响。方法:选择2015年1月~2016年12月在我院进行诊治的老年性阴道炎患者90例,随机分为两组。对照组采用阴道用乳杆菌活菌胶囊治疗,观察组联合采用六味地黄汤治疗。治疗一个月后,观察两组的临床治疗效果,检测两组患者治疗前后血清孕酮、雌二醇、促黄体生成激素以及促卵泡生成激素水平;并且随访1年,观察两组的复发情况。结果:治疗后,观察组的有效率为91.11%(41/45),明显高于对照组[71.11%(32/45)](P0.05)。两组治疗前后的血清孕酮、雌二醇、促黄体生成激素以及促卵泡生成激素水平与治疗前相比差异均无明显差异(P0.05)。两组治疗期间均未出现明显的药物不良反应,观察组治疗后6个月、1年的复发率分别为4.44%(2/45)、11.11%(5/45),均明显低于对照组[17.77%(8/45)、24.44%(11/45)](P0.05)。结论:阴道用乳杆菌活菌胶囊联合六味地黄汤可以有效提高老年性阴道炎的临床疗效,且不会影响机体的血清性激素水平丙可以有效降低其复发率。     

Experimental rat vaginal infection with Candida parapsilosis

The experimental vaginopathic potential of Candida parapsilosis was determined in ovariectomized rats maintained under pseudoestrus by estrogen administrations. Of the 3 strains of C. parapsilosis tested, that isolated from the vagina of a woman affected by vulvovaginal candidosis gave a prolonged and sustained experimental vaginitis, not different in extent and duration from that caused by a vaginal isolate of C. albicans from a vaginitis patient. The other two isolates of C. parapsilosis (one from the vagina of an asymptomatic subject and another from soil) were unable to infect rat vagina. Microscopic observations of PAS-stained vaginal smears from rats infected with the vaginopathic isolate of C. parapsilosis showed pronounced adherence of yeasts to exfoliated cells. In addition, this isolate of C. parapsilosis produced an elevated quantity of acid proteinase in vitro.     

抗生素对老年前期及老年患者所致肠菌群紊乱的探讨

本文对23例联合用广谱抗生素的老年前期及老年患者发生腹泻后,进行了肠菌群分析,部分做了难辨梭菌的培养。结果表明,全部被检患者应用广谱抗生素后都发生腹泻,应用抗生素种类繁多,其中以氨苄加庆大或先锋加庆大最多。取患者新鲜便作肠菌群分析,6例曾进行纤维结肠镜检查,其中2例肠粘膜有小片状伪膜附着。在使用大量、多种抗生素后,最短在半天内,大多在2周内即发生腹泻,菌群中肠杆菌、拟杆菌、双歧杆菌、乳杆菌,肠球菌、葡萄球菌、酵母菌、小梭菌及真杆菌有显著的差异,均明显低于正常,6/15例难辨梭菌为阳性,检出率40％。治疗先停用抗生素加强支持疗法或用健康人粪便滤液灌肠,15例停止腹泻,2例使用万古霉素才停止。