Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglio...Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglion cells and their axons,leading to axonal transport dysfuntion,subsequently causing secondary damage to anterior or posterior ends of the visual system.Accordingly,recent evidence indicates that glaucoma is a degenerative disease of the central nervous system that causes damage throughout the visual pathway.However,the effects of glaucoma on synaptic plasticity in the primary visual cortex remain unclear.In this study,we established a mouse model of unilateral chronic ocular hypertension by injecting magnetic microbeads into the anterior chamber of one eye.We found that,after 4 weeks of chronic ocular hypertension,the neuronal somas were smaller in the superior colliculus and lateral geniculate body regions of the brain contralateral to the affected eye.This was accompanied by glial cell activation and increased expression of inflammatory factors.After 8 weeks of ocular hypertension,we observed a reduction in the number of excitatory and inhibitory synapses,dendritic spines,and activation of glial cells in the primary visual cortex contralateral to the affected eye.These findings suggest that glaucoma not only directly damages the retina but also induces alterations in synapses and dendritic spines in the primary visual cortex,providing new insights into the pathogenesis of glaucoma.展开更多
Sepsis-induced myocardial dysfunction is a common complication in septic patients and is associated with increased mortality.In the clinical setting,it was once believed that myocardial dysfunction was not a major pat...Sepsis-induced myocardial dysfunction is a common complication in septic patients and is associated with increased mortality.In the clinical setting,it was once believed that myocardial dysfunction was not a major pathological process in the septic patients,at least in part,due to the unavailability of suitable clinical markers to assess intrinsic myocardial function during sepsis.Although sepsis-induced myocardial dysfunction has been studied in clinical and basic research for more than 30 years,its pathophysiology is not completely understood,and no specific therapies for this disorder exist.The purpose of this review is to summarize our current knowledge of sepsis-induced myocardial dysfunction with a special focus on pathogenesis and clinical characteristics.展开更多
AIM: To search for a new chronic pancreatitis model in mice suitable for investigating the pathophysiological processes leading to pancreatic fibrosis.METHODS: The mice were randomly divided into 2 groups(n = 50), con...AIM: To search for a new chronic pancreatitis model in mice suitable for investigating the pathophysiological processes leading to pancreatic fibrosis.METHODS: The mice were randomly divided into 2 groups(n = 50), control group and model group. The mice in model group were given ethanol(10%) in drinking water after injection of dibutyltin dichloride(DBTC)(8 mg/kg BW) in tail vein. The mice in control group were injected with only solvent into tail vein( 60 % ethanol, 20% glycerine and 20% normal saline) and drank common water. At days 1, 7, 14, 28, and 56 after application of DBTC or solvent, 10 mice in one group were killed at each time point respectively. Blood was obtained by inferior vena cava puncture. The activity of amylase, concentration of bilirubin and hyaluronic acid in serum were assayed. The pancreas was taken to observe the pancreatic morphology by HE staining, and to characterize the pancreatic fibrosis by Masson staining. The expression of F4/80, CD3 and fibronectin(FN) were assayed by immuno-histochemistry or Immunofluorescence technique. Collagen typeⅠ(COL1A1) in pancreas were detected by Western blot. The expression of matrix metalloproteinase-1(MMP-1) and tissue inhibitor of metalloproteinases-1(TIMP-1) m RNA in the pancreas was assessed by real time PCR.RESULTS: DBTC induced an acute edematous pancreatitis within 1 d. The dilated acini, scattered acinar cell necrosis, and inflammatory cells were found at day 7. Extensive infiltration with inflammatory cells following deposition of connective tissue was observed at day 14. At day 28, level of pancreatic fibrosis was aggravated. The pancreatic tissue was replaced by an extended interstitial fibrosis at the end of 2 mo. There was significant difference in the level of amylase, bilirubin and hyaluronic acid in serum between control group and model group(P < 0.05). The level of COL1A1 and FN in pancreas increased. The expression of MMP-1 m RNA in pancreas decreased, but TIMP-1 m RNA increased at model group.CONCLUSION: DBTC joint Ethanol drinking can induce chronic pancreatitis in accordance with the pathophysiological modification of human. DBTC joint Ethanol-induced pancreatitis in mice is an effective and handy experimental method. The model is suitable to study the mechanism of pancreatic fibrosis in chronic pancreatitis.展开更多
Heart failure(HF)is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target...Heart failure(HF)is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues.The sympathetic nervous system(SNS)is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes,circulating and neuronal catecholamine spillover,attenuated parasympathetic response,and augmented sympathetic outflow to the heart,kidneys and skeletal muscles.When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis,maladaptive ventricular and vascular remodeling,arrhythmogenesis,and poor prognosis in patients with HF.These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities.Therefore,this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF.Finally,special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.展开更多
Pathophysiology is set as a separated subject from others ever since its establishment in the medical schools in China in 1950s.Nowadays the curriculum of pathophysiology usually involves lectures and lab sessions,acc...Pathophysiology is set as a separated subject from others ever since its establishment in the medical schools in China in 1950s.Nowadays the curriculum of pathophysiology usually involves lectures and lab sessions,accounting for about two thirds and one third of the total class hours respectively.For a long time,traditional teaching mode is used predominantly in the instruction of pathophysiology in China.In the past decades,increasing problems of teaching have been gradually realized,among which the lose connection of lectures with clinical practices,the weakness of developing active learning abilities of students,and the insufficient laboratory training are most of note.As a subject investigating the mechanisms underlying the development of disease,pathophysiology helps medical students to develop skills to solve efficiently professional medical problems.How to teach the subject in a way that engages,enlightens and excites medical students to want to learn more?In recent years,great efforts have been made to establish student-centered and self-moti-vated learning mode in pathophysiology course in Nanjing Medical University.Emphasis has been placed on three aspects:the implementation of problem-based learning,the use of E-learning tools,and the increase of integrated or self-designed experiments.Challenges we are facing in continuing the teaching reforms are also presented.展开更多
AIM:To explore the effect of the periodic case analysis test on pathophysiology teaching.METHODS:We randomly selected two natural classes from Grade 2011 Clinical Medicine Specialty in our university and set them as e...AIM:To explore the effect of the periodic case analysis test on pathophysiology teaching.METHODS:We randomly selected two natural classes from Grade 2011 Clinical Medicine Specialty in our university and set them as experimental group and control group.There were 66 and 68 students in the two groups,respectively.For these two groups,the course background,pathophysiology course teaching and final exam conditions were all the same.In the teaching process,we had a written test every 8 teaching hours,5 times in each group.In experimental group,students were arranged to face some typical clinical cases,they must analyze and discuss the specific pathogenesis according to the recent theoretical knowledge.In the same teaching time,the control students need to complete a certain amount of traditional type homework which was mainly basic concepts,basic pathogenesis and no practical case analysis.We compared and analyzed the final test scores and the pass rates in the two groups,and calculated the mean rank sums of the examination results with nonparametric method Kruskal-Wallis test.RESULTS:The average score of the final exam was 82.69 in experimental group,but that in control group was 77.98.The pass rates were 89.5%and 81.2%in the two groups,respectively.The average test rank scores were 171.84 and 136.95,respectively.CONCLUSION:The periodic case analysis test can obviously improve the students'academic achievements,and has promoting effect on pathophysiology teaching.展开更多
Short international survey has been done among the members of International Society for Pathophysiology. 42 to 46 valid answers,which came from 22 countries,were accumulated and analyzed. The average of teaching hours...Short international survey has been done among the members of International Society for Pathophysiology. 42 to 46 valid answers,which came from 22 countries,were accumulated and analyzed. The average of teaching hours of pathophysiology course in various curricula is 146 out of 5 788 total teaching hours of medical curricula (lecture 58,seminars 44,practical 52). Average teaching materials consist of 863 pages of obligatory texts and 1 225 pages of recommended materials. An estimated students' 'study time' for successful mastering of the exam is 164 hours (along with 146 contact teaching/learning hours). A survey concerning an educational profile of the pathophysiologist (A),contents of teaching (B),a selective advantage of pathophysiology teaching (C) and personal advise of pathophysiologists with respect of educational curricula (D) have been quantified by number 1 through 10; one being the weakest and ten being the strongest. Each of the survey features (A through D) was described in advance by 8 different statements,among which participants gave their 'intensity of support' using numerical values 1-10. The outcome indicates that the best profile of pathophysiologists' education scheme is that with 'MD + PhD + postdoctoral training + any residency' (score 8.57) and weakest profile 'PhD in the field of molecular biology' (4.93). The strongest 'power and relevance of pathophysiology' has been given to type of the subject which '…represents an integrative frame of reference describing common principles of disease' (8.59),whereas the weakest to the 'It leads to the evidence based practice and reduces medical costs' (7.65). With reference to the teaching contents the highest rank was given to 'Symptoms/signs/dysfunctions correlations with molecular nature of etiopathogenetic processes' (8.67),whereas the weakest points were given to 'quantitative aspects of etiopathogenetic processes' (6.60). When pathophysiologists were asked to give 'an educated opinion' to his/her son to what kind of medical curricula is the most advisable the curriculum with 'preclinical courses + clinical courses + public health courses' was given 7.96 as the highest. The curriculum described as 'Therapy centered education,in which courses are organized according to the groups of therapeutical procedures and types of therapies (e.g. surgical procedures,antibiotics,etc.)' was selected the weakest (4.64).展开更多
Because the western medicine originates in western countries and those countries offer the cutting-edge technologies for current medical development,Chinese medical professionals need to learn from their foreign peers...Because the western medicine originates in western countries and those countries offer the cutting-edge technologies for current medical development,Chinese medical professionals need to learn from their foreign peers. When Chinese medical scholars go abroad,attend an international scientific conference or publish their research results,one issue they may face is the cross-culture academic English communication.展开更多
AIM:To develop the methods of PBL on pathophysiology teaching for the medical students.METHODS: We chose 1 class from the 7-year program students in China Medical University and conducted bilingual PBL course of patho...AIM:To develop the methods of PBL on pathophysiology teaching for the medical students.METHODS: We chose 1 class from the 7-year program students in China Medical University and conducted bilingual PBL course of pathophysiology,we also chose 1 class from the 5-year program students and conducted PBL course in Chinese,the other classes were in traditional curriculum. We used special textbook in PBL class.展开更多
Pathophysiology,dealing with the functional changes in the host with disease or particular syndrome,is regarded as a bridge to guide students from basic medicine to clinical medicine. However,the traditional way in te...Pathophysiology,dealing with the functional changes in the host with disease or particular syndrome,is regarded as a bridge to guide students from basic medicine to clinical medicine. However,the traditional way in teaching of pathophysiology is far from clinical practice,mainly focuses on the acquisition and mastery of theoretical knowledge. Moreover,it is difficult for students to master the basic theoretical knowledge specifically and effectively under the condition away from clinical patients. In order to enhance the association of basic course with clinic,to combine the lecture and learning knowledge and clinical skills,we try to perform the combination of teaching pathophysiology with clinical practice in the training program for teachers and teaching activities. 1. The object:(1)Based on typical clinical cases,students participate bed side teaching and study theoretical knowledge.(2)To create whole concept on association among organs and systems of human diseases.展开更多
Pathophysiology is a bridge discipline between preclinical medicine and clinical medicine. The course design is closely related to the teaching effectiveness. Continuously optimizing the traditional curriculum whole a...Pathophysiology is a bridge discipline between preclinical medicine and clinical medicine. The course design is closely related to the teaching effectiveness. Continuously optimizing the traditional curriculum whole and adaptively to the medical development in the new century,we achieve the best teaching results since the following setting up have been made. 1.展开更多
Pathophysiology, as a bridge discipline connecting basic medicine and clinical medicine, occupies an important position in medical education. Traditional teaching of pathophysiology has certain limitations, such as ov...Pathophysiology, as a bridge discipline connecting basic medicine and clinical medicine, occupies an important position in medical education. Traditional teaching of pathophysiology has certain limitations, such as overly emphasizing the imparting of theoretical knowledge and imprisoning students in a state of separation between teaching and learning, as well as between learning and application. Participatory teaching is student-centered, emphasizing interaction between teachers and students, as well as communication and cooperation among students. It can improve students’ abilities to utilize information, express themselves, and analyze comprehensively, cultivate their teamwork spirit, help break the limitations of traditional teaching, and improve the quality of pathophysiology teaching.展开更多
Course based ideological and political education (CIPE) is an important way to improve the quality of ideological and political work and talent cultivation. This study explores for the first time the implementation of...Course based ideological and political education (CIPE) is an important way to improve the quality of ideological and political work and talent cultivation. This study explores for the first time the implementation of ideological and political education in the teaching of pathophysiology courses, and also analyzes the evaluation of student psychological status and the importance of mental health education in the implementation of IPE courses. A survey was conducted on 211 students at Yangtze University to understand their motivation and behavior towards learning ideological, political, and pathophysiological courses. In addition, a questionnaire survey was used to explore the relationship between pathophysiology and ideological and political courses, as well as the importance of their satisfaction with the implementation of ideological and political courses in pathophysiology and mental health education. The research results indicate that factors such as educational background and gender differences affect the learning of CIPE. Graduate students are more interested in ideological and political courses, while female students find it difficult to study pathophysiology;In addition, the results of one-way ANOVA indicate that the implementation effect of IPE in pathophysiology courses depends on the level of interest in IPE and pathophysiology courses, the level of consideration for the importance of professional courses, the professional gains after studying pathophysiology, and the level of understanding of the relationship between IPE and CIPE. 81.04% of students believe that in the CIPE process, telling stories by teachers themselves is the most popular way of communication and education. This reflects the importance of mental health education from the perspective of CIPE. In addition, this study also indicates that PBL and flipped classroom teaching models are popular teaching models in CIPE. This study is beneficial for promoting the improvement and implementation of CIPE and mental health education in higher education curricula, thus providing valuable insights for educational decision-makers.展开更多
BACKGROUND Endoscopic ultrasound(EUS)is crucial for diagnosing solid pancreatic lesions,especially pancreatic ductal adenocarcinoma(PDAC),a highly aggressive cancer which represents the majority with a prevalence of a...BACKGROUND Endoscopic ultrasound(EUS)is crucial for diagnosing solid pancreatic lesions,especially pancreatic ductal adenocarcinoma(PDAC),a highly aggressive cancer which represents the majority with a prevalence of approximately 85%.AIM To identify EUS features that differentiate PDAC from other lesions such as neuroendocrine tumors(NETs)and helping in the differential diagnosis,by analyzing a large sample of solid pancreatic lesions.METHODS This observational,retrospective,multicenter study analyzed the endosonographic characteristics of 761 patients with a radiological diagnosis of solid pancreatic lesion,who underwent pancreatic EUS for typing and staging with needle biopsies between 2015 and 2023.General patient characteristics(age and sex)and solid lesion features were collected and described,such lesion size(Bmode),vessel involvement(compression or invasion),ductal dilation,lymphadenopathy,echogenicity,echopattern,margin regularity,multifocality,internal vascularization and elastography.Subsequently,a predictive analysis was performed through univariate and multivariate logistic regression to identify predictive features for PDAC or NET diagnoses.RESULTS Our study enrolled 761 patients,predominantly male with a mean age of 68.6.PDACs were generally larger(mean 33 mm×27 mm),often had irregular margins,and displayed significant upstream ductal dilation.Hypoechogenicity was common across malignant lesions.In contrast,NETs were smaller(mean 20 mm×17 mm)and typically had regular margins with multiple lesions.Vascular involvement,although predominant in PDAC,is a common feature of all malignant neoplasms.Multifocality,however,although a rare finding,is more typical of NETs and metastases,and practically absent in the remaining lesions.Predictive analyses showed that ductal dilation and irregular margins were the most significant predictors for PDAC[odds ratio(OR)=5.75 and 3.83],with hypoechogenicity,heterogeneous echopattern and lymphadenopathies also highly significant(OR=3.51,2.56 and 1.99).These features were inversely associated with NETs,with regular margins and absence of ductal involvement or lymphadenopathies(OR=0.24,0.86 and 0.45 respectively),as already shown by the descriptive analysis.Finally,age,despite achieving statistical significance,lacks clinical value given an OR trending towards 1.CONCLUSION This study provides a comprehensive overview of EUS features for solid pancreatic lesions,identifying distinct features like upstream ductal dilation and irregular margins for PDAC vs regular margins for NETs as strong diagnostic predictors.These findings enhance the understanding of pancreatic pathologies,offering valuable insights for improved differential diagnosis and clinical management,especially in complex cases.Further prospective studies could build on these results.展开更多
Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease(AD),which is closely related to tau pathology and hippocampal impairment.Due to the heterogeneity of brain neurons,the spec...Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease(AD),which is closely related to tau pathology and hippocampal impairment.Due to the heterogeneity of brain neurons,the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear.Therefore,further investigation is necessary.Methods:We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis,social behavioural tests,hippocampal electrophysiology,immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR.Additionally,we utilized optogenetics and administered ursolic acid(UA)via oral gavage to examine the effects of these agents on social memory in mice.Results:The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1(vCA1)under both physiological conditions and AD-like tau pathology.As tau progressively accumulated,vCA1,especially its excitatory and parvalbumin(PV)neurons,were fully filled with mislocated and phosphorylated tau(p-Tau).This finding was not observed for dorsal hippocampal CA1(dCA1).The overexpression of human tau(hTau)in excitatory and PV neurons mimicked AD-like tau accumulation,significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1.Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory.Notably,1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB(TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion:This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation.Notably,our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.展开更多
BACKGROUND Apolipoprotein E epsilon 4(APOE4)is recognized as a genetic risk factor for cognitive decline and neurodegeneration in both type 2 diabetes mellitus(T2DM)and Alzheimer’s disease,while glycated hemoglobin(H...BACKGROUND Apolipoprotein E epsilon 4(APOE4)is recognized as a genetic risk factor for cognitive decline and neurodegeneration in both type 2 diabetes mellitus(T2DM)and Alzheimer’s disease,while glycated hemoglobin(HbA1c)reflects persistent hyperglycemia and serves as a key indicator of long-term glycemic control in T2DM.Although both factors have been individually linked to neurobehavioral deficits,it remains uncertain whether HbA1c contributes to APOE4-related cognitive and olfactory impairment in individuals with T2DM.AIM To investigate the role of HbA1c in APOE4-associated cognitive and olfactory dysfunction in patients with T2DM.METHODS Of 636 T2DM patients were recruited from five medical centers in Wuhan,Hubei Province,China.APOE genotyping was evaluated by polymerase chain reaction using Gerard’s method.Cognitive and olfactory functions were assessed by mini-mental state examination and Connecticut chemosensory clinical research center test,respectively.Regression analysis was employed to assess the independent and interactive effects of HbA1c on APOE4-associated cognitive and olfactory function.RESULTS APOE4 was associated with increased risks of cognitive impairment[odds ratios(OR)=1.815,P=0.021]and olfactory dysfunction(OR=2.588,P<0.001).Higher HbA1c levels were also related to worse cognitive(OR=1.189,P<0.001)and olfactory performance(OR=1.149,P=0.011).HbA1c exerted a moderating effect,yet not a mediating effect,between APOE4 and its impacts on cognition and olfaction.Specifically,a higher level of HbA1c exacerbated the damaging effect of APOE4,as shown by significant interaction effects on both cognitive impairment(OR=2.687,P<0.001)and olfactory dysfunction(OR=1.440,P=0.027).CONCLUSION Elevated HbA1c levels are associated with increased risks of cognitive and olfactory impairments in patients with T2DM and may exacerbate the detrimental effects of APOE4.These findings underscore the need for early preventive strategies targeting individuals with both poor glycemic control and APOE4 carriage to mitigate neurodegenerative risk.展开更多
The discontinuation of denosumab[antibody targeting receptor activator of nuclear factor kappa B ligand(RANKL)]therapy may increase the risk of multiple vertebral fractures;however,the underlying pathophysiology is la...The discontinuation of denosumab[antibody targeting receptor activator of nuclear factor kappa B ligand(RANKL)]therapy may increase the risk of multiple vertebral fractures;however,the underlying pathophysiology is largely unknown.In patients who underwent discontinuation after multiple injections of denosumab,the levels of tartrate-resistant acid phosphatase 5b increased compared to pretreatment levels,indicating a phenomenon known as“overshoot.”The rate of decrease in bone mineral density during the withdrawal period was higher than the rate of decrease associated with aging,suggesting that the physiological bone metabolism had broken down.Overshoot and significant bone loss were also observed in mice receiving continuous administration of anti-RANKL antibody after treatment was interrupted,resembling the original pathology.In mice long out of overshoot,bone resorption recovered,but osteoblast numbers and bone formation remained markedly reduced.The bone marrow exhibited a significant reduction in stem cell(SC)antigen 1-and platelet-derived growth factor receptor alpha-expressing osteoblast progenitors(PαS cells)and alkaline phosphatase-positive early osteoblasts.Just before the overshoot phase,the osteoclast precursor cell population expands and RANKL-bearing extracellular vesicles(EVs)became abundant in the serum,leading to robust osteoclastogenesis after cessation of anti-RANKL treatment.Thus,accelerated bone resorption due to the accumulation of RANKLbearing EVs and long-term suppression of bone formation uncoupled from bone resorption leads to the severe bone loss characteristic of denosumab discontinuation.展开更多
Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute cour...Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.展开更多
Multiple sclerosis(MS) is a chronic, autoimmune and neuroinflammatory disease of the central nervous system(CNS) with a neurodegenerative component, characterized by demyelination and degeneration of nerve fibers. It ...Multiple sclerosis(MS) is a chronic, autoimmune and neuroinflammatory disease of the central nervous system(CNS) with a neurodegenerative component, characterized by demyelination and degeneration of nerve fibers. It affects mainly young adults(aged 20 to 45 years) and its causes are still unknown, but it is thought that external factors such as viruses and environmental factors trigger the disease in people with a genetic susceptibility.展开更多
Nonalcoholic fatty liver disease(NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases rangin...Nonalcoholic fatty liver disease(NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis(NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis(increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific lifestyle modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular disease improving overall prognosis and survival.展开更多
基金supported by the National Natural Science Foundation of China,No.82271115(to MY).
文摘Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglion cells and their axons,leading to axonal transport dysfuntion,subsequently causing secondary damage to anterior or posterior ends of the visual system.Accordingly,recent evidence indicates that glaucoma is a degenerative disease of the central nervous system that causes damage throughout the visual pathway.However,the effects of glaucoma on synaptic plasticity in the primary visual cortex remain unclear.In this study,we established a mouse model of unilateral chronic ocular hypertension by injecting magnetic microbeads into the anterior chamber of one eye.We found that,after 4 weeks of chronic ocular hypertension,the neuronal somas were smaller in the superior colliculus and lateral geniculate body regions of the brain contralateral to the affected eye.This was accompanied by glial cell activation and increased expression of inflammatory factors.After 8 weeks of ocular hypertension,we observed a reduction in the number of excitatory and inhibitory synapses,dendritic spines,and activation of glial cells in the primary visual cortex contralateral to the affected eye.These findings suggest that glaucoma not only directly damages the retina but also induces alterations in synapses and dendritic spines in the primary visual cortex,providing new insights into the pathogenesis of glaucoma.
基金supported by grants from the National Natural Science Foundation of China(81372028,81170222)the Guangzhou S cience and Technology Projec ts(201508020005)the Project of the Department of Education of Guangdong Province(No.2013KJCX0019)
文摘Sepsis-induced myocardial dysfunction is a common complication in septic patients and is associated with increased mortality.In the clinical setting,it was once believed that myocardial dysfunction was not a major pathological process in the septic patients,at least in part,due to the unavailability of suitable clinical markers to assess intrinsic myocardial function during sepsis.Although sepsis-induced myocardial dysfunction has been studied in clinical and basic research for more than 30 years,its pathophysiology is not completely understood,and no specific therapies for this disorder exist.The purpose of this review is to summarize our current knowledge of sepsis-induced myocardial dysfunction with a special focus on pathogenesis and clinical characteristics.
基金Supported by Funds of the National Natural Science Foundation of ChinaNo.80112725+1 种基金Administration of Traditional Chinese Medicine of Shaanxi Province of ChinaNo.jc10
文摘AIM: To search for a new chronic pancreatitis model in mice suitable for investigating the pathophysiological processes leading to pancreatic fibrosis.METHODS: The mice were randomly divided into 2 groups(n = 50), control group and model group. The mice in model group were given ethanol(10%) in drinking water after injection of dibutyltin dichloride(DBTC)(8 mg/kg BW) in tail vein. The mice in control group were injected with only solvent into tail vein( 60 % ethanol, 20% glycerine and 20% normal saline) and drank common water. At days 1, 7, 14, 28, and 56 after application of DBTC or solvent, 10 mice in one group were killed at each time point respectively. Blood was obtained by inferior vena cava puncture. The activity of amylase, concentration of bilirubin and hyaluronic acid in serum were assayed. The pancreas was taken to observe the pancreatic morphology by HE staining, and to characterize the pancreatic fibrosis by Masson staining. The expression of F4/80, CD3 and fibronectin(FN) were assayed by immuno-histochemistry or Immunofluorescence technique. Collagen typeⅠ(COL1A1) in pancreas were detected by Western blot. The expression of matrix metalloproteinase-1(MMP-1) and tissue inhibitor of metalloproteinases-1(TIMP-1) m RNA in the pancreas was assessed by real time PCR.RESULTS: DBTC induced an acute edematous pancreatitis within 1 d. The dilated acini, scattered acinar cell necrosis, and inflammatory cells were found at day 7. Extensive infiltration with inflammatory cells following deposition of connective tissue was observed at day 14. At day 28, level of pancreatic fibrosis was aggravated. The pancreatic tissue was replaced by an extended interstitial fibrosis at the end of 2 mo. There was significant difference in the level of amylase, bilirubin and hyaluronic acid in serum between control group and model group(P < 0.05). The level of COL1A1 and FN in pancreas increased. The expression of MMP-1 m RNA in pancreas decreased, but TIMP-1 m RNA increased at model group.CONCLUSION: DBTC joint Ethanol drinking can induce chronic pancreatitis in accordance with the pathophysiological modification of human. DBTC joint Ethanol-induced pancreatitis in mice is an effective and handy experimental method. The model is suitable to study the mechanism of pancreatic fibrosis in chronic pancreatitis.
文摘Heart failure(HF)is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues.The sympathetic nervous system(SNS)is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes,circulating and neuronal catecholamine spillover,attenuated parasympathetic response,and augmented sympathetic outflow to the heart,kidneys and skeletal muscles.When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis,maladaptive ventricular and vascular remodeling,arrhythmogenesis,and poor prognosis in patients with HF.These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities.Therefore,this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF.Finally,special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.
文摘Pathophysiology is set as a separated subject from others ever since its establishment in the medical schools in China in 1950s.Nowadays the curriculum of pathophysiology usually involves lectures and lab sessions,accounting for about two thirds and one third of the total class hours respectively.For a long time,traditional teaching mode is used predominantly in the instruction of pathophysiology in China.In the past decades,increasing problems of teaching have been gradually realized,among which the lose connection of lectures with clinical practices,the weakness of developing active learning abilities of students,and the insufficient laboratory training are most of note.As a subject investigating the mechanisms underlying the development of disease,pathophysiology helps medical students to develop skills to solve efficiently professional medical problems.How to teach the subject in a way that engages,enlightens and excites medical students to want to learn more?In recent years,great efforts have been made to establish student-centered and self-moti-vated learning mode in pathophysiology course in Nanjing Medical University.Emphasis has been placed on three aspects:the implementation of problem-based learning,the use of E-learning tools,and the increase of integrated or self-designed experiments.Challenges we are facing in continuing the teaching reforms are also presented.
文摘AIM:To explore the effect of the periodic case analysis test on pathophysiology teaching.METHODS:We randomly selected two natural classes from Grade 2011 Clinical Medicine Specialty in our university and set them as experimental group and control group.There were 66 and 68 students in the two groups,respectively.For these two groups,the course background,pathophysiology course teaching and final exam conditions were all the same.In the teaching process,we had a written test every 8 teaching hours,5 times in each group.In experimental group,students were arranged to face some typical clinical cases,they must analyze and discuss the specific pathogenesis according to the recent theoretical knowledge.In the same teaching time,the control students need to complete a certain amount of traditional type homework which was mainly basic concepts,basic pathogenesis and no practical case analysis.We compared and analyzed the final test scores and the pass rates in the two groups,and calculated the mean rank sums of the examination results with nonparametric method Kruskal-Wallis test.RESULTS:The average score of the final exam was 82.69 in experimental group,but that in control group was 77.98.The pass rates were 89.5%and 81.2%in the two groups,respectively.The average test rank scores were 171.84 and 136.95,respectively.CONCLUSION:The periodic case analysis test can obviously improve the students'academic achievements,and has promoting effect on pathophysiology teaching.
文摘Short international survey has been done among the members of International Society for Pathophysiology. 42 to 46 valid answers,which came from 22 countries,were accumulated and analyzed. The average of teaching hours of pathophysiology course in various curricula is 146 out of 5 788 total teaching hours of medical curricula (lecture 58,seminars 44,practical 52). Average teaching materials consist of 863 pages of obligatory texts and 1 225 pages of recommended materials. An estimated students' 'study time' for successful mastering of the exam is 164 hours (along with 146 contact teaching/learning hours). A survey concerning an educational profile of the pathophysiologist (A),contents of teaching (B),a selective advantage of pathophysiology teaching (C) and personal advise of pathophysiologists with respect of educational curricula (D) have been quantified by number 1 through 10; one being the weakest and ten being the strongest. Each of the survey features (A through D) was described in advance by 8 different statements,among which participants gave their 'intensity of support' using numerical values 1-10. The outcome indicates that the best profile of pathophysiologists' education scheme is that with 'MD + PhD + postdoctoral training + any residency' (score 8.57) and weakest profile 'PhD in the field of molecular biology' (4.93). The strongest 'power and relevance of pathophysiology' has been given to type of the subject which '…represents an integrative frame of reference describing common principles of disease' (8.59),whereas the weakest to the 'It leads to the evidence based practice and reduces medical costs' (7.65). With reference to the teaching contents the highest rank was given to 'Symptoms/signs/dysfunctions correlations with molecular nature of etiopathogenetic processes' (8.67),whereas the weakest points were given to 'quantitative aspects of etiopathogenetic processes' (6.60). When pathophysiologists were asked to give 'an educated opinion' to his/her son to what kind of medical curricula is the most advisable the curriculum with 'preclinical courses + clinical courses + public health courses' was given 7.96 as the highest. The curriculum described as 'Therapy centered education,in which courses are organized according to the groups of therapeutical procedures and types of therapies (e.g. surgical procedures,antibiotics,etc.)' was selected the weakest (4.64).
文摘Because the western medicine originates in western countries and those countries offer the cutting-edge technologies for current medical development,Chinese medical professionals need to learn from their foreign peers. When Chinese medical scholars go abroad,attend an international scientific conference or publish their research results,one issue they may face is the cross-culture academic English communication.
文摘AIM:To develop the methods of PBL on pathophysiology teaching for the medical students.METHODS: We chose 1 class from the 7-year program students in China Medical University and conducted bilingual PBL course of pathophysiology,we also chose 1 class from the 5-year program students and conducted PBL course in Chinese,the other classes were in traditional curriculum. We used special textbook in PBL class.
文摘Pathophysiology,dealing with the functional changes in the host with disease or particular syndrome,is regarded as a bridge to guide students from basic medicine to clinical medicine. However,the traditional way in teaching of pathophysiology is far from clinical practice,mainly focuses on the acquisition and mastery of theoretical knowledge. Moreover,it is difficult for students to master the basic theoretical knowledge specifically and effectively under the condition away from clinical patients. In order to enhance the association of basic course with clinic,to combine the lecture and learning knowledge and clinical skills,we try to perform the combination of teaching pathophysiology with clinical practice in the training program for teachers and teaching activities. 1. The object:(1)Based on typical clinical cases,students participate bed side teaching and study theoretical knowledge.(2)To create whole concept on association among organs and systems of human diseases.
文摘Pathophysiology is a bridge discipline between preclinical medicine and clinical medicine. The course design is closely related to the teaching effectiveness. Continuously optimizing the traditional curriculum whole and adaptively to the medical development in the new century,we achieve the best teaching results since the following setting up have been made. 1.
文摘Pathophysiology, as a bridge discipline connecting basic medicine and clinical medicine, occupies an important position in medical education. Traditional teaching of pathophysiology has certain limitations, such as overly emphasizing the imparting of theoretical knowledge and imprisoning students in a state of separation between teaching and learning, as well as between learning and application. Participatory teaching is student-centered, emphasizing interaction between teachers and students, as well as communication and cooperation among students. It can improve students’ abilities to utilize information, express themselves, and analyze comprehensively, cultivate their teamwork spirit, help break the limitations of traditional teaching, and improve the quality of pathophysiology teaching.
文摘Course based ideological and political education (CIPE) is an important way to improve the quality of ideological and political work and talent cultivation. This study explores for the first time the implementation of ideological and political education in the teaching of pathophysiology courses, and also analyzes the evaluation of student psychological status and the importance of mental health education in the implementation of IPE courses. A survey was conducted on 211 students at Yangtze University to understand their motivation and behavior towards learning ideological, political, and pathophysiological courses. In addition, a questionnaire survey was used to explore the relationship between pathophysiology and ideological and political courses, as well as the importance of their satisfaction with the implementation of ideological and political courses in pathophysiology and mental health education. The research results indicate that factors such as educational background and gender differences affect the learning of CIPE. Graduate students are more interested in ideological and political courses, while female students find it difficult to study pathophysiology;In addition, the results of one-way ANOVA indicate that the implementation effect of IPE in pathophysiology courses depends on the level of interest in IPE and pathophysiology courses, the level of consideration for the importance of professional courses, the professional gains after studying pathophysiology, and the level of understanding of the relationship between IPE and CIPE. 81.04% of students believe that in the CIPE process, telling stories by teachers themselves is the most popular way of communication and education. This reflects the importance of mental health education from the perspective of CIPE. In addition, this study also indicates that PBL and flipped classroom teaching models are popular teaching models in CIPE. This study is beneficial for promoting the improvement and implementation of CIPE and mental health education in higher education curricula, thus providing valuable insights for educational decision-makers.
基金Supported by the Italian Ministry of Health-Current research IRCCS(Funds Dedicated to the Research of the Gastroenterology and Digestive Endoscopy Unit,Fondazione IRCCS Ca’Granda,Ospedale Maggiore Policlinico,Milano).
文摘BACKGROUND Endoscopic ultrasound(EUS)is crucial for diagnosing solid pancreatic lesions,especially pancreatic ductal adenocarcinoma(PDAC),a highly aggressive cancer which represents the majority with a prevalence of approximately 85%.AIM To identify EUS features that differentiate PDAC from other lesions such as neuroendocrine tumors(NETs)and helping in the differential diagnosis,by analyzing a large sample of solid pancreatic lesions.METHODS This observational,retrospective,multicenter study analyzed the endosonographic characteristics of 761 patients with a radiological diagnosis of solid pancreatic lesion,who underwent pancreatic EUS for typing and staging with needle biopsies between 2015 and 2023.General patient characteristics(age and sex)and solid lesion features were collected and described,such lesion size(Bmode),vessel involvement(compression or invasion),ductal dilation,lymphadenopathy,echogenicity,echopattern,margin regularity,multifocality,internal vascularization and elastography.Subsequently,a predictive analysis was performed through univariate and multivariate logistic regression to identify predictive features for PDAC or NET diagnoses.RESULTS Our study enrolled 761 patients,predominantly male with a mean age of 68.6.PDACs were generally larger(mean 33 mm×27 mm),often had irregular margins,and displayed significant upstream ductal dilation.Hypoechogenicity was common across malignant lesions.In contrast,NETs were smaller(mean 20 mm×17 mm)and typically had regular margins with multiple lesions.Vascular involvement,although predominant in PDAC,is a common feature of all malignant neoplasms.Multifocality,however,although a rare finding,is more typical of NETs and metastases,and practically absent in the remaining lesions.Predictive analyses showed that ductal dilation and irregular margins were the most significant predictors for PDAC[odds ratio(OR)=5.75 and 3.83],with hypoechogenicity,heterogeneous echopattern and lymphadenopathies also highly significant(OR=3.51,2.56 and 1.99).These features were inversely associated with NETs,with regular margins and absence of ductal involvement or lymphadenopathies(OR=0.24,0.86 and 0.45 respectively),as already shown by the descriptive analysis.Finally,age,despite achieving statistical significance,lacks clinical value given an OR trending towards 1.CONCLUSION This study provides a comprehensive overview of EUS features for solid pancreatic lesions,identifying distinct features like upstream ductal dilation and irregular margins for PDAC vs regular margins for NETs as strong diagnostic predictors.These findings enhance the understanding of pancreatic pathologies,offering valuable insights for improved differential diagnosis and clinical management,especially in complex cases.Further prospective studies could build on these results.
基金supported in part by the National Natural Science Foundation of China(91949205,82071219,82001134,31730035,81721005,and 82201584)the Hubei Provincial Key S&T Program(2018ACA142)the Guangdong Provincial Key S&T Program(2018B030336001).
文摘Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease(AD),which is closely related to tau pathology and hippocampal impairment.Due to the heterogeneity of brain neurons,the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear.Therefore,further investigation is necessary.Methods:We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis,social behavioural tests,hippocampal electrophysiology,immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR.Additionally,we utilized optogenetics and administered ursolic acid(UA)via oral gavage to examine the effects of these agents on social memory in mice.Results:The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1(vCA1)under both physiological conditions and AD-like tau pathology.As tau progressively accumulated,vCA1,especially its excitatory and parvalbumin(PV)neurons,were fully filled with mislocated and phosphorylated tau(p-Tau).This finding was not observed for dorsal hippocampal CA1(dCA1).The overexpression of human tau(hTau)in excitatory and PV neurons mimicked AD-like tau accumulation,significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1.Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory.Notably,1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB(TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion:This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation.Notably,our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.
基金Supported by the China Postdoctoral Science Foundation General Program,No.2024M762504the Intramural Research Program of Liyuan Hospital,Tongji Medical College,Huazhong University of Science and Technology,No.2023 LYYYGZRP0004.
文摘BACKGROUND Apolipoprotein E epsilon 4(APOE4)is recognized as a genetic risk factor for cognitive decline and neurodegeneration in both type 2 diabetes mellitus(T2DM)and Alzheimer’s disease,while glycated hemoglobin(HbA1c)reflects persistent hyperglycemia and serves as a key indicator of long-term glycemic control in T2DM.Although both factors have been individually linked to neurobehavioral deficits,it remains uncertain whether HbA1c contributes to APOE4-related cognitive and olfactory impairment in individuals with T2DM.AIM To investigate the role of HbA1c in APOE4-associated cognitive and olfactory dysfunction in patients with T2DM.METHODS Of 636 T2DM patients were recruited from five medical centers in Wuhan,Hubei Province,China.APOE genotyping was evaluated by polymerase chain reaction using Gerard’s method.Cognitive and olfactory functions were assessed by mini-mental state examination and Connecticut chemosensory clinical research center test,respectively.Regression analysis was employed to assess the independent and interactive effects of HbA1c on APOE4-associated cognitive and olfactory function.RESULTS APOE4 was associated with increased risks of cognitive impairment[odds ratios(OR)=1.815,P=0.021]and olfactory dysfunction(OR=2.588,P<0.001).Higher HbA1c levels were also related to worse cognitive(OR=1.189,P<0.001)and olfactory performance(OR=1.149,P=0.011).HbA1c exerted a moderating effect,yet not a mediating effect,between APOE4 and its impacts on cognition and olfaction.Specifically,a higher level of HbA1c exacerbated the damaging effect of APOE4,as shown by significant interaction effects on both cognitive impairment(OR=2.687,P<0.001)and olfactory dysfunction(OR=1.440,P=0.027).CONCLUSION Elevated HbA1c levels are associated with increased risks of cognitive and olfactory impairments in patients with T2DM and may exacerbate the detrimental effects of APOE4.These findings underscore the need for early preventive strategies targeting individuals with both poor glycemic control and APOE4 carriage to mitigate neurodegenerative risk.
文摘The discontinuation of denosumab[antibody targeting receptor activator of nuclear factor kappa B ligand(RANKL)]therapy may increase the risk of multiple vertebral fractures;however,the underlying pathophysiology is largely unknown.In patients who underwent discontinuation after multiple injections of denosumab,the levels of tartrate-resistant acid phosphatase 5b increased compared to pretreatment levels,indicating a phenomenon known as“overshoot.”The rate of decrease in bone mineral density during the withdrawal period was higher than the rate of decrease associated with aging,suggesting that the physiological bone metabolism had broken down.Overshoot and significant bone loss were also observed in mice receiving continuous administration of anti-RANKL antibody after treatment was interrupted,resembling the original pathology.In mice long out of overshoot,bone resorption recovered,but osteoblast numbers and bone formation remained markedly reduced.The bone marrow exhibited a significant reduction in stem cell(SC)antigen 1-and platelet-derived growth factor receptor alpha-expressing osteoblast progenitors(PαS cells)and alkaline phosphatase-positive early osteoblasts.Just before the overshoot phase,the osteoclast precursor cell population expands and RANKL-bearing extracellular vesicles(EVs)became abundant in the serum,leading to robust osteoclastogenesis after cessation of anti-RANKL treatment.Thus,accelerated bone resorption due to the accumulation of RANKLbearing EVs and long-term suppression of bone formation uncoupled from bone resorption leads to the severe bone loss characteristic of denosumab discontinuation.
基金supported by the National Key Research and Development Program of China,No.2022YFC2703101(to YC)the National Natural Science Fundation of China,No.82371422(to YC)+1 种基金the National Innovation and Entrepreneurship Training Program for College Students,No.202310611408(to XW)the 1·3·5 Project for Disciplines of Excellence Clinical Research Fund,West China Hospital,Sichuan University,No.2023HXFH032(to YC)。
文摘Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.
基金supported by Italian Ministry of Health Ricerca Corrente [RC 2023] and RF-2016-02361294supported by#NEXTGENERATIONEU (NGEU)+3 种基金funded by the Ministry of University and Research (MUR)National Recovery and Resilience Plan (NRRP)project MNESYS (PE0000006)–A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022)(to FRG)partially supported by a grant from Fondazione Romeo ed Enrica Invernizzi (to FRG)。
文摘Multiple sclerosis(MS) is a chronic, autoimmune and neuroinflammatory disease of the central nervous system(CNS) with a neurodegenerative component, characterized by demyelination and degeneration of nerve fibers. It affects mainly young adults(aged 20 to 45 years) and its causes are still unknown, but it is thought that external factors such as viruses and environmental factors trigger the disease in people with a genetic susceptibility.
文摘Nonalcoholic fatty liver disease(NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis(NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis(increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific lifestyle modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular disease improving overall prognosis and survival.
