Genetic pathways in cerebral palsy:a review of the implications for precision diagnosis and understanding disease mechanisms

Ce rebral palsy is a diagnostic term utilized to describe a group of permanent disorders affecting movement and posture.Patients with cerebral palsy are often only capable of limited activity,resulting from non-progressive disturbances in the fetal or neonatal brain.These disturbances severely impact the child’s daily life and impose a substantial economic burden on the family.Although cerebral palsy encompasses various brain injuries leading to similar clinical outcomes,the unde rstanding of its etiological pathways remains incomplete owing to its complexity and heterogeneity.This review aims to summarize the current knowledge on the genetic factors influencing cerebral palsy development.It is now widely acknowledged that genetic mutations and alterations play a pivotal role in cerebral palsy development,which can be further influenced by environmental fa ctors.Des pite continuous research endeavors,the underlying fa ctors contributing to cerebral palsy remain are still elusive.However,significant progress has been made in genetic research that has markedly enhanced our comprehension of the genetic factors underlying cerebral palsy development.Moreove r,these genetic factors have been categorized based on the identified gene mutations in patients through clinical genotyping,including thrombosis,angiogenesis,mitochondrial and oxidative phosphorylation function,neuronal migration,and cellular autophagy.Furthermore,exploring targeted genotypes holds potential for precision treatment.In conclusion,advancements in genetic research have substantially improved our understanding of the genetic causes underlying cerebral palsy.These breakthroughs have the potential to pave the way for new treatments and therapies,consequently shaping the future of cerebral palsy research and its clinical management.The investigation of cerebral palsy genetics holds the potential to significantly advance treatments and management strategies.By elucidating the underlying cellular mechanisms,we can develop to rgeted interventions to optimize outcomes.A continued collaboration between researchers and clinicians is imperative to comprehensively unravel the intricate genetic etiology of cerebral palsy.

Exercise and Dietary Restriction for Promotion of Neurohealth Benefits

Physical exercise, whether aerobic, endurance or resistance types, plays a central role in establishing and maintaining the integrity of the brain and central nervous system (CNS). When exercise is adhered to in conjunction with selective food/drink intake and dietary restriction, it promotes neurohealth. In this article, we review the interactions of age and gender, as well as insulin and diabetes, with exercise, individuals’ cognitive-affective status and its interactions with exercise propensity, all of which modulate the eventual outcomes of the influence of exercise upon parameters of neurohealth. The combination of exercise with dietary restriction provides numerous factors pertaining to psychological, neurochemical and anti-pathological manifestations of neu-rophysiological resilience even through aging. The challenge evoked by the exercise-diet combination in the body mobilizes a multitude of adaptive cellular stress-response signaling pathways in neurons involving neurotrophic factors, anti-inflammatory cytokines, DNA-repair proteins, macroautophagy, and mitochondrial biogenesis.

Alexander disease:the road ahead

Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.

Internet-Based Support and Coaching for Adolescents and Young Adults with Neuropsychiatric Disorders—The Implementation of an Intervention from an Organizational Perspective

There is a documented and often unmet need for interventions aimed at supporting young people with attention-deficit/hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) in their transition between adolescence and adulthood. Difficulties with social interaction, initiation difficulties, and impairments in executive function can complicate visits at a clinic, i.e. traditional treatment, for individuals with neuropsychiatric disorders (NPD). A model for internet-based support and coaching aimed at young people with ASD and/or ADHD was developed and tested at three treatment sites in western Sweden. The implementation was analyzed against an inventory according to which implementations are more likely to be successful if an intervention: 1) has advantages compared to other existing methods, 2) matches the individual and organizational values, norms and work practices of its recipients, 3) is perceived as easy to use, and 4) is adaptable to local conditions and the recipients’ needs. Data were collected through group interviews with professionals involved in the implementation of the intervention. The implementation of the intervention showed promising results on measures such as access, delivery/quality of healthcare services, and equality of distribution of healthcare services. The identified impediments to successful implementation related to a wide range of factors and levels, including the design of the intervention, technical issues, attitudes of staff, organizational culture, and organizational structure at the implementation sites in terms of patient stock, work division, and resource allocation. The results are consistent with previous studies that stress the need for multi-component implementation strategies.

Kainic Acid, NMDA and Bicuculline Induce Elevation in Concentrations of Glutathione and Amino Acids <i>in Vivo</i>: Biomarkers for Seizure Predisposition?

The present study was carried out to investigate the effect of NMDA, bicuculline and kainic acid (KA) on the extracellular concentration of glutathione, phosphoethanolamine (PEA) and taurine in rat hippocampus in vivo. Rats were implanted with intrahippocampal microelectrodes perfused with free-glucose Krebs-Ringer solution and allowed to recover for about 2 h. After assaying baseline concentrations of amino acids, NMDA or bicuculline was administered intrahippocampally, whereas KA was given systemically. Either treatment resulted in significant high extracellular concentrations of glutathione, but only NMDA or KA resulted in high concentrations of PEA and taurine. Interestingly, the increase in glutathione concentration due to KA was followed by a delayed increase of glutamate and PEA. Our results demonstrated that increased efflux of glutathione, a common consequence of different neuroexcitotoxic agents, occurs in vivo. Given that the agents used in the present study were also convulsunts, the implication of the findings on seizure predisposition was also considered.

Potential role of PANoptosis in neuronal cell death:commentary on"PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons"

See related article,pp 357-363Extensive neuronal cell death occurs during nervous system development to remove surplus,unwanted,and damaged cells.This is a highly regulated physiological process that plays a pivotal role in nervous system homeostasis and normal development.In some brain regions,more than half of the neurons are removed during normal development without interfering with the remaining cells.This gene-regulated neuronal cell deletion process is called programmed cell death(Fricker et al.,2018).

The Single-Item Measure of Stress Symptoms after Myocardial Infarction and Its Association with Fatigue

Surviving a myocardial infarction (MI) can be a stressful event entailing challenges in daily life during the recovery period. Experiencing fatigue symptoms post-MI has been described as bothersome and occurs in nearly half of patients four months and two years after MI. The aetiology of fatigue disorder is unclear, but research has shown that fatigue plays an important role in the relationship between stress and perceived poor health. Previous findings indicate that having access to an easily administered stress measurement is worthwhile both in the clinic and in research. The single-item measure of stress symptoms has not been validated in persons treated for MI. The aim was to validate the single-item measure of stress symptoms and to explore its association with fatigue in a sample of persons treated for MI. Methods: 142 respondents completed the questionnaires of the Multidimensional Fatigue Inventory-20, the single-item measure of stress symptoms and the Perceived Stress Scale-10 (PPS-10) two months post-MI. Correlation analysis and t-tests were used to validate the single-item stress measure and its association with post-MI fatigue. Results: The convergent validity of the single-item measure of stress symptoms was confirmed. In analyses of relations between stress and fatigue, it was found that the single-item stress measure was strongly associated with both the global fatigue score and all four fatigue dimension scores (general, physical and mental fatigue as well as reduced activity). Conclusion: The single-item measure of stress symptoms was found to be a valid measure of post-MI stress. Also, the measure was useful in assessing associations between stress and fatigue and could therefore indicate that post-MI fatigue experiences should be further explored in full using multidimensional fatigue assessment.

Amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative disease that accounts for most of the 50-million dementia cases worldwide in 2018.A large amount of evidence supports the amyloid cascade hypothesis,which states that amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation in form of neurofibrillary tangles,and these aggregates lead to inflammation,synaptic impairment,neuronal loss,and thus to cognitive decline and behavioral abnormalities.The poor correlation found between cognitive decline and amyloid plaques,have led the scientific community to question whether amyloid-beta accumulation is actually triggering neurodegeneration in Alzheimer’s disease.The occurrence of tau neurofibrillary tangles better correlates to neuronal loss and clinical symptoms and,although amyloid-beta may initiate the cascade of events,tau impairment is likely the effector molecule of neurodegeneration.Recently,it has been shown that amyloid-beta and tau cooperatively work to impair transcription of genes involved in synaptic function and,more importantly,that downregulation of tau partially reverses transcriptional perturbations.Despite mounting evidence points to an interplay between amyloid-beta and tau,some factors could independently affect both pathologies.Thus,the dual pathway hypothesis,which states that there are common upstream triggers causing both amyloid-beta and tau abnormalities has been proposed.Among others,the immune system seems to be strongly involved in amyloid-beta and tau pathologies.Other factors,as the apolipoprotein Eε4 isoform has been suggested to act as a link between amyloid-beta and tau hyperphosphorylation.Interestingly,amyloid-beta-immunotherapy reduces not only amyloid-beta but also tau levels in animal models and in clinical trials.Likewise,it has been shown that tau-immunotherapy also reduces amyloid-beta levels.Thus,even though amyloid-beta immunotherapy is more advanced than tau-immunotherapy,combined amyloid-beta and tau-directed therapies at early stages of the disease have recently been proposed as a strategy to stop the progression of Alzheimer’s disease.

Role of apoptosis-inducing factor in perinatal hypoxic-ischemic brain injury

Perinatal complications,such as asphyxia,can cause brain injuries that are often associated with subsequent neurological deficits,such as cerebral palsy or mental retardation.The mechanisms of perinatal brain injury are not fully understood,but mitochondria play a prominent role not only due to their central function in metabolism but also because many proteins with apoptosis-related functions are located in the mitochondrion.Among these proteins,apoptosis-inducing factor has already been shown to be an important factor involved in neuronal cell death upon hypoxia-ischemia,but a better understanding of the mechanisms behind these processes is required for the development of more effective treatments during the early stages of perinatal brain injury.In this review,we focus on the molecular mechanisms of hypoxic-ischemic encephalopathy,specifically on the importance of apoptosis-inducing factor.The relevance of apoptosis-inducing factor is based not only because it participates in the caspase-independent apoptotic pathway but also because it plays a crucial role in mitochondrial energetic functionality,especially with regard to the maintenance of electron transport during oxidative phosphorylation and in oxidative stress,acting as a free radical scavenger.We also discuss all the different apoptosis-inducing factor isoforms discovered,focusing especially on apoptosis-inducing factor 2,which is only expressed in the brain and the functions of which are starting now to be clarified.Finally,we summarized the interaction of apoptosis-inducing factor with several proteins that are crucial for both apoptosis-inducing factor functions(prosurvival and pro-apoptotic)and that are highly important in order to develop promising therapeutic targets for improving outcomes after perinatal brain injury.

Local infusion of low, but not high, doses of alcohol into the anterior ventral tegmental area causes release of accumbal dopamine

The mesolimbic dopamine system consisting of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (N.Acc.) mediates the reinforcing effects of addictive drugs including alcohol. Given that VTA is a heterogeneous area and that alcohol, in rather low doses, interacts directly with ligand-gated ion channels, we hypothesised that low, rather than high, doses of alcohol into the VTA activate the mesolimbic dopamine system and that alcohol may have different effects in the anterior and posterior parts of the VTA. The present study was undertaken to investigate this hypothesis. The present series of experiment show that infusion of a low dose of alcohol (20 mM) into the anterior, but not posterior, part of the VTA increases accumbal dopamine release in rats. In addition, higher doses of alcohol (100 or 300 mM) into the anterior or posterior part of the VTA do not affect the release of dopamine in the N.Acc., suggesting that low doses of alcohol can activate the mesolimbic dopamine system via mechanisms in the VTA. These data contribute to understanding the neuronal mechanisms underlying the dependence-producing properties of alcohol and could tentatively contribute to that new treatment strategies for alcohol use disorder can be developed.

Is hydrotherapy an appropriate form of exercise for elderly patients with biventricular systolic heart failure?

Hydrotherapy (exercise in warm water) is considered to be a safe and beneficial method to use in the rehabilitation of stable heart failure patients, but there is little information on the effect of the increased venous return and enhanced preload in elderly patientswith biventricular heart failure. We present a case of an elderly man whowas recruited to participate in a hydrotherapy study. We compared echocardiographic data duringwarm water immersion with land measurements, and observed increases in stroke volume from 32 mL (land) to 42 mL (water), left ventricular ejection fraction from 22% to 24%, left ventricular systolic velocity from 4.8 cm/s to 5.0 cm/s and left atrioventricular plane displacement from 2.1 mm to 2.2 mm. By contrast, right ventricular systolic velocity decreased from 11.2 cm/s to 8.4 cm/s and right atrioventricular plane displacement from 8.1 mm to 4.7 mm. The tricuspid pressure gradient rose from 18 mmHg on land to 50mmHg during warm water immersion. Thus, although left ventricular systolic function was relatively unaffected during warm water immersion, we observed a decrease in right ventricular function with an augmented right ventricular pressure. We recommend further investigations to observe the cardiac effect of warm water immersion on patients with biventricular systolic heart failure and at risk of elevated right ventricular pressure.

A phase 1b randomized clinical trial of CT1812 to measure Aβoligomer displacement in Alzheimer’s disease using an indwelling CSF catheter

Trial Registration:May 11th,2018 ClinicalTrials.gov Identifier:NCT03522129 https://clini caltr ials.gov/ct2/show/NCT03522129.Investigational therapies for Alzheimer’s disease(AD)target a wide range of mechanisms,yet promising dis-ease-modifying therapies remain a huge unmet need.Much evidence indicates that the oligomeric form of amyloid-beta(Aβ)is a toxic species contributing to AD through synaptic damage and neuronal toxicity[1].

Advances in nano silver-based biomaterials and their biomedical applications

Silver nanoparticles are among the most widely researched and used for nanotechnology-derived structures due to their extraordinary inherent optical properties,chemical stability,catalytic activity,and high conductivity.These idiosyncratic properties can be attributed to their unique physico-chemical characteristics,such as ultrafine sizes,high surface area,diverse shapes,and strong localized surface plasmon resonance.These distinctive features can be tailored using various physical,chemical,and biological synthesis methods.Various physical techniques are viable for producing silver nanoparticles on a large scale,but they suffer from drawbacks such as high-power con-sumption,expensive set-up,and limited control over nanoparticle size distribution.Chemical methods provide benefits like high yield,consistent shape and size distribution,and cost efficiency,but the residual toxicity of the chemicals involved hinders their biological applications.Biological synthesis approaches effectively overcome the limitations of both physical and chemical methods by eliminating the need for hazardous chemicals,requiring less energy,enabling diverse nanoparticle morphologies,and offering eco-friendliness and exceptional biocom-patibility.The novel and promising properties of nanosilver-based biomaterials have been demonstrated to be suitable for a wide range of pharmacological and therapeutic biomedical applications.Their extensive application in wound healing,dentistry,cardiovascular disease treatment,nerve tissue engineering,cancer treatment,and biosensing can be attributed to their inherent antimicrobial and antibiofilm activity,antithrombotic properties,potential for nerve regeneration,photothermal conversion efficiency and sensitivity,respectively.This review discusses the different methods employed for synthesising silver nanoparticles and focuses on using nanosilver-based biomaterials for various biomedical applications.

补肾活血中药对TGF-β_2及高糖状态下体外培养的视网膜Müller细胞活力的影响

目的探讨高糖及转化生长因子-β2(Transforming growth factor,TGF-β2)和高糖同时存在条件对体外培养的Müller细胞活力的影响,以及补肾活血中药的干预作用。方法以改良酶消化法体外培养大鼠Müller细胞,将P3细胞分别置于模拟正常、高糖、TGF-β2及TGF-β2和高糖同时存在条件下进行培养,并以补肾活血中药复方含药血清进行干预。实验分为正常对照组、TGF-β2组、高糖组、TGF-β2+高糖组、正常中药干预组、TGF-β2+高糖中药干预组;分别在试验干预12h、24h及48h后,以490型酶标仪测定各组细胞外液中乳酸脱氢酶(lactate dehydrogenase,LDH)的漏出量。结果 TGF-β2组和高糖组12h和24h的LDH漏出量与正常对照组比较均无明显差异(P>0.05),但48h的LDH漏出量均较正常对照组增多(P<0.05);TGF-β2组24h的LDH漏出量较高糖组增多(P<0.05);TGF-β2+高糖组24h和48h的LDH漏出量均较TGF-β2组减少(P<0.05);TGF-β2+高糖组48h的LDH漏出量较高糖组减少(P<0.05);补肾活血中药血清能降低24h时TGF-β2和高糖同时存在条件下LDH的漏出量,降低各时段正常条件下的LDH漏出量(P<0.05)。结论 Müller细胞对短期高糖状态以及浓度为150pg/ml的TGF-β2短期干预可能有一定的耐受性,但当高糖(50mol/l)以及TGF-β2(150pg/ml)干预48h后Müller细胞活力明显降低;补肾活血中药复方含药血清能提高正常及高糖和TGF-β2同时存在条件下视网膜Müller细胞膜的稳定性、增强Müller细胞活力可能是补肾活血中药复方防治糖尿病性视网膜病变的另一药物干预途径。

ICF发展应用：康复学科知识体系与临床工具构建

WHO-FIC-FDRG专家委员会Stucki博士于2008年5月13日访问了中国康复研究中心康复信息研究所,并与WHO-FIC-FDRG专家邱卓英博士及其同事做了广泛交流。Stucki博士就ICF应用于康复科学体系建设以及开发基于ICF核心分类模板相关事宜做了专题讲座。作为《Journal of Rehabilitation Medicine》杂志编委,Stucki博士欣然接受本刊邀请成为本刊的国际编委,并代表德国国际分类家族WHO合作中心—ICF研究分中心(ICF Research Branch of WHO Collaborating Center for the Family of International Classifications,Germany(DMIDI))与中国康复信息研究所建立有关ICF研究国际合作,建立了《Journal of Rehabilitation Medicine》和《中国康复理论与实践》杂志间的学术联系。本专题的英文文章发表于《Journal of Rehabilitation Medicine》,由Stucki教授授权《中国康复理论与实践》杂志以中文形式独家发表。第一篇是由中外专家专门为本刊撰写的特稿。本专题的文章是在相关专家组织下翻译的,内容涉及基于ICF的康复学科体系的建立,面向功能的整合性康复学科体系的发展,从细胞到社会的功能结构分类摸板,基于ICF重新定义康复医学、康复科学和康复服务,以及开发应用于不同康复医疗领域的ICF核心分类等内容。这些研究反应了国际最新的理论和应用发展成果,对于依据ICF这一国际性的功能残疾模式和知识分类标准,建立符合科学发展规律和社会发展要求的学科体系以及实践领域具有十分重要的理论和实践意义。通过出版本专题,希望能使广大康复科技工作者关注国际相关发展,更新有关观念和方法,推动康复科学学科建设和发展,扩大国际合作与交流。鉴于ICF理论与方法相对较新,本专题中很多文章从科学学和方法论角度探讨学科建设和知识体系的构建,有的内容涉及到专业性很强的测量学方法,这些对于专题译校团队的专家学者也是一种挑战。作为当前国际康复界研究发展的热点领域,文章作者、译校者也衷心希望专家和读者就有关问题开展广泛讨论,促进残疾和康复科学发展。本研究相关研究是国家科技部科技基础性工作和社会公益研究专项项目:中国残疾分类系统和评定标准平台研究(2003DIB1J063);国家科技部科技基础性工作和社会公益研究专项项目:中国残疾人功能和健康评定研究(2004DIB5J183)和首都医学发展科研基金:基于ICF架构的功能、残疾和健康评定和研究(2007-3132)支持研究项目。

构建针对人类功能和康复研究的专门学科领域：发展一种从细胞到社会的综合性结构

为了克服康复研究的局限性,需要建立针对康复和相关研究的专门学科领域。基于在基础科学、应用科学和专门学科中的普遍特征,与康复相关的特征以及基于WHO的ICF模型的整合性观点,可以将功能性的生物医学领域划分出5个专门的人类功能和康复研究的学科领域。这些学科结构基于整合性观点,涉及人类功能学科和整合性康复学科,以及部分基于该观念建立的生物学科和生物医学康复学科和工程学,还有处于研究和实践分界边缘的专门康复学科。人类功能学科的目的在于明确人类功能,确定综合性干预目标,以达到人类所体验到的残疾程度最小化。康复中的生物学科的目标是解释身体损伤和修复,并且确定生物医学干预的目标。整合性的康复学科要设计和研究综合性的评定以及干预的方法,这种方法将生物医学的个人的因素以及环境的因素结合起来以达到人类活动的最佳表现。生物医学康复学科和工程研究适于将损伤最小化,包括疾病控制、对人的最佳能力的诊断方法和干预措施。专门康复学科研究如何提供最好的保健以使已经残疾或可能残疾的人在与环境的交互作用中达到和维持最佳功能。将人类功能和康复的研究划分为五个专门的学科领域,可以促进专业培训项目和职业生涯的发展,也可以促进建立人类功能和康复研究的研究架构。

Value of qualitative research in polycystic ovary syndrome

Objective This article aims to introduce the benefits of qualitative research and to discuss how such research can be applied to the study of polycystic ovary syndrome （PCOS）. Data sources Relevant articles were published in English as of May 2013 from Pubmed. Terms ＂polycystic ovary syndrome/PCOS, qualitative research and methodology＂ were used for searching. Study selection Articles studying PCOS with qualitative methods were reviewed. Articles associated with the use of qualitative research in clinical research were cited. Results Six qualitative studies related to PCOS were found in the literature search. These studies addressed different aspects in PCOS women including their womanhood, lived experience, information need, and experience of treatment with acupuncture. Five of these six studies used phenomenology as guiding theory. Conclusion Quantitative research has been the dominant approach in the field so far, qualitative research is relevant to the advancement of PCOS.

Long-Term Androgen-Induced Nonalcoholic Fatty Liver Disease in a Polycystic Ovary Syndrome Mouse Model is Related to Mitochondrial Dysfunction

Objective:Metabolic disorders are markedly common in women with polycystic ovary syndrome(PCOS),and nonalcoholic fatty liver disease(NAFLD)is observed in 30%-55%of all PCOS patients.Many studies have reported that autophagy and apoptosis,which are closely related to mitochondrial function,play important roles in the development of NAFLD.Therefore,in this study,we aimed to explore the role of mitochondrial dysfunction caused by liver apoptosis and autophagy imbalance in the development of NAFLD in a PCOS mouse model.Methods:We used a dihydrotestosterone(DHT)-induced PCOS model to mimic the pathological process of hyperandrogenism.Hematoxylin and eosin and Oil Red O staining assays were used to observe the pathological changes in the liver.Western blotting and quantitative real-time polymerase chain reaction were used to perform mitochondrion-related assays.Results:Hepatic steatosis and different degrees of inflammation were observed in the DHT-treated mice.The expression of molecules involved in the respiratory chain and aerobic respiration process was altered.The levels of the key molecules associated with apoptosis and autophagy were abnormal.Conclusions:Androgens may play a role in the process of hepatic steatosis development by affecting mitochondrial function and subsequently inducing apoptosis and autophagy.Such phenomena might be involved in the pathogenesis of NAFLD in women with PCOS.

Regulation ofα-cell glucagon secretion:The role of second messengers

Glucagon is a potent glucose-elevating hormone that is secreted by pancreaticα-cells.While well-controlled glucagon secretion plays an important role in maintaining systemic glucose homeostasis and preventing hypoglycaemia,it is increasingly apparent that defects in the regulation of glucagon secretion contribute to impaired counter-regulation and hyperglycaemia in diabetes.It has therefore been proposed that pharmacological interventions targeting glucagon secretion/signalling can have great potential in improving glycaemic control of patients with diabetes.However,despite decades of research,a consensus on the precise mechanisms of glucose regulation of glucagon secretion is yet to be reached.Second messengers are a group of small intracellular molecules that relay extracellular signals to the intracellular signalling cascade,modulating cellular functions.There is a growing body of evidence that second messengers,such as cAMP and Ca^(2+),play critical roles inα-cell glucose-sensing and glucagon secretion.In this review,we discuss the impact of second messengers onα-cell electrical activity,intracellular Ca^(2+)dynamics and cell exocytosis.We highlight the possibility that the interaction between different second messengers may play a key role in the glucose-regulation of glucagon secretion.

皮质下小血管病诊断的共识声明

血管性认知损害是用于描述一组涉及大血管和小血管的散发性和遗传性异质性疾病的诊断术语。皮质下小血管病可导致腔隙性梗死和进行性白质损害。被称为宾斯旺格病（Binswanger＇s disease, BD）的进行性白质损害患者构成了从单纯血管性疾病到合并神经变性病变的疾病谱。BD患者是一个相对同质性的亚组，存在缺氧缺血、腔隙性梗死和炎症，它们协同作用破坏血脑屏障和髓鞘。通过临床、脑脊液、神经心理学和影像学检查获得的多模式疾病标记物能促进该亚组患者的鉴别。本共识声明确定了一系列基于基础病理学改变的潜在生物学标记物，这将有助于诊断以及将来协作性治疗试验的患者选择。