Activation of cerebral Ras-related C3 botulinum toxin substrate(Rac) 1 promotes post-ischemic stroke functional recovery in aged mice

Brain functional impairment after stroke is common;however,the molecular mechanisms of post-stroke recovery remain unclear.It is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following stroke.Mounting evidence suggests that axonal regeneration and angiogenesis,the major forms of brain plasticity responsible for post-stroke recovery,diminished with advanced age.Previous studies suggest that Ras-related C3 botulinum toxin substrate(Rac)1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke model.Here,we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged(male,18 to 22 months old C57BL/6J)brain after ischemic stroke.We found that as mice aged,Rac1 expression declined in the brain.Delayed overexpression of Rac1,using lentivirus encoding Rac1 injected day 1 after ischemic stroke,promoted cognitive(assessed using novel object recognition test)and sensorimotor(assessed using adhesive removal tests)recovery on days 14–28.This was accompanied by the increase of neurite and proliferative endothelial cells in the periinfarct zone assessed by immunostaining.In a reverse approach,pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial cells.Furthermore,Rac1 inhibition reduced the activation of p21-activated kinase 1,the protein level of brain-derived neurotrophic factor,and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after stroke.Our work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.

Defining failure of endoluminal biliary drainage in the era of endoscopic ultrasound and lumen apposing metal stents

The role of endoscopy in pathologies of the bile duct and gallbladder has seen notable advancements over the past two decades.With advancements in stent technology,such as the development of lumen-apposing metal stents,and adoption of endoscopic ultrasound and electrosurgical principles in therapeutic endoscopy,what was once considered endoscopic failure has transformed into failure of an approach that could be salvaged by a second-or third-line endoscopic strategy.Incorporation of these advancements in routine patient care will require formal training and multidisciplinary acceptance of established techniques and collaboration for advancement of experimental techniques to generate robust evidence that can be utilized to serve patients to the best of our ability.

Transmission of amyloid-βpathology in humans:a perspective on clinical evidence

Transmission of misfolded amyloid-β(Aβ)aggregates between human subjects:Protein misfolding disorders are a family of diseases characterized by the accumulation of misfolded protein aggregates.These proteinaceous structures,also known as amyloids,are key drivers of fatal neurodegenerative disorders such as prion diseases,Alzheimer’s disease(AD),Parkinson’s disease,and others.

Role of peripheral amyloid-β aggregates in Alzheimer’s disease: mechanistic, diagnostic, and therapeutic implications

Compelling evidence demonstrates that the levels of peripheral amyloid-β(Aβ)fluctuate in Alzheimer’s disease(AD)patients.Moreover,Aβdeposits have been identified in peripheral tissues.However,the relevance of peripheral Aβ(misfolded or not)in pathological situations,and the temporal appearance of these pathological fluctuations,are not well understood.The presence of misfolded Aβin peripheral compartments raises concerns on potential inter-individual transmissions considering the well-reported prion-like properties of this disease-associated protein.The latter is supported by multiple reports demonstrating that Aβmisfolding can be transmitted between humans and experimental animals through multiple routes of exposure.In this mini-review,we discuss the potential implications of peripheral,disease-associated Aβin disease mechanisms,as well as in diagnostic and therapeutic approaches.

TDP-43 is a key molecule accelerating development of Alzheimer’s disease following traumatic brain injury

Currently,more than 55 million people have dementia worldwide and Alzheimer’s disease(AD)is one of the most common causes of dementia in aging.However,no effective therapies are currently available for the prevention and treatment of AD.This is largely due to our limited understanding of the mechanisms underlying the neuropathogenesis of AD.It has widely been recognized that AD is heterogeneous and that multi-factors are contributing to the pathogenesis of AD.Accumulated evidence suggests that traumatic brain injury(TBI)is an important risk factor for the development of AD and dementia later in life(Guo et al.,2000;Johnson et al.,2010).However,the precise mechanism by which TBI contributes to developing AD has yet to be elucidated.

Management of pancreaticobiliary disease using a new intra-ductal endoscope:The Texas experience

AIM:To evaluate a new single-operator mini-endoscope, Spyglass,for its performance,feasibility and safety in the management of pancreaticobiliary disease. METHODS:In a multicenter retrospective analysis of patients undergoing intraductal endoscopy,we evaluated 128 patients(71 men,mean age 57.6 years).Indications were therapeutic(TX)in 72(56%) and diagnostic(DX)in 56(44%). RESULTS:Peroral endoscopy was performed in 121 and percutaneous in seven.TX indications included CBD stones in 41,PD stones in six,and biliary strictures in 25.DX indications included abnormal LFT’s in 15, abnormal imaging in 38 and cholangiocarcinoma staging in three.Visualization of the stone(s)was considered good in 31,fair in six,and poor in four. Advancement of the electrohydraulic lithotripsy probe was not possible in three patients and proper targeting of the lesion was partial in four patients.A holmium laser was used successfully in three patients.Ductal clearance was achieved in 37 patients after one procedure and in four patients after two procedures.Diagnosis of biliary strictures was modified in 20/29 and confirmed to be malignant in 10/23.Of the modified patients,no diagnosis was available in 17.Spyglass demonstrated malignancy in 8/17 and non-malignancy in nine.Suspected pathology by imaging studies and abnormal LFT’s was modified in 43/63(66%).Staging of cholangiocarcinoma demonstrated multicentric cholangiocarcinoma in 2/3.There was no morbidity associated with the use of Spyglass. CONCLUSION:Spyglass Spyscopeis a first generation, single operator miniature endoscope that can evaluate and treat various biliary and pancreatic tract diseases.

Academic Nursing Center Primary Care Quality Improvement Using an Electronic Health Record and a Practice-Based Research Network

Practice-based research networks (PBRN) seek to improve healthcare through the use of research, quality improvement, and collaborative learning. When used by nontraditional models of care such as the nurse managed healthcare center (NMHC), PBRNs can be incorporated into successful quality improvement (QI) programs. UT Health Services is a NMHC utilizing a PBRN as one component of a comprehensive QI program in an effort to deliver high quality healthcare.

Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke

Ischemic stroke can cause blood-brain barrier(BBB)injury,which worsens brain damage induced by stroke.Abnormal expression of tight junction proteins in endothelial cells(ECs)can increase intracellular space and BBB leakage.Selective inhibition of mitogen-activated protein kinase,the negative regulatory substrate of mitogen-activated protein kinase phosphatase(MKP)-1,improves tight junction protein function in ECs,and genetic deletion of MKP-1 aggravates ischemic brain injury.However,whether the latter affects BBB integrity,and the cell type-specific mechanism underlying this process,remain unclear.In this study,we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke.We found that overexpression of MKP-1 in ECs reduced infarct volume,reduced the level of inflammatory factors interleukin-1β,interleukin-6,and chemokine C-C motif ligand-2,inhibited vascular injury,and promoted the recovery of sensorimotor and memory/cognitive function.Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase(ERK)1/2 and the downregulation of occludin expression.Finally,to investigate the mechanism by which MKP-1 exerted these functions in ECs,we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose,and pharmacologically inhibited the activity of MKP-1 and ERK1/2.Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death,cell monolayer leakage,and downregulation of occludin expression,and that inhibiting ERK1/2 can reverse these effects.In addition,co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2.These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2,thereby protecting the integrity of BBB,alleviating brain injury,and improving post-stroke prognosis.

Misfolded amyloid-βstrains and their potential roles in the clinical and pathological variability of Alzheimer’s disease

Potential causes for the clinical and pathological variability observed in Alzheimer’s disease(AD):AD is an age-related neurodegenerative disorder characterized by the impairment of cognitive functions such as memory,learning,and reasoning.These commonly described clinical symptoms are due to particular pathological changes in the brain,including inflammation,synaptic loss,and neuronal death.These changes are a consequence of the accumulation of abnormally folded amyloid-β(Aβ)and tau proteins in specific areas of the central nervous system.Considering the progressive aging of the world’s population,the number of people affected by AD is expected to substantially and consistently increase in the coming years.This positions AD as one of the main public health challenges in the near future.

Burden of nonalcoholic fatty liver disease and advanced fibrosis in a Texas Hispanic community cohort

AIM: To investigate the potential burden of nonalcoholic steatohepatitis(NASH) and advanced fibrosis in a hispanic community.METHODS: Four hundred and forty two participants with available ultrasonography data from the Cameron County Hispanic Cohort were included in this study. Each participant completed a comprehensive questionnaire regarding basic demographic information, medical history, medication use, and social and family history including alcohol use. Values of the nonalcoholic fatty liver disease fibrosis score(NFS), FIB4 index, BARD score, and Aspartate aminotransferase to Platelet Ratio Index(APRI) were computed using the blood samples collected within 6 mo of liver ultrasonography from each participant. Hepatic steatosis was determined by ultrasonography. As part of univariable analysis, for continuous variables, comparisons among groups were performed with student-t test, one way analysis of variance, and Mann-Whitney test. Pearson χ2 and the Fisher exact test are used to assess differences in categorical variables. For multivariable analyses, logistic regression analyses were performed to identify characteristics associated with hepatic steatosis. All reported P values are based two-sided tests, and a P value of less than 0.05 was considered to indicate statistical significance.RESULTS: The mean age and body mass index(BMI) of the study participants were 49.1 years and 31.3 kg/m2, respectively. Among them, 65.6% were females, 52% had hepatic steatosis, 49.5% had metabolic syndrome, and 29% had elevated aminotransferases. Based on established cut-offs for diagnostic panels, between 17%-63% of the entire cohort was predicted to have NASH with indeterminate or advanced fibrosis. Participants with hepatic steatosis had significantly higher BMI(32.9 ± 5.6 kg/m2 vs 29.6 ± 6.1 kg/m2, P < 0.001) and higher prevalence rates of elevation of ALT(42.2% vs 14.6%, P < 0.001), elevation of aspartate aminotransferase(38.7% vs 18.9%, P < 0.001), and metabolic syndrome(64.8% vs 33%, P < 0.001) than those without hepatic steatosis. The NFS scores(P = 0.002) and the APRI scores(P = 0.002) were significantly higher in those with steatosis but the scores of the FIB4 index and BARD were similar between the two groups. After adjusting for age, gender and BMI, elevated transaminases, metabolic syndrome and its components, intermediate NFS and APRI scores were associated hepatic steatosis in multivariable analysis. CONCLUSION: The burden of NASH and advanced fibrosis in the Hispanic community in South Texas may be more substantial than predicted from referral clinic studies.

Autologous mesenchymal stem cells offer a new paradigm for salivary gland regeneration

Salivary gland(SG)dysfunction,due to radiotherapy,disease,or aging,is a clinical manifestation that has the potential to cause severe oral and/or systemic diseases and compromise quality of life.Currently,the standard-of-care for this condition remains palliative.A variety of approaches have been employed to restore saliva production,but they have largely failed due to damage to both secretory cells and the extracellular matrix(niche).

Outcomes of total pancreatectomy with islet autotransplantation:A systematic review and meta-analysis

BACKGROUND Despite the increased use of total pancreatectomy with islet autotransplantation(TPIAT),systematic evidence of its outcomes remains limited.AIM To evaluate the outcomes of TPIAT.METHODS We searched PubMed,EMBASE,and Cochrane databases from inception through March 2019 for studies on TPIAT outcomes.Data were extracted and analyzed using comprehensive meta-analysis software.The random-effects model was used for all variables.Heterogeneity was assessed using the I2 measure and Cochrane Q-statistic.Publication bias was assessed using Egger’s test.RESULTS Twenty-one studies published between 1980 and 2017 examining 1011 patients were included.Eighteen studies were of adults,while three studied pediatric populations.Narcotic independence was achieved in 53.5%[95% Confidence Interval(CI):45-62,P<0.05,I2=81%]of adults compared to 51.9%(95%CI:17-85,P<0.05,I2=84%)of children.Insulinindependence post-procedure was achieved in 31.8%(95%CI:26-38,P<0.05,I2=64%)of adults with considerable heterogeneity compared to 47.7%(95%CI:20-77,P<0.05,I2=82%)in children.Glycated hemoglobin(HbA1C)12 mo post-surgery was reported in four studies with a pooled value of 6.76%(P=0.27).Neither stratification by age of the studied population nor metaregression analysis considering both the study publication date and the islet-cell-equivalent/kg weight explained the marked heterogeneity between studies.CONCLUSION These results indicate acceptable success for TPIAT.Future studies should evaluate the discussed measures before and after surgery for comparison.

Endocannabinoid control of neuroinflammation in traumatic brain injury by monoacylglycerol lipase in astrocytes

Traumatic brain injury(TBI)is a temporary or permanent disruption of brain function caused by external forces.TBI has been recognized as an important risk factor for the development of Alzheimer’s disease and dementia later in life.However,the mechanisms by which TBI contributes to developing Alzheimer’s disease are largely unknown.

Myelin lipid deficiency:a new key driver of Alzheimer’s disease

Lipids play essential biological functions that include acting as components of biological membranes,energy storage,signaling,nutrients,transporters,enzyme activators,among others.Compared with the multiple research methods to assess DNA,RNA,and protein content,location,and function in cells,there are relatively fewer methods to study lipids.Therefore,lipid-oriented mechanistic studies remain rare and challenging.

Exploring the mechanism of Yishen Daluo decoction in the treatment of multiple sclerosis based on network pharmacology and in vitro experiments

Objective:To explore the mechanism and related active components of Yishen Daluo decoction(YSDLD)in treating multiple sclerosis(MS).Methods:Targets of YSDLD were collected through the TCMSP,Chemistry,and TCMID databases.The MS targets were collected through OMIM,DrugBank,Gencards,TTD,and Pharmgkb databases.We built“componentetarget”network diagrams and proteineprotein interaction(PPI)diagrams and performed topological analysis.The targets were subjected to GO and KEGG enrichment analysis.Molecular docking verification was conducted on selected targets and molecules.Finally,in vitro experiments were con-ducted.BV2 cells were induced by lipopolysaccharide for model establishment.CCK8 experiment was conducted to explore the effect of YSDLD and RT-qPCR technology was used to explore the expression of key targets.Results:There were 184 active components in YSDLD and 898 targets of its action.There were 940 MS targets,and 215 targets were shared by YSDLD and MS.According to the“componentetarget”diagram,the top five key components included quercetin,kaempferol,beta-sitosterol,stigmasterol,and nar-ingenin.IL-6,IL-1 b,TNF-α,AKT1,and VEGFA were the important targets identified by PPI network to-pology analysis.A total of 564 functions were identified by GO enrichment analysis(P<0.01),mainly involving inflammatory response,hypoxia response,plasma membrane,neuronal cell body,protein phosphatase binding,and cytokine activity.KEGG enrichment analysis enriched 98 pathways(P<.01).YSDLD at the concentration of 20 m g/mL had no effect on BV2 cells.RT-qPCR indicated that YSDLD at the concentrations of 15 m g/mL and 20 m g/mL alleviated LPS-induced inflammatory injury and lowered the content of inflammatory factors(P<0.05).Conclusion:In this paper,the network pharmacology and in vitro experiments were used to explore the potential mechanism of YSDLD in treating MS.The research provides a good basis for the development of YSDLD and drugs for MS in future.

Functional phenotyping of microglia highlights the dark relationship between chronic traumatic brain injury and normal age-related pathology

Traumatic brain injury(TBI) is a major cause of death and disability worldwide. Age-related TBI differences demonstrate the third peak of prevalence and incidence of TBI within the elderly population. This is due to the elderly being at a higher risk of sustaining falls, which have been identified as the main cause(40–50%) of TBI.

Bridge plating in the setting of radiocarpal instability:Does distal fixation to the second or third metacarpal matter?A cadaveric study

BACKGROUND Radiocarpal dislocations are rare but potentially devastating injuries.Poorer outcomes are associated with inadequate or lost reduction,such as ulnar translocation,but no consensus exists on the ideal fixation technique.Dorsal bridge plate fixation has been described for various settings in the treatment of complex distal radius fractures and can be fixed distally to the second or third metacarpal,but its application for radiocarpal dislocations has not been established.AIM To determine whether distal fixation to the second or third metacarpal matters.METHODS Using a cadaveric radiocarpal dislocation model,the effect of distal fixation was studied in two stages:(1)A pilot study that investigated the effect of distal fixation alone;and(2)a more refined study that investigated the effect of described techniques for distal and proximal fixation.Radiographs were measured in various parameters to determine the quality of the reduction achieved.RESULTS The pilot study found that focusing on distal fixation alone without changing proximal fixation results in ulnar translocation and volar subluxation when fixing distally to the second metacarpal compared with the third.The second iteration demonstrated that anatomic alignment in coronal and sagittal planes could be achieved with each technique.CONCLUSION In a cadaveric radiocarpal dislocation model,anatomic alignment can be maintained with bridge plate fixation to the second metacarpal or the third metacarpal if the described technique is followed.When considering dorsal bridge plate fixation for radiocarpal dislocations,the surgeon is encouraged to understand the nuances of different fixation techniques and how implant design features may influence proximal placement.

A Comprehensive View on the Progress of Organoid Research with an Emphasis on its Relevance to Disease Characterization

INTRODUCTION Organoids are primary tissue or stem cells derived cell aggregates that have the capacity for self-organization,self-renewal,and the capacity to mimic cellular and tissue level functions.Organoids can overcome the shortcomings of traditional 2D cell culture models and closely mimic 3D primary tissue composition.

Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion?Findings from the NCAA and Department of Defense CARE Consortium

Background:Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion.Therefore,more accurate diagnostic markers are needed for sport-related concussion.Methods:This was a multicenter,prospective,case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association-Department of Defense Concussion Assessment,Research,and Education Consortium conducted between 2015 and 2019.The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints.Athletes with concussion were divided into 6 h post-injury(0-6 h post-injury)and after 6 h postinjury(7-48 h post-injury)groups.We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305proteins in plasma samples from athletes with and without sport-related concussion.Results:A total of 140 athletes with concussion(79.3%males;aged 18.71±1.10 years,mean±SD)and 21 non-concussed athletes(76.2%males;19.14±1.10 years)were included in this study.We identified 338 plasma proteins that significantly differed in abundance(319 upregulated and 19 downregulated)in concussed athletes compared to non-concussed athletes.The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve(AUC)of 0.954(95%confidence interval:0.922-0.986).Specifically,after 6 h of injury,the individual AUC of plasma erythrocyte membrane protein band 4.1(EPB41)and alpha-synuclein(SNCA)were 0.956 and 0.875,respectively.The combination of EPB41 and SNCA provided the best AUC(1.000),which suggests this combination of candidate plasma biomarkers is the best for diagnosing concussion in athletes after 6 h of injury.Conclusion:Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury.

Endoscopic retrograde cholangiopancreatography-related early perforations:A study of effects of procedure duration,complexity,and endoscopist experience

BACKGROUND Perforations(Perf)during endoscopic retrograde cholangiopancreatography(ERCP)are rare(<1%)but potentially fatal events(up to 20%mortality).Given its rarity,most data is through case series studies from centers or analysis of large databases.Although a meta-analysis has shown fewer adverse events as a composite(bleeding,pancreatitis,Perf)during ERCP performed at high-volume centers,there is very little real-world data on endoscopist and center procedural volumes,ERCP duration and complexity on the occurrence of Perf.AIM To study the profile of Perf related to ERCP by center and endoscopist procedure volume,ERCP time,and complexity from a national endoscopic repository.Patients from clinical outcomes research initiative-national endoscopic database(2000-2012)who underwent ERCP were stratified based on the endoscopist and center volume(quartiles),and total procedure duration and complexity grade of the ERCP based on procedure details.The effects of these variables on the Perf that occurred were studied.Continuous variables were compared between Perf and no perforations(NoPerf)using the Mann-Whitney U test as the data demonstrated significant skewness and kurtosis.RESULTS A total of 14153 ERCPs were performed by 258 endoscopists,with 20 reported Perf(0.14%)among 16 endoscopists.Mean patient age in years 61.6±14.8 vs 58.1±18.8(Perf vs.NoPerf,P=NS).The cannulation rate was 100%and 91.5%for Perf and NoPerf groups,respectively.13/20(65%)of endoscopists were high-volume performers in the 4th quartile,and 11/20(55%)of Perf occurred in centers with the highest volumes(4th quartile).Total procedure duration in minutes was 60.1±29.9 vs 40.33±23.5(Perf vs NoPerf,P<0.001).Fluoroscopy duration in minutes was 3.3±2.3 vs 3.3±2.6(Perf vs NoPerf P=NS).50%of the procedures were complex and greater than grade 1 difficulty.3/20(15%)patients had prior biliary surgery.13/20(65%)had sphincterotomies performed with stent insertion.Peritonitis occurred in only 1/20(0.5%).CONCLUSION Overall adverse events as a composite during ERCP are known to occur at a lower rate with higher volume endoscopists and centers.However,Perf studied from the national database show prolonged and more complex procedures performed by high-volume endoscopists at high-volume centers contribute to Perf.