Intracellular Clusterin Interacts with Brain Isoforms of the Bridging Integrator 1 and with the Microtubule-Associated Protein Tau in Alzheimer's Disease

Sporadic or late-onset Alzheimer''s disease (AD) is expected to affect 50% of individuals reaching 85 years of age. The most significant genetic risk factor for late-onset AD is the e4 allele of APOE gene encoding apolipoprotein E, a lipid carrier shown to modulate brain amyloid burden. Recent genome-wide association studies have uncovered additional single nucleotide polymorphisms (SNPs) linked to AD susceptibility, including those in the CLU and BIN1 genes encoding for clusterin (CLU) and the bridging integrator 1 (BIN1) proteins, respectively. Because CLU has been implicated in brain amyloid-β (Aβ) clearance in mouse models of amyloid deposition, we sought to investigate whether an AD-linked SNP in the CLU gene altered Aβ42 biomarker levels in the cerebrospinal fluid (CSF). Instead, we found that the CLU rs11136000 SNP modified CSF levels of the microtubule-associated protein Tau in AD patients. We also found that an intracellular form of CLU (iCLU) was upregulated in the brain of Tau overexpressing Tg4510 mice, but not in Tg2576 amyloid mouse model. By overexpressing iCLU and Tau in cell culture systems we discovered that iCLU was a Tau-interacting protein and that iCLU associated with brain-specific isoforms of BIN1, also recently identified as a Tau-binding protein. Through expression analysis of CLU and BIN1 variants, we found that CLU and BIN1 interacted via their coiled-coil motifs. In co-immunoprecipitation studies using human brain tissue, we showed that iCLU and the major BIN1 isoform expressed in neurons were associated with modified Tau species found in AD. Finally, we showed that expression of certain coding CLU variants linked to AD risk led to increased levels of iCLU. Together, our findings suggest that iCLU and BIN1 interaction might impact Tau function in neurons and uncover potential new mechanisms underlying the etiology of Tau pathology in AD.     

个体化低剂量CT 尿路造影在诊断输尿管结石中的应用

目的:评价低剂量的个体化在输尿管结石疾病中的应用价值。方法:收集160例疑有输尿管结石的病例,随机分为常规组和低剂量组,其中低剂量组分3组,每组患者按体重指数(BMI)分层,常规组给予160 mAs管电流进行扫描,低剂量组分别给予120mAs、100 mAs、80 mAs管电流进行扫描。常规剂量组与低剂量各亚组进行剂量及图像评估及真实性和收益评价进行比较。结果:在其它扫描参数默认设置条件下,将管电流由常规160mAs,降至80-120 mAs时,辐射剂量均有不同程度降低,差异有统计学意义(P<0.01),肾盂、输尿管、膀胱显影强度无明显差异(P>0.05),而图像质量无明显下降,不影响诊断。同时按BMI分类各组内分层间辐射剂量、显影强度及图像质量间均无显著差异(P>0.05)。结论:个体化低剂量CTU,既可以减少患者辐射剂量,对待病人个体化、人性化,又不影响影像诊断,是一项有价值的检查方法。     

Alzheimer's Disease

Peptide aldehyde inhibitors of the chymotrypsin-like activity of the proteasome (CLIP) such as N-acetyl-Leu-Leu-Nle-H (or ALLN) have been shown previously to inhibit the secretion of beta-amyloid peptide (A beta) from cells. To evaluate more fully the role of the proteasome in this process, we have tested the effects on A beta formation of a much wider range of peptide-based inhibitors of CLIP than published previously. The inhibitors tested included several peptide boronates, some of which proved to be the most potent peptide-based inhibitors of beta-amyloid production reported so far. We found that the ability of the peptide aldehyde and boronate inhibitors to suppress A beta formation from cells correlated extremely well with their potency as CLIP inhibitors. Thus, we conclude that the proteasome may be involved either directly or indirectly in A beta formation.     

GM抗原检测对血液病患者侵袭性曲霉病的诊断价值

目的:探讨血清半乳甘露聚糖(GM)抗原检测对于血液病患者侵袭性曲霉病(invasive aspergillosis,IA)的早期诊断和疗效评价的临床意义。方法:选取137例具有侵袭性真菌病IFD高危因素患者的468份血清标本,进行GM试验,检测抗真菌治疗前后GM抗原水平的变化,同时收集患者的临床资料,进行统计学分析,并评价GM检测对于血液病患者IA的诊断价值。结果:以GM检测单次I≥1.0作为阳性界值时,本试验的敏感性、特异性、阳性预测值和阴性预测值分别为90.91%,95.65%95.24%和91.67%,与试剂盒提供的血清GM试验结果的单次I≥1.5的阳性界值相比敏感性明显提高,而特异性无明显降低,因此能够有效区分临床诊断和拟诊两个IA级别。在其他实验室检测和影像学检查的基础上加入GM试验后,IA临床诊断组的人数明显增加。诊断级别与I值总体均数的分布具有相关性,回顾性确诊IA组、回顾性可疑IA组、回顾性排除IA组的I值呈现明显的由高到低的群落分布,且三个诊断级别的I值分布范围的差异有统计学意义。根据阳性界值标准I≥1.0,GM试验阳性早于痰培养阳性平均7.73±8.71 d,也早于CT影像学证据平均6.89±8.02 d。基于GM值阳性时的抢先抗曲霉治疗组的有效率明显提高(P=0.039)。结论:血清GM抗原检测是早期诊断IA的一种有效方法,将单次I≥1.0作为阳性界值具有较好的敏感性和特异性,在阳性检出率和阳性检出时间方面较主要影像学表现和微生物学证据具有一定优势。在高危血液病伴粒细胞缺乏患者中根据GM试验阳性进行抢先抗曲霉治疗,可提高治疗有效率,监测血清GM浓度的动态变化具有评价疗效的重要价值。该研究成果对临床侵袭性曲霉病的诊断和治疗具有一定指导意义。     

平山病的过屈位MRI 表现及其临床价值

目的：探讨平山病的过屈位颈椎MRI特征性影像学表现及其临床诊断价值。方法：总结分析经临床证实的5 例平山病患者 的临床及MRI资料,并结合相关文献报道进行回顾性分析。所有患者均行常规生化检查,脑脊液检查,肌电图检查及肌肉活检。结 果：5 例均为青少年男性,呈单侧上肢远端无力伴萎缩,其中1 例患者累及另一侧,尺侧肌萎缩明显,上肢呈斜坡样改变,均无感觉 障碍和锥体束征;肌电图检查显示神经源性改变,提示受损节段多在下颈髓前角细胞。屈颈MRI检查均可见下颈髓前移、硬脊膜 外间隙增宽,可见迂曲条状血管流空影。结论：平山病的过屈位MRI表现具有一定的特征性,对平山病的诊断具有重要价值。     

平山病的过屈位MRI表现及其临床价值

目的：探讨平山病的过屈位颈椎MRI特征性影像学表现及其临床诊断价值。方法：总结分析经临床证实的5例平山病患者的临床及MRI资料,并结合相关文献报道进行回顾性分析。所有患者均行常规生化检查,脑脊液检查,肌电图检查及肌肉活检。结果：5例均为青少年男性,呈单侧上肢远端无力伴萎缩,其中1例患者累及另一侧,尺侧肌萎缩明显,上肢呈斜坡样改变,均无感觉障碍和锥体束征;肌电图检查显示神经源性改变,提示受损节段多在下颈髓前角细胞。屈颈MRI检查均可见下颈髓前移、硬脊膜外间隙增宽,可见迂曲条状血管流空影。结论：平山病的过屈位MRI表现具有一定的特征性,对平山病的诊断具有重要价值。     

阴道镜配合病理活检应用于宫颈疾病的诊断价值

目的评价电子阴道镜及宫颈病理活检对宫颈疾病的诊断价值。方法收集我院妇科门诊2003年至2006年宫颈疾病患者行阴道镜检查病行宫颈活检的病理结果进行对照分析。结果电子阴道镜检查后行宫颈活检1060例,病理结果显示:宫颈癌16例,宫颈上皮内瘤样变342例,宫颈炎性病变702例,阴道镜诊断宫颈上皮内瘤样变及宫颈癌的符合率分别为:93.44%和93.75%。结论阴道镜检查配合病理活检诊断宫颈疾病结果及时可靠,尤其对宫颈上皮内瘤样变的早诊断及降低宫颈癌的发生率有重要价值。     

血浆HOTAIR在冠状动脉粥样硬化性心脏病的表达及诊断价值

目的:检测血浆HOX转录反义RNA(HOTAIR)表达水平,并初步探讨血浆HOTAIR作为冠状动脉粥样硬化性心脏病(CAD)标志物的诊断价值。方法:CAD患者和非CAD患者分别作为本研究的疾病组和对照组,血标本来自重庆大坪医院心内科介入室(2013年1月-9月)。运用实时荧光定量聚合酶链反应(q RT-PCR)分别检测疾病组和对照组各100例血浆HOTAIR水平,同时对上述血浆HOTAIR的表达值绘制受试者工作特征(ROC)曲线,并计算ROC曲线下面积(AUC)。结果:与对照组(0.25±0.10)相比,HOTAIR在CAD患者血浆(0.80±0.30)中表达显著升高(P0.05);ROC曲线分析表明,AUC为0.776,Cut-off值为0.55时,诊断CAD的灵敏度为75%,特异度为80%。结论:冠状动脉粥样硬化性心脏病患者血浆HOTAIR水平升高,血浆HOTAIR可作为诊断冠状动脉粥样硬化性心脏病的独立生物标志物。     

The Diagnostic Value of Treadmill Exercise Test Parameters for Coronary Artery Disease

The aim of this study was to determine the diagnostic value of treadmill exercise test (TET) in patients with coronary heart disease (CHD) by comparing the diagnostic conclusions with coronary angiography (CAG). Patients (445) with CHD and suspected CHD underwent TET and CAG, and the corresponding diagnostic conclusions were compared. (1) Out of the 200 cases that had the positive result with TET, 150 cases had been diagnosed CHD by means of CAG; Out of the 245 cases that had the negative result during TET, only 39 cases had been diagnosed CHD by means of CAG. The sensitivity, specificity, positive predictive value, negative predictive value, the false positive incidence, the false negative incidence, and agreement rate in diagnosis of CHD by TET were 79.36, 80.40, 75.00, 84.08, 25.00, 15.92, and 80.00 %, respectively. The patients with multi-vessel disease had a higher positive rate of TET as compared with those with single-vessel disease (P < 0.05). (2) The parameters for 189 cases positive CAG (patients diagnosed CHD by CAG) and 256 cases negative CAG (the control group), including the general exercise time, peak heart rate, and the beginning time of ST depression, were lower than that of control group (P < 0.05). However, the extent of ST depression and duration of ST depression were higher in these patients than in the control group (P < 0.05). (3) 189 cases positive CAG, include 87 cases of single coronary artery and 102 cases of binary or more coronary arteries (the control group). The parameters, including the general exercise time, peak heart rate, and the beginning time of ST depression, were lower than the control group (P < 0.05). However, the extent of ST depression and duration of ST depression were higher in these patients than the control group (P < 0.05). The TET is valuable for noninvasive diagnosis of CHD, especially for patients with multi-vessel disease.     

Plasma protein glycation in Alzheimer's disease

Recent studies have suggested that formation of advanced glycation end-products (AGEs) in some brain proteins could be associated with Alzheimer's disease.These AGEs can be produced by various sugars (hexose, pentose, glyceraldehyde and oxidative products of vitamin C). In this study, we quantified plasma protein glycation specifically derived from glucose in patients with Alzheimer's disease with different grades of cognitive disorders.Two groups of Alzheimer patients were studied: a group with moderate Alzheimer's disease (n=6, 9相似文献   

CD33 in Alzheimer's Disease

The amyloid-beta peptide (Aβ) cascade hypothesis posits that Aβ accumulation is the fundamental initiator of Alzheimer's disease (AD), and mounting evidence suggests that impaired Aβ clearance rather than its overproduction is the major pathogenic event for AD. Recent genetic studies have identified cluster of differentiation 33 (CD33) as a strong genetic locus linked to AD. As a type I transmembrane protein, CD33 belongs to the sialic acid-binding immunoglobulin-like lectins, mediating the cell–cell interaction and inhibiting normal functions of immune cells. In the brain, CD33 is mainly expressed on microglial cells. The level of CD33 was found to be increased in the AD brain, which positively correlated with amyloid plaque burden and disease severity. More importantly, CD33 led to the impairment of microglia-mediated clearance of Aβ, which resulted in the formation of amyloid plaques in the brain. In this article, we review the recent epidemiological findings of CD33 that related with AD and discuss the levels and pathogenic roles of CD33 in this disease. Based on the contributing effects of CD33 in AD pathogenesis, targeting CD33 may provide new opportunities for AD therapeutic strategies.     

Tau Aggregation in Alzheimer's Disease

The crucial role of the neuronal Tau protein in microtubule stabilization and axonal transport suggests that too little or too much Tau might lead to neuronal dysfunction. The presence of a hyper-phosphorylated but non-aggregated molecule as a toxic species that might sequester normal Tau is discussed. We present recent in vitro results that might allow to dissect the role of individual phosphorylation sites on its structure and function. We also discuss in this review the role of phosphorylation for the aggregation of the neuronal Tau protein, and compare it to the aggregation induced by external poly-anions.     

Diagnostic approaches to Alzheimer's disease

The importance of obtaining an accurate and early diagnosis for Alzheimer's disease is now becoming recognized. Nonpharmacological as well as pharmacological therapies can be best initiated once a diagnosis is obtained. Biochemical markers to identify Alzheimer's disease have been sought for many years, with many candidates proposed. Recently criteria were established to evaluate putative diagnostic tests. Several biomarkers now show utility in identifying those with Alzheimer's disease. The ApoE e4 allele, while a risk factor rather than a deterministic gene, in the context of an individual with suspicion of AD has a positive predictive value of 94-98% and may come to have utility in predicting response to certain classes of pharmacological agents. Independent groups have shown that the markers in cerebrospinal fluid tau and Ab42 are, respectively, elevated and reduced in patients with AD versus other patient groups and that the lumbar puncture itself is usually well tolerated. For early-onset AD, sequencing presenilin 1 has come into use and the positive frequency is similar to that found in other genetic-based laboratory tests.     

Olfactory Functions in Parkinson's Disease and Alzheimer's Disease

The aim of this investigation was to compare olfactory functionsof patients suffering from Parkinson's disease (PD) and Alzheimer'sdisease (AD). Olfactory threshold, odor identification abilityand odor memory performance were assessed in 21 non-dementedPD patients and in 22 AD patients. Both patient groups wereimpaired in relation to an age-matched control group for themeasure of odor identification. AD patients showed a higherolfactory threshold and poorer odor memory performance. ChemSenses 22: 105–110, 1997.