tbuckley/cabot-search huggingface dataset:
Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β
Authors: Laura Padrón-Barthe, María Villalba-Orero, Jesús M. Gómez-Salinero, Fernando Domínguez, Marta Román, Javier Larrasa-Alonso, Paula Ortiz-Sánchez, Fernando Martínez, Marina López-Olañeta, Elena Bonzón-Kulichenko, Jesús Vázquez, Carlos Martí-Gómez, Demetrio J. Santiago, Belén Prados, Giovanna Giovinazzo, María Victoria Gómez-Gaviro, Silvia Priori, Pablo Garcia-Pavia, Enrique Lara-Pezzi
Journal: Circulation (2019)

Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5.We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter.We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition.Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.
Long-term Cardiovascular Disease Risk Among Firefighters After the World Trade Center Disaster
Authors: Hillel W. Cohen, Rachel Zeig-Owens, Cynthia Joe, Charles B. Hall, Mayris P. Webber, Michael D. Weiden, Krystal L. Cleven, Nadia Jaber, Molly Skerker, Jennifer Yip, Theresa Schwartz, David J. Prezant
Journal: JAMA Network Open (2019)

Published studies examining the association between World Trade Center (WTC) exposure on and after September 11, 2001, and longer-term cardiovascular disease (CVD) outcomes have reported mixed findings.To assess whether WTC exposure was associated with elevated CVD risk in Fire Department of the City of New York (FDNY) firefighters.In this cohort study, the association between WTC exposure and the risk of CVD was assessed between September 11, 2001, and December 31, 2017, in FDNY male firefighters. Multivariable Cox regression analyses were used to estimate CVD risk in association with 2 measures of WTC exposure: arrival time to the WTC site and duration of work at the WTC site. Data analyses were conducted from May 1, 2018, to March 8, 2019.The primary CVD outcome included myocardial infarction, stroke, unstable angina, coronary artery surgery or angioplasty, or CVD death. The secondary outcome (all CVD) included all primary outcome events or any of the following: transient ischemic attack; stable angina, defined as either use of angina medication or cardiac catheterization without intervention; cardiomyopathy; and other CVD (aortic aneurysm, peripheral arterial vascular intervention, and carotid artery surgery).There were 489 primary outcome events among 9796 male firefighters (mean [SD] age on September 11, 2001, was 40.3 [7.4] years and 7210 individuals [73.6%] were never smokers). Age-adjusted incident rates of CVD were higher for firefighters with greater WTC exposure. The multivariable adjusted hazard ratio (HR) for the primary CVD outcome was 1.44 (95% CI, 1.09-1.90) for the earliest arrival group compared with those who arrived later. Similarly, those who worked at the WTC site for 6 or more months vs those who worked less time at the site were more likely to have a CVD event (HR, 1.30; 95% CI, 1.05-1.60). Well-established CVD risk factors, including hypertension (HR, 1.41; 95% CI, 1.10-1.80), hypercholesterolemia (HR, 1.56; 95% CI, 1.28-1.91), diabetes (HR, 1.99; 95% CI, 1.33-2.98), and smoking (current: HR, 2.13; 95% CI, 1.68-2.70; former: HR, 1.55; 95% CI, 1.23-1.95), were significantly associated with CVD in the multivariable models. Analyses with the all-CVD outcome were similar.The findings of the study suggest a significant association between greater WTC exposure and long-term CVD risk. The findings appear to reinforce the importance of long-term monitoring of the health of survivors of disasters.
SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis
Authors: Brendon L Neuen, Tamara Young, Hiddo J L Heerspink, Bruce Neal, Vlado Perkovic, Laurent Billot, Kenneth W Mahaffey, David M Charytan, David C Wheeler, Clare Arnott, Severine Bompoint, Adeera Levin, Meg J Jardine
Journal: The Lancet Diabetes & Endocrinology (2019)
Population Impact Attributable to Modifiable Risk Factors for Hyperuricemia
Authors: Hyon K. Choi, Natalie McCormick, Na Lu, Sharan K. Rai, Chio Yokose, Yuqing Zhang
Journal: Arthritis & Rheumatology (2019)

Objective To examine modifiable risk factors in relation to the presence of hyperuricemia and to estimate the proportion of hyperuricemia cases in the general population that could be prevented by risk factor modification, along with estimates of the variance explained. Methods Using data obtained from 14,624 adults representative of the US civilian noninstitutionalized population, we calculated adjusted prevalence ratios for hyperuricemia, population attributable risks ( PAR s), and the variance explained according to the following 4 factors: body mass index ( BMI ; ≥25 kg/m 2 ), alcohol intake, nonadherence to a Dietary Approaches to Stop Hypertension ( DASH ) diet, and diuretic use. Results BMI , alcohol intake, adherence to a DASH ‐style diet, and diuretic use were all associated with serum urate levels and the presence of hyperuricemia in a dose‐dependent manner. The corresponding PAR s of hyperuricemia cases for overweight/obesity (prevalence 60%), nonadherence to a DASH ‐style diet (prevalence 82%), alcohol use (prevalence 48%), and diuretic use (prevalence 8%) were 44% (95% confidence interval [95% CI ] 41%, 48%), 9% (95% CI 3%, 16%), 8% (95% CI 5%, 11%), and 12% (95% CI 11%, 14%), respectively, whereas the corresponding variances explained were 8.9%, 0.1%, 0.5%, and 5.0%. Our simulation study showed the variance nearing 0% as exposure prevalence neared 100%. Conclusion In this nationally representative study, 4 modifiable risk factors ( BMI , the DASH diet, alcohol use, and diuretic use) could be used to individually account for a notable proportion of hyperuricemia cases. However, the corresponding serum urate variance explained by these risk factors was very small and paradoxically masked their high prevalences, providing real‐life empirical evidence for its limitations in assessing common risk factors.
Antipsychotics for Treating Delirium in Hospitalized Adults
Authors: Roozbeh Nikooie, Karin J. Neufeld, Esther S. Oh, Lisa M. Wilson, Allen Zhang, Karen A. Robinson, Dale M. Needham
Journal: Annals of Internal Medicine (2019)

Delirium is common in hospitalized patients and is associated with worse outcomes. Antipsychotics are commonly used; however, the associated benefits and harms are unclear.To conduct a systematic review evaluating the benefits and harms of antipsychotics to treat delirium in adults.PubMed, Embase, CENTRAL, CINAHL, and PsycINFO from inception to July 2019 without language restrictions.Randomized controlled trials (RCTs) of antipsychotic versus placebo or another antipsychotic, and prospective observational studies reporting harms.One reviewer extracted data and assessed strength of evidence (SOE) for critical outcomes, with confirmation by another reviewer. Risk of bias was assessed independently by 2 reviewers.Across 16 RCTs and 10 observational studies of hospitalized adults, there was no difference in sedation status (low and moderate SOE), delirium duration, hospital length of stay (moderate SOE), or mortality between haloperidol and second-generation antipsychotics versus placebo. There was no difference in delirium severity (moderate SOE) and cognitive functioning (low SOE) for haloperidol versus second-generation antipsychotics, with insufficient or no evidence for antipsychotics versus placebo. For direct comparisons of different second-generation antipsychotics, there was no difference in mortality and insufficient or no evidence for multiple other outcomes. There was little evidence demonstrating neurologic harms associated with short-term use of antipsychotics for treating delirium in adult inpatients, but potentially harmful cardiac effects tended to occur more frequently.Heterogeneity was present in terms of dose and administration route of antipsychotics, outcomes, and measurement instruments. There was insufficient or no evidence regarding multiple clinically important outcomes.Current evidence does not support routine use of haloperidol or second-generation antipsychotics to treat delirium in adult inpatients.Agency for Healthcare Research and Quality. (PROSPERO: CRD42018109552).
P11.62 Brain distribution models to select polymer-delivered drugs for the intra-cavity treatment of malignant glioma
Authors: J Rowlinson, P McCrorie, S Smith, D Barrett, D Kim, R Grundy, D Scurr, R Rahman
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Conventional oral or intravenous chemotherapy distributes drugs to the whole body whereby systemic toxicity to healthy parts of the body (e.g. bone marrow failure) limits the maximum dose that can be achieved in the brain. This presents a particular concern for CNS tumours where the blood-brain-barrier (BBB) restricts drug influx from the circulation. The ability to deliver chemotherapy locally at the tumour site offers the opportunity to target residual cancer cells post-surgery whilst minimising systemic toxicity. We have developed a poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) polymer matrix that forms a porous paste at room temperature when mixed with chemotherapy-containing saline, solidifying only at body temperature, with close apposition to the irregular surgical cavity. It is important that we can observe whether the drugs released from PLGA/PEG can penetrate brain parenchyma beyond the surgical resection margin at therapeutic doses. Currently the only way to measure the distribution of drugs in the body is to inject radioactive drugs into an animal. We aim to establish drug distribution parameters using label-free mass spectrometry imaging methods, prior to selection of drug formulations for clinically-relevant in vivo models. Drugs that penetrate the brain the furthest will be identified as good candidates for localised brain cancer drug delivery using PLGA/PEG paste. MATERIAL AND METHODS Diffusion rates were measured by examining the proportion of olaparib, dasatnib, carboplatin, etoposide, paclitaxel and gemcitabine at 2mg/ml concentration, which passes through 1mm slices of rat brain tissue within Franz cell chambers over a 6 hour period. The spatio-temporal distribution of label-free olaparib and dasatinib within mouse brain homogenate was quantitatively measured using innovative 3D OrbiSIMS, a hybrid time-of-flight / OrbitrapTM secondary ion mass spectrometer. RESULTS Within the Franz cell model, carboplatin and gemcitabine showed the highest diffusion rate diffusion at 16.4 and 6.53 µg/cm2/h respectively whereas olaparib, etoposide and paclitaxel were relatively poorly diffused at 1.87, 3.82 and 2.27 µg/cm2/h respectively. The minimum threshold of OrbiSIMS detection for label-free olaparib and dasatinib ions was 0.025 mg/ml and 0.2 mg/ml respectively throughout brain homogenate. CONCLUSION This study demonstrates different diffusion rates through brain tissue, between label-free chemotherapy drugs of distinct chemistries, with highest diffusion rates observed for carboplatin and gemcitabine. We also demonstrate label-free detection of olaparib and dasatinib using the innovative 3D OrbiSIMS method. These models will facilitate the rapid identification of agents most amenable for localised biomaterial-based chemotherapy delivery with high brain penetrance.
A Manual of Venereal Diseases.
Journal: JAMA (1892)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
P11.29 Development of ex vivo models for deeper insights into the biology and therapeutic targeting of tumor microtube networks in gliomas
Authors: E Jung, D Domínguez Azorín, D Hausmann, M Mall, P Koch, W Wick, F Winkler
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The formation of multicellular networks via thin cellular protrusions named tumor microtubes (TMs) emerged as a novel mechanism of therapy resistance in malignant glioma. TMs are also involved in tumor cell invasion and growth. Within these tumor cell networks, connected tumor cells communicate via intercellular calcium waves (ICWs). Only few molecular drivers of TMs (Gap43, Ttyh1, Connexin 43) have been identified until now. Furthermore, the molecular mechanisms underlying ICWs as well as their specific biological role in glioma remains to be elucidated. A better understanding of the biology and the identification of molecular key drivers is essential for the development of drugs targeting TM formation and function. MATERIAL AND METHODS For this purpose, we have developed novel ex vivo models that not only provide insights into TM biology but further allow medium throughput drug screening. As classical response parameters such as the inhibition of cell growth or cytotoxicity do not necessarily correlate with effects on TM formation or function, a morphometrical approach employing laser scanning microscopy and machine-learning based image analysis tools is used. The application of fluorescent probes and genetic fluorescent reporter systems provides novel longitudinal insights into cytoskeletal dynamics, the role and exchange of organelles such as mitochondria, mechanisms of homeostasis within tumor cell networks (e.g. redox homeostasis) and ICWs in live cells. In addition to 2D glioma cell and co-culture models we have developed a fully human and mature brain organoid model. Here, complex 3D tumor cell networks corresponding to the morphology and exhibiting calcium communication patterns observed in our mouse model can be established and studied ex vivo. Furthermore, with these models not only the role of the brain microenvironment on TM formation but also direct interactions of glioma cells with neurons and glial cells as well as drug effects such as cytotoxicity on these brain cells can be investigated ex vivo. CONCLUSION In summary, novel tumor models enable further insights into TM biology and hence provide the basis for development of TM- and network disrupting drugs. First results of this screening opportunity will be presented.
Heeding Darwin but ignoring Bernard: External behaviors are not selected, internal goals are
Authors: Gary A. Cziko
Journal: Behavioral and Brain Sciences (2001)

Hull et al. see responses and properties of responses as units of selection in behavioral change. However, this perspective cannot account for goal-directed behavior in which organisms employ variable means to reliably attain intended consequences. An alternative perspective is offered in which the intended consequences (goals) of behavior serve as the units of selection in behavior change.
WHO international standard for anti-rubella: learning from its application
Authors: Sarah L Kempster, Neil Almond, Wayne Dimech, Liliane Grangeot-Keros, Daniela Huzly, Joseph Icenogle, Haja Sittana El Mubarak, Mick N Mulders, C Micha Nübling
Journal: The Lancet Infectious Diseases (2019)
P13.10 Glioblastoma within the subventricular zone associates with increased mesenchymal transition: an intratumoral gene expression analysis
Authors: S Berendsen, D Dalemans, K Draaisma, P A Robe, T J Snijders
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Involvement of the subventricular zone (SVZ) in GBM is associated with poor prognosis and suggested to associate with specific tumor-biological characteristics. The SVZ microenvironment can influence gene expression and migration in GBM cells in preclinical models. We aimed to investigate whether the SVZ microenvironment has any influence on intratumoral gene expression patterns in GBM patients. MATERIAL AND METHODS The publicly available Ivy GBM database contains clinical, radiological and whole exome sequencing data from multiple regions from en bloc resected GBMs. SVZ involvement of the various tissue samples was evaluated on MRI scans. In the tumors that contacted the SVZ, we performed gene expression analyses and gene set enrichment analyses to compare gene (set) expression in tumor regions within the SVZ to tumor regions outside the SVZ, within the same tumors. We also compared these samples to GBMs that made no contact with the SVZ. RESULTS Within GBMs that contacted the SVZ, tissue samples within the SVZ showed enrichment of gene sets involved in (epithelial-)mesenchymal transition, NF-κB and STAT3 signaling, angiogenesis and hypoxia, compared to the samples outside of the SVZ region from the same tumors (p&lt;0.05, FDR&lt;0.25). Comparison of GBM samples within the SVZ region to samples from tumors that did not contact the SVZ yielded similar results. In contrast, we observed no difference in gene set enrichment when comparing the samples outside of the SVZ from SVZ-contacting GBMs with samples from GBMs that did not contact the SVZ at all. CONCLUSION GBM samples in the SVZ region associate with increased (epithelial-)mesenchymal transition and angiogenesis/hypoxia signaling, possibly mediated by the SVZ microenvironment.
Risk factors for opioid abuse/dependence in hospitalized cancer patients in the United States.
Authors: Veli Bakalov, Amy Tang, Amulya Yellala, Laila Babar, Rupin Shah, Santhosh K. Sadashiv, Robert B. Kaplan, John Lister, Elizabeth Cuevas, Dulabh K. Monga
Journal: Journal of Clinical Oncology (2019)

11589 Background: Opioid medications are the mainstay for treating cancer pain. Goal of this study was to identify risk factors for opioid abuse/dependence in patients hospitalized with cancer, explore whether risk of opioid abuse/dependence varies by cancer type and to assess whether opioid abuse/dependence in cancer patients effects the outcomes of hospitalization. Methods: The Nationwide Inpatient Sample for the years of 2011-2015 was queried for the analysis. We used ICD-9-CM codes of solid tumors as a primary diagnosis for hospitalization, and opioid abuse/dependence as a secondary diagnosis of the hospitalization. We performed univariate and multivariate logistic regression analyses to examine the association between risk factors and opioid abuse/dependence. Data were analyzed using SAS v9.4 (SAS Institute, Cary, NC). Results: Total of 524,624 patients were included in our cohort. Rate of opioid abuse/dependence was highest in patients with liver cancer (1.77%). Opioid abuse/dependence was less associated with age (&gt;65 years old: OR 0.29, 95% CI 0.21-0.39). Patients with Medicaid insurance associated with increased risk of opioid abuse/dependence comparing to other insurances (OR 5.29, 95% CI 4.78-5.86). Strongest association with opioid abuse/dependence were in patients with liver cancer (OR 6.07, 95% CI 5.11-7.20) followed by head and neck cancer (OR 3.20, 95% CI 2.67-3.84). Substance abuse (OR 9.9, 95% CI 9.04-10.84), mental disease (OR-2.87, 95% CI 2.64-3.13) and nutrition deficiency (OR-2.09, 95% CI 1.90-2.31) were highly associated with opioid abuse dependence. Inhospital mortality rate, total cost of hospitalization, and length of stay were significantly higher in patients with opioid abuse/dependence (Table). Conclusions: We identified risk factors for opioid abuse/dependence in hospitalized patients with cancer and demonstrated that risk of opioid abuse varies by cancer type, and opioid abuse/dependence affects the outcomes of hospitalization. Findings of our study can be used for development of the screening tools with higher sensitivity and specificity for predicting the risk of opioid abuse/dependence in cancer patients.[Table: see text]