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Sodium glucose co-transporter 2 inhibition reduces succinate levels in diabetic mice

World Journal of Gastroenterology 2020年第23期26卷 3225-3235页

作者： Lakshini Y Herat Natalie C Ward Aaron L Magno elizabeth p rakoczy Marcio G Kiuchi Markus p Schlaich Vance B Matthews School of Biomedical Sciences Dobney Hypertension CentreRoyal Perth Hospital UnitUniversity of Western AustraliaPerth 6000Australia Faculty of Health and Medical Sciences University of Western AustraliaCrawley 6009Australia Faculty of Health Sciences School of Public HealthCurtin UniversityBentley 6102Australia Research Centre Royal Perth HospitalPerth 6000Australia Department of Molecular Ophthalmology University of Western AustraliaCrawley 6009Australia Dobney Hypertension Centre School of MedicineRoyal Perth Hospital UnitUniversity of Western AustraliaPerth 6000Australia Department of Cardiology and Department of Nephrology Royal Perth HospitalPerth 6000Australia

BACKGROUND Type 1 diabetes(T1D) is associated with major chronic microvascular complications which contribute significantly to diabetes associated morbidity.The protein primarily responsible for glucose reabsorption in the kidney is sodium glucose co-transporter 2(SGLT2). presently, SGLT2 inhibitors are widely used in diabetic patients to improve blood glucose levels and prevent cardiovascular and renal complications. Given the broad therapeutic application of SGLT2 inhibitors, we hypothesised that SGLT2 inhibition may exert its protective effects via alterations of the gut microbiome and tested this in a type 1 diabetic mouse model of diabetic retinopathy.AIM To determine whether the treatment with two independent SGLT2 inhibitors affects gut health in a type 1 diabetic mouse model.METHODS The SGLT2 inhibitors empagliflozin or dapagliflozin(25 mg/kg/d) or vehicle dimethylsulfoxide(DMSO) were administered to C57 BL/6 J, Akita, Kimba and Akimba mice at 10 wk of age for 8 wk via their drinking water. Serum samples were collected and the concentration of succinate and the short chain fatty acid(SCFA) butyric acid was measured using gas chromatography-mass spectrometry. Enzyme-linked immunosorbent assay(ELISA) was performed to determine the concentration of insulin and leptin. Furthermore, the norepinephrine content in kidney tissue was determined using ELISA. pancreatic tissue was collected and stained with haematoxylin and eosin and analysed using brightfield microscopy.RESULTS Due to the presence of the Akita allele, both Akita and Akimba mice showed a reduction in insulin production compared to C57 BL/6 J and Kimba mice.Furthermore, Akita mice also showed the presence of apoptotic bodies within the pancreatic islets. The acinar cells of Akita and Akimba mice showed swelling which is indicative of acute injury or pancreatitis. After 8 wk of SGLT2 inhibition with dapagliflozin, the intermediate metabolite of gut metabolism known as succinate was significantly reduced in Akimba mice when compared to DMSO treated mic

关键词： Sodium glucose co-transporter inhibitors Sodium glucose co-transporter 2 Diabetes Diabetic retinopathy Mouse Gut microbiota Empagliflozin Dapagliflozin Succinate Akimba

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A modular microfluidic platform to study how fluid shear stress alters estrogen receptor phenotype in ER+breast cancer cells

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Microsystems & Nanoengineering 2024年第1期10卷 287-299页

作者： Braulio Andrés Ortega Quesada Jonathan Cuccia Rachael Coates Blake Nassar Ethan Littlefield elizabeth C.Martin Adam T.Melvin Cain Department of Chemical Engineering Louisiana State UniversityBaton RougeLA 70803USA Department of Chemical and Biological Engineering Clemson UniversityClemsonSC 29634USA Biological and Agricultural Engineering Louisiana State UniversityBaton RougeLA 70803USA Department Medicine Section Hematology and Medical OncologyTulane UniversityNew OrleansLA 70118USA

Metastatic breast cancer leads to poor prognoses and worse outcomes in patients due to its invasive behavior and poor response to therapy.It is still unclear what biophysical and biochemical factors drive this more aggressive phenotype in metastatic cancer;however recent studies have suggested that exposure to fluid shear stress in the vasculature could cause this.In this study a modular microfluidic platform capable of mimicking the magnitude of fluid shear stress(FSS)found in human vasculature was designed and fabricated.This device provides a platform to evaluate the effects of FSS on MCF-7 cell line,an estrogen receptor positive(ER+)breast cancer cell line,during circulation in the vessels.Elucidation of the effects of FSS on MCF-7 cells was carried out utilizing two approaches:single cell analysis and bulk analysis.For single cell analysis,cells were trapped in a microarray after exiting the serpentine channel and followed by immunostaining on the device(on-chip).Bulk analysis was performed after cells were collected in a microtube at the outlet of the microfluidic serpentine channel for western blotting(off-chip).It was found that cells exposed to an FSS magnitude of 10 dyn/cm^(2) with a residence time of 60 s enhanced expression of the proliferation marker Ki67 in the MCF-7 cell line at a single cell level.To understand possible mechanisms for enhanced Ki67 expression,on-chip and off-chip analyses were performed for pro-growth and survival pathways ERK,AKT,and JAK/STAT.Results demonstrated that after shearing the cells phosphorylation of p-AKT,p-mTOR,and p-STAT3 were observed.However,there was no change in p-ERK1/2.AKT is a mediator of ER rapid signaling,analysis of phosphorylated ERαwas carried out and no significant differences between sheared and non-sheared populations were observed.Taken together these results demonstrate that FSS can increase phosphorylation of proteins associated with a more aggressive phenotype in circulating cancer cells.These findings provide additional information that may help

关键词： fluid breast estrogen

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Assessment of Online Transgender Healthcare Teaching Modules for Internal Medicine Residents and Fellows

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Open Journal of Internal Medicine 2024年第2期14卷 259-268页

作者： elizabeth M. Lamos Rana Malek Department of Medicine University of Maryland School of Medicine Baltimore MD USA

Background: Transgender healthcare is not a formal learning requirement in Internal Medicine residency or fellowship. The National LGBTQ Task Force appealed to urgently train clinicians on the effective care of transgender patients. Few studies address the successful implementation of transgender healthcare teaching and education in graduate medical education. purpose: The purpose was to design an online asynchronous curriculum to address the need for improved transgender healthcare education in graduate medical education and assess change in knowledge and comfort in transgender healthcare for residents and fellow learners. Methods: A 6-module curriculum was developed using established guidelines and ACGME competencies as a framework for content. To assess curriculum effectiveness, participants received anonymous pre- and post-curriculum surveys which included a multiple-choice knowledge assessment, Likert scale comfort questions focusing on healthcare skills, and open-ended feedback questions. Results: Twenty-six internal medicine residents and fellows participated in the curriculum (2022-2023). There was a 69% post-survey response rate. participants improved their gender-affirming knowledge after completing the curriculum (p Conclusion: This online curriculum was successful in increasing knowledge and comfort in transgender care for IM residents and fellows. It provides a promising framework to address this gap in curricular content.

关键词： Education Fellow Resident Transgender

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The Interventional Capacity of Community Health Volunteers for Screening and Linkages of Non-Communicable Diseases in Nyeri County, Kenya

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Open Journal of preventive Medicine 2024年第4期14卷 61-78页

作者： Kenneth Mugambi Jackline Nyaberi elizabeth Echoka Kemri Graduate School Nairobi Kenya Jomo Kenyatta University of Science & Technology Nairobi Kenya

Non-communicable diseases (NCDs) account for 63% of mortalities. Approximately 80% of these NCD-related deaths occur in LMICs. A quasi-experimental study utilizing a non-equivalent pre-and post-test was conducted from May 2022 to March 2023 with 370 study participants. Multistage cluster and random sampling were used to select ten community units, and therefore, 150 CHVs were chosen for the control unit, and 150 were used to form the interventional group. Data was collected from the KOBO app. Six (6) homogenous FGDs comprised ten members, and 10 KII were conducted across study sites. Quantitative data was analyzed using SpSS version 28.0, and qualitative data was audio-recorded, transcribed, and analyzed via N-Vivo 12. The study shows that 59.3% of respondents have minimal information, and 92.7% (n = 139) have no clear understanding of NCDs, with a pre-intervention capacity of 48.8%. Independent sample t-test showed a significant difference in capacity from a pre-intervention average of 48.75 (SD ± 5.7)%, which increased to 68.28 (SD ± 7.6)%, p plays a pivotal role in grassroots healthcare delivery but requires optimization for NCD management.

关键词： Intervention Community Health Volunteers Non-Communicable Disease Screening Linkages

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CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of pKM supports antitumor immunity

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Cellular & Molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand p.Sharda Mackenzie M.Lieberman Caitlin M.James Shivana M.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou Andrew M.Intlekofer Richard M.Higashi Teresa W.M.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal elizabeth A.Repasky Kelvin p.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of Medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and pathogenesis program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of Cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA present address:University of Colorado Boulder BoulderCO 80309USA present address:Dana Farber Cancer Institute BostonMA 02215USA present address:Massachusetts Institute of Technology BostonMA 02139USA present address:Melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202USA

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of pKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,pKM alternative splicing occurred independently of CD28-driven pI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 pKM2

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How completely are randomized controlled trials of non-pharmacological interventions following concussion reported? A systematic review

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Journal of Sport and Health Science 2024年第4期13卷 537-547页

作者： Jacqueline Josee van Ierssel Olivia Galea Kirsten Holte Caroline Luszawski elizabeth Jenkins Jennifer O’Neil Carolyn A Emery Rebekah Mannix Kathryn Schneider Keith Owen Yeates Roger Zemek Children’s Hospital of Eastern Ontario Research Institute OttawaON K1H 8L1Canada The Centre for Health Activity and Rehabilitation ResearchUniversity of OtagoDunedin 9016New Zealand Sport Injury prevention Research Centre Faculty of KinesiologyUniversity of CalgaryCalgaryAB T2N 1N4Canada Alberta Children’s Hospital Research Institute University of Calgary CalgaryAB T2N 1N4Canada Hotchkiss Brain Institute University of CalgaryCalgaryAB T2N 4N1Canada Department of psychology University of CalgaryCalgaryAB T2N 1N4Canada g Faculty of MedicineUniversity of OttawaOttawaON K1H 8M5Canada School of Rehabilitation Sciences University of OttawaOttawaON K1H 8M5Canada Bruyere Research Institute OttawaON K1N 5C8Canada Departments of pediatrics and Emergency Medicine Harvard Medical SchoolBostonMA 02115USA Departments of pediatrics and Emergency Medicine University of OttawaOttawaON K1H 8M5Canada

purpose:The study aimed to examine the reporting completeness of randomized controlled trials(RCTs)of non-pharmacological interventions following concussion.Methods:We searched MEDLINE,Embase,psycInfo,CINAHL,and Web of Science up to May 2022.Two reviewers independently screened studies and assessed reporting completeness using the Template for Intervention Description and Replication(TIDieR),Consensus on Exercise Reporting Template(CERT),and international Consensus on Therapeutic Exercise aNd Training(i-CONTENT)checklists.Additional information was sought my study authors where reporting was incomplete.Risk of bias(ROB)was assessed with the Cochrane ROB-2 Tool.RCTs examining non-pharmacological interventions following concussion.Results:We included 89 RCTs(n=53 high ROB)examining 11 different interventions for concussion:sub-symptom threshold aerobic exercise,cervicovestibular therapy,physical/cognitive rest,vision therapy,education,psychotherapy,hyperbaric oxygen therapy,transcranial magnetic stimulation,blue light therapy,osteopathic manipulation,and head/neck cooling.Median scores were:TIDieR 9/12(75%;interquartile range(IQR)=5;range:5-12),CERT 17/19(89%;IQR=2;range:10-19),and i-CONTENT 6/7(86%;IQR=1;range:5-7).percentage of studies completely reporting all items was TIDieR 35%(31/89),CERT 24%(5/21),and i-CONTENT 10%(2/21).Studies were more completely reported after publication of TIDieR(t_(87)=2.08;p=0.04)and CERT(t_(19)=2.72;p=0.01).Reporting completeness was not strongly associated with journal impact factor(TIDieR:rs=0.27;p=0.01;CERT:r_(s)=-0.44;p=0.06;i-CONTENT:r_(s)=-0.17;p=0.48)or ROB(TIDieR:rs=0.11;p=0.31;CERT:rs=0.04;p=0.86;i-CONTENT:rs=0.12;p=0.60).Conclusion:RCTs of non-pharmacological interventions following concussion demonstrate moderate to good reporting completeness,but are often missing key components,particularly modifications,motivational strategies,and qualified supervisor.Reporting completeness improved after TIDieR and CERT publication,but publication in highly cited journals and low ROB

关键词： Concussion Intervention Randomized controlled trial Systematic review

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A rat model of multicompartmental traumatic injury and hemorrhagic shock induces bone marrow dysfunction and profound anemia

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Animal Models and Experimental Medicine 2024年第3期7卷 367-376页

作者： Lauren S.Kelly Jennifer A.Munley Erick E.pons Kolenkode B.Kannan elizabeth M.Whitley Letitia E.Bible philip A.Efron Alicia M.Mohr Department of Surgery and Sepsis and Critical Illness Research Center University of Florida College of MedicineGainesvilleFloridaUSA pathogenesis LLCGainesvilleFloridaUSA

Background:Severe trauma is associated with systemic inflammation and organ dysfunction.preclinical rodent trauma models are the mainstay of postinjury research but have been criticized for not fully replicating severe human trauma.The aim of this study was to create a rat model of multicompartmental injury which recreates profound traumatic injury.Methods:Male Sprague-Dawley rats were subjected to unilateral lung contusion and hemorrhagic shock(LCHS),multicompartmental polytrauma(pT)(unilateral lung contusion,hemorrhagic shock,cecectomy,bifemoral pseudofracture),or na?ve controls.Weight,plasma toll-l ike receptor 4(TLR4),hemoglobin,spleen to body weight ratio,bone marrow(BM)erythroid progenitor(CFU-GEMM,BFU-E,and CFU-E)growth,plasma granulocyte colony-stimulating factor(G-CSF)and right lung histologic injury were assessed on day 7,with significance defined as p valuespolytrauma resulted in markedly more profound inhibition of weight gain compared to LCHS(p=0.0002)along with elevated plasma TLR4(pppleen to body weight ratios(p=0.004).Both LCHS and pT demonstrated suppression of CFU-E and BFU-E growth compared to na?ve(ppplasma G-CSF was elevated in pT compared to both na?ve and LCHS(pp=0.02).LCHS and pT demonstrated significant histologic right lung injury with poor alveolar wall integrity and interstitial edema.Conclusions:Multicompartmental injury as described here establishes a reproducible model of multicompartmental injury with worsened anemia,splenic tissue enlargement,weight loss,and increased inflammatory activity compared to a less severe model.This may serve as a more effective model to recreate profound traumatic injury to replicate the human inflammatory response postinjury.

关键词： anemia i nflammation polytrauma pseudofracture shock

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Immune response differences in degradable and non-degradable alloy implants

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Bioactive Materials 2023年第6期24卷 153-170页

作者： Taravat Khodaei elizabeth Schmitzer Abhirami p.Suresh Abhinav p.Acharya Biomedical Engineering School of Biological and Health System EngineeringArizona StateUniversityTempeAZ85281USA Biological Design Arizona State UniversityTempeAZ85281USA Chemical Engineering School for the Engineering of MatterTransportand EnergyArizona StateUniversityTempeAZ85281USA Materials Science and Engineering School for the Engineering of MatterTransportand EnergyArizona State UniversityTempeAZ85281USA Center for Immunotherapy Vaccines and VirotherapyArizona State UniversityTempeAZ85281USA

Alloy based implants have made a great impact in the clinic and in preclinical research.Immune responses are one of the major causes of failure of these implants in the clinic.Although the immune responses toward non-degradable alloy implants are well documented,there is a poor understanding of the immune responses against degradable alloy implants.Recently,there have been several reports suggesting that degradable implants may develop substantial immune responses.This phenomenon needs to be further studied in detail to make the case for the degradable implants to be utilized in clinics.Herein,we review these new recent reports suggesting the role of innate and potentially adaptive immune cells in inducing immune responses against degradable implants.First,we discussed immune responses to allergen components of non-degradable implants to give a better overview on differences in the immune response between non-degradable and degradable implants.Furthermore,we also provide potential areas of research that can be undertaken that may shed light on the local and global immune responses that are generated in response to degradable implants.

关键词： alloy utilized implants

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Importance of Standardizing Analytical Characterization Methodology for Improved Reliability of the Nanomedicine Literature

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Nano-Micro Letters 2022年第11期14卷 18-32页

作者： Shahriar Sharifi Nouf N.Mahmoud elizabeth Voke Markita p.Landry Morteza Mahmoudi Department of Radiology and precision Health program Michigan State UniversityEast LansingMIUSA Faculty of pharmacy Al-Zaytoonah University of JordanAmman 11733Jordan Department of Biomedical Sciences College of Health SciencesQU HealthQatar University2713 DohaQatar Department of Chemical and Biomolecular Engineering University of CaliforniaBerkeleyBerkeleyCAUSA Innovative Genomics Institute BerkeleyCAUSA California Institute for Quantitative Biosciences University of CaliforniaBerkeleyCAUSA Chan Zuckerberg Biohub San FranciscoCAUSA

Understanding the interaction between biological structures and nanoscale technologies,dubbed the nano-bio interface,is required for successful development of safe and efficient nanomedicine products.The lack of a universal reporting system and decentralized methodologies for nanomaterial characterization have resulted in a low degree of reliability and reproducibility in the nanomedicine literature.As such,there is a strong need to establish a characterization system to support the reproducibility of nanoscience data particularly for studies seeking clinical translation.Here,we discuss the existing key standards for addressing robust characterization of nanomaterials based on their intended use in medical devices or as pharmaceuticals.We also discuss the challenges surrounding implementation of such standard protocols and their implication for translation of nanotechnology into clinical practice.We,however,emphasize that practical implementation of standard protocols in experimental laboratories requires long-term planning through integration of stakeholders including institutions and funding agencies.

关键词： Characterization Nanomedicine Standard protocols Reproducibility Nanomedicine devices

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Quantifying Kinematic Tremor in an NGLY1-Deficient Individual: A Case Study

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Case Reports in Clinical Medicine 2024年第1期13卷 25-36页

作者： Brock Futrell Christopher Alexander Malaya Dacia Martinez Diaz Christian Alfaro Hannah elizabeth Gustafson Subhalakshmi Chandrasekaran Rhea Mohan phatak Bernhard Suter Charles Shannon Layne Department of Health and Human performance University of Houston Houston USA Center for Neuromotor and Biomechanics Research University of Houston Houston USA Department of Computer Science and Engineering Texas A&M University College Station USA Blue Bird Circle Rett Center Texas Children’s Hospital Houston USA Baylor College of Medicine Houston USA Center for NeuroEngineering and Cognitive Science University of Houston Houston USA

NGLY1 Deficiency is an autosomal recessive congenital disorder that has been identified in less than 100 individuals. Most individuals with NGLY1 Deficiency display hyperkinetic movement disorders, including choreiform, athetoid, dystonic myoclonic, dyskinetic, and dysmetric movements. Developing a consistent and concise consensus on the classification and evaluation of tremors is essential to forward the research and treatment of tremors. It has also been reported that some individuals with NGLY1 Deficiency demonstrate tremor, but such tremor has never been formally investigated. The primary objective of this study is to determine if an individual with NGLY1 Deficiency demonstrates an identifiable tremor during a series of arm movements and, if so, describe the frequency and power characteristics of that tremor. Arm movement kinematics were obtained using a 16-camera Vicon system, and time series trajectory waveforms for three planes of a marker placed on the hand were developed. Custom MATLAB scripts were utilized to compute Fast Fourier Transformations of the data within the identified waveform segments. A mean frequency of 2.30 Hz (SD = 1.05) with a mean power of 5.02 |p1(f)| (SD = 4.63) suggests that our participant’s kinematic data did display a persistent tremor in both hands across all tasks and movement planes. Analyses of the reaching hand and the non-reaching hand suggest the participant displayed an action tremor in both postural and intention (kinetic) tremors. Future directions should include assessing additional individuals with NGLY1 Deficiency to determine if the tremor is a distinguishable disorder behavior. Additionally, evaluating other anatomical sites, such as the elbow, head, and lower limbs, would provide further insights into the characteristics of this tremor.

关键词： Tremor NGLY Fast Fourier Transformation Reaching Hyperkinetic Movement

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