Sex- and APOE-specific genetic risk factors for late-onset Alzheimer's disease: Evidence from gene–gene interaction of longevity-related loci

Advanced age is the largest risk factor for late-onset Alzheimer's disease (LOAD), a disease in which susceptibility correlates to almost all hallmarks of aging. Shared genetic signatures between LOAD and longevity were frequently hypothesized, likely characterized by distinctive epistatic and pleiotropic interactions. Here, we applied a multidimensional reduction approach to detect gene–gene interactions affecting LOAD in a large dataset of genomic variants harbored by genes in the insulin/IGF1 signaling, DNA repair, and oxidative stress pathways, previously investigated in human longevity. The dataset was generated from a collection of publicly available Genome Wide Association Studies, comprising a total of 2,469 gene variants genotyped in 20,766 subjects of Northwestern European ancestry (11,038 LOAD cases and 9,728 controls). The stratified analysis according to APOE*4 status and sex corroborated evidence that pathways leading to longevity also contribute to LOAD. Among the significantly interacting genes, PTPN1, TXNRD1, and IGF1R were already found enriched in gene–gene interactions affecting survival to old age. Furthermore, interacting variants associated with LOAD in a sex- and APOE-specific way. Indeed, while in APOE*4 female carriers we found several inter-pathway interactions, no significant epistasis was found in APOE*4 negative females; conversely, in males, significant intra- and inter-pathways epistasis emerged according to APOE*4 status. These findings suggest that interactions of risk factors may drive different trajectories of cognitive aging. Beyond helping to disentangle the genetic architecture of LOAD, such knowledge may improve precision in predicting the risk of dementia and enable effective sex- and APOE-stratified preventive and therapeutic interventions for LOAD.     

呼吸机相关性肺炎患者血清NAMPT、YKL-40、sTREM-1水平与病情程度及预后的关系研究

摘要 目的：研究呼吸机相关性肺炎（VAP）患者血清烟酰胺磷酸核糖转移酶（NAMPT）、壳多糖酶3样蛋白1（YKL-40）、可溶性髓系细胞触发受体-1（sTREM-1）水平与病情程度及预后的关系。方法：选取我院2019年2月～2021年2月收治的120例VAP患者作为研究对象,将其按照病情程度分成低危组40例、中危组45例以及高危组35例,另取同期健康体检人员50例作为对照组,检测并比较各组血清NAMPT、YKL-40、sTREM-1水平。此外,将VAP患者按照28 d生存情况分成死亡组和生存组,比较两组各项基本资料、治疗情况以及血清NAMPT、YKL-40、sTREM-1水平,采用多因素Logistic回归分析VAP患者预后的影响因素。结果：VAP患者的血清NAMPT、YKL-40、sTREM-1水平均高于对照组体检人员,且VAP患者中上述三项血清指标水平随着病情程度的加重而升高（P＜0.05）。死亡组患者血清NAMPT、YKL-40、sTREM-1水平均高于生存组患者（P＜0.05）。单因素分析结果显示：年龄、合并糖尿病、体质量指数（BMI）、机械通气时间、预防性使用抗生素以及气管切开均与VAP患者预后有关（P＜0.05）。多因素Logistic回归分析结果显示：年龄≥65岁、机械通气时间较长、未预防性使用抗生素、气管切开以及血清NAMPT、YKL-40、sTREM-1水平异常升高均是VAP患者预后的不利影响因素（均OR＞1,P＜0.05）。结论：血清NAMPT、YKL-40、sTREM-1水平与VAP患者的病情程度及预后密切相关,VAP患者的预后受到年龄、机械通气时间、抗生素使用、气管切开以及血清NAMPT、YKL-40、sTREM-1水平等因素影响。     

脓毒症患儿高营养风险的影响因素及其对免疫功能、微量元素和疾病转归的影响

摘要 目的：研究脓毒症患儿高营养风险的影响因素及其对免疫功能、微量元素和疾病转归的影响。方法：选取2019年1月-2021年12月我院收治的168例脓毒症患儿,采用营养状况和生长风险筛查工具（STRONGkids）筛查其营养风险,根据评分结果将营养风险患儿分为中低营养风险组与高营养风险组。比较两组临床资料,采用Logistic回归模型分析高营养风险的影响因素;比较中低营养风险组与高营养风险组免疫功能指标（CD4⁺、CD8⁺、CD4⁺/CD8⁺）,微量元素[铜（Cu）、铁（Fe）、锌（Zn）]含量及疾病转归情况。结果：经STRONGkids营养风险筛查结果显示,151例脓毒症患儿存在营养风险,营养风险发生率为89.88%,其中存在中低营养风险110例（中低营养风险组）和高营养风险41例（高营养风险组）。高营养风险组急性生理与慢性健康状况评分系统Ⅱ（APACHE Ⅱ）评分、乳酸、降钙素原水平及严重脓毒症占比高于中低营养风险组,白蛋白水平低于中低营养风险组（P＜0.05）。多因素Logistic回归分析显示,APACHE Ⅱ评分升高、严重脓毒症是脓毒症患儿发生高营养风险的危险因素（P＜0.05）,白蛋白升高是脓毒症患儿发生高营养风险的保护因素（P＜0.05）。高营养风险组CD4⁺、CD4⁺/CD8⁺低于中低营养风险组,CD8⁺高于中低营养风险组（P＜0.05）。两组Cu含量差异无统计学意义（P＞0.05）,高营养风险组Fe、Zn含量低于中低营养风险组（P＜0.05）。中低营养风险组好转74例、未愈32例、死亡4例,高营养风险组好转19例、未愈15例、死亡7例,高营养风险组疾病转归良好率低于中低营养风险组（P＜0.05）。结论：脓毒症患儿高营养风险发生率较高,严重脓毒症、APACHE Ⅱ评分、白蛋白水平为高营养风险的影响因素,且高营养风险导致患儿免疫功能下降,体内Fe、Zn含量降低,疾病转归情况较差,建议早期实施营养干预,改善患儿的预后。     

血管内介入治疗颅内动脉瘤合并缺血性脑血管疾病的临床研究

摘要 目的：探讨血管内介入治疗颅内动脉瘤（IA）合并缺血性脑血管疾病的安全性和有效性。方法：回顾性分析了2018年1月至2020年12月使用血管内介入治疗IA合并缺血性脑血管疾病的32例临床资料。结果：32例中共发现了35枚IA,37处狭窄。IA平均大小为（5.17±3.12）mm,其中位于颈内动脉有26枚（74%）,位于椎基底动脉有9枚（26%）,7例（22%）患者术前检查发现存在两枚IA。37处狭窄中,位于椎基底动脉有9处（24%）,位于颅外段有8处（22%）,其余20处狭窄（54%）均位于颈内动脉,术前平均狭窄率为75.7%。所有病例手术过程顺利,术后IA中达到完全栓塞有31枚（89%）,4枚残留颈部（11%）。37处狭窄中,术后平均狭窄率为8.8%,所有患者术后造影脑血管远端均通畅。治疗期间1例支架内再狭窄,1例脑血管痉挛,出院时所有病例改良Rankin评分量表（mRS）均小于2分。32位患者均得到术后全脑血管造影（DSA）随访,随访时间为6到18个月（平均为8.8个月）,随访期间1例出现支架内再狭窄。结论：血管内介入治疗IA合并缺血性脑血管疾病是安全有效的,值得临床借鉴应用。     

Ion channel hypothesis for Alzheimer amyloid peptide neurotoxicity

Summary 1. Alzheimer's disease (AD) is a chronic dementia and neurodegenerative disorder affecting the oldest portions of the population. Brains of AD patients accumulate large amount of the AP peptide in amyloid plaques.2. The AP[1–40] peptide is derived by proteolytic processing from a much larger amyloid precursor protein (APP), and has been circumstantially identified as the toxic principle causing cell damage in the disease.4. The AP[1–40] peptide is able to form quite characteristic calcium channels in planar lipid bilayers. These channels have conductances in the nS range, and can dissipate ion gradients quickly. The peptide can also cause equivalent cation conductances in cells.5. We suggest that amyloid channel blocking agents might be therapeutically useful in Alzheimer's Disease, and have constructed molecular models of the channels to aid in the design of such compounds.     

Identification of RAPD markers linked to the Tm-2 locus in tomato

Tm-2 and Tm-2a are genes conferring resistance to tomato mosaic virus in Lycopersicon esculentum. They are allelic and originated from different lines of L. peruvianum, a wild relative of tomato. In this study, random amplified polymorphic DNA (RAPD) markers linked to these genes were screened in nearly isogenic lines (NILs). To detect RAPDs differentiating NILs, 220 different 10-base oligonucleotide primers were examined by the polymerase chain reaction (PCR), and 43 of them generated 53 consistent polymorphic fragments among the NILs. Out of these 53 fragments, 13 were arbitrarily chosen and examined in respect of whether they were linked to the netted virescent (nv) gene, since nv is tightly linked to the Tm-2 locus and its phenotype is more easily distinguishable. As a result, all 13 markers were shown to be linked to nv, and hence to the Tm-2 locus. Among them, two fragments specific to the NIL carrying Tm-2 three specific to the NIL carrying Tm-2a, and four specific to both of these NILs were closely linked to nv.     

Pathogen recognition and signal transduction by the Pto kinase

In tomato, the disease resistance genePto confers resistance to bacterial speck disease by recognizing the expression of a corresponding avirulence gene,avrPto, in the pathogenPseudomonas syringae pv.tomato (Martinet al. 1993). Similar “gene-for-gene” interactions occur in many plant-pathogen associations (Flor 1971). Such recognition events often lead to the activation in the plant of a variety of defense responses including a rapid induction of localized necrosis at the site of infection (the hypersensitive response, HR), increased expression of defense-related genes, production of antimicrobial compounds, lignin formation, and the oxidative burst (Lambet al. 1989, Mehdy 1994). As a result, the pathogen is contained at the infection site and its growth is inhibited.Pto encodes a serine/threonine protein kinase and belongs to a clustered multigene family. Another member of thePto family calledFen confers no known disease resistance, but mediates a hypersensitive-like reaction in the plant to the insecticide fenthion (Martinet al. 1994). We are interested in a number of fundamental questions concerning the Pto signaling pathways. What is the molecular basis of thePto-avrPto gene-for-gene interaction? What are the components involved in thePto-mediated signal transduction chain? How does thePto kinase activate complex defense responses? This paper summarizes our recent progress towards understanding these questions.     

Growth arrest of Schizosaccharomyces pombe following overexpression of mouse type 1 protein phosphatases

The rice disease resistance gene Xa21, which encodes a receptor-like kinase, is a member of a multigene family. Based on comparisons of genomic␣sequences of seven family members, seventeen transposon-like elements were identified in the 5′ and 3′ flanking regions and introns of these genes. Sequence characterization revealed that these elements are diverse, showing similarity to maize Ds, CACTA and miniature inverted repeat-like elements, as well as novel elements. Only two elements were located in presumed coding regions, indicating that integration of transposable elements at the Xa21 disease resistance locus occurred preferentially in noncoding regions. Received: 17 October 1997 / Accepted: 3 February 1998     

Increase in a heat-shock protein from blood cells in response of nestling house martins (Delichon urbica) to parasitism: an experimental approach

Heat-shock proteins (HSPs) are synthesized by animals and plants in response to various stressors. The level of the HSP60 stress protein was measured from the cell fraction of peripheral blood obtained from nestling house martins (Delichon urbica) to test whether ectoparasitism increased the concentration of stress protein. We assessed HSP from nestlings raised in nests previously treated with an insecticide or infested with 50 martin bugs (Oeciacus hirundinis). In addition, haematozoa infections were checked in blood smears. Nestlings from parasite-infested nests, or nestlings infected with trypanosomes, had increased levels of HSP in their blood cells. Nestling growth as determined from wing length was negatively related to HSP60 levels and within-brood variation in wing length increased with increasing levels of the stress protein independently of treatment and infection by trypanosomes. These results suggest HSPs may play a role in host-parasite interactions, and that they can be used reliably for measuring physiological responses to parasites. Received: 4 February 1998 / Accepted: 4 May 1998     

Examination of the roles of selenium in the Kaschin-Beck Disease

The Kaschin-Beck Disease, an endemic disease in China, occurs in low-selenium areas. Using human embryonic cartilage cell as a system, the effect of selenite and another etiological factors, such as, organic matters in water, and grain from disease regions, were studied. It was shown that Se(IV), as well as superoxide dismutase, could prevent the cells from damage by organic matters, and increase the activity of GSHpx and decrease the production of lipid peroxide. A model test of adrenalin autooxidation was carried out, and it was found that the oxy-radical can be eliminated by Se(IV). Thus, it was assumed, that selenium was a protective factor and free radical scavenger for Kaschin-Beck Disease.