Background: The Veterans Administration (VA) has been using telehealth to enhance Veteran access to high quality VA care for over a decade. Clinical video telehealth (CVT) is one such telehealth tool that allows Veter...Background: The Veterans Administration (VA) has been using telehealth to enhance Veteran access to high quality VA care for over a decade. Clinical video telehealth (CVT) is one such telehealth tool that allows Veterans the opportunity to be evaluated by specialists at the Indianapolis VA while they actually remain in their community (in their local healthcare setting). Such tools are reported to improve satisfaction by avoiding the need to make the long, stressful, and often costly trips to the Medical Center. Our goal is to describe the results of CVT implementation at the Indianapolis VA. Methods: A retrospective review of the data from 2011-2014 related to the use of CVT at the Indianapolis VA was undertaken. The data collected during this time period included: the number of CVT visits per year by specialty, the number of miles in travel avoided per visit, and patient satisfaction survey data, which are obtained after each CVT visit. Results: A total of 14,708 Veterans have enrolled in our CVT telehealth program since 2011. There were 23,267 visits in 2013. 486,170 miles related to travel were avoided (calculating the number of miles avoided in travel from home to a local satellite site as compared to having to travel from home to the Indianapolis VA). At the current Government reimbursement rate of $0.42/mile, this is expressed in a cost avoidance of $209,053. In total, since 2011, the telehealth CVT program has saved the Government $331,132, a total of 770,075 miles saved in travel for our Veterans. In addition, the CVT program has been very well received by our Veterans with an overall satisfaction score of 96%. Conclusion: Our results indicate that the implementation of CVT is cost effective and is well received by Veterans. Telehealth modalities such as CVT are viable options that enhance Veteran satisfaction by decreasing the time and the costs related to travel while continuing to offer high quality health care.展开更多
Vaccination against Coronavirus disease-19(COVID-19)was pivotal to limit spread,morbidity and mortality.Our aim is to find out whether vaccines against COVID-19 lead to an immunological response stimulating the produc...Vaccination against Coronavirus disease-19(COVID-19)was pivotal to limit spread,morbidity and mortality.Our aim is to find out whether vaccines against COVID-19 lead to an immunological response stimulating the production of de novo donor specific antibodies(DSAs)or increase in mean fluorescence intensity(MFI)of pre-existing DSAs in kidney transplant recipients(KTRs).This study involved a detailed literature search through December 2nd,2023 using PubMed as the primary database.The search strategy incorporated a combination of relevant Medical Subject Headings terms and keywords:"COVID-19","SARS-CoV-2 Vaccination","Kidney,Renal Transplant",and"Donor specific antibodies".The results from related studies were collated and analyzed.A total of 6 studies were identified,encompassing 460 KTRs vaccinated against COVID-19.Immunological responses were detected in 8 KTRs of which 5 had increased MFIs,1 had de novo DSA,and 2 were categorized as either having de novo DSA or increased MFI.There were 48 KTRs with pre-existing DSAs prior to vaccination,but one study(Massa et al)did not report whether pre-existing DSAs were associated with post vaccination outcomes.Of the remaining 5 studies,35 KTRs with pre-existing DSAs were identified of which 7 KTRs(20%)developed de novo DSAs or increased MFIs.Overall,no immunological response was detected in 452(98.3%)KTRs.Our study affirms prior reports that COVID-19 vaccination is safe for KTRs,especially if there are no pre-existing DSAs.However,if KTRs have pre-existing DSAs,then an increased immunological risk may be present.These findings need to be taken cautiously as they are based on a limited number of patients so further studies are still needed for confirmation.展开更多
Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive fa...Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive factor in the pathogenesis of the neurodevelopmental and metabolic derangements in FASD has not been determined. Methods: Control and ethanol-exposed human PNET2 cerebellar neuronal cells and rat cerebellar slice cultures were treated with vehicle or pyrithiamine (Pyr) to assess independent and additive effects of thiamine deficiency on ethanol-mediated neurotoxicity, mitochondrial dysfunction, insulin resistance, inhibition of neuronal and glial genes, and oxidative stress. Results: Pyr treatments (0 - 200 µM) caused dose-dependent cell loss (Crystal Violet assay) and reduced mitochondrial function (MTT assay) in PNET2 neuronal cultures. Ethanol alone (100 mM) significantly reduced PNET2 neuronal viability, MTT activity, and ATP production. Over the broad dose range of Pyr treatment, ethanol significantly reduced ATP content and cell number and increased mitochondrial mass (MitoTracker Green). Ex vivo cerebellar slice culture studies revealed ethanol-induced developmental architectural disruption that was substantially worsened by Pyr. The adverse effects of ethanol were linked to increased lipid peroxidation and inhibition of asparatyl-asparaginyl-β-hydroxylase (ASPH) expression. The independent and additive effects of Pyr were associated with increased cytotoxicity, lipid peroxidation, Caspase 3 activation, and Tau accumulation. Conclusions: During development, alcohol exposure and thiamine deficiency exert distinct but overlapping molecular pathologies that ultimately impair the structure and function of cerebellar neurons. While both insults drive cell loss and mitochondrial dysfunction with increased lipid peroxidation, ethanol’s additional inhibitory effects on ASPH reflect impairments in insulin and IGF signaling. In contrast, Pyr’s main adverse effects were likely due to neurotoxicity and the activation of apoptosis cascades. The findings suggest that FASD severity may be reduced by thiamine supplementation, but without additional support for insulin/IGF signaling networks, FASD would not be prevented.展开更多
BACKGROUND A few randomized clinical trials(RCT) and their meta-analyses have found patent foramen ovale closure(PFOC) to be beneficial in prevention of stroke compared to medical therapy. Whether the benefit is exten...BACKGROUND A few randomized clinical trials(RCT) and their meta-analyses have found patent foramen ovale closure(PFOC) to be beneficial in prevention of stroke compared to medical therapy. Whether the benefit is extended across all groups of patients remains unclear.AIM To evaluate the efficacy and safety of PFOC vs medical therapy in different groups of patients presenting with stroke, we performed this meta-analysis of RCTs.METHODS Electronic search of PubMed, EMBASE, Cochrane Central, CINAHL and ProQuest Central and manual search were performed from inception through September 2018 for RCTs. Ischemic stroke(IS), transient ischemic attack(TIA), a composite of IS, TIA and systemic embolism(SE), mortality, major bleeding,atrial fibrillation(AF) and procedural complications were the major outcomes.Random-effects model was used to perform analyses.RESULTS Meta-analysis of 6 RCTs including 3560 patients showed that the PFOC,compared to medical therapy reduced the risk of IS [odds ratio: 0.34; 95%confidence interval: 0.15-0.78; P = 0.01] and the composite of IS, TIA and SE [0.55(0.32-0.93); P = 0.02] and increased the AF risk [4.79(2.35-9.77); P < 0.0001]. No statistical difference was observed in the risk of TIA [0.86(0.54-1.38); P = 0.54],mortality [0.74(0.28-1.93); P = 0.53] and major bleeding [0.81(0.42-1.56); P = 0.53]between two strategies. Subgroup analyses showed that compared to medical therapy, PFOC reduced the risk of stroke in persons who were males, ≤ 45 years of age and had large shunt or atrial septal aneurysm.CONCLUSION In certain groups of patients presenting with stroke, PFOC is beneficial in preventing future stroke compared to medical therapy.展开更多
BACKGROUND Cirrhosis and its complications develop in a subgroup of patients with nonalcoholic fatty liver disease(NASH).Early detection of liver fibrosis represents an important goal of clinical care.AIM To test the ...BACKGROUND Cirrhosis and its complications develop in a subgroup of patients with nonalcoholic fatty liver disease(NASH).Early detection of liver fibrosis represents an important goal of clinical care.AIM To test the hypothesis that the development of cirrhosis in nonalcoholic fatty liver disease patients is preceded by the long-term trends of platelet counts and Fib-4 scores.METHODS We identified all patients in our healthcare system who had undergone fibrosis staging by liver biopsy or magnetic resonance elastography(MRE)for nonalcoholic fatty liver disease during the past decade(n=310).Platelet counts,serum glutamic-pyruvic transaminase and serum glutamic oxalacetic transaminase values preceding the staging tests were extracted from the electronic medical record system,and Fib-4 scores were calculated.Potential predictors of advanced fibrosis were evaluated using multivariate regression analysis.RESULTS Significant decreases in platelet counts and increases in Fib-4 scores were observed in all fibrosis stages,particularly in patients with cirrhosis.In the liver biopsy group,the presence of cirrhosis was best predicted by the combination of the Fib-4 score at the time closest to staging(P<0.0001),the presence of diabetes(P=0.0001),and the correlation coefficient of the preceding timedependent drop in platelet count(P=0.044).In the MRE group,Fib4 score(P=0.0025)and platelet drop(P=0.0373)were significant predictors.In comparison,the time-dependent rise of the Fib-4 score did not contribute in a statistically significant way.CONCLUSION Time-dependent changes in platelet counts and Fib-4 scores contribute to the prediction of cirrhosis in NASH patients with biopsy-or MRE-staged fibrosis.Their incorporation into predictive algorithms may assist in the earlier identification of high-risk patients.展开更多
Background: The apolipoprotein E (APOE, gene;apoE, protein) ε4 allele is the most commonly identified genetic risk factor for typical late-onset sporadic Alzheimer’s disease (AD). Each APOE ε4 allele roughly triple...Background: The apolipoprotein E (APOE, gene;apoE, protein) ε4 allele is the most commonly identified genetic risk factor for typical late-onset sporadic Alzheimer’s disease (AD). Each APOE ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, APOE ε3. Methods: We have employed hyperspectral fluorescence imaging with an amyloid-specific, conformation-sensing probe, p-FTAA, to elucidate protein aggregate structure and morphology in fresh frozen prefrontal cortex samples from human postmortem AD brain tissue samples from patients homozygous for either APOE ε3 or APOE ε4. Results: As expected APOE ε4/ε4 tissues had a significantly larger load of CAA than APOE ε3/ε3. APOE isoform-dependent morphological differences in amyloid plaques were also observed. Amyloid plaques in APOE ε3/ε3 tissue had small spherical cores and large coronas while amyloid plaques in APOE ε4/ε4 tissues had large irregular and multi-lobulated plaques with relatively smaller coronas. Despite the different morphologies of their cores, the p-FTAA stained APOE ε3/ε3 amyloid plaque cores had spectral properties identical to those of APOE ε4/ε4 plaque cores. Conclusions: These data support the hypothesis that one mechanism by which the APOE ε4 allele affects AD is by modulating the macrostructure of pathological protein deposits in the brain. APOE ε4 is associated with a higher density of amyloid plaques (as compared to APOE ε3). We speculate that multilobulated APOE ε4-associated plaques arise from multiple initiation foci that coalesce as the plaques grow.展开更多
In this editorial we comment on the manuscript describing a case of adenocarcinoma mixed with a neuroendocrine carcinoma of the gastroesophageal junction.Mixed neuroendocrine and non-neuroendocrine neoplasms of the ga...In this editorial we comment on the manuscript describing a case of adenocarcinoma mixed with a neuroendocrine carcinoma of the gastroesophageal junction.Mixed neuroendocrine and non-neuroendocrine neoplasms of the gastrointestinal system are rare heterogeneous group of tumors characterized by a high malignant potential,rapid growth,and poor prognosis.Due to the rarity of these cancers,the standard therapy is poorly defined.The diagnosis of these tumors is based on combination of morphological features,immunohistochemical and neuroendocrine and epithelial cell markers.Both endocrine and epithelial cell components can act independently of each other and thus,careful grading of each component separately is required.These cancers are aggressive in nature and the potential of each component has paramount importance in the choice of treatment and response.Regardless of the organ of origin,these tumors portend poor prognosis with increased proportion of neuroendocrine component.Multidisciplinary services and strategies are required for the management of these mixed malignancies to provide the best oncological outcomes.The etiopathogenesis of these mixed tumors remains obscure but poses interesting question.We briefly discuss a few salient points in this editorial.展开更多
Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease.The majority of ALS cases are sporadic with only about 20%of familial forms.Even in families with genetic predisposition,there is significan...Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease.The majority of ALS cases are sporadic with only about 20%of familial forms.Even in families with genetic predisposition,there is significant phenotypic variability,suggesting that ALS onset may be triggered by a combination of genetic factors.展开更多
Intestinal homeostasis is maintained by specialized host cells and the gut microbiota.Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis,and its dysregulation has been implicated in...Intestinal homeostasis is maintained by specialized host cells and the gut microbiota.Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis,and its dysregulation has been implicated in inflammation and colorectal cancer.Axin1 negatively regulates activated Wnt/β-catenin signaling,but little is known regarding its role in regulating host–microbial interactions in health and disease.Here,we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation.Axin1 expression was analyzed in human inflammatory bowel disease datasets.To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis,we generated new mouse models with Axin1 conditional knockout in intestinal epithelial cell(IEC;Axin1^(ΔIEC))and Paneth cell(PC;Axin1^(ΔPC))to compare with control(Axin1^(LoxP);LoxP:locus of X-over,P1)mice.We found increased Axin1 expression in the colonic epithelium of human inflammatory bowel disease(IBD).Axin1^(ΔIEC) mice exhibited altered goblet cell spatial distribution,PC morphology,reduced lysozyme expression,and enriched Akkermansia muciniphila(A.muciniphila).The absence of intestinal epithelial and PC Axin1 decreased susceptibility to dextran sulfate sodium(DSS)-induced colitis in vivo.Axin1^(ΔIEC) and Axin1^(ΔPC)mice became more susceptible to DSS-colitis after cohousing with control mice.Treatment with A.muciniphila reduced DSS-colitis severity.Antibiotic treatment did not change the IEC proliferation in the Axin1Loxp mice.However,the intestinal proliferative cells in Axin1^(ΔIEC)mice with antibiotic treatment were reduced compared with those in Axin1^(ΔIEC) mice without treatment.These data suggest non-colitogenic effects driven by the gut microbiome.In conclusion,we found that the loss of intestinal Axin1 protects against colitis,likely driven by epithelial Axin1 and Axin1-associated A.muciniphila.Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the microbiota.Further mechanistic studies using specific Axin1 mutations elucidating how Axin1 modulates the microbiome and host inflammatory response will provide new therapeutic strategies for human IBD.展开更多
Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types,including osteoblast(OB)differentiation and function.Exactly how Wnt/β-catenin signaling is regulated in OBs remain elusive.A...Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types,including osteoblast(OB)differentiation and function.Exactly how Wnt/β-catenin signaling is regulated in OBs remain elusive.ATP6AP2,an accessory subunit of V-ATPase,plays important roles in multiple cell types/organs and multiple signaling pathways.However,little is known whether and how ATP6AP2 in OBs regulates Wnt/β-catenin signaling and bone formation.Here we provide evidence for ATP6AP2 in the OB-lineage cells to promote OB-mediated bone formation and bone homeostasis selectively in the trabecular bone regions.Conditionally knocking out(CKO)ATP6AP2 in the OB-lineage cells(Atp6ap2^(Ocn-Cre))reduced trabecular,but not cortical,bone formation and bone mass.Proteomic and cellular biochemical studies revealed that LRP6 and N-cadherin were reduced in ATP6AP2-KO BMSCs and OBs,but not osteocytes.Additional in vitro and in vivo studies revealed impairedβ-catenin signaling in ATP6AP2-KO BMSCs and OBs,but not osteocytes,under both basal and Wnt stimulated conditions,although LRP5 was decreased in ATP6AP2-KO osteocytes,but not BMSCs.Further cell biological studies uncovered that osteoblastic ATP6AP2 is not required for Wnt3a suppression ofβ-catenin phosphorylation,but necessary for LRP6/β-catenin and N-cadherin/β-catenin protein complex distribution at the cell membrane,thus preventing their degradation.Expression of activeβ-catenin diminished the OB differentiation deficit in ATP6AP2-KO BMSCs.Taken together,these results support the view for ATP6AP2 as a critical regulator of both LRP6 and N-cadherin protein trafficking and stability,and thus regulatingβ-catenin levels,demonstrating an un-recognized function of osteoblastic ATP6AP2 in promoting Wnt/LRP6/β-catenin signaling and trabecular bone formation.展开更多
In this editorial we comment on the manuscript,describing management and surveillance strategies in synchronous and metachronous,gastric and colon cancers.Synchronous or metachronous primary malignancies at different ...In this editorial we comment on the manuscript,describing management and surveillance strategies in synchronous and metachronous,gastric and colon cancers.Synchronous or metachronous primary malignancies at different sites of the gastrointestinal tract pose a unique diagnostic and therapeutic challenge.Multidisciplinary services and strategies are required for the management of multiple site primary malignancies,to provide the best oncological outcomes.Although this study highlights the dual cancers in 76 sporadic cases,the authors excluded 55 patients due to combination of factors which includes;incomplete clinical data,genetic syndrome,gastric stump cancers.In addition,the authors did not elaborate if any patients presented with signet ring cell morphology,E-cadherin mutations or presence of inflammatory bowel disease.Genetic and mutational errors and epithelial field defects from chronic inflammatory diseases of the gastrointestinal tract are important when considering synchronous gastric and colonic cancers.We will briefly discuss these in this editorial.展开更多
Traumatic brain inju ry-induced unfavorable outcomes in human patients have independently been associated with dysregulated levels of monoamines,especially epinephrine,although few preclinical studies have examined th...Traumatic brain inju ry-induced unfavorable outcomes in human patients have independently been associated with dysregulated levels of monoamines,especially epinephrine,although few preclinical studies have examined the epinephrine level in the central nervous system after traumatic brain injury.Epinephrine has been shown to regulate the activities of spinal motoneurons as well as increase the heart rate,blood pressure,and blood flow to the hindlimb muscles.Therefore,the purpose of the present study was to determine the impact of repeated blast-induced traumatic brain injury on the epinephrine levels in seve ral function-s pecific central nervous system regions in rats.Following three repeated blast injuries at 3-day intervals,the hippocampus,motor cortex,locus coeruleus,vestibular nuclei,and lumbar spinal cord were harvested at post-injury day eight and processed for epinephrine assays using a high-sensitive electrochemical detector cou pled with high-performance liquid chromatography.Our results showed that the epinephrine levels were significantly decreased in the lumbar spinal cord tissues of blast-induced traumatic brain injury animals compared to the levels detected in age-and sex-matched sham controls.In other function-specific central nervous system regions,although the epinephrine levels were slightly altered following blast-induced tra u matic brain injury,they were not statistically significant.These results suggest that blast injury-induced significant downregulation of epinephrine in the lumbar spinal cord could negatively impact the motor and cardiovascular function.This is the first repo rt to show altered epinephrine levels in the spinal cord following repetitive mild blast-induced traumatic brain injury.展开更多
BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented...BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented in vitro but not in vivo.The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo.AIM To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin(CTX)in mice.METHODS CTX was given orally to C57BL/6 mice to induce diarrhea.Calcium and calci-mimetic R568 were used to activate CaSR.To maximize their local intestinal actions,calcium was administered luminally via oral rehydration solution(ORS),whereas R568 was applied serosally using an intraperitoneal route.To verify that their actions resulted from the intestine,effects were also examined on Cre-lox intestine-specific CaSR knockouts.Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl-or clinically by assessing stool consistency and weight loss.RESULTS CTX induced secretory diarrhea,as evidenced by increases in fecal Cl-,stool consistency,and weight loss following CTX exposure,but did not alter CaSR,neither in content nor in function.Accordingly,calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines.Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts(villinCre/Casrflox/flox)and neuronal CaSR knockouts(nestinCre/Casrflox/flox).CONCLUSION Treatment of acute secretory diarrheas remains a global challenge.Despite advances in diarrhea research,few have been made in the realm of diarrhea therapeutics.ORS therapy has remained the standard of care,although it does not halt the losses of intestinal fluid and ions caused by pathogens.There is no cost-effective therapeutic for diarrhea.This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases.展开更多
The education-practice gap, also known as the academic-practice gap is recognized as the difference between what a nursing student is taught and what the new nurse will experience in practice. This study evaluated spe...The education-practice gap, also known as the academic-practice gap is recognized as the difference between what a nursing student is taught and what the new nurse will experience in practice. This study evaluated specific education outcomes of schools of nursing in New Hampshire through surveys of new nurses and their employers. The responses were explored in relation to identified factors such as curriculum and clinical hours. The findings suggest that the new nurses felt prepared for practice, except in relationship to provision of care and medication administration for six or more patients. Of note is that 61% percent of participants were involved in errors and of these, 37.5% indicated that their education did not prepare them to administer medications to large groups. Evaluation of employer responses points to at least one and sometimes two levels of lower perception of perceived preparedness by the employer. The results highlight the differences between perceptions of preparedness of new nurse and employer, differences in perception of preparedness based on program type for specific gap elements, and the high rate of errors among new nurses. These results underscore the need for further research regarding the education practice gap, error factors, perceptions of preparedness for practice, and practice-readiness expectations of employers.展开更多
Mitochondrial organelle transplantation (MOT) is an innovative strategy for the treatment of mitochondrial dysfunction such as cardiac ischemic reperfusion injuries, traumatic brain and spinal cord injuries, cerebral ...Mitochondrial organelle transplantation (MOT) is an innovative strategy for the treatment of mitochondrial dysfunction such as cardiac ischemic reperfusion injuries, traumatic brain and spinal cord injuries, cerebral stroke, and neurodegenerative diseases. The earlier MOT results in better efficacy in animal models of urgent diseases such as ischemic stroke, and traumatic brain and spinal cord injuries. There is no long-term method to preserve mitochondria. Routine MOT procedure from cell growth to mitochondrial injection often takes serval weeks and is not satisfactory for urgent use cases. Hypothesis: Cryopreserved cells might be mitochondrial donors for MOT. Methods: We isolated mitochondria from cryopreserved human fibroblasts and mesenchymal stem cells (MSCs) in cell banks and compared the mitochondrial viability and transplantation with the mitochondria from fresh cells. Key findings: We found that mitochondria from fresh and cryopreserved cells are comparable in mitochondrial viability and transplantation. We also obtained data showing that mitochondria of fibroblasts and MSCs had similar membrane potential and transfer ability, but MSC’s mitochondria had higher ATP content than fibroblast’s mitochondria. In addition, oxygen consumption rates (OCRs) were higher in MSC’s mitochondria compared to fibroblast’s mitochondria and did not change between fresh and frozen cells. Conclusion: Cryopreserved fibroblasts and MSCs are alternative mitochondrial donors for MOT to fresh cells. MSCs could provide higher ATP-produced mitochondria than fibroblasts.展开更多
Spinal cord injury(SCI)population with injury below T10 or injury to the cauda equina region is characterized by denervated muscles,extensive muscle atrophy,infiltration of intramuscular fat and formation of fibrous t...Spinal cord injury(SCI)population with injury below T10 or injury to the cauda equina region is characterized by denervated muscles,extensive muscle atrophy,infiltration of intramuscular fat and formation of fibrous tissue.These morphological changes may put individuals with SCI at higher risk for developing other diseases such as various cardiovascular diseases,diabetes,obesity and osteoporosis.Currently,there is no available rehabilitation intervention to rescue the muscles or restore muscle size in SCI individuals with lower motor neuron denervation.We,hereby,performed a review of the available evidence that supports the use of electrical stimulation in restoration of denervated muscle following SCI.Long pulse width stimulation(LPWS)technique is an upcoming method of stimulating denervated muscles.Our primary objective is to explore the best stimulation paradigms(stimulation parameters,stimulation technique and stimulation wave)to achieve restoration of the denervated muscle.Stimulation parameters,such as the pulse duration,need to be 100–1000 times longer than in innervated muscles to achieve desirable excitability and contraction.The use of electrical stimulation in animal and human models induces muscle hypertrophy.Findings in animal models indicate that electrical stimulation,with a combination of exercise and pharmacological interventions,have proven to be effective in improving various aspects like relative muscle weight,muscle cross sectional area,number of myelinated regenerated fibers,and restoring some level of muscle function.Human studies have shown similar outcomes,identifying the use of LPWS as an effective strategy in increasing muscle cross sectional area,the size of muscle fibers,and improving muscle function.Therefore,displaying promise is an effective future stimulation intervention.In summary,LPWS is a novel stimulation technique for denervated muscles in humans with SCI.Successful studies on LPWS of denervated muscles will help in translating this stimulation technique to the clinical level as a rehabilitation intervention after SCI.展开更多
Spinal cord injury(SCI)is associated with high production and excessive accumulation of pathological 4-hydroxy-trans-2-nonenal(4-HNE),a reactive aldehyde,formed by SCI-induced metabolic dysregulation of membrane lipid...Spinal cord injury(SCI)is associated with high production and excessive accumulation of pathological 4-hydroxy-trans-2-nonenal(4-HNE),a reactive aldehyde,formed by SCI-induced metabolic dysregulation of membrane lipids.Reactive aldehyde load causes redox alteration,neuroinflammation,neurodegeneration,pain-like behaviors,and locomotion deficits.Pharmacological scavenging of reactive aldehydes results in limited improved motor and sensory functions.In this study,we targeted the activity of mitochondrial enzyme aldehyde dehydrogenase 2(ALDH2)to detoxify 4-HNE for accelerated functional recovery and improved pain-like behavior in a male mouse model of contusion SCI.N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide(Alda-1),a selective activator of ALDH2,was used as a therapeutic tool to suppress the 4-HNE load.SCI was induced by an impactor at the T9–10 vertebral level.Injured animals were initially treated with Alda-1 at 2 hours after injury,followed by once-daily treatment with Alda-1 for 30 consecutive days.Locomotor function was evaluated by the Basso Mouse Scale,and pain-like behaviors were assessed by mechanical allodynia and thermal algesia.ALDH2 activity was measured by enzymatic assay.4-HNE protein adducts and enzyme/protein expression levels were determined by western blot analysis and histology/immunohistochemistry.SCI resulted in a sustained and prolonged overload of 4-HNE,which parallels with the decreased activity of ALDH2 and low functional recovery.Alda-1 treatment of SCI decreased 4-HNE load and enhanced the activity of ALDH2 in both the acute and the chronic phases of SCI.Furthermore,the treatment with Alda-1 reduced neuroinflammation,oxidative stress,and neuronal loss and increased adenosine 5′-triphosphate levels stimulated the neurorepair process and improved locomotor and sensory functions.Conclusively,the results provide evidence that enhancing the ALDH2 activity by Alda-1 treatment of SCI mice suppresses the 4-HNE load that attenuates neuroinflammation and neurodegeneration,promotes the neurorepair process,and improves functional outcomes.Consequently,we suggest that Alda-1 may have therapeutic potential for the treatment of human SCI.Animal procedures were approved by the Institutional Animal Care and Use Committee(IACUC)of MUSC(IACUC-2019-00864)on December 21,2019.展开更多
Deep brain stimulation(DBS) is emerging as a pow-erful tool for the alleviation of targeted symptoms in treatment-resistant neuropsychiatric disorders. Despite the expanding use of neuropsychiatric DBS, the mecha-nism...Deep brain stimulation(DBS) is emerging as a pow-erful tool for the alleviation of targeted symptoms in treatment-resistant neuropsychiatric disorders. Despite the expanding use of neuropsychiatric DBS, the mecha-nisms responsible for its effects are only starting to be elucidated. Several modalities such as quantitative elec-troencephalography as well a intraoperative recordings have been utilized to attempt to understand the under-pinnings of this new treatment modality, but functional imaging appears to offer several unique advantages. Functional imaging techniques like positron emission tomography, single photon emission computed tomog-raphy and functional magnetic resonance imaging have been used to examine the effects of focal DBS on activ-ity in a distributed neural network. These investigations are critical for advancing the field of invasive neuro-modulation in a safe and effective manner, particularly in terms of defining the neuroanatomical targets and refining the stimulation protocols. The purpose of this review is to summarize the current functional neuroim-aging findings from neuropsychiatric DBS implantation for three disorders: treatment-resistant depression, obsessive-compulsive disorder, and Tourette syndrome. All of the major targets will be discussed(Nucleus ac-cumbens, anterior limb of internal capsule, subcallosal cingulate, Subthalamic nucleus, Centromedial nucleus of the thalamus-Parafasicular complex, frontal pole, and dorsolateral prefrontal cortex). We will also address some apparent inconsistencies within this literature, and suggest potential future directions for this promis-ing area.展开更多
Cardiovascular disease(CVD) is an important cause of mortality and morbidity in India.Mortality statistics and morbidity surveys indicate substantial regional variations in CVD prevalence and mortality rates.Data from...Cardiovascular disease(CVD) is an important cause of mortality and morbidity in India.Mortality statistics and morbidity surveys indicate substantial regional variations in CVD prevalence and mortality rates.Data from the Registrar General of India reported greater ageadjusted cardiovascular mortality in southern and eastern states of the country.Coronary heart disease(CHD) mortality is greater in south India while stroke is more common in the eastern Indian states.CHD prevalence is higher in urban Indian populations while stroke mortality is similar in urban and rural regions.Case-control studies in India have identified that the common major risk factors account for more than 90% of incident myocardial infarctions and stroke.The case-control INTERHEART and INTERSTROKE studies reported that hypertension,lipid abnormalities,smoking,obesity,diabetes,sedentary lifestyle,low fruit and vegetable intake,and psychosocial stress are as important in India as in other populations of the world.Individual studies have reported that there are substantial regional variations in risk factors in India.At a macro-level these regional variations in risk factors explain some of the regional differences in CVD mortality.However,there is need to study the prevalence of multiple cardiovascular risk factors in different regions of India and to correlate them with variations in CVD mortality using a uniform protocol.There is also a need to determine the 'causes of the causes' or fundamental determinants of these risk factors.The India Heart Watch study has been designed to study socioeconomic,anthropometric and biochemical risk factors in urban populations in different regions of the country in order to identify regional differences.展开更多
BACKGROUND Acute gallstone pancreatitis(AGP) is the most common cause of acute pancreatitis(AP) in the United States. Patients with AGP may also present with choledocholithiasis. In 2010, the American Society for Gast...BACKGROUND Acute gallstone pancreatitis(AGP) is the most common cause of acute pancreatitis(AP) in the United States. Patients with AGP may also present with choledocholithiasis. In 2010, the American Society for Gastrointestinal Endoscopy(ASGE) suggested a management algorithm based on probability for choledocholithiasis, recommending additional imaging for patients at intermediate risk and endoscopic retrograde cholangiopancreatography(ERCP) for patients at high risk of choledocholithiasis. In 2019, the ASGE guidelines were updated using more specific criteria to categorize individuals at high risk for choledocholithiasis. Neither ASGE guideline has been studied in AGP to determine the probability of having choledocholithiasis.AIM To determine compliance with ASGE guidelines, assess outcomes, and compare 2019 vs 2010 ASGE criteria for suspected choledocholithiasis in AGP.METHODS We conducted a retrospective cohort study of 882 patients admitted with AP to a single tertiary care center from 2008-2018. AP was diagnosed using revised Atlanta criteria and AGP was defined as the presence of gallstones on imaging or with cholestatic pattern of liver injury in the absence of another cause. Patients with chronic pancreatitis and pancreatic malignancy were excluded as were those who went directly to cholecystectomy prior to assessment for choledocholithiasis. Patients were assigned low, intermediate or high risk based on ASGE guidelines. Our primary outcomes of interest were the proportion of patients in the intermediate risk group undergoing magnetic resonance cholangiopancreatography(MRCP) first and the proportion of patients in the high risk group undergoing ERCP directly without preceding imaging. Secondary outcomes of interest included outcome differences based on if guidelines were not adhered to. We then evaluated the diagnostic accuracy of 2019 in comparison to the 2010 ASGE criteria for patients with suspected choledocholithiasis. We performed the t test or Wilcoxon rank sum test, as appropriate, to analyze if there were outcome differences based on if guidelines were not adhered to. Kappa coefficients were calculated to measure the degree of agreement between pairs of variables.RESULTS In this cohort, we identified 235 patients with AGP of which 79 patients were excluded as they went directly to surgery for cholecystectomy without prior MRCP or ERCP. Of the remaining 156 patients, 79 patients were categorized as intermediate risk and 77 patients were high risk for choledocholithiasis according to the 2010 ASGE guidelines. Among 79 intermediate risk patients, 54(68%) underwent MRCP first whereas 25 patients(32%) went directly to ERCP. For the 54 patients with intermediate risk who had MRCP first, 36 patients had no choledocholithiasis while 18 patients had evidence of choledocholithiasis prompting ERCP. Of these patients, ERCP confirmed stone disease in 11 patients. Of the 25 intermediate risk patients who directly underwent ERCP, 18 patients had stone disease. One patient with a normal ERCP developed post ERCP pancreatitis. Patients undergoing MRCP in this group had a significantly longer length of stay(5.0 vs 4.0 d, P = 0.02). In the high risk group, 64 patients(83%) had ERCP without preceding imaging, of which, 53 patients had findings consistent with choledocholithiasis, of which 13 patients(17%) underwent MRCP before ERCP, all of which showed evidence of stone disease. Furthermore, all of these patients ultimately had an ERCP, of which 8 patients had evidence of stones and 5 had normal examination.RESULTS Our cohort also demonstrated that 58% of all 156 patients with AGP had confirmed choledocholithiasis(79% of the high risk group and 37% of the intermediate group when risk was assigned based on the 2010 ASGE guidelines). When the updated 2019 ASGE guidelines were applied instead of the original 2010 guidelines, there was moderate agreement between the 2010 and 2019 guidelines(kappa = 0.46, 95%CI: 0.34-0.58). Forty-two of 77 patients were still deemed to be high risk and 35 patients were downgraded to intermediate risk. Thirty-five patients who were originally assigned high risk were reclassified as intermediate risk. For these 35 patients, 26 patients had ERCP findings consistent with choledocholithiasis and 9 patients had a normal examination. Based on the 2019 criteria, 9/35 patients who were downgraded to intermediate risk had an unnecessary ERCP with normal findings(without a preceding MRCP).CONCLUSION Two-thirds in intermediate risk and 83% in high risk group followed ASGE guidelines for choledocholithiasis. One intermediate-group patient with normal ERCP had post-ERCP AP, highlighting the risk of unnecessary procedures.展开更多
文摘Background: The Veterans Administration (VA) has been using telehealth to enhance Veteran access to high quality VA care for over a decade. Clinical video telehealth (CVT) is one such telehealth tool that allows Veterans the opportunity to be evaluated by specialists at the Indianapolis VA while they actually remain in their community (in their local healthcare setting). Such tools are reported to improve satisfaction by avoiding the need to make the long, stressful, and often costly trips to the Medical Center. Our goal is to describe the results of CVT implementation at the Indianapolis VA. Methods: A retrospective review of the data from 2011-2014 related to the use of CVT at the Indianapolis VA was undertaken. The data collected during this time period included: the number of CVT visits per year by specialty, the number of miles in travel avoided per visit, and patient satisfaction survey data, which are obtained after each CVT visit. Results: A total of 14,708 Veterans have enrolled in our CVT telehealth program since 2011. There were 23,267 visits in 2013. 486,170 miles related to travel were avoided (calculating the number of miles avoided in travel from home to a local satellite site as compared to having to travel from home to the Indianapolis VA). At the current Government reimbursement rate of $0.42/mile, this is expressed in a cost avoidance of $209,053. In total, since 2011, the telehealth CVT program has saved the Government $331,132, a total of 770,075 miles saved in travel for our Veterans. In addition, the CVT program has been very well received by our Veterans with an overall satisfaction score of 96%. Conclusion: Our results indicate that the implementation of CVT is cost effective and is well received by Veterans. Telehealth modalities such as CVT are viable options that enhance Veteran satisfaction by decreasing the time and the costs related to travel while continuing to offer high quality health care.
文摘Vaccination against Coronavirus disease-19(COVID-19)was pivotal to limit spread,morbidity and mortality.Our aim is to find out whether vaccines against COVID-19 lead to an immunological response stimulating the production of de novo donor specific antibodies(DSAs)or increase in mean fluorescence intensity(MFI)of pre-existing DSAs in kidney transplant recipients(KTRs).This study involved a detailed literature search through December 2nd,2023 using PubMed as the primary database.The search strategy incorporated a combination of relevant Medical Subject Headings terms and keywords:"COVID-19","SARS-CoV-2 Vaccination","Kidney,Renal Transplant",and"Donor specific antibodies".The results from related studies were collated and analyzed.A total of 6 studies were identified,encompassing 460 KTRs vaccinated against COVID-19.Immunological responses were detected in 8 KTRs of which 5 had increased MFIs,1 had de novo DSA,and 2 were categorized as either having de novo DSA or increased MFI.There were 48 KTRs with pre-existing DSAs prior to vaccination,but one study(Massa et al)did not report whether pre-existing DSAs were associated with post vaccination outcomes.Of the remaining 5 studies,35 KTRs with pre-existing DSAs were identified of which 7 KTRs(20%)developed de novo DSAs or increased MFIs.Overall,no immunological response was detected in 452(98.3%)KTRs.Our study affirms prior reports that COVID-19 vaccination is safe for KTRs,especially if there are no pre-existing DSAs.However,if KTRs have pre-existing DSAs,then an increased immunological risk may be present.These findings need to be taken cautiously as they are based on a limited number of patients so further studies are still needed for confirmation.
文摘Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive factor in the pathogenesis of the neurodevelopmental and metabolic derangements in FASD has not been determined. Methods: Control and ethanol-exposed human PNET2 cerebellar neuronal cells and rat cerebellar slice cultures were treated with vehicle or pyrithiamine (Pyr) to assess independent and additive effects of thiamine deficiency on ethanol-mediated neurotoxicity, mitochondrial dysfunction, insulin resistance, inhibition of neuronal and glial genes, and oxidative stress. Results: Pyr treatments (0 - 200 µM) caused dose-dependent cell loss (Crystal Violet assay) and reduced mitochondrial function (MTT assay) in PNET2 neuronal cultures. Ethanol alone (100 mM) significantly reduced PNET2 neuronal viability, MTT activity, and ATP production. Over the broad dose range of Pyr treatment, ethanol significantly reduced ATP content and cell number and increased mitochondrial mass (MitoTracker Green). Ex vivo cerebellar slice culture studies revealed ethanol-induced developmental architectural disruption that was substantially worsened by Pyr. The adverse effects of ethanol were linked to increased lipid peroxidation and inhibition of asparatyl-asparaginyl-β-hydroxylase (ASPH) expression. The independent and additive effects of Pyr were associated with increased cytotoxicity, lipid peroxidation, Caspase 3 activation, and Tau accumulation. Conclusions: During development, alcohol exposure and thiamine deficiency exert distinct but overlapping molecular pathologies that ultimately impair the structure and function of cerebellar neurons. While both insults drive cell loss and mitochondrial dysfunction with increased lipid peroxidation, ethanol’s additional inhibitory effects on ASPH reflect impairments in insulin and IGF signaling. In contrast, Pyr’s main adverse effects were likely due to neurotoxicity and the activation of apoptosis cascades. The findings suggest that FASD severity may be reduced by thiamine supplementation, but without additional support for insulin/IGF signaling networks, FASD would not be prevented.
文摘BACKGROUND A few randomized clinical trials(RCT) and their meta-analyses have found patent foramen ovale closure(PFOC) to be beneficial in prevention of stroke compared to medical therapy. Whether the benefit is extended across all groups of patients remains unclear.AIM To evaluate the efficacy and safety of PFOC vs medical therapy in different groups of patients presenting with stroke, we performed this meta-analysis of RCTs.METHODS Electronic search of PubMed, EMBASE, Cochrane Central, CINAHL and ProQuest Central and manual search were performed from inception through September 2018 for RCTs. Ischemic stroke(IS), transient ischemic attack(TIA), a composite of IS, TIA and systemic embolism(SE), mortality, major bleeding,atrial fibrillation(AF) and procedural complications were the major outcomes.Random-effects model was used to perform analyses.RESULTS Meta-analysis of 6 RCTs including 3560 patients showed that the PFOC,compared to medical therapy reduced the risk of IS [odds ratio: 0.34; 95%confidence interval: 0.15-0.78; P = 0.01] and the composite of IS, TIA and SE [0.55(0.32-0.93); P = 0.02] and increased the AF risk [4.79(2.35-9.77); P < 0.0001]. No statistical difference was observed in the risk of TIA [0.86(0.54-1.38); P = 0.54],mortality [0.74(0.28-1.93); P = 0.53] and major bleeding [0.81(0.42-1.56); P = 0.53]between two strategies. Subgroup analyses showed that compared to medical therapy, PFOC reduced the risk of stroke in persons who were males, ≤ 45 years of age and had large shunt or atrial septal aneurysm.CONCLUSION In certain groups of patients presenting with stroke, PFOC is beneficial in preventing future stroke compared to medical therapy.
文摘BACKGROUND Cirrhosis and its complications develop in a subgroup of patients with nonalcoholic fatty liver disease(NASH).Early detection of liver fibrosis represents an important goal of clinical care.AIM To test the hypothesis that the development of cirrhosis in nonalcoholic fatty liver disease patients is preceded by the long-term trends of platelet counts and Fib-4 scores.METHODS We identified all patients in our healthcare system who had undergone fibrosis staging by liver biopsy or magnetic resonance elastography(MRE)for nonalcoholic fatty liver disease during the past decade(n=310).Platelet counts,serum glutamic-pyruvic transaminase and serum glutamic oxalacetic transaminase values preceding the staging tests were extracted from the electronic medical record system,and Fib-4 scores were calculated.Potential predictors of advanced fibrosis were evaluated using multivariate regression analysis.RESULTS Significant decreases in platelet counts and increases in Fib-4 scores were observed in all fibrosis stages,particularly in patients with cirrhosis.In the liver biopsy group,the presence of cirrhosis was best predicted by the combination of the Fib-4 score at the time closest to staging(P<0.0001),the presence of diabetes(P=0.0001),and the correlation coefficient of the preceding timedependent drop in platelet count(P=0.044).In the MRE group,Fib4 score(P=0.0025)and platelet drop(P=0.0373)were significant predictors.In comparison,the time-dependent rise of the Fib-4 score did not contribute in a statistically significant way.CONCLUSION Time-dependent changes in platelet counts and Fib-4 scores contribute to the prediction of cirrhosis in NASH patients with biopsy-or MRE-staged fibrosis.Their incorporation into predictive algorithms may assist in the earlier identification of high-risk patients.
文摘Background: The apolipoprotein E (APOE, gene;apoE, protein) ε4 allele is the most commonly identified genetic risk factor for typical late-onset sporadic Alzheimer’s disease (AD). Each APOE ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, APOE ε3. Methods: We have employed hyperspectral fluorescence imaging with an amyloid-specific, conformation-sensing probe, p-FTAA, to elucidate protein aggregate structure and morphology in fresh frozen prefrontal cortex samples from human postmortem AD brain tissue samples from patients homozygous for either APOE ε3 or APOE ε4. Results: As expected APOE ε4/ε4 tissues had a significantly larger load of CAA than APOE ε3/ε3. APOE isoform-dependent morphological differences in amyloid plaques were also observed. Amyloid plaques in APOE ε3/ε3 tissue had small spherical cores and large coronas while amyloid plaques in APOE ε4/ε4 tissues had large irregular and multi-lobulated plaques with relatively smaller coronas. Despite the different morphologies of their cores, the p-FTAA stained APOE ε3/ε3 amyloid plaque cores had spectral properties identical to those of APOE ε4/ε4 plaque cores. Conclusions: These data support the hypothesis that one mechanism by which the APOE ε4 allele affects AD is by modulating the macrostructure of pathological protein deposits in the brain. APOE ε4 is associated with a higher density of amyloid plaques (as compared to APOE ε3). We speculate that multilobulated APOE ε4-associated plaques arise from multiple initiation foci that coalesce as the plaques grow.
文摘In this editorial we comment on the manuscript describing a case of adenocarcinoma mixed with a neuroendocrine carcinoma of the gastroesophageal junction.Mixed neuroendocrine and non-neuroendocrine neoplasms of the gastrointestinal system are rare heterogeneous group of tumors characterized by a high malignant potential,rapid growth,and poor prognosis.Due to the rarity of these cancers,the standard therapy is poorly defined.The diagnosis of these tumors is based on combination of morphological features,immunohistochemical and neuroendocrine and epithelial cell markers.Both endocrine and epithelial cell components can act independently of each other and thus,careful grading of each component separately is required.These cancers are aggressive in nature and the potential of each component has paramount importance in the choice of treatment and response.Regardless of the organ of origin,these tumors portend poor prognosis with increased proportion of neuroendocrine component.Multidisciplinary services and strategies are required for the management of these mixed malignancies to provide the best oncological outcomes.The etiopathogenesis of these mixed tumors remains obscure but poses interesting question.We briefly discuss a few salient points in this editorial.
基金supported by VA Merit Award 1 I01 BX004824-01National Institute of Diabetes and Digestive and Kidney Diseases(R01DK105118-01 and R01DK114126)United States Department of Defense Congressionally Directed Medical Research Programs(BC191198)(all to JS)。
文摘Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease.The majority of ALS cases are sporadic with only about 20%of familial forms.Even in families with genetic predisposition,there is significant phenotypic variability,suggesting that ALS onset may be triggered by a combination of genetic factors.
基金the VA Merit Award(1 I01BX004824-01)the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health Grants(R01 DK105118 and R01DK114126)the Crohn’s&Colitis Foundation Senior Research Award(902766)to Jun Sun.
文摘Intestinal homeostasis is maintained by specialized host cells and the gut microbiota.Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis,and its dysregulation has been implicated in inflammation and colorectal cancer.Axin1 negatively regulates activated Wnt/β-catenin signaling,but little is known regarding its role in regulating host–microbial interactions in health and disease.Here,we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation.Axin1 expression was analyzed in human inflammatory bowel disease datasets.To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis,we generated new mouse models with Axin1 conditional knockout in intestinal epithelial cell(IEC;Axin1^(ΔIEC))and Paneth cell(PC;Axin1^(ΔPC))to compare with control(Axin1^(LoxP);LoxP:locus of X-over,P1)mice.We found increased Axin1 expression in the colonic epithelium of human inflammatory bowel disease(IBD).Axin1^(ΔIEC) mice exhibited altered goblet cell spatial distribution,PC morphology,reduced lysozyme expression,and enriched Akkermansia muciniphila(A.muciniphila).The absence of intestinal epithelial and PC Axin1 decreased susceptibility to dextran sulfate sodium(DSS)-induced colitis in vivo.Axin1^(ΔIEC) and Axin1^(ΔPC)mice became more susceptible to DSS-colitis after cohousing with control mice.Treatment with A.muciniphila reduced DSS-colitis severity.Antibiotic treatment did not change the IEC proliferation in the Axin1Loxp mice.However,the intestinal proliferative cells in Axin1^(ΔIEC)mice with antibiotic treatment were reduced compared with those in Axin1^(ΔIEC) mice without treatment.These data suggest non-colitogenic effects driven by the gut microbiome.In conclusion,we found that the loss of intestinal Axin1 protects against colitis,likely driven by epithelial Axin1 and Axin1-associated A.muciniphila.Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the microbiota.Further mechanistic studies using specific Axin1 mutations elucidating how Axin1 modulates the microbiome and host inflammatory response will provide new therapeutic strategies for human IBD.
基金supported in part by grants from the National Institutes of Health(AG045781,AG051510,and AG066526)(to WCX).
文摘Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types,including osteoblast(OB)differentiation and function.Exactly how Wnt/β-catenin signaling is regulated in OBs remain elusive.ATP6AP2,an accessory subunit of V-ATPase,plays important roles in multiple cell types/organs and multiple signaling pathways.However,little is known whether and how ATP6AP2 in OBs regulates Wnt/β-catenin signaling and bone formation.Here we provide evidence for ATP6AP2 in the OB-lineage cells to promote OB-mediated bone formation and bone homeostasis selectively in the trabecular bone regions.Conditionally knocking out(CKO)ATP6AP2 in the OB-lineage cells(Atp6ap2^(Ocn-Cre))reduced trabecular,but not cortical,bone formation and bone mass.Proteomic and cellular biochemical studies revealed that LRP6 and N-cadherin were reduced in ATP6AP2-KO BMSCs and OBs,but not osteocytes.Additional in vitro and in vivo studies revealed impairedβ-catenin signaling in ATP6AP2-KO BMSCs and OBs,but not osteocytes,under both basal and Wnt stimulated conditions,although LRP5 was decreased in ATP6AP2-KO osteocytes,but not BMSCs.Further cell biological studies uncovered that osteoblastic ATP6AP2 is not required for Wnt3a suppression ofβ-catenin phosphorylation,but necessary for LRP6/β-catenin and N-cadherin/β-catenin protein complex distribution at the cell membrane,thus preventing their degradation.Expression of activeβ-catenin diminished the OB differentiation deficit in ATP6AP2-KO BMSCs.Taken together,these results support the view for ATP6AP2 as a critical regulator of both LRP6 and N-cadherin protein trafficking and stability,and thus regulatingβ-catenin levels,demonstrating an un-recognized function of osteoblastic ATP6AP2 in promoting Wnt/LRP6/β-catenin signaling and trabecular bone formation.
文摘In this editorial we comment on the manuscript,describing management and surveillance strategies in synchronous and metachronous,gastric and colon cancers.Synchronous or metachronous primary malignancies at different sites of the gastrointestinal tract pose a unique diagnostic and therapeutic challenge.Multidisciplinary services and strategies are required for the management of multiple site primary malignancies,to provide the best oncological outcomes.Although this study highlights the dual cancers in 76 sporadic cases,the authors excluded 55 patients due to combination of factors which includes;incomplete clinical data,genetic syndrome,gastric stump cancers.In addition,the authors did not elaborate if any patients presented with signet ring cell morphology,E-cadherin mutations or presence of inflammatory bowel disease.Genetic and mutational errors and epithelial field defects from chronic inflammatory diseases of the gastrointestinal tract are important when considering synchronous gastric and colonic cancers.We will briefly discuss these in this editorial.
基金supported by the United States Department of Veterans Affairs Rehabilitation Research and Development Service (RR&D)[Merit Review Award numbers B3123-I/101 RX003123 and B3986-R/I01 RX003986-01A1]。
文摘Traumatic brain inju ry-induced unfavorable outcomes in human patients have independently been associated with dysregulated levels of monoamines,especially epinephrine,although few preclinical studies have examined the epinephrine level in the central nervous system after traumatic brain injury.Epinephrine has been shown to regulate the activities of spinal motoneurons as well as increase the heart rate,blood pressure,and blood flow to the hindlimb muscles.Therefore,the purpose of the present study was to determine the impact of repeated blast-induced traumatic brain injury on the epinephrine levels in seve ral function-s pecific central nervous system regions in rats.Following three repeated blast injuries at 3-day intervals,the hippocampus,motor cortex,locus coeruleus,vestibular nuclei,and lumbar spinal cord were harvested at post-injury day eight and processed for epinephrine assays using a high-sensitive electrochemical detector cou pled with high-performance liquid chromatography.Our results showed that the epinephrine levels were significantly decreased in the lumbar spinal cord tissues of blast-induced traumatic brain injury animals compared to the levels detected in age-and sex-matched sham controls.In other function-specific central nervous system regions,although the epinephrine levels were slightly altered following blast-induced tra u matic brain injury,they were not statistically significant.These results suggest that blast injury-induced significant downregulation of epinephrine in the lumbar spinal cord could negatively impact the motor and cardiovascular function.This is the first repo rt to show altered epinephrine levels in the spinal cord following repetitive mild blast-induced traumatic brain injury.
基金Supported by Eunice Kennedy Shriver National Institute of Child Health&Human Development of the National Institutes of Health,No.1K08HD079674-01 and 1R41HD092133-01National Institute of Allergy and Infectious Diseases,No.1A21AI169282and VA Research Career Scientist Award,No.1IK6BX004835.
文摘BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented in vitro but not in vivo.The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo.AIM To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin(CTX)in mice.METHODS CTX was given orally to C57BL/6 mice to induce diarrhea.Calcium and calci-mimetic R568 were used to activate CaSR.To maximize their local intestinal actions,calcium was administered luminally via oral rehydration solution(ORS),whereas R568 was applied serosally using an intraperitoneal route.To verify that their actions resulted from the intestine,effects were also examined on Cre-lox intestine-specific CaSR knockouts.Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl-or clinically by assessing stool consistency and weight loss.RESULTS CTX induced secretory diarrhea,as evidenced by increases in fecal Cl-,stool consistency,and weight loss following CTX exposure,but did not alter CaSR,neither in content nor in function.Accordingly,calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines.Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts(villinCre/Casrflox/flox)and neuronal CaSR knockouts(nestinCre/Casrflox/flox).CONCLUSION Treatment of acute secretory diarrheas remains a global challenge.Despite advances in diarrhea research,few have been made in the realm of diarrhea therapeutics.ORS therapy has remained the standard of care,although it does not halt the losses of intestinal fluid and ions caused by pathogens.There is no cost-effective therapeutic for diarrhea.This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases.
文摘The education-practice gap, also known as the academic-practice gap is recognized as the difference between what a nursing student is taught and what the new nurse will experience in practice. This study evaluated specific education outcomes of schools of nursing in New Hampshire through surveys of new nurses and their employers. The responses were explored in relation to identified factors such as curriculum and clinical hours. The findings suggest that the new nurses felt prepared for practice, except in relationship to provision of care and medication administration for six or more patients. Of note is that 61% percent of participants were involved in errors and of these, 37.5% indicated that their education did not prepare them to administer medications to large groups. Evaluation of employer responses points to at least one and sometimes two levels of lower perception of perceived preparedness by the employer. The results highlight the differences between perceptions of preparedness of new nurse and employer, differences in perception of preparedness based on program type for specific gap elements, and the high rate of errors among new nurses. These results underscore the need for further research regarding the education practice gap, error factors, perceptions of preparedness for practice, and practice-readiness expectations of employers.
文摘Mitochondrial organelle transplantation (MOT) is an innovative strategy for the treatment of mitochondrial dysfunction such as cardiac ischemic reperfusion injuries, traumatic brain and spinal cord injuries, cerebral stroke, and neurodegenerative diseases. The earlier MOT results in better efficacy in animal models of urgent diseases such as ischemic stroke, and traumatic brain and spinal cord injuries. There is no long-term method to preserve mitochondria. Routine MOT procedure from cell growth to mitochondrial injection often takes serval weeks and is not satisfactory for urgent use cases. Hypothesis: Cryopreserved cells might be mitochondrial donors for MOT. Methods: We isolated mitochondria from cryopreserved human fibroblasts and mesenchymal stem cells (MSCs) in cell banks and compared the mitochondrial viability and transplantation with the mitochondria from fresh cells. Key findings: We found that mitochondria from fresh and cryopreserved cells are comparable in mitochondrial viability and transplantation. We also obtained data showing that mitochondria of fibroblasts and MSCs had similar membrane potential and transfer ability, but MSC’s mitochondria had higher ATP content than fibroblast’s mitochondria. In addition, oxygen consumption rates (OCRs) were higher in MSC’s mitochondria compared to fibroblast’s mitochondria and did not change between fresh and frozen cells. Conclusion: Cryopreserved fibroblasts and MSCs are alternative mitochondrial donors for MOT to fresh cells. MSCs could provide higher ATP-produced mitochondria than fibroblasts.
文摘Spinal cord injury(SCI)population with injury below T10 or injury to the cauda equina region is characterized by denervated muscles,extensive muscle atrophy,infiltration of intramuscular fat and formation of fibrous tissue.These morphological changes may put individuals with SCI at higher risk for developing other diseases such as various cardiovascular diseases,diabetes,obesity and osteoporosis.Currently,there is no available rehabilitation intervention to rescue the muscles or restore muscle size in SCI individuals with lower motor neuron denervation.We,hereby,performed a review of the available evidence that supports the use of electrical stimulation in restoration of denervated muscle following SCI.Long pulse width stimulation(LPWS)technique is an upcoming method of stimulating denervated muscles.Our primary objective is to explore the best stimulation paradigms(stimulation parameters,stimulation technique and stimulation wave)to achieve restoration of the denervated muscle.Stimulation parameters,such as the pulse duration,need to be 100–1000 times longer than in innervated muscles to achieve desirable excitability and contraction.The use of electrical stimulation in animal and human models induces muscle hypertrophy.Findings in animal models indicate that electrical stimulation,with a combination of exercise and pharmacological interventions,have proven to be effective in improving various aspects like relative muscle weight,muscle cross sectional area,number of myelinated regenerated fibers,and restoring some level of muscle function.Human studies have shown similar outcomes,identifying the use of LPWS as an effective strategy in increasing muscle cross sectional area,the size of muscle fibers,and improving muscle function.Therefore,displaying promise is an effective future stimulation intervention.In summary,LPWS is a novel stimulation technique for denervated muscles in humans with SCI.Successful studies on LPWS of denervated muscles will help in translating this stimulation technique to the clinical level as a rehabilitation intervention after SCI.
基金supported by a grant from the State of South Carolina Spinal Cord Injury Research Fund Boardgrant No.SCIRF#2017(to MK)+2 种基金the NIH grant No.R21 NS114433(to JW and MK)supported by grants from the U.S.Department of Veterans Affairs,grant Nos.RX002090(IS)and BX003401(to AKS)The NIH Grants C06 RR018823 and No C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources also supported the animal work。
文摘Spinal cord injury(SCI)is associated with high production and excessive accumulation of pathological 4-hydroxy-trans-2-nonenal(4-HNE),a reactive aldehyde,formed by SCI-induced metabolic dysregulation of membrane lipids.Reactive aldehyde load causes redox alteration,neuroinflammation,neurodegeneration,pain-like behaviors,and locomotion deficits.Pharmacological scavenging of reactive aldehydes results in limited improved motor and sensory functions.In this study,we targeted the activity of mitochondrial enzyme aldehyde dehydrogenase 2(ALDH2)to detoxify 4-HNE for accelerated functional recovery and improved pain-like behavior in a male mouse model of contusion SCI.N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide(Alda-1),a selective activator of ALDH2,was used as a therapeutic tool to suppress the 4-HNE load.SCI was induced by an impactor at the T9–10 vertebral level.Injured animals were initially treated with Alda-1 at 2 hours after injury,followed by once-daily treatment with Alda-1 for 30 consecutive days.Locomotor function was evaluated by the Basso Mouse Scale,and pain-like behaviors were assessed by mechanical allodynia and thermal algesia.ALDH2 activity was measured by enzymatic assay.4-HNE protein adducts and enzyme/protein expression levels were determined by western blot analysis and histology/immunohistochemistry.SCI resulted in a sustained and prolonged overload of 4-HNE,which parallels with the decreased activity of ALDH2 and low functional recovery.Alda-1 treatment of SCI decreased 4-HNE load and enhanced the activity of ALDH2 in both the acute and the chronic phases of SCI.Furthermore,the treatment with Alda-1 reduced neuroinflammation,oxidative stress,and neuronal loss and increased adenosine 5′-triphosphate levels stimulated the neurorepair process and improved locomotor and sensory functions.Conclusively,the results provide evidence that enhancing the ALDH2 activity by Alda-1 treatment of SCI mice suppresses the 4-HNE load that attenuates neuroinflammation and neurodegeneration,promotes the neurorepair process,and improves functional outcomes.Consequently,we suggest that Alda-1 may have therapeutic potential for the treatment of human SCI.Animal procedures were approved by the Institutional Animal Care and Use Committee(IACUC)of MUSC(IACUC-2019-00864)on December 21,2019.
文摘Deep brain stimulation(DBS) is emerging as a pow-erful tool for the alleviation of targeted symptoms in treatment-resistant neuropsychiatric disorders. Despite the expanding use of neuropsychiatric DBS, the mecha-nisms responsible for its effects are only starting to be elucidated. Several modalities such as quantitative elec-troencephalography as well a intraoperative recordings have been utilized to attempt to understand the under-pinnings of this new treatment modality, but functional imaging appears to offer several unique advantages. Functional imaging techniques like positron emission tomography, single photon emission computed tomog-raphy and functional magnetic resonance imaging have been used to examine the effects of focal DBS on activ-ity in a distributed neural network. These investigations are critical for advancing the field of invasive neuro-modulation in a safe and effective manner, particularly in terms of defining the neuroanatomical targets and refining the stimulation protocols. The purpose of this review is to summarize the current functional neuroim-aging findings from neuropsychiatric DBS implantation for three disorders: treatment-resistant depression, obsessive-compulsive disorder, and Tourette syndrome. All of the major targets will be discussed(Nucleus ac-cumbens, anterior limb of internal capsule, subcallosal cingulate, Subthalamic nucleus, Centromedial nucleus of the thalamus-Parafasicular complex, frontal pole, and dorsolateral prefrontal cortex). We will also address some apparent inconsistencies within this literature, and suggest potential future directions for this promis-ing area.
基金Supported by Ad hoc research grant from South Asian Society of Atherosclerosis and Thrombosis,Bangalore,India and Min-neapolis,United States
文摘Cardiovascular disease(CVD) is an important cause of mortality and morbidity in India.Mortality statistics and morbidity surveys indicate substantial regional variations in CVD prevalence and mortality rates.Data from the Registrar General of India reported greater ageadjusted cardiovascular mortality in southern and eastern states of the country.Coronary heart disease(CHD) mortality is greater in south India while stroke is more common in the eastern Indian states.CHD prevalence is higher in urban Indian populations while stroke mortality is similar in urban and rural regions.Case-control studies in India have identified that the common major risk factors account for more than 90% of incident myocardial infarctions and stroke.The case-control INTERHEART and INTERSTROKE studies reported that hypertension,lipid abnormalities,smoking,obesity,diabetes,sedentary lifestyle,low fruit and vegetable intake,and psychosocial stress are as important in India as in other populations of the world.Individual studies have reported that there are substantial regional variations in risk factors in India.At a macro-level these regional variations in risk factors explain some of the regional differences in CVD mortality.However,there is need to study the prevalence of multiple cardiovascular risk factors in different regions of India and to correlate them with variations in CVD mortality using a uniform protocol.There is also a need to determine the 'causes of the causes' or fundamental determinants of these risk factors.The India Heart Watch study has been designed to study socioeconomic,anthropometric and biochemical risk factors in urban populations in different regions of the country in order to identify regional differences.
文摘BACKGROUND Acute gallstone pancreatitis(AGP) is the most common cause of acute pancreatitis(AP) in the United States. Patients with AGP may also present with choledocholithiasis. In 2010, the American Society for Gastrointestinal Endoscopy(ASGE) suggested a management algorithm based on probability for choledocholithiasis, recommending additional imaging for patients at intermediate risk and endoscopic retrograde cholangiopancreatography(ERCP) for patients at high risk of choledocholithiasis. In 2019, the ASGE guidelines were updated using more specific criteria to categorize individuals at high risk for choledocholithiasis. Neither ASGE guideline has been studied in AGP to determine the probability of having choledocholithiasis.AIM To determine compliance with ASGE guidelines, assess outcomes, and compare 2019 vs 2010 ASGE criteria for suspected choledocholithiasis in AGP.METHODS We conducted a retrospective cohort study of 882 patients admitted with AP to a single tertiary care center from 2008-2018. AP was diagnosed using revised Atlanta criteria and AGP was defined as the presence of gallstones on imaging or with cholestatic pattern of liver injury in the absence of another cause. Patients with chronic pancreatitis and pancreatic malignancy were excluded as were those who went directly to cholecystectomy prior to assessment for choledocholithiasis. Patients were assigned low, intermediate or high risk based on ASGE guidelines. Our primary outcomes of interest were the proportion of patients in the intermediate risk group undergoing magnetic resonance cholangiopancreatography(MRCP) first and the proportion of patients in the high risk group undergoing ERCP directly without preceding imaging. Secondary outcomes of interest included outcome differences based on if guidelines were not adhered to. We then evaluated the diagnostic accuracy of 2019 in comparison to the 2010 ASGE criteria for patients with suspected choledocholithiasis. We performed the t test or Wilcoxon rank sum test, as appropriate, to analyze if there were outcome differences based on if guidelines were not adhered to. Kappa coefficients were calculated to measure the degree of agreement between pairs of variables.RESULTS In this cohort, we identified 235 patients with AGP of which 79 patients were excluded as they went directly to surgery for cholecystectomy without prior MRCP or ERCP. Of the remaining 156 patients, 79 patients were categorized as intermediate risk and 77 patients were high risk for choledocholithiasis according to the 2010 ASGE guidelines. Among 79 intermediate risk patients, 54(68%) underwent MRCP first whereas 25 patients(32%) went directly to ERCP. For the 54 patients with intermediate risk who had MRCP first, 36 patients had no choledocholithiasis while 18 patients had evidence of choledocholithiasis prompting ERCP. Of these patients, ERCP confirmed stone disease in 11 patients. Of the 25 intermediate risk patients who directly underwent ERCP, 18 patients had stone disease. One patient with a normal ERCP developed post ERCP pancreatitis. Patients undergoing MRCP in this group had a significantly longer length of stay(5.0 vs 4.0 d, P = 0.02). In the high risk group, 64 patients(83%) had ERCP without preceding imaging, of which, 53 patients had findings consistent with choledocholithiasis, of which 13 patients(17%) underwent MRCP before ERCP, all of which showed evidence of stone disease. Furthermore, all of these patients ultimately had an ERCP, of which 8 patients had evidence of stones and 5 had normal examination.RESULTS Our cohort also demonstrated that 58% of all 156 patients with AGP had confirmed choledocholithiasis(79% of the high risk group and 37% of the intermediate group when risk was assigned based on the 2010 ASGE guidelines). When the updated 2019 ASGE guidelines were applied instead of the original 2010 guidelines, there was moderate agreement between the 2010 and 2019 guidelines(kappa = 0.46, 95%CI: 0.34-0.58). Forty-two of 77 patients were still deemed to be high risk and 35 patients were downgraded to intermediate risk. Thirty-five patients who were originally assigned high risk were reclassified as intermediate risk. For these 35 patients, 26 patients had ERCP findings consistent with choledocholithiasis and 9 patients had a normal examination. Based on the 2019 criteria, 9/35 patients who were downgraded to intermediate risk had an unnecessary ERCP with normal findings(without a preceding MRCP).CONCLUSION Two-thirds in intermediate risk and 83% in high risk group followed ASGE guidelines for choledocholithiasis. One intermediate-group patient with normal ERCP had post-ERCP AP, highlighting the risk of unnecessary procedures.
