Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to r...Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis.The only two treatments actually approved,riluzole and edaravone,have shown mitigated beneficial effects.The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis.Among mechanisms,abnormal RNA metabolism,nucleocytoplasmic transport defects,accumulation of unfolded protein,and mitochondrial dysfunction would in fine induce oxidative damage and vice versa.A potent therapeutic strategy will be to find molecules that break this vicious circle.Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense,mitochondrial functioning,and inflammation.We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.展开更多
Harmful and helpful roles of astrocytes in spinal cord injury(SCI):SCI induce gradable sensory,motor and autonomic impairments that correlate with the lesion severity and the rostro-caudal location of the injury site....Harmful and helpful roles of astrocytes in spinal cord injury(SCI):SCI induce gradable sensory,motor and autonomic impairments that correlate with the lesion severity and the rostro-caudal location of the injury site.The absence of spontaneous axonal regeneration after injury results from neuron-intrinsic and neuron-extrinsic parameters.Indeed,not only adult neurons display limited capability to regrow axons but also the injury environment contains inhibitors to axonal regeneration and a lack of growth-promoting factors.Amongst other cell populations that respond to the lesion,reactive astrocytes were first considered as only detrimental to spontaneous axonal regeneration.Indeed,astrocytes.展开更多
Spinal cord injury results in significant sensorimotor deficits,currently,there is no curative treatment for the symptoms induced by spinal cord injury.Basic and pre-clinical research on spinal cord injury relies on t...Spinal cord injury results in significant sensorimotor deficits,currently,there is no curative treatment for the symptoms induced by spinal cord injury.Basic and pre-clinical research on spinal cord injury relies on the development and characterization of appropriate animal models.These models should replicate the symptoms observed in human,allowing for the exploration of functional deficits and investigation into various aspects of physiopathology of spinal cord injury.Non-human primates,due to their close phylogenetic association with humans,share more neuroanatomical,genetic,and physiological similarities with humans than rodents.Therefore,the responses to spinal cord injury in nonhuman primates most likely resemble the responses to traumatism in humans.In this review,we will discuss nonhuman primate models of spinal cord injury,focusing on in vivo assessments,including behavioral tests,magnetic resonance imaging,and electrical activity recordings,as well as ex vivo histological analyses.Additionally,we will present therapeutic strategies developed in non-human primates and discuss the unique specificities of non-human primate models of spinal cord injury.展开更多
Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve deve...Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve development and maturation.Its cleavable extracellular domain(ECD)is readily detectable in various biological fluids including plasma,serum and urine.There is evidence for increased p75NTR ECD levels in neurodegenerative diseases such as Alzheimer’s disease,amyotrophic lateral sclerosis,age-related dementia,schizophrenia,and diabetic neuropathy.Whether p75^(NTR) ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders,and whether it could potentially lead to the development of targeted therapies,remains an open question.In this review,we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases.We also highlight areas that require further investigation to better understand the role of p75^(NTR) ECD in the clinical diagnosis and management of neurodegenerative disorders.展开更多
Exploring the aptitude of the human brain to compensate functional consequences of a lesion damaging its structural architecture is a key challenge to improve patient care in various neurological diseases,to optimize ...Exploring the aptitude of the human brain to compensate functional consequences of a lesion damaging its structural architecture is a key challenge to improve patient care in various neurological diseases,to optimize neuroscientifically-informed strategies of postlesional rehabilitation,and ultimately to develop innovative neuro-regenerative therapies.The term‘plasticity’,initially referring to the intrinsic propensity of neurons to modulate their synaptic transmission in a learning situation,was progressively transposed to brain injury research and clinical neurosciences.Indeed,in the event of brain damage,adaptive mechanisms of compensation allow a partial reshaping of the structure and activities of the central nervous system,thus permitting to some extent the maintenance of brain functions.展开更多
Cardiac rehabilitation helps improve the prognosis and quality of life for patients with heart disease. To show its interest in the African context, in the management of heart disease, a prospective study was carried ...Cardiac rehabilitation helps improve the prognosis and quality of life for patients with heart disease. To show its interest in the African context, in the management of heart disease, a prospective study was carried out. Its objective was to evaluate the effects of physical rehabilitation on cardiac function. Methods: Patients were evaluated at the beginning and at the end of cardiovascular rehabilitation by cardiovascular, biological, and echocardiographic parameters including the size of the heart chambers, the kinetics of the walls, and the systolic function of the ventricles. Results: The study involved 12 patients, 67% of whom were men. After cardiac rehabilitation, the mean hemodynamic constants had not been significantly modified. However, a significant decrease in Total-Cholesterol, LDL-Cholesterol and triglyceride levels was noted. Mean fasting blood sugar decreased from 1.25 ± 0.48 g/L to 0.92 ± 0.18 g/L and glycated hemoglobin from 7.72% ± 0.01% to 6.45% ± 0.008%. The echocardiographic parameters studied showed an improvement in the dilation of the heart chambers in 8.33% of the patients, the normalization of the ejection fraction of the left ventricle in 16% patients, the improvement of the kinetic disorders in 16% of patients and recovery of right ventricular systolic function in all patients. Conclusion: Cardiac rehabilitation as a secondary preventive measure for cardiovascular disease has contributed significantly to improving the clinico-biological parameters of the disease.展开更多
Taurine is considered a non-essential amino acid because it is synthesized by most mammals.However,dietary intake of taurine may be necessary to achieve the physiological levels required for the development,maintenanc...Taurine is considered a non-essential amino acid because it is synthesized by most mammals.However,dietary intake of taurine may be necessary to achieve the physiological levels required for the development,maintenance,and function of certain tissues.Taurine may be especially important for the retina.The concentration of taurine in the retina is higher than that in any other tissue in the body and taurine deficiency causes retinal oxidative stress,apoptosis,and degeneration of photoreceptors and retinal ganglion cells.Low plasma taurine levels may also underlie retinal degeneration in humans and therefore,taurine administration could exert retinal neuroprotective effects.Taurine has antioxidant,anti-apoptotic,immunomodulatory,and calcium homeostasis-regulatory properties.This review summarizes the role of taurine in retinal health and disease,where it appears that taurine may be a promising nutraceutical.展开更多
Thedirectdeliveryofinhaledantibioticstothe respiratory tract has been a subject of enduring interest among medical practitioners and researchers due to the associated favorable pharmacokinetics.This interest has been ...Thedirectdeliveryofinhaledantibioticstothe respiratory tract has been a subject of enduring interest among medical practitioners and researchers due to the associated favorable pharmacokinetics.This interest has been particularly pronounced in the context of critically illpatients,wherehealthcare-associatedpulmonary infections represent a significant challenge,driving continued exploration of inhaled antibiotics for intubated patients.Recent high-level evidence has shown a very promising application in the field of ventilator-associated pneumonia (VAP) prevention.^([1]).展开更多
Adult neurogenesis,the process of creating new neurons,involves the coordinated division,migration,and differentiation of neural stem cells.This process is restricted to neurogenic niches located in two distinct areas...Adult neurogenesis,the process of creating new neurons,involves the coordinated division,migration,and differentiation of neural stem cells.This process is restricted to neurogenic niches located in two distinct areas of the brain:the subgranular zone of the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle,where new neurons are generated and then migrate to the olfactory bulb.Neurogenesis has been thought to occur only during the embryonic and early postnatal stages and to decline with age due to a continuous depletion of neural stem cells.Interestingly,recent years have seen tremendous progress in our understanding of adult brain neurogenesis,bridging the knowledge gap between embryonic and adult neurogenesis.Here,we discuss the current status of adult brain neurogenesis in light of what we know about neural stem cells.In this notion,we talk about the importance of intra cellular signaling molecules in mobilizing endogenous neural stem cell prolife ration.Based on the current understanding,we can declare that these molecules play a role in targeting neurogenesis in the mature brain.However,to achieve this goal,we need to avoid the undesired proliferation of neural stem cells by controlling the necessary checkpoints,which can lead to tumorigenesis and prove to be a curse instead of a blessing or hope.展开更多
BACKGROUND Colorectal signet-ring cell carcinoma(CSRCC)is a rare clinical entity which accounts for approximately 1%of all colorectal cancers.Although multiple studies concerning this specific topic have been publishe...BACKGROUND Colorectal signet-ring cell carcinoma(CSRCC)is a rare clinical entity which accounts for approximately 1%of all colorectal cancers.Although multiple studies concerning this specific topic have been published in the past decades,the pathogenesis,associated risk factors,and potential implications on treatment are still poorly understood.Besides the low incidence,historically confusing histological criteria have resulted in confusing data.Nevertheless,the rising incidence of CSRCC along with relatively young age at presentation and associated dismal prognosis,highlight the actual interest to synthesize the known literature regarding CSRCC.AIM To provide an updated overview of risk factors,prognosis,and management of CSRCC.METHODS A literature search in the MEDLINE/PubMed database was conducted with the following search terms used:‘Signet ring cell carcinoma’and‘colorectal’.Studies in English language,published after January 1980,were included.Studies included in the qualitative synthesis were evaluated for content concerning epidemiology,risk factors,and clinical,diagnostic,histological,and molecular features,as well as metastatic pattern and therapeutic management.If possible,presented data was extracted in order to present a more detailed overview of the literature.RESULTS In total,67 articles were included for qualitative analysis,of which 54 were eligible for detailed data extraction.CSRCC has a reported incidence between 0.1%-2.4%and frequently presents with advanced disease stage at the time of diagnosis.CSRCC is associated with an impaired overall survival(5-year OS:0%-46%)and a worse stagecorrected outcome compared to mucinous and not otherwise specified adenocarcinoma.The systematic use of exploratory laparoscopy to determine the presence of peritoneal metastases has been advised.Surgery is the mainstay of treatment,although the rates of curative resection in CSRCC(21%-82%)are lower compared to those in other histological types.In case of peritoneal metastasis,cytoreductive surgery with hyperthermic intraperitoneal chemotherapy should only be proposed in selected patients.CONCLUSION CSRCC is a rare clinical entity most often characterized by young age and advanced disease at presentation.As such,diagnostic modalities and therapeutic approach should be tailored accordingly.展开更多
Objectives: More than a year after its introduction, COVID-19 vaccination coverage was low in the Togolese population and little data were available on its benefits for hospitalized patients. This study aimed to descr...Objectives: More than a year after its introduction, COVID-19 vaccination coverage was low in the Togolese population and little data were available on its benefits for hospitalized patients. This study aimed to describe the impact of COVID-19 vaccination on the prognosis of hospitalized patients. Methods: This was a retrospective cohort study of patients admitted to the Centre Hospitalier Régional Lomé Commune (Togo) between June 1, 2021 and May 31, 2022. Primary outcomes (admission to the intensive care unit and death) were presented with frequency and proportion. Mortality rates were presented by sociodemographic and clinical characteristics and compared by appropriate statistical tests. Factors associated with inpatient death were described by performing a Cox proportional hazard regression. Results: A total of 604 patients were hospitalized (50.0% women). The mean age was 54.03 ±17.1 years. Only 55 patients were fully vaccinated (9.1%). ICU admission was significantly more frequent in unvaccinated patients than in vaccinated ones (63.0% vs. 38.2%;p Conclusion: COVID-19 vaccination had a significant benefit for patients with COVID-19 infection in terms of reducing the risk of death. Based on real-world data from sub-Saharan Africa, this information can help optimize the benefit of COVID-19 vaccination by raising community awareness and increasing vaccine coverage while reducing hesitancy.展开更多
Neuropathic pain is a severe and chronic condition widely found in the general population.The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients....Neuropathic pain is a severe and chronic condition widely found in the general population.The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients.During the processing of pain,the dorsal root ganglia constitute an important region where dorsal root ganglion neurons play a crucial role in the transmission and propagation of sensory electrical stimulation.Furthermore,the dorsal root ganglia have recently exhibited a regenerative capacity that should not be neglected in the understanding of the development and resolution of neuropathic pain and in the elucidation of innovative therapies.Here,we will review the complex interplay between cells(satellite glial cells and inflammatory cells)and factors(cytokines,neurotrophic factors and genetic factors)that takes place within the dorsal root ganglia and accounts for the generation of the aberrant excitation of primary sensory neurons occurring in neuropathic pain.More importantly,we will summarize an updated view of the current pharmacologic and nonpharmacologic therapies targeting the dorsal root ganglia for the treatment of neuropathic pain.展开更多
Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the pho...Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.展开更多
Candida auris since it discovery in 2009 is becoming a severe threat to human health due to its very quickly spread, its worldwide high resistance to systemic antifungal drugs. In resource-constrained settings where s...Candida auris since it discovery in 2009 is becoming a severe threat to human health due to its very quickly spread, its worldwide high resistance to systemic antifungal drugs. In resource-constrained settings where several conditions are met for its emergence and spread, this worrisome fungus could cause large hospital and/or community-based outbreaks. This review aimed to summarize the available data on C. auris in Africa focusing on its epidemiology and antifungal resistance profile. Major databases were searched for articles on the epidemiology and antifungal resistance profile of C. auris in Africa. Out of 2,521 articles identified 22 met the inclusion criteria. In Africa, nearly 89% of African countries have no published data on C. auris. The prevalence of C. auris in Africa was 8.74%. The case fatality rate of C. auris infection in Africa was 39.46%. The main C. auris risk factors reported in Africa were cardiovascular disease, renal failure, diabetes, HIV, recent intake of antimicrobial drugs, ICU admissions, surgery, hemodialysis, parenteral nutrition and indwelling devices. Four phylogenetic clades were reported in Africa, namely clades I, II, III and IV. Candida auris showed a pan-African very high resistance rate to fluconazole, moderate resistance to amphotericin B, and high susceptibility to echinocandins. Finally, C. auris clade-specific mutations were observed within the ERG2, ERG3, ERG9, ERG11, FKS1, TAC1b and MRR1 genes in Africa. This systematic review showed the presence of C. auris in the African continent and a worrying unavailability of data on this resilient fungus in most African countries.展开更多
Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are inv...Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.展开更多
Rheumatoid arthritis(RA)and periodontitis are chronic inflammatory diseases leading to increased bone resorption.Preventing this inflammatory bone resorption is a major health challenge.Both diseases share immunopatho...Rheumatoid arthritis(RA)and periodontitis are chronic inflammatory diseases leading to increased bone resorption.Preventing this inflammatory bone resorption is a major health challenge.Both diseases share immunopathogenic similarities and a common inflammatory environment.The autoimmune response or periodontal infection stimulates certain immune actors,leading in both cases to chronic inflammation that perpetuates bone resorption.Moreover,RA and periodontitis have a strong epidemiological association that could be explained by periodontal microbial dysbiosis.This dysbiosis is believed to be involved in the initiation of RA via three mechanisms.(i)The dissemination of periodontal pathogens triggers systemic inflammation.(ii)Periodontal pathogens can induce the generation of citrullinated neoepitopes,leading to the generation of anti-citrullinated peptide autoantibodies.(iii)Intracellular danger-associated molecular patterns accelerate local and systemic inflammation.Therefore,periodontal dysbiosis could promote or sustain bone resorption in distant inflamed joints.Interestingly,in inflammatory conditions,the existence of osteoclasts distinct from“classical osteoclasts”has recently been reported.They have proinflammatory origins and functions.Several populations of osteoclast precursors have been described in RA,such as classical monocytes,a dendritic cell subtype,and arthritis-associated osteoclastogenic macrophages.The aim of this review is to synthesize knowledge on osteoclasts and their precursors in inflammatory conditions,especially in RA and periodontitis.Special attention will be given to recent data related to RA that could be of potential value in periodontitis due to the immunopathogenic similarities between the two diseases.Improving our understanding of these pathogenic mechanisms should lead to the identification of new therapeutic targets involved in the pathological inflammatory bone resorption associated with these diseases.展开更多
Alteration of the outer retina leads to various diseases such as age-related macular degeneration or retinitis pigmentosa characterized by decreased visual acuity and ultimately blindness.Despite intensive research in...Alteration of the outer retina leads to various diseases such as age-related macular degeneration or retinitis pigmentosa characterized by decreased visual acuity and ultimately blindness.Despite intensive research in the field of retinal disorders,there is currently no curative treatment.Several therapeutic approaches such as cell-based replacement and gene therapies are currently in development.In the context of cell-based therapies,different cell sources such as embryonic stem cells,induced pluripotent stem cells,or multipotent stem cells can be used for transplantation.In the vast majority of human clinical trials,retinal pigment epithelial cells and photoreceptors are the cell types considered for replacement cell therapies.In this review,we summarize the progress made in stem cell therapies ranging from the pre-clinical studies to clinical trials for retinal disease.展开更多
Epilepsy is a neurological disorder caused by the pathological hyper-synchronization of neuronal discharges.The fundamental research of epilepsy mechanisms and the targets of drug design options for its treatment have...Epilepsy is a neurological disorder caused by the pathological hyper-synchronization of neuronal discharges.The fundamental research of epilepsy mechanisms and the targets of drug design options for its treatment have focused on neurons.However,approximately 30%of patients suffering from epilepsy show resistance to standard anti-epileptic chemotherapeutic agents while the symptoms of the remaining 70%of patients can be alleviated but not completely removed by the current medications.Thus,new strategies for the treatment of epilepsy are in urgent demand.Over the past decades,with the increase in knowledge on the role of glia in the genesis and development of epilepsy,glial cells are receiving renewed attention.In a normal brain,glial cells maintain neuronal health and in partnership with neurons regulate virtually every aspect of brain function.In epilepsy,however,the supportive roles of glial cells are compromised,and their interaction with neurons is altered,which disrupts brain function.In this review,we will focus on the role of glia-related processes in epileptogenesis and their contribution to abnormal neuronal activity,with the major focus on the dysfunction of astroglial potassium channels,water channels,gap junctions,glutamate transporters,purinergic signaling,synaptogenesis,on the roles of microglial inflammatory cytokines,microglia-astrocyte interactions in epilepsy,and on the oligodendroglial potassium channels and myelin abnormalities in the epileptic brain.These recent findings suggest that glia should be considered as the promising next-generation targets for designing anti-epileptic drugs that may improve epilepsy and drug-resistant epilepsy.展开更多
Crohn’s disease(CD)is an inflammatory bowel disease characterized by immunemediated flares affecting any region of the intestine alternating with remission periods.In CD,the ileum is frequently affected and about one...Crohn’s disease(CD)is an inflammatory bowel disease characterized by immunemediated flares affecting any region of the intestine alternating with remission periods.In CD,the ileum is frequently affected and about one third of patients presents with a pure ileal type.Moreover,the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes.Most of these genes are associated with Paneth cell dysfunction,a cell type found in the intestinal crypts of the ileum.Besides,a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota,which in turn modulates the susceptibility of the ileum to inflammation.Thus,the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis.Indeed,both immune response and cellular healing processes harbour differences between ileal and non-ileal CD.Taken together,these findings advocate for a dedicated therapeutic approach to managing ileal CD.Currently,interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site.However,the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.展开更多
基金supported by a grant from the Association Française contre les Myopathies(AFM Téléthongrant 23667,to JCL).
文摘Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis.The only two treatments actually approved,riluzole and edaravone,have shown mitigated beneficial effects.The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis.Among mechanisms,abnormal RNA metabolism,nucleocytoplasmic transport defects,accumulation of unfolded protein,and mitochondrial dysfunction would in fine induce oxidative damage and vice versa.A potent therapeutic strategy will be to find molecules that break this vicious circle.Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense,mitochondrial functioning,and inflammation.We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.
基金supported by the patient organizations“Verticale”(to YNG and FEP).
文摘Harmful and helpful roles of astrocytes in spinal cord injury(SCI):SCI induce gradable sensory,motor and autonomic impairments that correlate with the lesion severity and the rostro-caudal location of the injury site.The absence of spontaneous axonal regeneration after injury results from neuron-intrinsic and neuron-extrinsic parameters.Indeed,not only adult neurons display limited capability to regrow axons but also the injury environment contains inhibitors to axonal regeneration and a lack of growth-promoting factors.Amongst other cell populations that respond to the lesion,reactive astrocytes were first considered as only detrimental to spontaneous axonal regeneration.Indeed,astrocytes.
基金supported by the patient organizations“Verticale”(to FEP).
文摘Spinal cord injury results in significant sensorimotor deficits,currently,there is no curative treatment for the symptoms induced by spinal cord injury.Basic and pre-clinical research on spinal cord injury relies on the development and characterization of appropriate animal models.These models should replicate the symptoms observed in human,allowing for the exploration of functional deficits and investigation into various aspects of physiopathology of spinal cord injury.Non-human primates,due to their close phylogenetic association with humans,share more neuroanatomical,genetic,and physiological similarities with humans than rodents.Therefore,the responses to spinal cord injury in nonhuman primates most likely resemble the responses to traumatism in humans.In this review,we will discuss nonhuman primate models of spinal cord injury,focusing on in vivo assessments,including behavioral tests,magnetic resonance imaging,and electrical activity recordings,as well as ex vivo histological analyses.Additionally,we will present therapeutic strategies developed in non-human primates and discuss the unique specificities of non-human primate models of spinal cord injury.
文摘Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve development and maturation.Its cleavable extracellular domain(ECD)is readily detectable in various biological fluids including plasma,serum and urine.There is evidence for increased p75NTR ECD levels in neurodegenerative diseases such as Alzheimer’s disease,amyotrophic lateral sclerosis,age-related dementia,schizophrenia,and diabetic neuropathy.Whether p75^(NTR) ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders,and whether it could potentially lead to the development of targeted therapies,remains an open question.In this review,we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases.We also highlight areas that require further investigation to better understand the role of p75^(NTR) ECD in the clinical diagnosis and management of neurodegenerative disorders.
文摘Exploring the aptitude of the human brain to compensate functional consequences of a lesion damaging its structural architecture is a key challenge to improve patient care in various neurological diseases,to optimize neuroscientifically-informed strategies of postlesional rehabilitation,and ultimately to develop innovative neuro-regenerative therapies.The term‘plasticity’,initially referring to the intrinsic propensity of neurons to modulate their synaptic transmission in a learning situation,was progressively transposed to brain injury research and clinical neurosciences.Indeed,in the event of brain damage,adaptive mechanisms of compensation allow a partial reshaping of the structure and activities of the central nervous system,thus permitting to some extent the maintenance of brain functions.
文摘Cardiac rehabilitation helps improve the prognosis and quality of life for patients with heart disease. To show its interest in the African context, in the management of heart disease, a prospective study was carried out. Its objective was to evaluate the effects of physical rehabilitation on cardiac function. Methods: Patients were evaluated at the beginning and at the end of cardiovascular rehabilitation by cardiovascular, biological, and echocardiographic parameters including the size of the heart chambers, the kinetics of the walls, and the systolic function of the ventricles. Results: The study involved 12 patients, 67% of whom were men. After cardiac rehabilitation, the mean hemodynamic constants had not been significantly modified. However, a significant decrease in Total-Cholesterol, LDL-Cholesterol and triglyceride levels was noted. Mean fasting blood sugar decreased from 1.25 ± 0.48 g/L to 0.92 ± 0.18 g/L and glycated hemoglobin from 7.72% ± 0.01% to 6.45% ± 0.008%. The echocardiographic parameters studied showed an improvement in the dilation of the heart chambers in 8.33% of the patients, the normalization of the ejection fraction of the left ventricle in 16% patients, the improvement of the kinetic disorders in 16% of patients and recovery of right ventricular systolic function in all patients. Conclusion: Cardiac rehabilitation as a secondary preventive measure for cardiovascular disease has contributed significantly to improving the clinico-biological parameters of the disease.
基金supported by Instituto de Salud CarlosⅢ(ISCⅢ):PI19/00203cofunded by ERDF+9 种基金"A way to make Europe"to MPVP and DGAP122/00900RD16/0008/0026 co-funded by ERDF"A way to make Europe"to MPVP and RD21/0002/0014financiado porla Unión Europea-NextGenerationEUFundación Robles Chillida to DGARED2018-102499-TPID201 9-106498GB-I00funded by MCIN/AEI/10.13039/501100011 033 to MVSIHU FOReSIGHT[ANR-18-IAHU-0001] to SP
文摘Taurine is considered a non-essential amino acid because it is synthesized by most mammals.However,dietary intake of taurine may be necessary to achieve the physiological levels required for the development,maintenance,and function of certain tissues.Taurine may be especially important for the retina.The concentration of taurine in the retina is higher than that in any other tissue in the body and taurine deficiency causes retinal oxidative stress,apoptosis,and degeneration of photoreceptors and retinal ganglion cells.Low plasma taurine levels may also underlie retinal degeneration in humans and therefore,taurine administration could exert retinal neuroprotective effects.Taurine has antioxidant,anti-apoptotic,immunomodulatory,and calcium homeostasis-regulatory properties.This review summarizes the role of taurine in retinal health and disease,where it appears that taurine may be a promising nutraceutical.
文摘Thedirectdeliveryofinhaledantibioticstothe respiratory tract has been a subject of enduring interest among medical practitioners and researchers due to the associated favorable pharmacokinetics.This interest has been particularly pronounced in the context of critically illpatients,wherehealthcare-associatedpulmonary infections represent a significant challenge,driving continued exploration of inhaled antibiotics for intubated patients.Recent high-level evidence has shown a very promising application in the field of ventilator-associated pneumonia (VAP) prevention.^([1]).
文摘Adult neurogenesis,the process of creating new neurons,involves the coordinated division,migration,and differentiation of neural stem cells.This process is restricted to neurogenic niches located in two distinct areas of the brain:the subgranular zone of the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle,where new neurons are generated and then migrate to the olfactory bulb.Neurogenesis has been thought to occur only during the embryonic and early postnatal stages and to decline with age due to a continuous depletion of neural stem cells.Interestingly,recent years have seen tremendous progress in our understanding of adult brain neurogenesis,bridging the knowledge gap between embryonic and adult neurogenesis.Here,we discuss the current status of adult brain neurogenesis in light of what we know about neural stem cells.In this notion,we talk about the importance of intra cellular signaling molecules in mobilizing endogenous neural stem cell prolife ration.Based on the current understanding,we can declare that these molecules play a role in targeting neurogenesis in the mature brain.However,to achieve this goal,we need to avoid the undesired proliferation of neural stem cells by controlling the necessary checkpoints,which can lead to tumorigenesis and prove to be a curse instead of a blessing or hope.
文摘BACKGROUND Colorectal signet-ring cell carcinoma(CSRCC)is a rare clinical entity which accounts for approximately 1%of all colorectal cancers.Although multiple studies concerning this specific topic have been published in the past decades,the pathogenesis,associated risk factors,and potential implications on treatment are still poorly understood.Besides the low incidence,historically confusing histological criteria have resulted in confusing data.Nevertheless,the rising incidence of CSRCC along with relatively young age at presentation and associated dismal prognosis,highlight the actual interest to synthesize the known literature regarding CSRCC.AIM To provide an updated overview of risk factors,prognosis,and management of CSRCC.METHODS A literature search in the MEDLINE/PubMed database was conducted with the following search terms used:‘Signet ring cell carcinoma’and‘colorectal’.Studies in English language,published after January 1980,were included.Studies included in the qualitative synthesis were evaluated for content concerning epidemiology,risk factors,and clinical,diagnostic,histological,and molecular features,as well as metastatic pattern and therapeutic management.If possible,presented data was extracted in order to present a more detailed overview of the literature.RESULTS In total,67 articles were included for qualitative analysis,of which 54 were eligible for detailed data extraction.CSRCC has a reported incidence between 0.1%-2.4%and frequently presents with advanced disease stage at the time of diagnosis.CSRCC is associated with an impaired overall survival(5-year OS:0%-46%)and a worse stagecorrected outcome compared to mucinous and not otherwise specified adenocarcinoma.The systematic use of exploratory laparoscopy to determine the presence of peritoneal metastases has been advised.Surgery is the mainstay of treatment,although the rates of curative resection in CSRCC(21%-82%)are lower compared to those in other histological types.In case of peritoneal metastasis,cytoreductive surgery with hyperthermic intraperitoneal chemotherapy should only be proposed in selected patients.CONCLUSION CSRCC is a rare clinical entity most often characterized by young age and advanced disease at presentation.As such,diagnostic modalities and therapeutic approach should be tailored accordingly.
文摘Objectives: More than a year after its introduction, COVID-19 vaccination coverage was low in the Togolese population and little data were available on its benefits for hospitalized patients. This study aimed to describe the impact of COVID-19 vaccination on the prognosis of hospitalized patients. Methods: This was a retrospective cohort study of patients admitted to the Centre Hospitalier Régional Lomé Commune (Togo) between June 1, 2021 and May 31, 2022. Primary outcomes (admission to the intensive care unit and death) were presented with frequency and proportion. Mortality rates were presented by sociodemographic and clinical characteristics and compared by appropriate statistical tests. Factors associated with inpatient death were described by performing a Cox proportional hazard regression. Results: A total of 604 patients were hospitalized (50.0% women). The mean age was 54.03 ±17.1 years. Only 55 patients were fully vaccinated (9.1%). ICU admission was significantly more frequent in unvaccinated patients than in vaccinated ones (63.0% vs. 38.2%;p Conclusion: COVID-19 vaccination had a significant benefit for patients with COVID-19 infection in terms of reducing the risk of death. Based on real-world data from sub-Saharan Africa, this information can help optimize the benefit of COVID-19 vaccination by raising community awareness and increasing vaccine coverage while reducing hesitancy.
基金under a contract of the“Nicolás Monardes”program(RC-0002-2021)from the Andalusian Health Service,Andalusian Regional Ministry of Health and Consumptionfunds from the Excellent Project from Andalusian Government(Proy Excel_00996)+8 种基金funded by the French Multiple Sclerosis Foundation(ARSEP,1259&1254)the National Multiple Sclerosis Society(NMSS,RG 5088-A-1)the program“Investissements d’Avenir”(ANR-10-IAIHU-06 and ANR-11-INBS-0011–Neur ATRIS)under a“Miguel Servet”contract(CP20-0049)from the Health Institute CarlosⅢ,Ministry of Science and Innovation,Spainreceived grants from Andalusian Government and the European Commission under the Seventh Framework Program of the European Union(agreement Num.291730,contract TAHUB-II-107)ARSEP 1254IBRO Return Home FellowshipAES2022 from Health Institute CarlosⅢ(PI22/01141)the Excellent Project from Andalusian Regional Ministry of University,Research and Innovation(Proy Excel_00996)。
文摘Neuropathic pain is a severe and chronic condition widely found in the general population.The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients.During the processing of pain,the dorsal root ganglia constitute an important region where dorsal root ganglion neurons play a crucial role in the transmission and propagation of sensory electrical stimulation.Furthermore,the dorsal root ganglia have recently exhibited a regenerative capacity that should not be neglected in the understanding of the development and resolution of neuropathic pain and in the elucidation of innovative therapies.Here,we will review the complex interplay between cells(satellite glial cells and inflammatory cells)and factors(cytokines,neurotrophic factors and genetic factors)that takes place within the dorsal root ganglia and accounts for the generation of the aberrant excitation of primary sensory neurons occurring in neuropathic pain.More importantly,we will summarize an updated view of the current pharmacologic and nonpharmacologic therapies targeting the dorsal root ganglia for the treatment of neuropathic pain.
基金supported by the European Regional Development Funds-European Union(ERDF-EU),FATZHEIMER project(EU-LAC HEALTH 2020,16/T010131 to FRdF),“Una manera de hacer Europa”Ministerio de Economía,Industria y Competitividad,Gobierno de Espa?a,Programa Estatal de Investigación,Desarrollo e Innovación Orientada a los Retos de la Sociedad(RTC2019-007329-1 to FRdF)+2 种基金Consejería de Economía,Conocimiento y Universidad,Junta de Andalucía,Plan Andaluz de Investigación,Desarrollo e Innovación(P18TP-5194 to FRdF)Instituto de Salud CarlosⅢ(DTS22/00021 to FRdF)DMV(FI20/00227)holds a“PFIS’’predoctoral contract from the National System of Health,EU-ERDF-Instituto de Salud CarlosⅢ。
文摘Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.
文摘Candida auris since it discovery in 2009 is becoming a severe threat to human health due to its very quickly spread, its worldwide high resistance to systemic antifungal drugs. In resource-constrained settings where several conditions are met for its emergence and spread, this worrisome fungus could cause large hospital and/or community-based outbreaks. This review aimed to summarize the available data on C. auris in Africa focusing on its epidemiology and antifungal resistance profile. Major databases were searched for articles on the epidemiology and antifungal resistance profile of C. auris in Africa. Out of 2,521 articles identified 22 met the inclusion criteria. In Africa, nearly 89% of African countries have no published data on C. auris. The prevalence of C. auris in Africa was 8.74%. The case fatality rate of C. auris infection in Africa was 39.46%. The main C. auris risk factors reported in Africa were cardiovascular disease, renal failure, diabetes, HIV, recent intake of antimicrobial drugs, ICU admissions, surgery, hemodialysis, parenteral nutrition and indwelling devices. Four phylogenetic clades were reported in Africa, namely clades I, II, III and IV. Candida auris showed a pan-African very high resistance rate to fluconazole, moderate resistance to amphotericin B, and high susceptibility to echinocandins. Finally, C. auris clade-specific mutations were observed within the ERG2, ERG3, ERG9, ERG11, FKS1, TAC1b and MRR1 genes in Africa. This systematic review showed the presence of C. auris in the African continent and a worrying unavailability of data on this resilient fungus in most African countries.
基金supported by the Ministerio de Economía,Industria y Competitividad(Agencia Estatal de Investigación,AEI,to CGF and MP)Fondo Europeo de Desarrollo Regional(MINECO-FEDER)(PID2022-139016OA-I00,PDC2022-133441-I00,to CGF and MP),Generalitat de Catalunya(2021 SGR 00357+3 种基金to CGF and MP)co-financed by Secretaria d’Universitats i Recerca del Departament d’Empresai Coneixement de la Generalitat de Catalunya 2021(Llavor 00086,to CGF)the recipient of an Alzheimer’s Association Research Fellowship(AARF-21-848511)the Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)for her FI-SDUR fellowship(2021FISDU 00182).
文摘Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.
文摘Rheumatoid arthritis(RA)and periodontitis are chronic inflammatory diseases leading to increased bone resorption.Preventing this inflammatory bone resorption is a major health challenge.Both diseases share immunopathogenic similarities and a common inflammatory environment.The autoimmune response or periodontal infection stimulates certain immune actors,leading in both cases to chronic inflammation that perpetuates bone resorption.Moreover,RA and periodontitis have a strong epidemiological association that could be explained by periodontal microbial dysbiosis.This dysbiosis is believed to be involved in the initiation of RA via three mechanisms.(i)The dissemination of periodontal pathogens triggers systemic inflammation.(ii)Periodontal pathogens can induce the generation of citrullinated neoepitopes,leading to the generation of anti-citrullinated peptide autoantibodies.(iii)Intracellular danger-associated molecular patterns accelerate local and systemic inflammation.Therefore,periodontal dysbiosis could promote or sustain bone resorption in distant inflamed joints.Interestingly,in inflammatory conditions,the existence of osteoclasts distinct from“classical osteoclasts”has recently been reported.They have proinflammatory origins and functions.Several populations of osteoclast precursors have been described in RA,such as classical monocytes,a dendritic cell subtype,and arthritis-associated osteoclastogenic macrophages.The aim of this review is to synthesize knowledge on osteoclasts and their precursors in inflammatory conditions,especially in RA and periodontitis.Special attention will be given to recent data related to RA that could be of potential value in periodontitis due to the immunopathogenic similarities between the two diseases.Improving our understanding of these pathogenic mechanisms should lead to the identification of new therapeutic targets involved in the pathological inflammatory bone resorption associated with these diseases.
文摘Alteration of the outer retina leads to various diseases such as age-related macular degeneration or retinitis pigmentosa characterized by decreased visual acuity and ultimately blindness.Despite intensive research in the field of retinal disorders,there is currently no curative treatment.Several therapeutic approaches such as cell-based replacement and gene therapies are currently in development.In the context of cell-based therapies,different cell sources such as embryonic stem cells,induced pluripotent stem cells,or multipotent stem cells can be used for transplantation.In the vast majority of human clinical trials,retinal pigment epithelial cells and photoreceptors are the cell types considered for replacement cell therapies.In this review,we summarize the progress made in stem cell therapies ranging from the pre-clinical studies to clinical trials for retinal disease.
基金supported by the Ministry of Education,Science and Technological Development of Republic of Serbia,Nos.451-03-68/2022-14/200007 and 451-03-68/2022-14/200053(to LN and JBP),Grants from European Commission(H2020 MSCA-ITN EU-GliaPhD No.72205)(to PN)Agence Nationale de la Recherche,Nos.ANR-19-CE16-0018-03 and ANR-20CE16-0003-02(to PN)+1 种基金Grants from Science and Technology Department of Zhejiang Province,China,No.2021RC051(to WS)Scientific Research Foundation for Returned Scholars of Hangzhou City,China,No.2019(to WS).
文摘Epilepsy is a neurological disorder caused by the pathological hyper-synchronization of neuronal discharges.The fundamental research of epilepsy mechanisms and the targets of drug design options for its treatment have focused on neurons.However,approximately 30%of patients suffering from epilepsy show resistance to standard anti-epileptic chemotherapeutic agents while the symptoms of the remaining 70%of patients can be alleviated but not completely removed by the current medications.Thus,new strategies for the treatment of epilepsy are in urgent demand.Over the past decades,with the increase in knowledge on the role of glia in the genesis and development of epilepsy,glial cells are receiving renewed attention.In a normal brain,glial cells maintain neuronal health and in partnership with neurons regulate virtually every aspect of brain function.In epilepsy,however,the supportive roles of glial cells are compromised,and their interaction with neurons is altered,which disrupts brain function.In this review,we will focus on the role of glia-related processes in epileptogenesis and their contribution to abnormal neuronal activity,with the major focus on the dysfunction of astroglial potassium channels,water channels,gap junctions,glutamate transporters,purinergic signaling,synaptogenesis,on the roles of microglial inflammatory cytokines,microglia-astrocyte interactions in epilepsy,and on the oligodendroglial potassium channels and myelin abnormalities in the epileptic brain.These recent findings suggest that glia should be considered as the promising next-generation targets for designing anti-epileptic drugs that may improve epilepsy and drug-resistant epilepsy.
文摘Crohn’s disease(CD)is an inflammatory bowel disease characterized by immunemediated flares affecting any region of the intestine alternating with remission periods.In CD,the ileum is frequently affected and about one third of patients presents with a pure ileal type.Moreover,the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes.Most of these genes are associated with Paneth cell dysfunction,a cell type found in the intestinal crypts of the ileum.Besides,a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota,which in turn modulates the susceptibility of the ileum to inflammation.Thus,the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis.Indeed,both immune response and cellular healing processes harbour differences between ileal and non-ileal CD.Taken together,these findings advocate for a dedicated therapeutic approach to managing ileal CD.Currently,interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site.However,the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.
