Design and redesign journey of a drug for transthyretin amyloidosis

The misfolding and subsequent aggregation of proteins into amyloid fibrils underlie the onset of a variety of human disorders collectively known as amyloidosis.Transthyretin(TTR)is one of the>30 amyloidogenic proteins identified to date and is associated with a group of highly debilitating and life-threatening disorders called TTR amyloidosis(ATTR).ATTR comprises senile systemic amyloidosis,which is linked to wild-type(WT)TTR aggregation,and hereditary ATTR,a dominantly inherited disorder caused by the deposition of one of over 130 TTR genetic variants.Senile systemic amyloidosis is a prevalent age-related amyloidosis,affecting up to 25%of the population over 80 years of age,and is characterized by the build-up of TTR fibrils in the myocardium.Regarding hereditary ATTR,the clinical presentation is highly heterogeneous,primarily affecting the peripheral nervous system(familial amyloid polyneuropathy-FAP)or the heart(familial amyloid cardiomyopathy).In rare cases,aggregation develops in the central nervous system,giving rise to a phenotype known as familial leptomeningeal amyloidosis(Carroll et al.,2022).

Insight into endoplasmic reticulum-mitochondria contacts in human amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS) is a fastprogressing fatal neurodegenerative disease and the most common form of motor neuron disease.There is currently no cure and approximately 90% of cases are sporadic.ALS shares genetic causes,clinical and neuropathological features with frontotemporal dementia,the second most common form of presenile dementia.ALS and frontotemporal dementia are therefore considered a disease spectrum(Abramzon et al.,2020).

Assessing the current situation and the influencing factors affecting perceived stigma among older patients after leukemia diagnosis

BACKGROUND Psychological problems are becoming increasingly prominent among older patients with leukemia,with patients potentially facing stigmatization after diagnosis.However,there is limited research on the stigma experienced by these patients and the factors that may contribute to it.AIM To investigate the stigma faced by older patients after being diagnosed with leukemia and to analyze the potential influencing factors.METHODS A retrospective analysis was conducted using clinical data obtained from questionnaire surveys,interviews,and the medical records of older patients with leukemia admitted to the Hengyang Medical School from June 2020 to June 2023.The data obtained included participants’basic demographic information,medical history,leukemia type,family history of leukemia,average monthly family income,pension,and tendency to conceal illness.The Chinese versions of the Social Impact Scale(SIS),Perceived Social Support Scale(PSSS),Self-Rating Anxiety Scale(SAS),and Self-Rating Depression Scale(SDS)were used to assess indicators related to stigma,social support,and mental health status.We used Pearson’s correlation coefficient to analyze the strength and direction of the relationship between the scores of each scale,and regression analysis to explore the factors related to the stigma of older patients with leukemia after diagnosis.RESULTS Data from 120 patients with leukemia aged 65-80 years were analyzed.The total score on the SIS and PSSS was 43.60±4.07 and 37.06±2.87,respectively.The SAS score was 58.35±8.32 and the SDS score was 60.58±5.97.The stigma experienced by older leukemia patients was negatively correlated with social support(r=-0.691,P<0.05)and positively correlated with anxiety and depression(r=0.506,0.382,P<0.05).Age,education level,smoking status,average monthly family income,pension,and tendency to conceal illness were significantly associated with the participants’level of stigma(P<0.05).Age,smoking status,social support,anxiety,and depression were predictive factors of stigmatization among older leukemia patients after diagnosis(all P<0.05),with a coefficient of determination(R2)of 0.644 and an adjusted R2 of 0.607.CONCLUSION Older patients commonly experience stigmatization after being diagnosed with leukemia.Factors such as age,smoking status,social support,and psychological well-being may influence older patients’reported experience of stigma.

PROGRESS AND PERSPECTIVE OF ACUPUNCTURE AND MOXIBUSTION IN DELAYING SENILITY

In this paper, we reviewed the developing history of delaying senility of acupunctureand moxibustion, summarized 41 reports about the effects of acupuncture and moxibustion on elderly,normal subject and the "deficiency syndrome" model animal, and expounded the rnechanisms in the aspects of immunology, endocrinology and biology. In addition, we also discussed the influence fac-tors and the developing trends of delaying senility of acupuncture and moxibustion in corning years.

老年性白内障患者晶体及血清硒含量的变化

迄今为止,有关硒自内障的报告很多,但它与老年性白内障的关系尚不明确。一般认为氧化损伤是白内障形成的主要原因。在正常代谢或某些应激状态下,晶体内会产生过氧化氢和脂质过氧化物并且主要靠谷胱甘肽过氧化物酶来消除这些过氧化物。硒是人体所必需的微量元素,它参与构成谷胱甘肽过氧化物酶的活性中心。一般认为,晶体中谷胱甘肽过氧化物酶的活性与硒含量呈正相关。曾有报道。

Advancing age and heart failure:the Influencing factors of prognosis in patients with acute myocardial infarction

The purpose of this study is to determine whether advancing age andheart failure are independent predictors of increased mortality afrer acutemyocardial infarction(AMI)We reviewed the clinical data of 1068 in-patients(344 senile/724 nonsenile)with AMI.The results showed atypicalpresentations of infarction-related symptoms in the elderly are common,with consequent delay in the diagnosis and treatment The elderly patientshad a high proportion of systemic hypertension(43.9%),non Q wave AM/(36%)and heart failure(35.5%),On the contrast,the proportion of that innonsenile patients were 33%,8Vo and 16.4% respectively.In elderlypatients,several complications:of AMI are more common,asinterventricular septum perforation(2%),cardiogenic shock(19.8%),arthythmia(61.9%).Heart failure was more frequent in patients with leftventricular ejection fraction(LVEF)≤35%,previous heart failure ormyocardial infarction,and anterior location infarction.Those with severecongestive heart failure had a mortality of 33.2% compared with 24.5% forthose with moderate heart failure and 13.51% for those with no heart failurein the first eight weeks.The following factors were associated with anincreased risk of death:older age,longer delay before admission to hospital,no prescription of beta-blaekers and a previous history of infarctionOur data suggested that the prognosis after AMI was directly related toadvaneeing age and the severity of congestive heart failure.Thedevelopment of congestive heart failure was an independent predictor ofdeath.The increasing incidence and mortality were closely related toimpaired myocardial reserve.The present benefits,as pointed out by therecent progress in AMI therapy,must be employed in the treatment of olderinfarcted patients More aggressive management in elderly patients shouldoe evaluated for its potential to reduce mortality.

Rho GTP酶在阿尔茨海默病中的研究进展

阿尔茨海默病（Alzheimer′s disease,AD）是最常见的进行性神经系统退行性疾病,以渐进性的认知和记忆的障碍和情志的异常改变为主要临床特征。AD的标志性病理改变为β-淀粉样蛋白（β-amyloid protein,Aβ）沉积形成的老年斑（senile plaques）和由磷酸化的不溶性tau蛋白组成的神经原纤维缠结（neurofibrillary tangles,NFTs）。

阿尔茨海默病的临床诊断流程

随着全球人口老龄化进程的加速,阿尔茨海默病（Alzheimer′s type senile dementia,AD）的发病率也与年俱增。在发达国家,继心脏病、恶性肿瘤和脑卒中后,AD已成为现代社会死亡原因的第四大杀手和严重公共卫生问题。AD是指在意识清醒状态下,出现的获得性、全面进展性、不可逆性、慢性中枢神经系统（CNS）变性的多项认知功能（记忆、语言、定向、注意、学习、计算、思维、判断、

Therapeutic effect of Cistanche deserticola on defecation in senile constipation rat model through stem cell factor/C-kit signaling pathway

BACKGROUND Constipation is one of the chronic gastrointestinal functional diseases.It seriously affects the quality of life.Cistanche deserticola(C.deserticola)can treat constipation obviously,but its mechanism has not been clarified.We supposed that mechanism of it improved the intestinal motility by stimulating interstitial Cajal cells(ICC).Activation of the C-kit receptor on the surface of ICC is closely related to ICC function,and the stem cell factor(SCF)/C-kit signaling pathways plays an important role on it.To investigate the mechanism of how C.deserticola treats constipation,this study aimed to establish a constipation model in rats and explore the role of SCF/C-kit signaling pathway in the treatment.AIM To explore the SCF/C-kit signaling pathways in the role of C.deserticola for treatment of constipation by a constipation rat model.METHODS Forty-eight 8-mo-old Sprague–Dawley rats were divided into 4 groups by random weight method:Normal group(n=12),model group(n=12),C.deserticola group(n=12)and blocker group(n=12).The normal group received normal saline by gavage;the model group received loperamide by gavage;the blocker group received loperamide and C.deserticola by gavage,and STI571 was injected by intraperitoneally.During treatment,the weight,fecal granules and fecal quality were recorded every 10 d.On day 20 after model induction,the colon tissues of each group were removed.Hematoxylin and eosin staining was used to observe pathological changes.Expression levels of SCF,C-kit and Aquaporin genes were detected by immunohistochemistry,western blotting,and real-time-quantitative polymerase chain reaction.The colonic epithelial mitochondria and goblet cells were observed by transmission electron microscopy.RESULTS Compared with the normal group,as treatment progressed,the weight of rats in the model and blocker groups decreased significantly,the stool weight decreased,and the stool quality was dry(P<0.05).C.deserticola reversed the decrease in body weight and stool weight and improved stool quality.Histopathological analysis indicated that the colonic mucosal epithelium in the model group was incomplete,and the arrangement of the glands was irregular or damaged.Treatment with C.deserticola improved the integrity and continuity of the epithelial cells and regular arrangement of the glands.The blocking agents inhibited the effects of C.deserticola Immunohistochemistry and real-timequantitative polymerase chain reaction showed that expression of SCF and C-kit protein or genes in the colonic tissue of the model group was decreased(P<0.05),while treatment with C.deserticola increased protein or gene expression(P<0.05).Western blotting showed that expression of aquaporin APQ3 was increased,while the expression of Cx43 decreased in the model group.Treatment with C.deserticola inhibited expression of APQ3 and promoted expression of Cx43.Transmission electron microscopy showed that the mitochondria of the colonic epithelium in the model group were swollen and arranged disorderly,and microvilli were sparse.The condition was better in the C.deserticola group.Mice treated with STI571 blocker confirmed that blocking the SCF/C-kit pathway inhibited the improvement of constipation by C.deserticola.CONCLUSION C.deserticola improved defecation in rats with constipation,and the SCF/C-kit signaling pathway,which is a key link of ICC function,played an important role of the treatment.

Effect of tankyrase 1 on autophagy in the corpus cavernosum smooth muscle cells from ageing rats with erectile dysfunction and its potential mechanism

This study compared tankyrase 1 expression and autophagy quantity between erectile dysfunction （ED） and non-ED rats＇ corpus cavernosum smooth muscle cells （CSMCs）. This study aslo explored the effect and possible mechanism of tankyrase 1 on autophagy and cell proliferation in ageing ED rats＇ CSMCs. The intracavernous pres- sure and mean systemic arterial pressure were measured to investigate erectile function so that eight 24-month-old ED and eight 8-month-old male Wistar rats were choosed respectively. The rat CSMCs were isolated and cultured by enzyme digestion, in which tankyrase 1 expression and autophagy quantity were compared. Tankyrase 1 over-expression was induced with plasmid transfection by Lipofectamine^TM. The effect of tankyrase 1 overexpression on proliferation, autophagy and mTOR pathway in 24-month-old ED rats＇ CSMCs was measured by the cell growth curve in MTT assay, cell cycle analysis in flow cytometry （FCM）, key protein expression in Western blot, autophagy quantity in transmission electron microscopy, monodansylcadaverine staining and GFP-LC3 fluorescence. The primary CSMCs were confirmed by immunofluorescence, and the purity was 99.1% in FCM. Compared with that of 8-month-old rats, tankyrase 1 expression and autophagy quantity significantly decreased in 24-month-old ED rats＇ primary CSMCs （P 〈 0.01）. Tankyrase 1 overexpression significantly increased the growth rate （P 〈 0.05） and increased the S phase of cell cycle （P 〈 0.01）. The autophagosome quantity was remarkably increased （P 〈 0.01）, LC3-Ⅰ/Ⅱ and Beclin 1 were upregulated （P 〈 0.01 and P 〈 0.05）, and p-p70S6K （Thr389） was downregulated in 24-month-old ED rat CSMCs （P 〈 0.05）. In conclusion, Tankyrase 1 and autophagy decrease in the CSMCs from aging rats with ED, and tankyrase 1 may have a positive effect on proliferation by enhancing autophagy and regulating the mTOR signalling pathway.

Use of curcumin in diagnosis,prevention,and treatment of Alzheimer＇s disease

This review summarizes and describes the use of curcumin in diagnosis,prevention,and treatment of Alzheimer＇s disease.For diagnosis of Alzheimer＇s disease,amyloid-β and highly phosphorylated tau protein are the major biomarkers.Curcumin was developed as an early diagnostic probe based on its natural fluorescence and high binding affinity to amyloid-β.Because of its multi-target effects,curcumin has protective and preventive effects on many chronic diseases such as cerebrovascular disease,hypertension,and hyperlipidemia.For prevention and treatment of Alzheimer＇s disease,curcumin has been shown to effectively maintain the normal structure and function of cerebral vessels,mitochondria,and synapses,reduce risk factors for a variety of chronic diseases,and decrease the risk of Alzheimer＇s disease.The effect of curcumin on Alzheimer＇s disease involves multiple signaling pathways：anti-amyloid and metal iron chelating properties,antioxidation and anti-inflammatory activities.Indeed,there is a scientific basis for the rational application of curcumin in prevention and treatment of Alzheimer＇s disease.

Key determinants of misdiagnosis of tracheobronchial tuberculosis among senile patients in contemporary clinical practice:A retrospective analysis

BACKGROUND Tracheobronchial tuberculosis(TBTB)is a common subtype of pulmonary tuberculosis.Concomitant diseases often obscure the diagnosis of senile TBTB.AIM To characterize senile patients with TBTB and to identify the potential causes of misdiagnosis.METHODS One hundred twenty patients with senile TBTB who were admitted to the Anhui Chest hospital between May 2017 and May 2019 were retrospectively analyzed.Patients were classified as diagnosed group(n=58)and misdiagnosed group(n=62).Clinical manifestations,laboratory results,radiographic data,and endoscopic findings were compared between the two groups.RESULTS Patients in the misdiagnosed group were most commonly diagnosed as pulmonary tuberculosis(non-TBTB,29/62,46.8%),general pneumonia(9/62,14.5%),chronic obstructive pulmonary disease(8/62,12.9%),and tracheobronchial carcinoma(7/62,11.3%).The time elapsed between disease onset and confirmation of diagnosis was significantly longer in the misdiagnosed group[median(first quartile,third quartile):6.32(4.94,16.02)mo vs 3.73(2.37,8.52)mo].The misdiagnosed group had lower proportion of patients who underwent bronchoscopy[33.87%(21/62)vs 87.93%(51/58)],chest computed tomography(CT)scan[69.35%(43/62)vs 98.28%(57/58)],and those who showed CT signs of tuberculosis[27.91%(12/62)vs 50%(29/58)]as compared to that in the diagnosed group(P<0.05).There were no significant between-group differences with respect to age,gender,occupation,clinical manifestations,or prevalence of comorbid chronic diseases(P>0.05).CONCLUSION Insufficient or inaccurate radiographic or bronchoscopic assessment was the predominant cause of delayed diagnosis of TBTB.Increased implementation and better interpretation of CT scan and early implementation of bronchoscopy can help reduce misdiagnosis of senile TBTB.

Age-associated changes in amyloid-β and formaldehyde concentrations in cerebrospinal fluid of rhesus monkeys

DEAR EDITOR,Rhesus monkeys(Macaca mulatta)are valuable experimental animals for studies on neurodegenerative diseases due to their evolutionarily close relationship to humans(Zhang et al.,2014).Rhesus monkeys also display similar hallmarks of aging and neurodegeneration as humans,including formation of senile plaques in the brain(Beckman et al.,2019;Paspalas et al.,2018).

Anisometropia magnitude and visual deficits in previously untreated anisometropic amblyopia

AIM:To assess the quantitative association between anisometropia magnitude(AM) and the losses of resolution and contrast sensitivity;and to exemplify how the function of fusion and stereopsis vary with AM in previously untreated anisometropic amblyopia. METHODS:A total of 57 patients with previously untreated anisometropic amblyopia without strabismus(range:8-35 years),were measured refractive error,best corrected visual acuity(BCVA),fusion and stereopsis,and 48 patients have completed contrast sensitivity function test.AM was determined by dioptric vector addition model,and the amblyopia depth was determined by the difference of BCVA in logMAR units between the amblyopic and fellow eyes.RESULTS:AM was significantly correlated with both amblyopia depth(Pearson R=0.728,P【0.001) and the inter-ocular difference of the area under the log contrast sensitivity function(AULCSF)(R=0.505,P【0.001).Depth of amblyopia and the inter-ocular difference of AULCSF was also significantly correlated(R=0.761,P【0.001).The more severity of amblyopia,the poorer levels of contrast sensitivity.Most pure anisometropes with AM was less than 3.0D retain fusion and some stereopsis,but when AM were more than 3.0D,especially for the anisometropes whose AM was more than 6.0D,fusion and stereopsis function were seriously impaired.CONCLUSION:In the patients with previously untreated anisometropic amblyopia,higher degree of anisometropia is significantly associated with deeper amblyopia,worse contrast sensitivity,fusion and stereopsis functions.

Central Venous Catheter-related Thrombosis in Senile Male Patients: New Risk Factors and Predictors

Central venous catheterization（CVC）-related venous thrombosis is a common but serious clinical complication, thus prevention and treatment on this problem should be extensively investigated. In this research, we aimed to investigate the incidence rate of CVC-related venous thrombosis in senile patients and give a further discussion on the related risk factors and predictors. A total of 324 hospitalized senile male patients subjected to CVC were selected. Retrospective investigation and analysis were conducted on age, underlying diseases, clinical medications, catheterization position and side, catheter retention time, and incidence of CVC-related venous thrombosis complications. Basic laboratory test results during catheterization and thrombogenesis were also collected and analyzed. Among the 324 patients, 20 cases（6.17%） of CVC-related venous thrombosis were diagnoseds. The incidence rate of CVC-related venous thrombosis in subclavian vein catheterization was significantly lower than that in femoral vein catheterization（P〈0.01） and that in internal jugular vein catheterization（P〈0.05）. No statistically significant difference was found between femoral vein catheterization and internal jugular vein catheterization（P〉0.05）. Previous venous thrombosis history（P〈0.01）, high lactate dehydrogenase level（P〈0.01）, low high-density lipoprotein（HDL） level（P〈0.05）, and low albumin level（P〈0.05） were found as risk factors or predictors of CVC-related venous thrombosis in senile male patients. Subclavian vein catheterization was the most appropriate choice among senile patients to decrease the incidence of CVC-related venous thrombosis. Previous venous thrombosis history, high lactate dehydrogenase level, low HDL level, and low albumin level were important risk factors in predicting CVC-related venous thrombosis.

Apolipoprotein A1,the neglected relative of Apolipoprotein E and its potential role in Alzheimer’s disease

Lipoproteins are multi-molecule assemblies with the primary function of transportation and processing of lipophilic substances within aqueous bodily fluids(blood,cerebrospinal fluid).Nevertheless,they also exert other physiological functions such as immune regulation.In particular,neurons are both sensitive to uncontrolled responses of the immune system and highly dependent on a controlled and sufficient supply of lipids.For this reason,the role of certain lipoproteins and their protein-component(apolipoproteins,Apo’s)in neurological diseases is perceivable.ApoE,for example,is well-accepted as one of the major risk factors for sporadic Alzheimer’s disease with a protective allele variant(ε2)and a risk-causing allele variant(ε4).ApoA1,the major protein component of high-density lipoproteins,is responsible for transportation of excess cholesterol from peripheral tissues to the liver.The protein is synthesized in the liver and intestine but also can enter the brain via the choroid plexus and thereby might have an impact on brain lipid homeostasis.This review focuses on the role of ApoA1 in Alzheimer’s disease and discusses whether its role within this neurodegenerative disorder is specific or represents a general neuroprotective mechanism.

Mens sana in corpore sano: lifestyle changes modify astrocytes to contain Alzheimer's disease

Alzheimer's disease(AD) is the widespread and the most feared neurodegenerative disorder leading to dementia in the elderly.ADy by eliminating intelligence,diminishes a man to helpless body,places an unbearable strain on patients,families,and fuels socioeconomic healthcare crises around the world.The main histopathological hallmarks of AD are the accumulation of extracellular amyloid depositions known as senile plaques and intracellular neurofibrillary to ngles,together with severe dysfunctional synaptic connectivity and neuronal death leading to brain atrophy.

Mitochondrial proteomic analysis of ecdysterone protection against oxidative damage in human lens epithelial cells

AIM: To investigate the protective effects of the natural medicinal monomer ecdysterone(ECR) with estrogenic activity against oxidative damage in human lens epithelial cells B3(HLE-B3) caused by hydrogen peroxide 21(H2 O2) and to pursue the possible mitochondrial proteomic regularity of the protective effects. · METHODS: HLE-B3 cells were treated with H2O2(300μmol/L),β-estuarial(E2; 10-8mol/L) and H2 O2,ECR(10-6mol/L) and H2 O2,or left untreated. Altered expression of all mitochondrial proteins was analyzed by protein array and surface-enhanced laser desorption ionization time of flight mass spectrometry(SELDI-TOF-MS). The mass/charge(M/Z) ratios of each peak were tested by the Kruskal-Wallis rank sum test,and the protein peak value of the M/Z ratio for each treatment by pair comparison was analyzed with the Nemenyi test. ·RESULTS: H2O2 up-regulated expression of two protein spots(with M/Z of 6 532 and 6 809). When E2 mitigated the oxidative damage,the expression of one protein spot(M/Z 6 532) was down-regulated. In contrast,ECR downregulated both of protein spots(M/Z 6 532 and 6 809). · CONCLUSION: ECR could effectively inhibite H2O2 induced oxidative damage in HLE-B3 cells. The protein spot at M/Z of 6 532 might be the target spot of ECR against oxidative damage induced by H2 O2.

老年痴呆的预防保健与社区服务

老年性痴呆是老年期出现的慢性渐进性精神衰退性疾病，是患者在意识清醒状态下出现的持久的全面的智能衰退。主要表现在记忆力、计算力减退，情感行为障碍，独立生活和工作能力丧失等。近年来，随着老年人口不断增加，据资料统计，我国60岁以上人群的老年性痴呆患病率达0．75％～4．69％，而且其患病率随着年龄的增长而增加。如此多的痴呆老人给家属、照料者、社会都带来了巨大的负担。

Diagnosis related group grouping study of senile cataract patients based on E-CHAID algorithm

AIM： To figure out the contributed factors of the hospitalization expenses of senile cataract patients（HECP） and build up an area-specified senile cataract diagnosis related group（DRG） of Shanghai thereby formulating the reference range of HECP and providing scientific basis for the fair use and supervision of the health care insurance fund.METHODS： The data was collected from the first page of the medical records of 22 097 hospitalized patients from tertiary hospitals in Shanghai from 2010 to 2012 whose major diagnosis were senile cataract. Firstly, we analyzed the influence factors of HECP using univariate and multivariate analysis. DRG grouping was conducted according to the exhaustive Chi-squared automatic interaction detector（E-CHAID） model, using HECP as target variable. Finally we evaluated the grouping results using non-parametric test such as Kruskal-Wallis H test, RIV, CV, etc.RESULTS： The 6 DRGs were established as well as criterion of HECP, using age, sex, type of surgery and whether complications/comorbidities occurred as the key variables of classification node of senile cataract cases.CONCLUSION： The grouping of senile cataract cases based on E-CHAID algorithm is reasonable. And the criterion of HECP based on DRG can provide a feasible way of management in the fair use and supervision of medical insurance fund.