N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory lo...N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.展开更多
Background:There exist few maximal oxygen uptake(VO_(2max))non-exercise-based prediction equations,fewer using machine learning(ML),and none specifically for older adults.Since direct measurement of VO_(2max)is infeas...Background:There exist few maximal oxygen uptake(VO_(2max))non-exercise-based prediction equations,fewer using machine learning(ML),and none specifically for older adults.Since direct measurement of VO_(2max)is infeasible in large epidemiologic cohort studies,we sought to develop,validate,compare,and assess the transportability of several ML VO_(2max)prediction algorithms.Methods:The Baltimore Longitudinal Study of Aging(BLSA)participants with valid VO2_(max)tests were included(n=1080).Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine(SVM)algorithms were trained to predict VO_(2max)values.We developed these algorithms for:(a)the overall BLSA,(b)by sex,(c)using all BLSA variables,and(d)variables common in aging cohorts.Finally,we quantified the associations between measured and predicted VO_(2max)and mortality.Results:The age was 69.0±10.4 years(mean±SD)and the measured VO_(2max)was 21.6±5.9 mL/kg/min.Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine yielded root mean squared errors of 3.4 mL/kg/min,3.6 mL/kg/min,3.4 mL/kg/min,3.6 mL/kg/min,and 3.5 mL/kg/min,respectively.Incremental quartiles of measured VO_(2max)showed an inverse gradient in mortality risk.Predicted VO_(2max)variables yielded similar effect estimates but were not robust to adjustment.Conclusion:Measured VO_(2max)is a strong predictor of mortality.Using ML can improve the accuracy of prediction as compared to simpler approaches but estimates of association with mortality remain sensitive to adjustment.Future studies should seek to reproduce these results so that VO_(2max),an important vital sign,can be more broadly studied as a modifiable target for promoting functional resiliency and healthy aging.展开更多
BACKGROUND Here,we report a case of jejunal diverticulosis from an anatomical and histological view.During the“Gross Anatomy course,”we found multiple jejunal diverticula along a total length of 208 cm of intestine....BACKGROUND Here,we report a case of jejunal diverticulosis from an anatomical and histological view.During the“Gross Anatomy course,”we found multiple jejunal diverticula along a total length of 208 cm of intestine.CASE SUMMARY After opening the intestinal tract,we counted 232 jejunal diverticulum entry points with a diameter of up to 2 cm and observed connections between the diverticula that created shortcuts between two distinct intestinal parts.Interestingly,we observed an extreme longitudinal striation on the intestinal parts hosting diverticula.Thorough vessel preparation utilizing a dissecting microscope confirmed that all investigated arteriae rectae ended in a diverticulum.Histological and immunohistochemical investigations revealed that intestinal villi of diverticula were smaller and less prominent than control tissue and that the stratum longitudinale,as well as the stratum circular,were much thinner in the diverticula compared to control tissue.Neither submucosal nor mesenteric plexus could be detected in the diverticula.However,vasoactive intestinal peptidepositive nerve fibers and villin-positive brush border could only be detected in control tissue.This indicates that jejunal diverticulosis is associated with abnormalities of the smooth muscles and a disorder of innervation.CONCLUSION Jejunal diverticulosis originates from mesenteric vessels,featuring smooth muscle changes,absent innervation,and thinning of tissue layers.展开更多
Background Elevated resting heart rate and hypertension independently increase the risk of mortality. However, their combined ef- fect on mortality in stages of hypertension according to updated clinical guidelines am...Background Elevated resting heart rate and hypertension independently increase the risk of mortality. However, their combined ef- fect on mortality in stages of hypertension according to updated clinical guidelines among dderly population is unclear. Methods We fol- lowed a cohort of 6100 residents （2600 males and 3500 females） of Kangwha County, Korea, ranging from 55 to 99 year-olds as of March 1985, for all-cause and cardiovascular mortality for 20.8 years until December 31, 2005. Mortality data were collected through telephone calls and visits （to 1991）, and were confirmed by death record matching with the National Statistical Office （1992-2005）. Hazard ratios were calculated for all-cause and cardiovascular mortality by resting heart rate and hypertension defined by Eighth Joint National Committee crite- ria using the Cox proportional hazard model after controlling for confounding factors. Results The hazard ratios associated with resting heart rate 〉 80 beats/min were higher in hypertensive men compared with normotensives with heart rate of 61-79 beats/rain, with hazard ratios values of 1.43 （95% CI： 1.00-1.92） on all-cause mortality for prehypertension, 3.01 （95% CI： 1.07-8.28） on cardiovascular mortality for prehypertension, and 8.34 （95% CI： 2.52-28.19） for stage 2 hypertension. Increased risk （HR： 3.54, 95% CI： 1.16-9.21） was observed among those with both a resting heart rate 〉 80 beats/rain and prehypertension on cardiovascular mortality in women. Conclusions Indi- viduals with coexisting elevated resting heart rate and hypertension, even in prehypertension, have a greater risk for all-cause and cardiovas- cular mortality compared to those with elevated resting heart rate or hypertension alone. These findings suggest that elevated resting heart rate should not be regarded as a less serious risk factor in elderly hypertensive patients.展开更多
Erythropoietin (Epo) is the regulator of red blood cell formation. Its receptor (EpoR) is now found in many cells and tissues of the body. EpoR is also shown to occur in tumor cells and Epo enhances the proliferation ...Erythropoietin (Epo) is the regulator of red blood cell formation. Its receptor (EpoR) is now found in many cells and tissues of the body. EpoR is also shown to occur in tumor cells and Epo enhances the proliferation of these cells through cell signaling. EpoR antagonist can reduce the growth of the tumor in vivo. In view of our current knowledge of Epo, its recombinant forms and receptor, use of Epo in cancer patients to enhance the recovery of hematocrit after chemotherapy treatment has to be carefully evaluated.展开更多
Chronic neuroinflammation is thought to play an etiological role in Alzheimer’s disease (AD) which is characterized pathologically by amyloid and tau formation, as well as neuritic dystrophy and synaptic degeneration...Chronic neuroinflammation is thought to play an etiological role in Alzheimer’s disease (AD) which is characterized pathologically by amyloid and tau formation, as well as neuritic dystrophy and synaptic degeneration. The causal relationship between these pathological events is a topic of ongoing research and discussion. Recent data from transgenic AD models point to a tight spatio-temporal link between neuritic and amyloid pathology, with the obligatory enzyme for β-amyloid (Aβ) production, namely β-secretase-1 (BACE1), being overexpressed in axon terminals undergoing dystrophic change. However, the axonal pathology inherent with BACE1 elevation seen in transgenic AD mice may be secondary to increased soluble Aβ in these genetically modified animals. Further, it is unclear whether the inflammation seen in AD is the result of , or the cause of neuritic dystrophy. Here we explored the occurrence of AD-like axonal and dendritic pathology in adult rat brains affected by LPS-induced chronic neuroinflammation. Unilateral intracerebral LPS injection induced prominent inflammatory response in glial cells in the ipsilateral cortex and hippocampal formation. BACE1 protein levels were elevated in the ipsilateral hippocampal lysates in the LPS-treated animals relative to controls. BACE1 immunoreactive dystrophic axons appeared in the LPS-treated ipsilateral cortex and hippocampal formation, colocalizing with increased β-amyloid precursor protein and Aβ antibody (4G8) immunolabeling. Quantitative Golgi studies revealed reduction of dendritic branching points and spine density on cortical layer III and hippocampal CA3 pyramidal neurons in the LPS-treated ipsilateral cerebrum. These findings suggest that Alzheimer-like amyloidogenic axonal pathology and dendritic degeneration occur in wildtype mammalian brain in partnership with neuroinflammation following LPS injection.展开更多
Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis,a common disease of the elderly population. Here, unbiased kinome RNAi screening in p...Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis,a common disease of the elderly population. Here, unbiased kinome RNAi screening in primary murine osteoblasts identified cyclin-dependent kinase 5(Cdk5) as a suppressor of osteoblast differentiation in both murine and human preosteoblastic cells. Cdk5 knockdown by si RNA, genetic deletion using the Cre-lox P system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro. Roscovitine treatment significantly enhanced bone mass by increasing osteoblastogenesis and improved fracture healing in mice. Mechanistically, downregulation of Cdk5 expression increased Erk phosphorylation, resulting in enhanced osteoblast-specific gene expression. Notably, simultaneous Cdk5 and Erk depletion abrogated the osteoblastogenesis conferred by Cdk5 depletion alone, suggesting that Cdk5 regulates osteoblast differentiation through MAPK pathway modulation. We conclude that Cdk5 is a potential therapeutic target to treat osteoporosis and improve fracture healing.展开更多
Mitochondria are well cha racterized by their fundamental functions in regulating cellular homeostasis,including energy and iron metabolism.These functions are essential in neurons with high metabolic demands and elon...Mitochondria are well cha racterized by their fundamental functions in regulating cellular homeostasis,including energy and iron metabolism.These functions are essential in neurons with high metabolic demands and elongated neuronal processes.Mitochondria dynamically change morphology,localization,and activity to match neurons'spatial and temporal demands.Mitochondrial dysfunctions have been associated with many neurological disorders.展开更多
Despite the existence of colorectal cancer (CRC) screening guidelines, population-based studies have consistently shown under-utilization of CRC screening procedures among older adults in the United States. We examine...Despite the existence of colorectal cancer (CRC) screening guidelines, population-based studies have consistently shown under-utilization of CRC screening procedures among older adults in the United States. We examined whether symptoms of anxiety and depression are associated with colorectal cancer (CRC) screening perceptions and behaviors among older adults in a primary care setting. A cross-sectional study was conducted by using a sample of 143 family medicine patients who completed an 88-item anonymous self-administered questionnaire covering symptoms of anxiety and depression as well as CRC screening perceptions (defined based on the Health Belief Model) and behaviors (defined as ever use of or adherence to CRC testing). Moderate-to-clinically significant anxiety and depressive symptoms were, respectively, prevalent in 47% and 42% of participants. Perceived benefits and barriers were the only Health Belief Model constructs associated with anxiety. Perceived barriers were positively associated with anxiety symptoms after adjustment for confounders, including age, gender, race/ ethnicity, marital status, education, smoking history, body mass index and self-rated health. By contrast, perceived benefits were negatively associated with anxiety symptoms only in the unadjusted model. Neither anxiety nor depression was associated with ever use of or adherence to CRC testing. Symptoms of anxiety, but not depression, may potentially influence CRC screening perceptions, with implications for behavioral interventions targeting CRC testing.展开更多
Background: In the past we have shown the preservation and improvement of cognitive tasks in depressed and demented patients after 24 and 36 months of combined pharmacological and non-pharmacological treatment. Here w...Background: In the past we have shown the preservation and improvement of cognitive tasks in depressed and demented patients after 24 and 36 months of combined pharmacological and non-pharmacological treatment. Here we present the results of our ongoing, naturalistic study, in the same outpatient setting, at 60 month follow up. Materials and Methods: The study group consisted of 156 medically ill, physically disabled patients with mild to moderate dementia and depression. Patients were treated with antidepressants, cholinesterase inhibitors, and NMDA antagonists, along with their regular medication regimen. Non-pharmacological intervention was centered on a home-based program of physical and cognitive exercises paired with vitamins and supplements (multivitamins, vitamin E, L-methylfolate, alphalipoic acid, acetyl-L-carnitine, omega-3, and coenzyme Q-10) and diet modification. Cognitive assessments were performed yearly. Results: After 60 months of treatment, performance of all tasks remained at or above baseline. The MMSE, Cognistat-Attention, Cognistat-Judgment, and RFFT-Total Unique Designs demonstrated significant improvement. Conclusion: Our results, for the first time, demonstrate arrest in cognitive decline in demented/depressed patients with multiple medical co-morbidities for 60 months. Future investigations addressing the application of a combined, integrative treatment model are warranted.展开更多
Background: Evidence suggests that childhood physical activity may play a role in the etiology and prevention of adult chronic diseases. Because researchers must often depend on self-recalled physical activity data ma...Background: Evidence suggests that childhood physical activity may play a role in the etiology and prevention of adult chronic diseases. Because researchers must often depend on self-recalled physical activity data many years after the exposure, it is important to understand factors which may influence adult recall of childhood physical activity. This study evaluated the influence of adult characteristics on reported childhood physical activity and the association between adult physical activity and self-recalled childhood physical activity. Methods: 48,066 post-menopausal women from the Women’s Health Initiative Observational Study reported their physical activity level during ages 5-9, 10-14, and 15-19. Results: In this cohort, over 65% of the population reported the same category of physical activity over the three childhood age groups. While higher levels of childhood physical activity were significantly associated with higher adult physical activity, this association varied by race/ethnicity, education, smoking, body mass index, history of diabetes or cardiovascular disease, social support and physical functional status. Women who were consistently highly active reported adult physical activity levels that were 2.82 MET-hr/week (95% C.I. = 2.43, 3.20) higher compared to women who were always physically inactive during childhood. Conclusions: It is important for researchers to understand the influence of adult characteristics on reported childhood physical activity.展开更多
New technologies are constantly being introduced into the medical and surgical fields. These technologies come in the form of newer medicines, imaging methods and prognostic tools, among others, and allow clinicians t...New technologies are constantly being introduced into the medical and surgical fields. These technologies come in the form of newer medicines, imaging methods and prognostic tools, among others, and allow clinicians to make more rational and informed decisions on the care of their patients. Many of these technologies utilize advanced techniques which are at the forefront of many research fields and represent a transition of bench advances into the clinical realm. This review will highlight four technologies that are at the forefront in the treatment of oncology patients treated by surgeons on a daily basis. Circulating tumor cells, microarray analysis, proteomic studies and rapid sequencing technologies will be highlighted. These technologies will be reviewed and their potential use in the care o surgical patients will be discussed.展开更多
Parkinson’s disease(PD)is the second most common degenerative neurological disorder after Alzheimer’s disease.As one of fastest growing neurological conditions,PD affects millions of elderly people worldwide.PD pati...Parkinson’s disease(PD)is the second most common degenerative neurological disorder after Alzheimer’s disease.As one of fastest growing neurological conditions,PD affects millions of elderly people worldwide.PD patients display progressive motor symptoms,including resting tremor,slowed movement,impaired posture and balance,and rigid muscles[1].Additionally,they also often suffer from chronic pain,depression,dementia,and other non-motor symptoms[2].Medications and surgery can improve patient’s motor performance to some degree,while the treatment for non-motor conditions is limited.Moreover,long-term medication can cause severe side effects,such as dyskinesia and impulse control disorders[3,4].Therefore,new mechanistic insights and therapeutic agents/procedures are still needed to improve the treatment of increasing number of PD patients.展开更多
A recent study published in Nature has uncovered a novel regulatory mechanism that enhances start-codon selection during mitosis in mammalian cells by intensifying the interaction between the 40S ribosome subunit,whic...A recent study published in Nature has uncovered a novel regulatory mechanism that enhances start-codon selection during mitosis in mammalian cells by intensifying the interaction between the 40S ribosome subunit,which binds messenger RNA(mRNA)and initiates translation,and the eukaryotic translation initiation factor 1(eIF1),a central regulator of start-codon selection.1 This discovery reveals a sophisticated layer of translational control that helps maintain cell viability and cell cycle stability,with potential implications for understanding cellular regulation and improving cancer therapies.展开更多
Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has ev...Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease,owing to its rapid advancement over the recent decade.Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets,including those that were once considered undruggable.However,lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application,necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the bloodbrain barrier.Nanotechnology has emerged as a possible solution,and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery.By reducing the enzymatic breakdown of genetic components,nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy.Liposomes,polymeric nanoparticles,magnetic nanoparticles,dendrimers,and micelles are examples of nanocarriers that have been designed,and each has its own set of features.Furthermore,recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities.In this paper,we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease.展开更多
Exosomes are small vesicles secreted by all cell types in the brain and play a role in cell-cell communication through the transfer of cargo or encapsulation.Exosomes in the brain have considerable impact on neuronal ...Exosomes are small vesicles secreted by all cell types in the brain and play a role in cell-cell communication through the transfer of cargo or encapsulation.Exosomes in the brain have considerable impact on neuronal development,activation,and regeneration.In addition,exosomes are reported to be involved in the onset and propagation of various neurodegenerative diseases.In this review,we discuss the content of exosomes derived from major cell types in the brain,and their function under physiological and pathological conditions.展开更多
Observational studies have shown that the use of angiotensin-converting enzyme(ACE) inhibitors is associated with the maintenance of greater muscle strength and physical performance in older subjects. However, the mec...Observational studies have shown that the use of angiotensin-converting enzyme(ACE) inhibitors is associated with the maintenance of greater muscle strength and physical performance in older subjects. However, the mechanism that underlies these beneficial effects remains poorly understood. Because ACE inhibitors block the production of angiotensin II, which is a potent inhibitor of insulin-like growth factor-1(IGF-1) production, it was hypothesized that treatment with ACE inhibitors is associated with higher levels of IGF-1. This hypothesis was tested in 745 subjects(417 women, 328 men)enrolled in the Invecchiare in Chianti study. Of these, 160 were receiving ACE inhibitors. The association between ACE inhibitor use and serum IGF-1 was tested by linear regression models. After adjusting for multiple potential confounders, serum levels of total IGF-1 were significantly higher in participants receiving ACE inhibitors(mean±SD 129.0±56.1 ng/ml) compared with the rest of the study population(mean±SD 116.5±54.8 ng/ml)(p< 0.001). Participants with short(< 3 years) and long(3 to 9 years) treatment durations had higher serum IGF-1 levels than participants who were not receiving ACE inhibitor treatment, but the difference was statistically significant only for the short-duration group(p< 0.05). In conclusion, in older subjects, treatment with ACE inhibitors for< 3 years is associated with significantly higher levels of IGF-1. This may be 1 of the mechanisms by which ACE inhibitors might slow the decreases in muscle strength and physical function that are often observed in older subjects.展开更多
Alzheimer’s disease(AD)is a progressive neurodegenerative disorder that affects both cognition and non-cognition functions.The disease follows a continuum,starting with preclinical stages,progressing to mild cognitiv...Alzheimer’s disease(AD)is a progressive neurodegenerative disorder that affects both cognition and non-cognition functions.The disease follows a continuum,starting with preclinical stages,progressing to mild cognitive and behavioral impairment,ultimately leading to dementia.Early detection of AD is crucial for better diagnosis and more effective treatment.However,the current AD diagnostic tests of biomarkers using cerebrospinal fluid and/or brain imaging are invasive or expensive,and mostly are still not able to detect early disease state.Consequently,there is an urgent need to develop new diagnostic techniques with higher sensitivity and specificity during the preclinical stages of AD.Various non-cognitive manifestations,including behavioral abnormalities,sleep disturbances,sensory dysfunctions,and physical changes,have been observed in the preclinical AD stage before occurrence of notable cognitive decline.Recent research advances have identified several biofluid biomarkers as early indicators of AD.This review focuses on these non-cognitive changes and newly discovered biomarkers in AD,specifically addressing the preclinical stages of the disease.Furthermore,it is of importance to explore the potential for developing a predictive system or network to forecast disease onset and progression at the early stage of AD.展开更多
After a number of failed drug studies on Alzheimer’s disease(AD)over the past decade,clinical trials of AD started to show encouraging results and were approved or pending approval for clinical use.However,controvers...After a number of failed drug studies on Alzheimer’s disease(AD)over the past decade,clinical trials of AD started to show encouraging results and were approved or pending approval for clinical use.However,controversies on the clinically meaningful benefits and risks of brain edema and microhemorrhages have reminded us to think further about monitoring treatment and developing new drug targets.The goal of this review is to find insights from clinical trials that aimed at two key pathological features of AD,i.e.,amyloid-β(Aβ)and tau protein,and to explore other targets such as anti-inflammation in AD.The complex pathophysiology of AD may require combination therapies rather than monotherapy.Throughout the course of AD,multiple pathways are disrupted,presenting a multitude of possible therapeutic targets for designing prevention and intervention for AD.展开更多
BACKGROUND Type Ⅰ diabetes(T1D)is characterized by insulin loss caused by inflammatory cells that excessively infiltrate and destroy the pancreas,resulting in dysregulation of tissue homeostasis,mechanobiological pro...BACKGROUND Type Ⅰ diabetes(T1D)is characterized by insulin loss caused by inflammatory cells that excessively infiltrate and destroy the pancreas,resulting in dysregulation of tissue homeostasis,mechanobiological properties,and the immune response.The streptozotocin(STZ)-induced mouse model exhibits multiple features of human T1D and enables mechanistic analysis of disease progression.However,the relationship between the mechanochemical signaling regulation of STZ-induced T1D and macrophage migration and phagocytosis is unclear.AIM To study the mechanochemical regulation of STZ-induced macrophage response on pancreatic beta islet cells to gain a clearer understanding of T1D.METHODS We performed experiments using different methods.We stimulated isolated pancreatic beta islet cells with STZ and then tested the macrophage migration and phagocytosis.RESULTS In this study,we discovered that the integrin-associated surface factor CD47 played a critical role in immune defense in the STZ-induced T1D model by preventing pancreatic beta islet inflammation.In comparison with healthy mice,STZ-treated mice showed decreased levels of CD47 on islet cells and reduced interaction of CD47 with signal regulatory proteinα(SIRPα),which negatively regulates macrophage-mediated phagocytosis.This resulted in weakened islet cell immune defense and promoted macrophage migration and phagocytosis of target inflammatory cells.Moreover,lipopolysaccharide-activated human acute monocytic leukemia THP-1 cells also exhibited enhanced phagocytosis in the STZ-treated islets,and the aggressive attack of the inflammatory islets correlated with impaired CD47-SIRPαinteractions.In addition,CD47 overexpression rescued the pre-labeled targeted cells.CONCLUSION This study indicates that CD47 deficiency promotes the migration and phagocytosis of macrophages and provides mechanistic insights into T1D by associating the interactions between membrane structures and inflammatory disease progression.展开更多
基金supported by the National Institute on Aging(Nos.AG000723 and AG000578)(to VAB)the Fondation Sante(No.19656),Greece 2.0+1 种基金the National Recovery and Resilience Plan’s flagship program TAEDR-0535850the European Research Council(No.101077374-Synapto Mitophagy)(to KP)。
文摘N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.
基金supported in part by the Intramural Research Program of the National Institute on Agingsupported by the National Cancer Institute(K01 CA234317)+1 种基金the San Diego State University/UC San Diego Comprehensive Cancer Center Partnership(U54 CA132384 and U54 CA132379)the Alzheimer's Disease Resource Center for Minority Aging Research at the University of California San Diego(P30 AG059299)。
文摘Background:There exist few maximal oxygen uptake(VO_(2max))non-exercise-based prediction equations,fewer using machine learning(ML),and none specifically for older adults.Since direct measurement of VO_(2max)is infeasible in large epidemiologic cohort studies,we sought to develop,validate,compare,and assess the transportability of several ML VO_(2max)prediction algorithms.Methods:The Baltimore Longitudinal Study of Aging(BLSA)participants with valid VO2_(max)tests were included(n=1080).Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine(SVM)algorithms were trained to predict VO_(2max)values.We developed these algorithms for:(a)the overall BLSA,(b)by sex,(c)using all BLSA variables,and(d)variables common in aging cohorts.Finally,we quantified the associations between measured and predicted VO_(2max)and mortality.Results:The age was 69.0±10.4 years(mean±SD)and the measured VO_(2max)was 21.6±5.9 mL/kg/min.Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine yielded root mean squared errors of 3.4 mL/kg/min,3.6 mL/kg/min,3.4 mL/kg/min,3.6 mL/kg/min,and 3.5 mL/kg/min,respectively.Incremental quartiles of measured VO_(2max)showed an inverse gradient in mortality risk.Predicted VO_(2max)variables yielded similar effect estimates but were not robust to adjustment.Conclusion:Measured VO_(2max)is a strong predictor of mortality.Using ML can improve the accuracy of prediction as compared to simpler approaches but estimates of association with mortality remain sensitive to adjustment.Future studies should seek to reproduce these results so that VO_(2max),an important vital sign,can be more broadly studied as a modifiable target for promoting functional resiliency and healthy aging.
基金Supported by University Hospital of Giessen and Marburg(UKGM)-Justus-Liebig-University(JLU)-Cooperation Grant,No.7/2016 GIthe Else Kröner-Fresenius-Stiftung,No.2016_A90and the German Research Foundation,No.544054869.
文摘BACKGROUND Here,we report a case of jejunal diverticulosis from an anatomical and histological view.During the“Gross Anatomy course,”we found multiple jejunal diverticula along a total length of 208 cm of intestine.CASE SUMMARY After opening the intestinal tract,we counted 232 jejunal diverticulum entry points with a diameter of up to 2 cm and observed connections between the diverticula that created shortcuts between two distinct intestinal parts.Interestingly,we observed an extreme longitudinal striation on the intestinal parts hosting diverticula.Thorough vessel preparation utilizing a dissecting microscope confirmed that all investigated arteriae rectae ended in a diverticulum.Histological and immunohistochemical investigations revealed that intestinal villi of diverticula were smaller and less prominent than control tissue and that the stratum longitudinale,as well as the stratum circular,were much thinner in the diverticula compared to control tissue.Neither submucosal nor mesenteric plexus could be detected in the diverticula.However,vasoactive intestinal peptidepositive nerve fibers and villin-positive brush border could only be detected in control tissue.This indicates that jejunal diverticulosis is associated with abnormalities of the smooth muscles and a disorder of innervation.CONCLUSION Jejunal diverticulosis originates from mesenteric vessels,featuring smooth muscle changes,absent innervation,and thinning of tissue layers.
文摘Background Elevated resting heart rate and hypertension independently increase the risk of mortality. However, their combined ef- fect on mortality in stages of hypertension according to updated clinical guidelines among dderly population is unclear. Methods We fol- lowed a cohort of 6100 residents （2600 males and 3500 females） of Kangwha County, Korea, ranging from 55 to 99 year-olds as of March 1985, for all-cause and cardiovascular mortality for 20.8 years until December 31, 2005. Mortality data were collected through telephone calls and visits （to 1991）, and were confirmed by death record matching with the National Statistical Office （1992-2005）. Hazard ratios were calculated for all-cause and cardiovascular mortality by resting heart rate and hypertension defined by Eighth Joint National Committee crite- ria using the Cox proportional hazard model after controlling for confounding factors. Results The hazard ratios associated with resting heart rate 〉 80 beats/min were higher in hypertensive men compared with normotensives with heart rate of 61-79 beats/rain, with hazard ratios values of 1.43 （95% CI： 1.00-1.92） on all-cause mortality for prehypertension, 3.01 （95% CI： 1.07-8.28） on cardiovascular mortality for prehypertension, and 8.34 （95% CI： 2.52-28.19） for stage 2 hypertension. Increased risk （HR： 3.54, 95% CI： 1.16-9.21） was observed among those with both a resting heart rate 〉 80 beats/rain and prehypertension on cardiovascular mortality in women. Conclusions Indi- viduals with coexisting elevated resting heart rate and hypertension, even in prehypertension, have a greater risk for all-cause and cardiovas- cular mortality compared to those with elevated resting heart rate or hypertension alone. These findings suggest that elevated resting heart rate should not be regarded as a less serious risk factor in elderly hypertensive patients.
基金Supported in part by the funds from Central Arkansas Veterans Healthcare System
文摘Erythropoietin (Epo) is the regulator of red blood cell formation. Its receptor (EpoR) is now found in many cells and tissues of the body. EpoR is also shown to occur in tumor cells and Epo enhances the proliferation of these cells through cell signaling. EpoR antagonist can reduce the growth of the tumor in vivo. In view of our current knowledge of Epo, its recombinant forms and receptor, use of Epo in cancer patients to enhance the recovery of hematocrit after chemotherapy treatment has to be carefully evaluated.
文摘Chronic neuroinflammation is thought to play an etiological role in Alzheimer’s disease (AD) which is characterized pathologically by amyloid and tau formation, as well as neuritic dystrophy and synaptic degeneration. The causal relationship between these pathological events is a topic of ongoing research and discussion. Recent data from transgenic AD models point to a tight spatio-temporal link between neuritic and amyloid pathology, with the obligatory enzyme for β-amyloid (Aβ) production, namely β-secretase-1 (BACE1), being overexpressed in axon terminals undergoing dystrophic change. However, the axonal pathology inherent with BACE1 elevation seen in transgenic AD mice may be secondary to increased soluble Aβ in these genetically modified animals. Further, it is unclear whether the inflammation seen in AD is the result of , or the cause of neuritic dystrophy. Here we explored the occurrence of AD-like axonal and dendritic pathology in adult rat brains affected by LPS-induced chronic neuroinflammation. Unilateral intracerebral LPS injection induced prominent inflammatory response in glial cells in the ipsilateral cortex and hippocampal formation. BACE1 protein levels were elevated in the ipsilateral hippocampal lysates in the LPS-treated animals relative to controls. BACE1 immunoreactive dystrophic axons appeared in the LPS-treated ipsilateral cortex and hippocampal formation, colocalizing with increased β-amyloid precursor protein and Aβ antibody (4G8) immunolabeling. Quantitative Golgi studies revealed reduction of dendritic branching points and spine density on cortical layer III and hippocampal CA3 pyramidal neurons in the LPS-treated ipsilateral cerebrum. These findings suggest that Alzheimer-like amyloidogenic axonal pathology and dendritic degeneration occur in wildtype mammalian brain in partnership with neuroinflammation following LPS injection.
基金supported by grants from the“PAKT für Forschung und Innovation2010(Leibniz Age Net:signaling pathways in age-related diseases)”German Research Foundation(DFG)Tu220/14-1,DFG(No.Ci 216/2-1)+1 种基金DFG in the framework of Collaborative Research Center CRC1149“Danger Response,Disturbance Factors and Regenerative Potential after Trauma”(No.251293561—CRC 1149,INST 40/492-1 and INST 40/492-2)Open Access funding enabled and organized by Projekt DEAL。
文摘Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis,a common disease of the elderly population. Here, unbiased kinome RNAi screening in primary murine osteoblasts identified cyclin-dependent kinase 5(Cdk5) as a suppressor of osteoblast differentiation in both murine and human preosteoblastic cells. Cdk5 knockdown by si RNA, genetic deletion using the Cre-lox P system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro. Roscovitine treatment significantly enhanced bone mass by increasing osteoblastogenesis and improved fracture healing in mice. Mechanistically, downregulation of Cdk5 expression increased Erk phosphorylation, resulting in enhanced osteoblast-specific gene expression. Notably, simultaneous Cdk5 and Erk depletion abrogated the osteoblastogenesis conferred by Cdk5 depletion alone, suggesting that Cdk5 regulates osteoblast differentiation through MAPK pathway modulation. We conclude that Cdk5 is a potential therapeutic target to treat osteoporosis and improve fracture healing.
基金supported by grants from the National Institute on Aging(AG063766and AG028740 to RX,AG066654 to SMH,T32AG062728 to TM)the American Cancer Society(RSG-17-171-01-DMC to RX)the American Federation for Aging Research(AGR DT07-2502019 and AGR DTD 09-15-2021 to SMH)。
文摘Mitochondria are well cha racterized by their fundamental functions in regulating cellular homeostasis,including energy and iron metabolism.These functions are essential in neurons with high metabolic demands and elongated neuronal processes.Mitochondria dynamically change morphology,localization,and activity to match neurons'spatial and temporal demands.Mitochondrial dysfunctions have been associated with many neurological disorders.
文摘Despite the existence of colorectal cancer (CRC) screening guidelines, population-based studies have consistently shown under-utilization of CRC screening procedures among older adults in the United States. We examined whether symptoms of anxiety and depression are associated with colorectal cancer (CRC) screening perceptions and behaviors among older adults in a primary care setting. A cross-sectional study was conducted by using a sample of 143 family medicine patients who completed an 88-item anonymous self-administered questionnaire covering symptoms of anxiety and depression as well as CRC screening perceptions (defined based on the Health Belief Model) and behaviors (defined as ever use of or adherence to CRC testing). Moderate-to-clinically significant anxiety and depressive symptoms were, respectively, prevalent in 47% and 42% of participants. Perceived benefits and barriers were the only Health Belief Model constructs associated with anxiety. Perceived barriers were positively associated with anxiety symptoms after adjustment for confounders, including age, gender, race/ ethnicity, marital status, education, smoking history, body mass index and self-rated health. By contrast, perceived benefits were negatively associated with anxiety symptoms only in the unadjusted model. Neither anxiety nor depression was associated with ever use of or adherence to CRC testing. Symptoms of anxiety, but not depression, may potentially influence CRC screening perceptions, with implications for behavioral interventions targeting CRC testing.
文摘Background: In the past we have shown the preservation and improvement of cognitive tasks in depressed and demented patients after 24 and 36 months of combined pharmacological and non-pharmacological treatment. Here we present the results of our ongoing, naturalistic study, in the same outpatient setting, at 60 month follow up. Materials and Methods: The study group consisted of 156 medically ill, physically disabled patients with mild to moderate dementia and depression. Patients were treated with antidepressants, cholinesterase inhibitors, and NMDA antagonists, along with their regular medication regimen. Non-pharmacological intervention was centered on a home-based program of physical and cognitive exercises paired with vitamins and supplements (multivitamins, vitamin E, L-methylfolate, alphalipoic acid, acetyl-L-carnitine, omega-3, and coenzyme Q-10) and diet modification. Cognitive assessments were performed yearly. Results: After 60 months of treatment, performance of all tasks remained at or above baseline. The MMSE, Cognistat-Attention, Cognistat-Judgment, and RFFT-Total Unique Designs demonstrated significant improvement. Conclusion: Our results, for the first time, demonstrate arrest in cognitive decline in demented/depressed patients with multiple medical co-morbidities for 60 months. Future investigations addressing the application of a combined, integrative treatment model are warranted.
文摘Background: Evidence suggests that childhood physical activity may play a role in the etiology and prevention of adult chronic diseases. Because researchers must often depend on self-recalled physical activity data many years after the exposure, it is important to understand factors which may influence adult recall of childhood physical activity. This study evaluated the influence of adult characteristics on reported childhood physical activity and the association between adult physical activity and self-recalled childhood physical activity. Methods: 48,066 post-menopausal women from the Women’s Health Initiative Observational Study reported their physical activity level during ages 5-9, 10-14, and 15-19. Results: In this cohort, over 65% of the population reported the same category of physical activity over the three childhood age groups. While higher levels of childhood physical activity were significantly associated with higher adult physical activity, this association varied by race/ethnicity, education, smoking, body mass index, history of diabetes or cardiovascular disease, social support and physical functional status. Women who were consistently highly active reported adult physical activity levels that were 2.82 MET-hr/week (95% C.I. = 2.43, 3.20) higher compared to women who were always physically inactive during childhood. Conclusions: It is important for researchers to understand the influence of adult characteristics on reported childhood physical activity.
基金Supported by The National Institute on Aging-Intramural Research Program,National Institutes of Health
文摘New technologies are constantly being introduced into the medical and surgical fields. These technologies come in the form of newer medicines, imaging methods and prognostic tools, among others, and allow clinicians to make more rational and informed decisions on the care of their patients. Many of these technologies utilize advanced techniques which are at the forefront of many research fields and represent a transition of bench advances into the clinical realm. This review will highlight four technologies that are at the forefront in the treatment of oncology patients treated by surgeons on a daily basis. Circulating tumor cells, microarray analysis, proteomic studies and rapid sequencing technologies will be highlighted. These technologies will be reviewed and their potential use in the care o surgical patients will be discussed.
基金supported by the Intramural Research Programs of National Institute on Aging,NIH(HC,ZIA AG000944,AG000928).
文摘Parkinson’s disease(PD)is the second most common degenerative neurological disorder after Alzheimer’s disease.As one of fastest growing neurological conditions,PD affects millions of elderly people worldwide.PD patients display progressive motor symptoms,including resting tremor,slowed movement,impaired posture and balance,and rigid muscles[1].Additionally,they also often suffer from chronic pain,depression,dementia,and other non-motor symptoms[2].Medications and surgery can improve patient’s motor performance to some degree,while the treatment for non-motor conditions is limited.Moreover,long-term medication can cause severe side effects,such as dyskinesia and impulse control disorders[3,4].Therefore,new mechanistic insights and therapeutic agents/procedures are still needed to improve the treatment of increasing number of PD patients.
文摘A recent study published in Nature has uncovered a novel regulatory mechanism that enhances start-codon selection during mitosis in mammalian cells by intensifying the interaction between the 40S ribosome subunit,which binds messenger RNA(mRNA)and initiates translation,and the eukaryotic translation initiation factor 1(eIF1),a central regulator of start-codon selection.1 This discovery reveals a sophisticated layer of translational control that helps maintain cell viability and cell cycle stability,with potential implications for understanding cellular regulation and improving cancer therapies.
基金supported by the Intramural Research Program National Institute on Aginq,NIH。
文摘Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease,owing to its rapid advancement over the recent decade.Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets,including those that were once considered undruggable.However,lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application,necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the bloodbrain barrier.Nanotechnology has emerged as a possible solution,and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery.By reducing the enzymatic breakdown of genetic components,nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy.Liposomes,polymeric nanoparticles,magnetic nanoparticles,dendrimers,and micelles are examples of nanocarriers that have been designed,and each has its own set of features.Furthermore,recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities.In this paper,we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease.
基金This research was supported by the National Natural Science Foundation of China(31871082,91849101,81601221)The Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000)+3 种基金Key Research Program of Frontier Sciences of CAS(QYZDB-SSW-SMC035)the Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology(2018CXFX005)the Fundamental Research Funds for the Central Universities,and China Postdoctoral Science Foundation(2019M662178)The Open Fund of State Key Laboratory of Tea Plant Biology and Utilization(SKLTOF20150101)。
文摘Exosomes are small vesicles secreted by all cell types in the brain and play a role in cell-cell communication through the transfer of cargo or encapsulation.Exosomes in the brain have considerable impact on neuronal development,activation,and regeneration.In addition,exosomes are reported to be involved in the onset and propagation of various neurodegenerative diseases.In this review,we discuss the content of exosomes derived from major cell types in the brain,and their function under physiological and pathological conditions.
文摘Observational studies have shown that the use of angiotensin-converting enzyme(ACE) inhibitors is associated with the maintenance of greater muscle strength and physical performance in older subjects. However, the mechanism that underlies these beneficial effects remains poorly understood. Because ACE inhibitors block the production of angiotensin II, which is a potent inhibitor of insulin-like growth factor-1(IGF-1) production, it was hypothesized that treatment with ACE inhibitors is associated with higher levels of IGF-1. This hypothesis was tested in 745 subjects(417 women, 328 men)enrolled in the Invecchiare in Chianti study. Of these, 160 were receiving ACE inhibitors. The association between ACE inhibitor use and serum IGF-1 was tested by linear regression models. After adjusting for multiple potential confounders, serum levels of total IGF-1 were significantly higher in participants receiving ACE inhibitors(mean±SD 129.0±56.1 ng/ml) compared with the rest of the study population(mean±SD 116.5±54.8 ng/ml)(p< 0.001). Participants with short(< 3 years) and long(3 to 9 years) treatment durations had higher serum IGF-1 levels than participants who were not receiving ACE inhibitor treatment, but the difference was statistically significant only for the short-duration group(p< 0.05). In conclusion, in older subjects, treatment with ACE inhibitors for< 3 years is associated with significantly higher levels of IGF-1. This may be 1 of the mechanisms by which ACE inhibitors might slow the decreases in muscle strength and physical function that are often observed in older subjects.
基金supported by funding from the National Natural Science Foundation of China(Nos.32220103006 and 82271524)the Intramural Research Program of NIH,National Institute on Aging(Nos.ZIA AG000944 and AG000928).
文摘Alzheimer’s disease(AD)is a progressive neurodegenerative disorder that affects both cognition and non-cognition functions.The disease follows a continuum,starting with preclinical stages,progressing to mild cognitive and behavioral impairment,ultimately leading to dementia.Early detection of AD is crucial for better diagnosis and more effective treatment.However,the current AD diagnostic tests of biomarkers using cerebrospinal fluid and/or brain imaging are invasive or expensive,and mostly are still not able to detect early disease state.Consequently,there is an urgent need to develop new diagnostic techniques with higher sensitivity and specificity during the preclinical stages of AD.Various non-cognitive manifestations,including behavioral abnormalities,sleep disturbances,sensory dysfunctions,and physical changes,have been observed in the preclinical AD stage before occurrence of notable cognitive decline.Recent research advances have identified several biofluid biomarkers as early indicators of AD.This review focuses on these non-cognitive changes and newly discovered biomarkers in AD,specifically addressing the preclinical stages of the disease.Furthermore,it is of importance to explore the potential for developing a predictive system or network to forecast disease onset and progression at the early stage of AD.
基金supported by the National Key Plan for Scientific Research and Development of China(2020YFA0509304)the Chinese Academy of Sciences(XDB39000000)+4 种基金the National Natural Sciences Foundation of China(82030034 and 32121002)CAMS Innovation Fund for Medical Sciences(IFMS)(2021-I2M-C&T-B012)the Fundamental Research Funds for the Central Universities(YD9110002027 and YD9110002033)Anhui Provincial Key R&D Programs(202304295107020056)the Guangzhou Key Research Program on Brain Science(202007030008)。
文摘After a number of failed drug studies on Alzheimer’s disease(AD)over the past decade,clinical trials of AD started to show encouraging results and were approved or pending approval for clinical use.However,controversies on the clinically meaningful benefits and risks of brain edema and microhemorrhages have reminded us to think further about monitoring treatment and developing new drug targets.The goal of this review is to find insights from clinical trials that aimed at two key pathological features of AD,i.e.,amyloid-β(Aβ)and tau protein,and to explore other targets such as anti-inflammation in AD.The complex pathophysiology of AD may require combination therapies rather than monotherapy.Throughout the course of AD,multiple pathways are disrupted,presenting a multitude of possible therapeutic targets for designing prevention and intervention for AD.
基金Supported by the National Natural Science Foundation of China,No.31701179the China Postdoctoral Science Foundation,No.2016M591877。
文摘BACKGROUND Type Ⅰ diabetes(T1D)is characterized by insulin loss caused by inflammatory cells that excessively infiltrate and destroy the pancreas,resulting in dysregulation of tissue homeostasis,mechanobiological properties,and the immune response.The streptozotocin(STZ)-induced mouse model exhibits multiple features of human T1D and enables mechanistic analysis of disease progression.However,the relationship between the mechanochemical signaling regulation of STZ-induced T1D and macrophage migration and phagocytosis is unclear.AIM To study the mechanochemical regulation of STZ-induced macrophage response on pancreatic beta islet cells to gain a clearer understanding of T1D.METHODS We performed experiments using different methods.We stimulated isolated pancreatic beta islet cells with STZ and then tested the macrophage migration and phagocytosis.RESULTS In this study,we discovered that the integrin-associated surface factor CD47 played a critical role in immune defense in the STZ-induced T1D model by preventing pancreatic beta islet inflammation.In comparison with healthy mice,STZ-treated mice showed decreased levels of CD47 on islet cells and reduced interaction of CD47 with signal regulatory proteinα(SIRPα),which negatively regulates macrophage-mediated phagocytosis.This resulted in weakened islet cell immune defense and promoted macrophage migration and phagocytosis of target inflammatory cells.Moreover,lipopolysaccharide-activated human acute monocytic leukemia THP-1 cells also exhibited enhanced phagocytosis in the STZ-treated islets,and the aggressive attack of the inflammatory islets correlated with impaired CD47-SIRPαinteractions.In addition,CD47 overexpression rescued the pre-labeled targeted cells.CONCLUSION This study indicates that CD47 deficiency promotes the migration and phagocytosis of macrophages and provides mechanistic insights into T1D by associating the interactions between membrane structures and inflammatory disease progression.
