Dementia is a syndrome with various underlying pathologies acting independently or in concert to cause cognitive dysfunction.The development of disease-specific treatments and targeted prevention strategies requires p...Dementia is a syndrome with various underlying pathologies acting independently or in concert to cause cognitive dysfunction.The development of disease-specific treatments and targeted prevention strategies requires precise clinical sub-typing via etiology and pathophysiological processes.Furthermore,recent research advances in biomarkers,especially for Alzheimer's disease(AD)diagnosis,have improved diagnostic precision for dementia.展开更多
Psychiatrists and other mental health clinicians are often tasked with assessing patients’risk of violence.Approaches to this vary and include both unstructured(based on individual clinicians’judgement)and structure...Psychiatrists and other mental health clinicians are often tasked with assessing patients’risk of violence.Approaches to this vary and include both unstructured(based on individual clinicians’judgement)and structured methods(based on formalised scoring and algorithms with varying scope for clinicians’judgement).The end result is usually a categorisation of risk,which may,in turn,reference a probability estimate of violence over a certain time period.Research over recent decades has made considerable improvements in refining structured approaches and categorising patients’risk classifications at a group level.The ability,however,to apply these findings clinically to predict the outcomes of individual patients remains contested.In this article,we review methods of assessing violence risk and empirical findings on their predictive validity.We note,in particular,limitations in calibration(accuracy at predicting absolute risk)as distinct from discrimination(accuracy at separating patients by outcome).We also consider clinical applications of these findings,including challenges applying statistics to individual patients,and broader conceptual issues in distinguishing risk and uncertainty.Based on this,we argue that there remain significant limits to assessing violence risk for individuals and that this requires careful consideration in clinical and legal contexts.展开更多
Objectives To assess the feasibility of methods and estimate the potential effect of interrupting sedentary behaviour,with intermittent or continuous physical activity breaks,on cognitive performance in young people w...Objectives To assess the feasibility of methods and estimate the potential effect of interrupting sedentary behaviour,with intermittent or continuous physical activity breaks,on cognitive performance in young people with Cerebral Palsy.Methods A randomised three-arm exposure response cross-over design with process evaluation.Participants were recruited throughout the Thames Valley,UK between 01/11/2018 to 31/03/2020.The three 2 h activity exposure visits included:(i)sitting only(controls),(ii)sitting plus 20 min of moderate-to-vigorous activity burst,or(iii)4×5 min of moderate-to-vigorous activity bursts,during a 2.5 h sedentary session.Measures of feasibility were sought.Cognitive performance outcomes(using the Eriksen Flanker task and Forward and Backward Digit Span)were delivered before and after the 2 h testing period.Results 36 participants were randomised(age 13.2±2.7,Gross-Motor Functional Classification System 1–3).Study retention was 83%across all three interventions and overall missing data for measures was 4%.A small intervention effect was found in reaction time in the 4×5 min physical activity exposure session compared to the sedentary control condition(0.42;95%CI 0.40 to 0.79).There were two research-related minor adverse effects,an allergic reaction to the FreeStyle Libre and feeling faint and vomiting after consumption of glucose solution.Both events were resolved and participants continued with the study.Conclusions The study design and intervention implementing short bursts of physical activity was feasible and indicated a potential effect on reaction time as a measure of cognitive performance in young people with cerebral palsy.展开更多
BACKGROUND Type 2 diabetes(T2D)is a major health concern globally and its prevalence is expected to continue to escalate.Lifestyle intervention is an integral part of T2D management.Meal replacements are often used as...BACKGROUND Type 2 diabetes(T2D)is a major health concern globally and its prevalence is expected to continue to escalate.Lifestyle intervention is an integral part of T2D management.Meal replacements are often used as part of lifestyle intervention programs in T2D and weight management programs.There are various trials being carried out to date;however,a thorough review regarding the usage of meal replacement on its types,dosage and associated outcomes and adverse events is still lacking.AIM To provide a comprehensive overview on existing studies regarding meal replacement usage among patients with T2D,and map out glycemic and weightrelated outcomes along with adverse effects incidences.METHODS This scoping review is conducted based on Arksey and O’Malley’s seminal framework for scoping reviews.A systematic search has been done for studies published between January 2020 and January 2024 across six online databases(Cochrane Library,PubMed,Science Direct,Scopus,Web of Science and Ebscohost Discovery)using specific keywords.Two researchers independently assessed the eligibility of the studies and extracted the data.The selected articles and extracted data were reviewed by all researchers.RESULTS The initial search resulted in an initial count of 53922 articles from which 133 articles were included in this review after eligibility screening.Included studies were categorized based on meal replacement type into low calorie/energy,low glycemic index,protein-rich,low-fat,diabetes-specific formulas,and combined lifestyle intervention programs.Fifty-nine studies reported improvements on hemoglobin A1c,and 70 studies reported positive changes in weight or BMI after the meal replacement intervention.The combination of meal replacements with education,counseling or structured lifestyle interventions has proved to be effective.Only 13 studies reported occurrence of adverse events related to the intervention.Most of the reported incidents were of mild occurrences with constipation being the most reported adverse event.CONCLUSION The results suggest that meal replacements,especially when combined with lifestyle intervention programs and counseling,are an effective and safe strategy in glycemic and weight management among patients with T2D.展开更多
BACKGROUND Herbal supplements are increasingly used to manage menopausal symptoms.Physta®is a commercial herbal ingredient containing Eurycoma longifolia standardized water extract,traditionally used for vitality...BACKGROUND Herbal supplements are increasingly used to manage menopausal symptoms.Physta®is a commercial herbal ingredient containing Eurycoma longifolia standardized water extract,traditionally used for vitality.Its adaptogenic and anti-inflammatory properties promote hormonal balance,physical function,and sexual health,supporting its potential benefits for menopausal health.AIM To investigate Physta®’s role in improving menopausal quality of life,mood states,and overall safety profile compared with placebo.METHODS In this 12-week,randomized,double-blind,placebo-controlled trial,138 females aged 40-55 with menopausal symptoms were randomly assigned to receive Physta®50 mg,Physta®100 mg,or placebo.MENQOL and POMS were assessed at baseline,week 6,and week 12.Safety outcomes were evaluated through biochemical tests,vital signs,and female reproductive hormonal profile.RESULTS Physta®100 mg significantly reduced total MENQOL scores by 33.9%from baseline to week 12(P=0.049)with notable improvements in the physical(-36.4%,P=0.046)and sexual(-36.3%,P=0.043)domains.Total mood disturbance also declined more in the Physta®100 mg group(-38.6%)compared with placebo(-30.1%),although not statistically significant.No significant changes were observed in the vital signs and biochemical parameters,indicating the safety and tolerability of Physta®.No significant alterations were found in the female reproductive hormone profile,supporting its hormonal neutrality.CONCLUSION Physta®100 mg improved menopausal quality of life and mood without adverse effects,supporting its potential as a safe herbal therapy.Further studies with higher doses and longer durations are needed.展开更多
Background:The investigation of ovarian development,dysfunction,and aging is essential for female reproductive health.Despite extensive research on the cellular functions of Brefeldin A(BFA)as an intracellular transpo...Background:The investigation of ovarian development,dysfunction,and aging is essential for female reproductive health.Despite extensive research on the cellular functions of Brefeldin A(BFA)as an intracellular transport inhibitor,its specific effects and mechanisms on ovarian development/aging remain inadequately understood.Methods:Mice and porcine oocytes/granulosa cells(GCs)were treated with BFA.Morphological and omics analyses(including Western blot,real-time polymerase chain reaction(RT-PCR),transcriptomics,and metabolomics)were conducted.Results:In 3-week-old female mice,BFA treatment significantly suppressed oocyte maturation,induced apoptosis,and increased estradiol and LH levels.This treatment upregulated apoptosis-related genes while downregulating proliferation-associated genes.Additionally,BFA elevated senescence markers(p21 and p26)and decreased the activity of the longevity gene SIRT6.In porcine oocytes,BFA reduced the maturation rate and lowered m RNA levels of key maturation-related genes,LHX8 and GDF9.In porcine GCs,BFA increased apoptosis and upregulated genes such as Caspase-3,BAX,and P21,while downregulating genes associated with proliferation and longevity.Similar effects were observed in 12-month-old female mice,indicating consistency across age groups.Metabolomic analysis in these mice revealed that BFA primarily impacted pathways related to steroid biosynthesis,ovarian steroidogenesis,and estrogen signaling.Transcriptomic analysis in 12-month-old female mice further demonstrated that BFA disrupted ovarian function through multiple mechanisms,including modulation of the Gn RH signaling pathway,activation of the FOXO pathway,and interference with meiosis-related gene expression.Conclusion:Our findings are pivotal for advancing the understanding of ovarian aging,dysfunctions,and diseases,and ultimately facilitate addressing BFA's potential adverse effects on reproductive health/aging.展开更多
Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by...Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β（Aβ） peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein（APP） processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic（Tg） mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type（WT） mice, contributing to the development of an Alzheimer＇s-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.展开更多
Immune-mediated activation of tryptophan（TRYP） catabolism via the kynurenine pathway（KP） is a consistent finding in all inflammatory disorders.Several studies by our group and others have examined the neurotoxic p...Immune-mediated activation of tryptophan（TRYP） catabolism via the kynurenine pathway（KP） is a consistent finding in all inflammatory disorders.Several studies by our group and others have examined the neurotoxic potential of neuroreactive TRYP metabolites,including quinolinic acid（QUIN） in neuroinflammatory neurological disorders,including Alzheimer＇s disease（AD）,multiple sclerosis,amylotropic lateral sclerosis（ALS）,and AIDS related dementia complex（ADC）.Our current work aims to determine whether there is any benefit to the affected individuals in enhancing the catabolism of TRYP via the KP during an immune response.Under physiological conditions,QUIN is metabolized to the essential pyridine nucleotide,nicotinamide adenine dinucleotide（NAD＋）,which represents an important metabolic cofactor and electron transporter.NAD＋ also serves as a substrate for the DNA ‘nick sensor＇ and putative nuclear repair enzyme,poly（ADP-ribose） polymerase（PARP）.Free radical initiated DNA damage,PARP activation and NAD＋ depletion may contribute to brain dysfunction and cell death in neuroinflammatory disease.展开更多
BACKGROUND Cognitive frailty,characterized by the coexistence of cognitive impairment and physical frailty,represents a multifaceted challenge in the aging population.The role of cardiovascular risk factors in this co...BACKGROUND Cognitive frailty,characterized by the coexistence of cognitive impairment and physical frailty,represents a multifaceted challenge in the aging population.The role of cardiovascular risk factors in this complex interplay is not yet fully understood.AIM To investigate the relationships between cardiovascular risk factors and older persons with cognitive frailty by pooling data from two cohorts of studies in Malaysia.METHODS A comprehensive approach was employed,with a total of 512 communitydwelling older persons aged 60 years and above,involving two cohorts of older persons from previous studies.Datasets related to cardiovascular risks,namely sociodemographic factors,and cardiovascular risk factors,including hypertension,diabetes,hypercholesterolemia,anthropometric characteristics and biochemical profiles,were pooled for analysis.Cognitive frailty was defined based on the Clinical Dementia Rating scale and Fried frailty score.Cardiovascular risk was determined using Framingham risk score.Statistical analyses were conducted using SPSS version 21.RESULTS Of the study participants,46.3%exhibited cognitive frailty.Cardiovascular risk factors including hypertension(OR:1.60;95%CI:1.12-2.30),low fat-free mass(OR:0.96;95%CI:0.94-0.98),high percentage body fat(OR:1.04;95%CI:1.02-1.06),high waist circumference(OR:1.02;95%CI:1.01-1.04),high fasting blood glucose(OR:1.64;95%CI:1.11-2.43),high Framingham risk score(OR:1.65;95%CI:1.17-2.31),together with sociodemographic factors,i.e.,being single(OR 3.38;95%CI:2.26-5.05)and low household income(OR 2.18;95%CI:1.44-3.30)were found to be associated with cognitive frailty.CONCLUSION Cardiovascular-risk specific risk factors and sociodemographic factors were associated with risk of cognitive frailty,a prodromal stage of dementia.Early identification and management of cardiovascular risk factors,particularly among specific group of the population might mitigate the risk of cognitive frailty,hence preventing dementia.展开更多
Dementia has emerged as one of the main threats to human health in the modern civilization.Increased aging of world population and unhealthy lifestyle habits have been identified as critical factors able to facilitate...Dementia has emerged as one of the main threats to human health in the modern civilization.Increased aging of world population and unhealthy lifestyle habits have been identified as critical factors able to facilitate dementia establishment.In this context,according to the Alzheimer’s Research International,Alzheimer’s disease(AD)constitutes the primary cause of dementia worldwide and its numbers are expected to grow during the following years.Clinically,AD is characterized by the progressive decline in the cognitive performance as well as by an altered social behavior.Initially affecting the short-term memory,the long-term memory becomes compromised as the pathology progresses.展开更多
Background:One of the pathological hallmarks distinguishing Alzheimer’s disease from other dementias is the accumulation of amyloid beta(Aβ).Higher physical activity is associated with decreased dementia risk,and on...Background:One of the pathological hallmarks distinguishing Alzheimer’s disease from other dementias is the accumulation of amyloid beta(Aβ).Higher physical activity is associated with decreased dementia risk,and one potential path could be through Aβlevels modulation.We aimed to explore the relationship between physical activity and Aβin middle-aged and older adults.Methods:A systematic search of PubMed,Web of Science,PsycINFO,Cochrane Central Register of Controlled Trials,and SPORTDiscus was performed from inception to April 28,2022.Studies were eligible if they included physical activity and Aβdata in adults aged 45 years or older.Multi-level metaanalyses of intervention and observational studies were performed to examine the role of physical activity in modulating Aβlevels.Results:In total,37 articles were included(8 randomized controlled trials,3 non-randomized controlled trials,4 prospective longitudinal studies,and 22 cross-sectional studies).The overall effect size of physical activity interventions on changes in blood Aβwas medium(pooled standardized mean difference=-0.69,95%confidence interval(95%CI):-1.41 to 0.03;I^(2)=74.6%).However,these results were not statistically significant,and there were not enough studies to explore the effects of physical activity on cerebrospinal fluid(CSF)and brain Aβ.Data from observational studies were examined based on measurements of Aβin the brain using positron emission tomography scans,CSF,and blood.Higher physical activity was positively associated with Aβonly in the CSF(Estimate r=0.12;95%CI:0.05-0.18;I^(2)=38.00%).Conclusion:Physical activity might moderately reduce blood Aβin middle-aged and older adults.However,results were only near statistical significance and might be interpreted with caution given the methodological limitations observed in some of the included studies.In observational studies,higher levels of physical activity were positively associated with Aβonly in CSF.Therefore,further research is needed to understand the modulating role of physical activity in the brain,CSF,and blood Aβ,as well as its implication for cognitive health.展开更多
This pilot study examined the psychometric properties and clinical utility of a brief neuropsychological instrument (Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The test-retest reliabil...This pilot study examined the psychometric properties and clinical utility of a brief neuropsychological instrument (Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The test-retest reliability, practice effects and convergent validity of RBANS were examined in participants without objective cognitive impairment. The tests were administered at two time points at approximately a two weeks’ interval, with 30 cognitively intact participants with a mean age of 63.3 ± 5.8 years. Adequate test-retest reliabilities were found for RBANS subtests, index and total scale scores with significant gain scores in immediate memory and visuospatial function. The RBANS showed good convergent validity and the RBANS supplemented with executive and language measures (Colour Trails Test and 30-item modified Boston Naming Test, respectively) demonstrated excellent convergent validity with a formal neuropsychological battery. This pilot study has provided the preliminary evidence of reliability and convergent validity of the RBANS. Additionally, it also provides insight on the practice effects so that clinicians may assess significant changes in RBANS subtests and domain indexes for clinical practice.展开更多
Brain aging is typically associated with a significant decline in cognitive performance.Vascular risk factors(VRF)and subsequent atherosclerosis(AS)play a major role in this process.Brain resilience reflects the brain...Brain aging is typically associated with a significant decline in cognitive performance.Vascular risk factors(VRF)and subsequent atherosclerosis(AS)play a major role in this process.Brain resilience reflects the brain’s ability to withstand external perturbations,but the relationship of brain resilience with cognition during the aging process remains unclear.Here,we investigated how brain topological resilience(BTR)is associated with cognitive performance in the face of aging and vascular risk factors.We used data from two cross-ethnicity community cohorts,PolyvasculaR Evaluation for Cognitive Impairment and Vascular Events(PRECISE,n=2220)and Sydney Memory and Ageing Study(MAS,n=246).We conducted an attack simulation on brain structural networks based on k-shell decomposition and node degree centrality.BTR was defined based on changes in the size of the largest subgroup of the network during the simulation process.Subsequently,we explored the negative correlations of BTR with age,VRF,and AS,and its positive correlation with cognitive performance.Furthermore,using structural equation modeling(SEM),we constructed path models to analyze the directional dependencies among these variables,demonstrating that aging,AS,and VRF affect cognition by disrupting BTR.Our results also indicated the specificity of this metric,independent of brain volume.Overall,these findings underscore the supportive role of BTR on cognition during aging and highlight its potential application as an imaging marker for objective assessment of brain cognitive performance.展开更多
Objective To examine general practitioners’(GPs)referral patterns to allied health services for people with dementia compared with those without dementia across two large Australian Primary Health Networks(PHNs).Desi...Objective To examine general practitioners’(GPs)referral patterns to allied health services for people with dementia compared with those without dementia across two large Australian Primary Health Networks(PHNs).Design A retrospective cohort study using routinely collected general practice data.Logistic regression was used to compare odds of allied health referrals,adjusting for age,sex and socioeconomic status.Setting De-identified patient and episode activity data from 537 GP practices across two PHNs in Australia between 2018 and 2023.Participants Data from 1153304 patients and 28667517 GP episodes of care were analysed.After merging records,693328 unique patients were identified,including 16610 patients with dementia.Subcohorts included patients with dementia,stroke,Parkinson’s disease and combinations of these conditions.Results The dementia cohort(n=16610)had a similar overall allied health referral rate(36.1%)to the control cohort(n=48977)(35.4%).Patients with dementia only were significantly less likely to receive any allied health referral compared with those with stroke(adjusted OR(aOR)0.76,95%CI 0.72 to 0.80;p<0.001)or Parkinson’s disease(aOR 0.72,95%CI 0.66 to 0.78;p<0.001).Those with dementia and stroke were also less likely to receive referrals than those with stroke only(aOR 0.71,95%CI 0.61 to 0.82;p<0.001).No significant difference was found between dementia with Parkinson’s and Parkinson’s only groups(p=0.48).Patients with dementia were consistently less likely to be referred to key allied health services(p<0.05).Conclusion Despite strong evidence supporting allied health interventions for dementia,referral rates remain comparatively low.Enhancing GP referral resources and education,integrating dementia-specific care pathways and implementing supportive policy changes are needed to improve access and equity in dementia care.展开更多
There is a marked inflammatory and hypermetabolic response following a burn injury.The inter-linked responses are more pronounced than for other forms of trauma and can persist for≥3 years post-injury in burned patie...There is a marked inflammatory and hypermetabolic response following a burn injury.The inter-linked responses are more pronounced than for other forms of trauma and can persist for≥3 years post-injury in burned patients.After a burn,patients have an increased risk of diseases of ageing including cancer,diabetes and cardiovascular disease,highlighting the need for effective long-term strategies to ameliorate the stress response post-burn.Current therapeutic strategies for post-burn recovery include removal of damaged tissue with surgical excision and wound repair,nutritional supplementation and rehabilitative exercise.These strategies aim to minimize the hypermetabolic and inflammatory responses,as well as reducing the loss of lean body mass.This review briefly summarises the inflammatory and hypermetabolic responses and provides an update on the current therapeutic strategies for burned patients.The review examines the persistent nutritional challenge of ensuring sufficient energy intake of each macronutrient to fuel the hypermetabolic and counteract the catabolic response of burn injury,whilst reducing periods of hyperglycaemia and hypertriglyceridemia.Patients require individualized treatment options tailored to unique systemic responses following a burn,facilitated by a precision medicine approach to improve clinical and physiological outcomes in burned patients.Thus,this review discusses the utility of metabolic flexibility assessment to aid clinical decision making and prescription relating to nutritional supplementation and rehabilitative exercise in the burned patient.展开更多
The accumulation and aggregation of alpha-synuclein(α-syn)in several tissue including the brain is a major pathological hallmark in Parkinson’s disease(PD).In this study,we show that α-syn can be taken up by primar...The accumulation and aggregation of alpha-synuclein(α-syn)in several tissue including the brain is a major pathological hallmark in Parkinson’s disease(PD).In this study,we show that α-syn can be taken up by primary human cortical neurons,astrocytes and skin-derived fibroblasts in vitro.Our findings that brain and peripheral cells exposed to α-syn can lead to impaired mitochondrial function,leading to cellular degeneration and cell death,provides additional evidence for the involvement of mitochondrial dysfunction as a mechanism of toxicity of α-syn in human cells.展开更多
Burn injuries can be devastating,with life-long impacts including an increased risk of hospitalization for a wide range of secondary morbidities.One area that remains not fully understood is the impact of burn trauma ...Burn injuries can be devastating,with life-long impacts including an increased risk of hospitalization for a wide range of secondary morbidities.One area that remains not fully understood is the impact of burn trauma on the central nervous system(CNS).This review will outline the current findings on the physiological impact that burns have on the CNS and how this may contribute to the development of neural comorbidities including mental health conditions.This review highlights the damaging effects caused by burn injuries on the CNS,characterized by changes to metabolism,molecular damage to cells and their organelles,and disturbance to sensory,motor and cognitive functions in the CNS.This damage is likely initiated by the inflammatory response that accompanies burn injury,and it is often long-lasting.Treatments used to relieve the symptoms of damage to the CNS due to burn injury often target inflammatory pathways.However,there are non-invasive treatments for burn patients that target the functional and cognitive damage caused by the burn,including transcranial magnetic stimulation and virtual reality.Future research should focus on understanding the mechanisms that underpin the impact of a burn injury on the CNS,burn severity thresholds required to inflict damage to the CNS,and acute and long-term therapies to ameliorate deleterious CNS changes after a burn.展开更多
Primordial germ cells(PGCs) are regarded as unipotent cells that can produce only either spermatogonia or oocytes. However, PGCs can be converted into the pluripotent state by ?rst dedifferentiation to embryonic germ ...Primordial germ cells(PGCs) are regarded as unipotent cells that can produce only either spermatogonia or oocytes. However, PGCs can be converted into the pluripotent state by ?rst dedifferentiation to embryonic germ cells and then by reprogramming to induce them to become pluripotent stem cells(iPSCs). These two stages can be completely implemented with mouse cells. However, authentic porcine iPSCs have not been established.Here, we discuss recent advances in the stem cell ?eld for obtaining iPSCs from PGCs. This knowledge will provide some clues which will contribute to the regulation of reprogramming to pluripotency in farm species.展开更多
Background:Excessive scarring and fibrosis are the most severe and common complications of burn injury.Prolonged exposure to high levels of glucocorticoids detrimentally impacts on skin,leading to skin thinning and im...Background:Excessive scarring and fibrosis are the most severe and common complications of burn injury.Prolonged exposure to high levels of glucocorticoids detrimentally impacts on skin,leading to skin thinning and impaired wound healing.Skin can generate active glucocorticoids locally through expression and activity of the 11β-hydroxysteroid dehydrogenase type 1 enzyme(11β-HSD1).We hypothesised that burn injury would induce 11β-HSD1 expression and local glucocorticoid metabolism,which would have important impacts on wound healing,fibrosis and scarring.We additionally proposed that pharmacological manipulation of this system could improve aspects of post-burn scarring.Methods:Skin 11β-HSD1 expression in burns patients and mice was examined.The impacts of 11β-HSD1 mediating glucocorticoid metabolism on burn wound healing,scar formation and scar elas-ticity and quality were additionally examined using a murine 11β-HSD1 genetic knockout model.Slow-release scaffolds containing therapeutic agents,including active and inactive glucocorticoids,were developed and pre-clinically tested in mice with burn injury.Results:We demonstrate that 11β-HSD1 expression levels increased substantially in both human and mouse skin after burn injury.11β-HSD1 knockout mice experienced faster wound healing than wild type mice but the healed wounds manifested significantly more collagen deposition,tensile strength and stiffness,features characteristic of excessive scarring.Application of slow-release prednisone,an inactive glucocorticoid,slowed the initial rate of wound closure but significantly reduced post-burn scarring via reductions in inflammation,myofibroblast generation,collagen production and scar stiffness.Conclusions:Skin 11β-HSD1 expression is a key regulator of wound healing and scarring after burn injury.Application of an inactive glucocorticoid capable of activation by local 11β-HSD1 in skin slows the initial rate of wound closure but significantlyimproves scar characteristics post burn injury.展开更多
基金supported by the Japan Society for the Promotion of Science Overseas Research Fellow,the fellowship of Astellas Foundation for Research on Metabolic Disorders and the Japanese Society of Neurology grants for overseas study“Young Researcher Overseas Training Program” (SH)and NHMRC CRE grant 2006765 (to PSS)。
文摘Dementia is a syndrome with various underlying pathologies acting independently or in concert to cause cognitive dysfunction.The development of disease-specific treatments and targeted prevention strategies requires precise clinical sub-typing via etiology and pathophysiological processes.Furthermore,recent research advances in biomarkers,especially for Alzheimer's disease(AD)diagnosis,have improved diagnostic precision for dementia.
文摘Psychiatrists and other mental health clinicians are often tasked with assessing patients’risk of violence.Approaches to this vary and include both unstructured(based on individual clinicians’judgement)and structured methods(based on formalised scoring and algorithms with varying scope for clinicians’judgement).The end result is usually a categorisation of risk,which may,in turn,reference a probability estimate of violence over a certain time period.Research over recent decades has made considerable improvements in refining structured approaches and categorising patients’risk classifications at a group level.The ability,however,to apply these findings clinically to predict the outcomes of individual patients remains contested.In this article,we review methods of assessing violence risk and empirical findings on their predictive validity.We note,in particular,limitations in calibration(accuracy at predicting absolute risk)as distinct from discrimination(accuracy at separating patients by outcome).We also consider clinical applications of these findings,including challenges applying statistics to individual patients,and broader conceptual issues in distinguishing risk and uncertainty.Based on this,we argue that there remain significant limits to assessing violence risk for individuals and that this requires careful consideration in clinical and legal contexts.
基金supported by the NIHR Exeter Health Biomedical Research Centre.The views expressed are those of the authors and not necessarily those of the NHS,the NIHR or the Department of Health.Johnny Collett is supported NIHR Oxford Health Biomedical research centre。
文摘Objectives To assess the feasibility of methods and estimate the potential effect of interrupting sedentary behaviour,with intermittent or continuous physical activity breaks,on cognitive performance in young people with Cerebral Palsy.Methods A randomised three-arm exposure response cross-over design with process evaluation.Participants were recruited throughout the Thames Valley,UK between 01/11/2018 to 31/03/2020.The three 2 h activity exposure visits included:(i)sitting only(controls),(ii)sitting plus 20 min of moderate-to-vigorous activity burst,or(iii)4×5 min of moderate-to-vigorous activity bursts,during a 2.5 h sedentary session.Measures of feasibility were sought.Cognitive performance outcomes(using the Eriksen Flanker task and Forward and Backward Digit Span)were delivered before and after the 2 h testing period.Results 36 participants were randomised(age 13.2±2.7,Gross-Motor Functional Classification System 1–3).Study retention was 83%across all three interventions and overall missing data for measures was 4%.A small intervention effect was found in reaction time in the 4×5 min physical activity exposure session compared to the sedentary control condition(0.42;95%CI 0.40 to 0.79).There were two research-related minor adverse effects,an allergic reaction to the FreeStyle Libre and feeling faint and vomiting after consumption of glucose solution.Both events were resolved and participants continued with the study.Conclusions The study design and intervention implementing short bursts of physical activity was feasible and indicated a potential effect on reaction time as a measure of cognitive performance in young people with cerebral palsy.
文摘BACKGROUND Type 2 diabetes(T2D)is a major health concern globally and its prevalence is expected to continue to escalate.Lifestyle intervention is an integral part of T2D management.Meal replacements are often used as part of lifestyle intervention programs in T2D and weight management programs.There are various trials being carried out to date;however,a thorough review regarding the usage of meal replacement on its types,dosage and associated outcomes and adverse events is still lacking.AIM To provide a comprehensive overview on existing studies regarding meal replacement usage among patients with T2D,and map out glycemic and weightrelated outcomes along with adverse effects incidences.METHODS This scoping review is conducted based on Arksey and O’Malley’s seminal framework for scoping reviews.A systematic search has been done for studies published between January 2020 and January 2024 across six online databases(Cochrane Library,PubMed,Science Direct,Scopus,Web of Science and Ebscohost Discovery)using specific keywords.Two researchers independently assessed the eligibility of the studies and extracted the data.The selected articles and extracted data were reviewed by all researchers.RESULTS The initial search resulted in an initial count of 53922 articles from which 133 articles were included in this review after eligibility screening.Included studies were categorized based on meal replacement type into low calorie/energy,low glycemic index,protein-rich,low-fat,diabetes-specific formulas,and combined lifestyle intervention programs.Fifty-nine studies reported improvements on hemoglobin A1c,and 70 studies reported positive changes in weight or BMI after the meal replacement intervention.The combination of meal replacements with education,counseling or structured lifestyle interventions has proved to be effective.Only 13 studies reported occurrence of adverse events related to the intervention.Most of the reported incidents were of mild occurrences with constipation being the most reported adverse event.CONCLUSION The results suggest that meal replacements,especially when combined with lifestyle intervention programs and counseling,are an effective and safe strategy in glycemic and weight management among patients with T2D.
基金Supported by Biotropics Malaysia Berhad,Malaysia,NN-2021-016.
文摘BACKGROUND Herbal supplements are increasingly used to manage menopausal symptoms.Physta®is a commercial herbal ingredient containing Eurycoma longifolia standardized water extract,traditionally used for vitality.Its adaptogenic and anti-inflammatory properties promote hormonal balance,physical function,and sexual health,supporting its potential benefits for menopausal health.AIM To investigate Physta®’s role in improving menopausal quality of life,mood states,and overall safety profile compared with placebo.METHODS In this 12-week,randomized,double-blind,placebo-controlled trial,138 females aged 40-55 with menopausal symptoms were randomly assigned to receive Physta®50 mg,Physta®100 mg,or placebo.MENQOL and POMS were assessed at baseline,week 6,and week 12.Safety outcomes were evaluated through biochemical tests,vital signs,and female reproductive hormonal profile.RESULTS Physta®100 mg significantly reduced total MENQOL scores by 33.9%from baseline to week 12(P=0.049)with notable improvements in the physical(-36.4%,P=0.046)and sexual(-36.3%,P=0.043)domains.Total mood disturbance also declined more in the Physta®100 mg group(-38.6%)compared with placebo(-30.1%),although not statistically significant.No significant changes were observed in the vital signs and biochemical parameters,indicating the safety and tolerability of Physta®.No significant alterations were found in the female reproductive hormone profile,supporting its hormonal neutrality.CONCLUSION Physta®100 mg improved menopausal quality of life and mood without adverse effects,supporting its potential as a safe herbal therapy.Further studies with higher doses and longer durations are needed.
基金Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2023A1515030054,2024A1515012999 and 2024B1515020112Science and Technology Project of Guangzhou,Grant/Award Number:2024B03J1305。
文摘Background:The investigation of ovarian development,dysfunction,and aging is essential for female reproductive health.Despite extensive research on the cellular functions of Brefeldin A(BFA)as an intracellular transport inhibitor,its specific effects and mechanisms on ovarian development/aging remain inadequately understood.Methods:Mice and porcine oocytes/granulosa cells(GCs)were treated with BFA.Morphological and omics analyses(including Western blot,real-time polymerase chain reaction(RT-PCR),transcriptomics,and metabolomics)were conducted.Results:In 3-week-old female mice,BFA treatment significantly suppressed oocyte maturation,induced apoptosis,and increased estradiol and LH levels.This treatment upregulated apoptosis-related genes while downregulating proliferation-associated genes.Additionally,BFA elevated senescence markers(p21 and p26)and decreased the activity of the longevity gene SIRT6.In porcine oocytes,BFA reduced the maturation rate and lowered m RNA levels of key maturation-related genes,LHX8 and GDF9.In porcine GCs,BFA increased apoptosis and upregulated genes such as Caspase-3,BAX,and P21,while downregulating genes associated with proliferation and longevity.Similar effects were observed in 12-month-old female mice,indicating consistency across age groups.Metabolomic analysis in these mice revealed that BFA primarily impacted pathways related to steroid biosynthesis,ovarian steroidogenesis,and estrogen signaling.Transcriptomic analysis in 12-month-old female mice further demonstrated that BFA disrupted ovarian function through multiple mechanisms,including modulation of the Gn RH signaling pathway,activation of the FOXO pathway,and interference with meiosis-related gene expression.Conclusion:Our findings are pivotal for advancing the understanding of ovarian aging,dysfunctions,and diseases,and ultimately facilitate addressing BFA's potential adverse effects on reproductive health/aging.
基金supported by grants PFB (Basal Financing Program) 12/2007 from the Basal Centre for Excellence in Science and Technology and FONDECYT,No.1120156(to NCI)a pre-doctoral fellowship from the National Commission of Science and Technology of Chile(CONICYT)(to CTR)
文摘Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β（Aβ） peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein（APP） processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic（Tg） mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type（WT） mice, contributing to the development of an Alzheimer＇s-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.
基金NHMRC Postdoctoral Fellowship at the University of New South Wales
文摘Immune-mediated activation of tryptophan（TRYP） catabolism via the kynurenine pathway（KP） is a consistent finding in all inflammatory disorders.Several studies by our group and others have examined the neurotoxic potential of neuroreactive TRYP metabolites,including quinolinic acid（QUIN） in neuroinflammatory neurological disorders,including Alzheimer＇s disease（AD）,multiple sclerosis,amylotropic lateral sclerosis（ALS）,and AIDS related dementia complex（ADC）.Our current work aims to determine whether there is any benefit to the affected individuals in enhancing the catabolism of TRYP via the KP during an immune response.Under physiological conditions,QUIN is metabolized to the essential pyridine nucleotide,nicotinamide adenine dinucleotide（NAD＋）,which represents an important metabolic cofactor and electron transporter.NAD＋ also serves as a substrate for the DNA ‘nick sensor＇ and putative nuclear repair enzyme,poly（ADP-ribose） polymerase（PARP）.Free radical initiated DNA damage,PARP activation and NAD＋ depletion may contribute to brain dysfunction and cell death in neuroinflammatory disease.
基金Supported by Long-term Research Grant Scheme provided by Ministry of Education Malaysia,No.LRGS/1/2019/UM-UKM/1/4Grand Challenge Grant Project 1 and Project 2,No.DCP-2017-002/1,No.DCP-2017-002/2.
文摘BACKGROUND Cognitive frailty,characterized by the coexistence of cognitive impairment and physical frailty,represents a multifaceted challenge in the aging population.The role of cardiovascular risk factors in this complex interplay is not yet fully understood.AIM To investigate the relationships between cardiovascular risk factors and older persons with cognitive frailty by pooling data from two cohorts of studies in Malaysia.METHODS A comprehensive approach was employed,with a total of 512 communitydwelling older persons aged 60 years and above,involving two cohorts of older persons from previous studies.Datasets related to cardiovascular risks,namely sociodemographic factors,and cardiovascular risk factors,including hypertension,diabetes,hypercholesterolemia,anthropometric characteristics and biochemical profiles,were pooled for analysis.Cognitive frailty was defined based on the Clinical Dementia Rating scale and Fried frailty score.Cardiovascular risk was determined using Framingham risk score.Statistical analyses were conducted using SPSS version 21.RESULTS Of the study participants,46.3%exhibited cognitive frailty.Cardiovascular risk factors including hypertension(OR:1.60;95%CI:1.12-2.30),low fat-free mass(OR:0.96;95%CI:0.94-0.98),high percentage body fat(OR:1.04;95%CI:1.02-1.06),high waist circumference(OR:1.02;95%CI:1.01-1.04),high fasting blood glucose(OR:1.64;95%CI:1.11-2.43),high Framingham risk score(OR:1.65;95%CI:1.17-2.31),together with sociodemographic factors,i.e.,being single(OR 3.38;95%CI:2.26-5.05)and low household income(OR 2.18;95%CI:1.44-3.30)were found to be associated with cognitive frailty.CONCLUSION Cardiovascular-risk specific risk factors and sociodemographic factors were associated with risk of cognitive frailty,a prodromal stage of dementia.Early identification and management of cardiovascular risk factors,particularly among specific group of the population might mitigate the risk of cognitive frailty,hence preventing dementia.
基金supported by grants from the Basal Center of Excellence in Aging and Regeneration AFB 170005FONDECYT(1160724,to NCI)
文摘Dementia has emerged as one of the main threats to human health in the modern civilization.Increased aging of world population and unhealthy lifestyle habits have been identified as critical factors able to facilitate dementia establishment.In this context,according to the Alzheimer’s Research International,Alzheimer’s disease(AD)constitutes the primary cause of dementia worldwide and its numbers are expected to grow during the following years.Clinically,AD is characterized by the progressive decline in the cognitive performance as well as by an altered social behavior.Initially affecting the short-term memory,the long-term memory becomes compromised as the pathology progresses.
基金funded by the Ramón Areces Foundation.IEC is supported by the Spanish Ministry of Science and Innovation(RYC2019-027287-I)the Spanish Ministry of Economy and Competitiveness(RTI2018-095284-J-100)+1 种基金supported by a grant from ANID/BECAS Chile(Grant No.72180543)through a Margarita Salas grant from the Spanish Ministry Universities。
文摘Background:One of the pathological hallmarks distinguishing Alzheimer’s disease from other dementias is the accumulation of amyloid beta(Aβ).Higher physical activity is associated with decreased dementia risk,and one potential path could be through Aβlevels modulation.We aimed to explore the relationship between physical activity and Aβin middle-aged and older adults.Methods:A systematic search of PubMed,Web of Science,PsycINFO,Cochrane Central Register of Controlled Trials,and SPORTDiscus was performed from inception to April 28,2022.Studies were eligible if they included physical activity and Aβdata in adults aged 45 years or older.Multi-level metaanalyses of intervention and observational studies were performed to examine the role of physical activity in modulating Aβlevels.Results:In total,37 articles were included(8 randomized controlled trials,3 non-randomized controlled trials,4 prospective longitudinal studies,and 22 cross-sectional studies).The overall effect size of physical activity interventions on changes in blood Aβwas medium(pooled standardized mean difference=-0.69,95%confidence interval(95%CI):-1.41 to 0.03;I^(2)=74.6%).However,these results were not statistically significant,and there were not enough studies to explore the effects of physical activity on cerebrospinal fluid(CSF)and brain Aβ.Data from observational studies were examined based on measurements of Aβin the brain using positron emission tomography scans,CSF,and blood.Higher physical activity was positively associated with Aβonly in the CSF(Estimate r=0.12;95%CI:0.05-0.18;I^(2)=38.00%).Conclusion:Physical activity might moderately reduce blood Aβin middle-aged and older adults.However,results were only near statistical significance and might be interpreted with caution given the methodological limitations observed in some of the included studies.In observational studies,higher levels of physical activity were positively associated with Aβonly in CSF.Therefore,further research is needed to understand the modulating role of physical activity in the brain,CSF,and blood Aβ,as well as its implication for cognitive health.
文摘This pilot study examined the psychometric properties and clinical utility of a brief neuropsychological instrument (Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The test-retest reliability, practice effects and convergent validity of RBANS were examined in participants without objective cognitive impairment. The tests were administered at two time points at approximately a two weeks’ interval, with 30 cognitively intact participants with a mean age of 63.3 ± 5.8 years. Adequate test-retest reliabilities were found for RBANS subtests, index and total scale scores with significant gain scores in immediate memory and visuospatial function. The RBANS showed good convergent validity and the RBANS supplemented with executive and language measures (Colour Trails Test and 30-item modified Boston Naming Test, respectively) demonstrated excellent convergent validity with a formal neuropsychological battery. This pilot study has provided the preliminary evidence of reliability and convergent validity of the RBANS. Additionally, it also provides insight on the practice effects so that clinicians may assess significant changes in RBANS subtests and domain indexes for clinical practice.
基金National Natural Science Foundation of China(82372040 and 82271329)National Key Research and Development Program of China(2022YFC2504900and 2016YFC0901002)+3 种基金Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2019-I2M-5-029)Key Science&Technologies R&D Program of Lishui City(2019ZDYF18)AstraZeneca Investment(China)and Beijing Natural Science Foundation(Z200016)The Sydney Memory and Ageing Study has been funded by three National Health&Medical Research Council(NHMRC)Program Grants(ID350833,ID568969,and APP1093083)。
文摘Brain aging is typically associated with a significant decline in cognitive performance.Vascular risk factors(VRF)and subsequent atherosclerosis(AS)play a major role in this process.Brain resilience reflects the brain’s ability to withstand external perturbations,but the relationship of brain resilience with cognition during the aging process remains unclear.Here,we investigated how brain topological resilience(BTR)is associated with cognitive performance in the face of aging and vascular risk factors.We used data from two cross-ethnicity community cohorts,PolyvasculaR Evaluation for Cognitive Impairment and Vascular Events(PRECISE,n=2220)and Sydney Memory and Ageing Study(MAS,n=246).We conducted an attack simulation on brain structural networks based on k-shell decomposition and node degree centrality.BTR was defined based on changes in the size of the largest subgroup of the network during the simulation process.Subsequently,we explored the negative correlations of BTR with age,VRF,and AS,and its positive correlation with cognitive performance.Furthermore,using structural equation modeling(SEM),we constructed path models to analyze the directional dependencies among these variables,demonstrating that aging,AS,and VRF affect cognition by disrupting BTR.Our results also indicated the specificity of this metric,independent of brain volume.Overall,these findings underscore the supportive role of BTR on cognition during aging and highlight its potential application as an imaging marker for objective assessment of brain cognitive performance.
基金funded by the Australian Government Medical Research Future Fund(MRFF),Grant number 2015947.
文摘Objective To examine general practitioners’(GPs)referral patterns to allied health services for people with dementia compared with those without dementia across two large Australian Primary Health Networks(PHNs).Design A retrospective cohort study using routinely collected general practice data.Logistic regression was used to compare odds of allied health referrals,adjusting for age,sex and socioeconomic status.Setting De-identified patient and episode activity data from 537 GP practices across two PHNs in Australia between 2018 and 2023.Participants Data from 1153304 patients and 28667517 GP episodes of care were analysed.After merging records,693328 unique patients were identified,including 16610 patients with dementia.Subcohorts included patients with dementia,stroke,Parkinson’s disease and combinations of these conditions.Results The dementia cohort(n=16610)had a similar overall allied health referral rate(36.1%)to the control cohort(n=48977)(35.4%).Patients with dementia only were significantly less likely to receive any allied health referral compared with those with stroke(adjusted OR(aOR)0.76,95%CI 0.72 to 0.80;p<0.001)or Parkinson’s disease(aOR 0.72,95%CI 0.66 to 0.78;p<0.001).Those with dementia and stroke were also less likely to receive referrals than those with stroke only(aOR 0.71,95%CI 0.61 to 0.82;p<0.001).No significant difference was found between dementia with Parkinson’s and Parkinson’s only groups(p=0.48).Patients with dementia were consistently less likely to be referred to key allied health services(p<0.05).Conclusion Despite strong evidence supporting allied health interventions for dementia,referral rates remain comparatively low.Enhancing GP referral resources and education,integrating dementia-specific care pathways and implementing supportive policy changes are needed to improve access and equity in dementia care.
文摘There is a marked inflammatory and hypermetabolic response following a burn injury.The inter-linked responses are more pronounced than for other forms of trauma and can persist for≥3 years post-injury in burned patients.After a burn,patients have an increased risk of diseases of ageing including cancer,diabetes and cardiovascular disease,highlighting the need for effective long-term strategies to ameliorate the stress response post-burn.Current therapeutic strategies for post-burn recovery include removal of damaged tissue with surgical excision and wound repair,nutritional supplementation and rehabilitative exercise.These strategies aim to minimize the hypermetabolic and inflammatory responses,as well as reducing the loss of lean body mass.This review briefly summarises the inflammatory and hypermetabolic responses and provides an update on the current therapeutic strategies for burned patients.The review examines the persistent nutritional challenge of ensuring sufficient energy intake of each macronutrient to fuel the hypermetabolic and counteract the catabolic response of burn injury,whilst reducing periods of hyperglycaemia and hypertriglyceridemia.Patients require individualized treatment options tailored to unique systemic responses following a burn,facilitated by a precision medicine approach to improve clinical and physiological outcomes in burned patients.Thus,this review discusses the utility of metabolic flexibility assessment to aid clinical decision making and prescription relating to nutritional supplementation and rehabilitative exercise in the burned patient.
基金This work was supported by the UNSW Faculty of Medicine Research Grant to Dr Nady BraidyDr Nady Braidy is also the recipient of an Alzheimer’s Australia Viertel Foundation and the National Health and Medical Research Council Early Career Research Fellowship at the University of New South Wales.This work has been also supported by the Alzheimer’s Association(grant#IIRG-08–89545)the Rebecca Cooper foundation(Australia).
文摘The accumulation and aggregation of alpha-synuclein(α-syn)in several tissue including the brain is a major pathological hallmark in Parkinson’s disease(PD).In this study,we show that α-syn can be taken up by primary human cortical neurons,astrocytes and skin-derived fibroblasts in vitro.Our findings that brain and peripheral cells exposed to α-syn can lead to impaired mitochondrial function,leading to cellular degeneration and cell death,provides additional evidence for the involvement of mitochondrial dysfunction as a mechanism of toxicity of α-syn in human cells.
基金AA is funded by the University of Western Australia’s RTP Stipend scholarship,AS is funded by the University of Western Australia,MWF is funded by the Stan Perron Centre of Excellence for Childhood Burns and the Perth Children’s Hospital Foundation,FMW is funded by the WA Department of Health.
文摘Burn injuries can be devastating,with life-long impacts including an increased risk of hospitalization for a wide range of secondary morbidities.One area that remains not fully understood is the impact of burn trauma on the central nervous system(CNS).This review will outline the current findings on the physiological impact that burns have on the CNS and how this may contribute to the development of neural comorbidities including mental health conditions.This review highlights the damaging effects caused by burn injuries on the CNS,characterized by changes to metabolism,molecular damage to cells and their organelles,and disturbance to sensory,motor and cognitive functions in the CNS.This damage is likely initiated by the inflammatory response that accompanies burn injury,and it is often long-lasting.Treatments used to relieve the symptoms of damage to the CNS due to burn injury often target inflammatory pathways.However,there are non-invasive treatments for burn patients that target the functional and cognitive damage caused by the burn,including transcranial magnetic stimulation and virtual reality.Future research should focus on understanding the mechanisms that underpin the impact of a burn injury on the CNS,burn severity thresholds required to inflict damage to the CNS,and acute and long-term therapies to ameliorate deleterious CNS changes after a burn.
基金supported by the National Basic Research Program of China (2016YFA0100203)the National Natural Science Foundation of China (31572399, 31272518)
文摘Primordial germ cells(PGCs) are regarded as unipotent cells that can produce only either spermatogonia or oocytes. However, PGCs can be converted into the pluripotent state by ?rst dedifferentiation to embryonic germ cells and then by reprogramming to induce them to become pluripotent stem cells(iPSCs). These two stages can be completely implemented with mouse cells. However, authentic porcine iPSCs have not been established.Here, we discuss recent advances in the stem cell ?eld for obtaining iPSCs from PGCs. This knowledge will provide some clues which will contribute to the regulation of reprogramming to pluripotency in farm species.
基金supported by National Health and Medical Research Council(NHMRC)fund(APP1101879)National Science Foundation of China(82172217)and ANZAC Research Institute near miss funding.
文摘Background:Excessive scarring and fibrosis are the most severe and common complications of burn injury.Prolonged exposure to high levels of glucocorticoids detrimentally impacts on skin,leading to skin thinning and impaired wound healing.Skin can generate active glucocorticoids locally through expression and activity of the 11β-hydroxysteroid dehydrogenase type 1 enzyme(11β-HSD1).We hypothesised that burn injury would induce 11β-HSD1 expression and local glucocorticoid metabolism,which would have important impacts on wound healing,fibrosis and scarring.We additionally proposed that pharmacological manipulation of this system could improve aspects of post-burn scarring.Methods:Skin 11β-HSD1 expression in burns patients and mice was examined.The impacts of 11β-HSD1 mediating glucocorticoid metabolism on burn wound healing,scar formation and scar elas-ticity and quality were additionally examined using a murine 11β-HSD1 genetic knockout model.Slow-release scaffolds containing therapeutic agents,including active and inactive glucocorticoids,were developed and pre-clinically tested in mice with burn injury.Results:We demonstrate that 11β-HSD1 expression levels increased substantially in both human and mouse skin after burn injury.11β-HSD1 knockout mice experienced faster wound healing than wild type mice but the healed wounds manifested significantly more collagen deposition,tensile strength and stiffness,features characteristic of excessive scarring.Application of slow-release prednisone,an inactive glucocorticoid,slowed the initial rate of wound closure but significantly reduced post-burn scarring via reductions in inflammation,myofibroblast generation,collagen production and scar stiffness.Conclusions:Skin 11β-HSD1 expression is a key regulator of wound healing and scarring after burn injury.Application of an inactive glucocorticoid capable of activation by local 11β-HSD1 in skin slows the initial rate of wound closure but significantlyimproves scar characteristics post burn injury.
