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News Article | April 26, 2017

Scientists believe that schizophrenia, a disorder caused by an imbalance in the brain's chemical reactions, is triggered by a genetic interaction with environmental factors. A new Tel Aviv University study published in Human Molecular Genetics now points to cannabis as a trigger for schizophrenia. The research, conducted by Dr. Ran Barzilay and led by Prof. Dani Offen, both of TAU's Sackler School of Medicine, finds that smoking pot or using cannabis in other ways during adolescence may serve as a catalyst for schizophrenia in individuals already susceptible to the disorder. "Our research demonstrates that cannabis has a differential risk on susceptible versus non-susceptible individuals," said Dr. Barzilay, principal investigator of the study. "In other words, young people with a genetic susceptibility to schizophrenia -- those who have psychiatric disorders in their families -- should bear in mind that they're playing with fire if they smoke pot during adolescence." The research team included Prof. Inna Slutsky and Hadar Segal-Gavish, both of TAU's Sackler School of Medicine, and Prof. Abraham Weizman of Geha Medical Health Center and Prof. Akira Sawa of Johns Hopkins Medical Center. Researchers exposed mouse models with a genetic susceptibility to schizophrenia -- the mutant DISC-1 gene -- to THC, the psychoactive compound in cannabis. During a time period similar to that of human adolescence, the susceptible mice were found to be at a far higher risk for lasting brain defects associated with the onset of schizophrenia. Four categories of mice were used in the experiment: Genetically susceptible and exposed to cannabis; genetically susceptible and not exposed to cannabis; genetically intact and exposed to cannabis; and, finally, genetically intact and not exposed to cannabis. Only the genetically susceptible mice developed behavioral and biochemical brain pathologies related to schizophrenia after being exposed to cannabis, behavioral tests and neurological biochemical analyses revealed. "The study was conducted on mice but it mimics a clinical picture of 'first episode' schizophrenia, which presents during adolescence in proximity to robust cannabis use," said Dr. Barzilay, a child and adolescent psychiatrist. The researchers also discovered the mechanism through which the cannabis and the specific gene interact. "A protective mechanism was observed in the non-susceptible mice," said Prof. Offen. "This mechanism involves the upregulation of a protective neurotrophic factor, BDNF, in the hippocampus. We showed in the study that if we artificially deliver BDNF to the genetically susceptible mice, they could be protected from the deleterious effect of THC during adolescence. "This research clearly has implications in terms of public health," Prof. Offen concluded. "The novel protective mechanism identified in the study may serve as a basis for the future development of compounds capable of attenuating the deleterious effect of cannabis on brain development. However, until that time, it is important that young people at risk for psychiatric disorders (i.e., have psychiatric disorders in their family or have reacted strongly to drugs in the past) should be particularly cautious with cannabis use during adolescence." American Friends of Tel Aviv University supports Israel's most influential, comprehensive, and sought-after center of higher learning, Tel Aviv University (TAU). TAU is recognized and celebrated internationally for creating an innovative, entrepreneurial culture on campus that generates inventions, startups and economic development in Israel. For three years in a row, TAU ranked 9th in the world, and first in Israel, for alumni going on to become successful entrepreneurs backed by significant venture capital, a ranking that surpassed several Ivy League universities. To date, 2,400 patents have been filed out of the University, making TAU 29th in the world for patents among academic institutions.

Smyth J.W.,Cedars Sinai Medical Center | Zhang S..-S.,Cedars Sinai Medical Center | Sanchez J.M.,University of California at San Francisco | Lamouille S.,University of California at San Francisco | And 7 more authors.
Traffic | Year: 2014

Altered phosphorylation and trafficking of connexin 43 (Cx43) during acute ischemia contributes to arrhythmogenic gap junction remodeling, yet the critical sequence and accessory proteins necessary for Cx43 internalization remain unresolved. 14-3-3 proteins can regulate protein trafficking, and a 14-3-3 mode-1 binding motif is activated upon phosphorylation of Ser373 of the Cx43 C-terminus. We hypothesized that Cx43Ser373 phosphorylation is important to pathological gap junction remodeling. Immunofluorescence in human heart reveals the enrichment of 14-3-3 proteins at intercalated discs, suggesting interaction with gap junctions. Knockdown of 14-3-3τ in cell lines increases gap junction plaque size at cell-cell borders. Cx43S373A mutation prevents Cx43/14-3-3 complexing and stabilizes Cx43 at the cell surface, indicating avoidance of degradation. Using Langendorff-perfused mouse hearts, we detect phosphorylation of newly internalized Cx43 at Ser373 and Ser368 within 30min of no-flow ischemia. Phosphorylation of Cx43 at Ser368 by protein kinase C and Ser255 by mitogen-activated protein kinase has previously been implicated in Cx43 internalization. The Cx43S373A mutant is resistant to phosphorylation at both these residues and does not undergo ubiquitination, revealing Ser373 phosphorylation as an upstream gatekeeper of a posttranslational modification cascade necessary for Cx43 internalization. Cx43Ser373 phosphorylation is a potent target for therapeutic interventions to preserve gap junction coupling in the stressed myocardium. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

News Article | December 9, 2016

HOUSTON - (Dec. 8, 2016) - Unlocking the mystery of how the brain processes the written word into language is the focus of a $3 million federal grant awarded to Nitin Tandon, M.D., professor of neurosurgery at McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth) and a member of Memorial Hermann Mischer Neuroscience Institute. Tandon will use intracranial electroencephalogram (icEEG) - devised to detect abnormalities related to electrical activity of the brain in patients with epilepsy - to record the sequence from visual perception of words to selection to speaking those words. "Humans didn't have a written language until about 10,000 B.C.," Tandon said about the evolution of reading. "Evolutionarily, nature took a brain that was not made to read or write and imprinted symbolic representation upon it. For this it used the existing architecture of the brain - the same place where you recognize a familiar face or that a twig is not a snake -- to build reading and writing. The question is how that region interacts with the rest of our language system, which is a good deal older." The study, done in collaboration with the Texas Comprehensive Epilepsy Program and Johns Hopkins Medical Center, will enroll a total of 80 patients who are already undergoing icEEG for seizures. It is funded by the National Institute of Neurological Disorders and Stroke (RFA-NS-16-008), part of the National Institutes of Health. "This research is important because it gives us unique insight into the mechanisms of reading, which is a highly evolved human behavior. If we know how the system normally works, we can evaluate patients with dyslexia to understand how their brain works differently and how we might find better therapies for them," Tandon said. "In a more futuristic view, after a person has suffered a stroke or brain injury, these recordings might help us develop a prosthetic device that could decode what's happening in the brain and use it to interface with a computer to allow people to compensate for the deficit they have."

Camargo Jr. C.A.,Harvard University | Budinger G.R.S.,Northwestern University | Escobar G.J.,Kaiser Permanente | Hansel N.N.,Johns Hopkins Medical Center | And 3 more authors.
Annals of the American Thoracic Society | Year: 2014

Lung-related research primarily focuses on the etiology and management of diseases. In recent years, interest in primary prevention has grown. However, primary prevention also includes "health promotion" (actions in a population that keep an individual healthy). We encourage more research on population-based (public health) strategies that could not only maximize lung health but also mitigate "normal" age-related declines - not only for spirometry but across multiple measures of lung health. In developing a successful strategy, a "life course" approach is important. Unfortunately, we are unable to achieve the full benefit of this approach until we have better measures of lung health and an improved understanding of the normal trajectory, both over an individual's life span and possibly across generations. We discuss key questions in lung health promotion, with an emphasis on the upper (healthier) end of the distribution of lung functioning and resiliency and briefly summarize the few interventions that have been studied to date. We conclude with suggestions regarding the most promising future research for this important, but largely neglected, area of lung research. Copyright © 2014 by the American Thoracic Society.

Dua A.,Medical College of Wisconsin | Dua A.,University of Houston | Desai S.S.,University of Illinois at Springfield | Heller J.A.,Johns Hopkins Medical Center
Vascular | Year: 2015

Introduction This study aimed to describe the practice patterns of primary healthcare practitioners who diagnose and manage venous disease to determine differences in clinical evaluation of disease, recognition of venous ulcers, and referral patterns. Methods A survey was distributed at the August 2011 Primary Care Medical Conference (Pri-Med) in Baltimore, Maryland. Pri-med is a medical education company that caters to the continued professional development needs of a variety of physicians. Results A total of 305 surveys were completed. Of the respondents, 91% were physicians and 9% were advanced level practitioners. In all, 93% prescribed compression stockings as first-line treatment. Heterogeneous referral patterns were reported with 81% referring to vascular surgery, 25% to a vein clinic, 10% to interventional radiology, and 3% to interventional cardiology. Up to 35% responded that they met resistance (did not have their referral accepted) when attempting referral to a vascular surgery colleague. There was substantial variation when asked about the treatment of deep vein thrombosis with 88% starting anticoagulation therapy, 54% prescribing compression stockings, 40% doing a thrombophilia workup, and 25% referring for lytic therapy. Conclusion Diagnosis and management aptitude of venous disease is highly variable. Further grassroots education is required to improve diagnosis and treatment in patients with chronic venous disease. © 2014, © The Author(s) 2014.

Han S.M.,University of Southern California | Weaver F.A.,University of Southern California | Comerota A.J.,Toledo Vascular Institute | Perler B.A.,Johns Hopkins Medical Center | Joing M.,ARCA biopharma
Journal of Vascular Surgery | Year: 2010

Purpose: To investigate the safety and effectiveness of a novel thrombolytic, alfimeprase, in catheter-directed thrombolysis (CDT) of acute peripheral arterial occlusions (PAO). Methods: Between April 2005 and March 2007, patients with acute PAO (Rutherford class I or IIa) of a lower extremity and onset of symptoms within 14 days prior to randomization were included. Studies HA004 and HA007 enrolled respectively 300 and 102 patients. Both studies HA004 and HA007 were placebo-controlled. HA004 had two placebo arms, intrathrombus and perithrombus, while HA007 had intrathrombus placebo arm. HA004 was partially double-blind (perithrombus group was not blinded) and HA007 was double-blind. Patients were randomized to intrathrombus alfimeprase (0.3 mg/kg), intrathrombus (IT) placebo, or perithrombus (PT) placebo (HA004 only) in two divided weight-based infusions 2 hours apart. Depending on arteriographic results after treatment, patients received no further intervention or underwent endovascular therapy or open vascular surgery. The primary endpoint of both studies was efficacy of alfimeprase compared with placebo as measured by avoidance of an open vascular surgery procedure at 30 days. Results: The avoidance of open vascular surgery at 30 days was seen in 52 (34.9%), 42 (37.2%), and 7 patients (18.4%) with alfimeprase, IT placebo, and PT placebo in HA004 and 15 (29.4%) and 9 patients (17.6%) with alfimeprase and IT placebo in HA007; differences between alfimeprase and IT placebo were not statistically significant. Results were similar for secondary endpoints, including arterial flow restoration in 4 hours, 30-day ankle-brachial index, index limb pain severity, and hospital stay duration. The overall rate of adverse events was higher with alfimeprase than placebo. Hemorrhagic and peripheral embolic event rates with alfimeprase were 23% (34 patients) and 10.1% (15 patients) in HA004 and 9.4% (5 patients) and 9.8% (5 patients) in HA007; rates with IT placebo were 11% (12 patients, P = .107) and 5% (5 patients, P = .148) in HA004 and 10% (5 patients, P = .982) and 0% in HA007 (P = .07). No deaths were related to study drug administration. Conclusions: CDT for acute PAO with alfimeprase was as safe as placebo. However, alfimeprase was no more effective than placebo in increasing 30-day surgery-free survival. The surprising effectiveness of placebo alone demonstrates that the inclusion of a placebo arm is essential to the design of future lytic trials. © 2010 Society for Vascular Surgery.

Walsh K.E.,University of Cincinnati | Walsh K.E.,University of Massachusetts Medical School | Walsh K.E.,Meyers Primary Care Institute | Cutrona S.L.,Meyers Primary Care Institute | And 6 more authors.
Pediatrics | Year: 2014

OBJECTIVES: Describe rates of adherence for sickle cell disease (SCD) medications, identify patient and medication characteristics associated with nonadherence, and determine the effect of nonadherence and moderate adherence (defined as taking 60%-80% of doses) on clinical outcomes. METHODS: In February 2012 we systematically searched 6 databases for peer-reviewed articles published after 1940. We identified articles evaluating medication adherence among patients <25 years old with SCD. Two authors reviewed each article to determine whether it should be included. Two authors extracted data, including medication studied, adherence measures used, rates of adherence, and barriers to adherence. RESULTS: Of 24 articles in the final review, 23 focused on 1 medication type: antibiotic prophylaxis (13 articles), iron chelation (5 articles), or hydroxyurea (5 articles). Adherence rates ranged from 16% to 89%; most reported moderate adherence. Medication factors contributed to adherence. For example, prophylactic antibiotic adherence was better with intramuscular than oral administration. Barriers included fear of side effects, incorrect dosing, and forgetting. Nonadherence was associated with more vaso-occlusive crises and hospitalizations. The limited data available on moderate adherence to iron chelation and hydroxyurea indicates some clinical benefit. CONCLUSIONS: Moderate adherence is typical among pediatric patients with SCD. Multicomponent interventions are needed to optimally deliver life-changing medications to these children and should include routine monitoring of adherence, support to prevent mistakes, and education to improve understanding of medication risks and benefits. Copyright © 2014 by the American Academy of Pediatrics.

Leonard B.E.,International Academy of Hi Technology Services | Thompson R.E.,Johns Hopkins Medical Center | Beecher G.C.,International Academy of Hi Technology Services
Dose-Response | Year: 2011

In the prior Part I, the potential influence of the low level alpha radiation induced bystander effect (BE) on human lung cancer risks was examined. Recent analysis of adaptive response (AR) research results with a Microdose Model has shown that single low LET radiation induced charged particles traversals through the cell nucleus activates AR. We have here conducted an analysis based on what is presently known about adaptive response and the bystander effect (BE) and what new research is needed that can assist in the further evaluation human cancer risks from radon. We find that, at the UNSCEAR (2000) worldwide average human exposures from natural background and man-made radiations, the human lung receives about a 25% adaptive response protection against the radon alpha bystander damage. At the UNSCEAR (2000) minimum range of background exposure levels, the lung receives minimal AR protection but at higher background levels, in the high UNSCEAR (2000) range, the lung receives essentially 100% protection from both the radon alpha damage and also the endogenic, spontaneously occurring, potentially carcinogenic, lung cellular damage. © 2011 University of Massachusetts.

Leonard B.E.,International Academy of Hi Technology Services | Thompson R.E.,Johns Hopkins Medical Center | Beecher G.C.,International Academy of Hi Technology Services
Dose-Response | Year: 2011

Since the publication of the BEIR VI report in 1999 on health risks from radon, a significantamount of new data has been published showing various mechanisms that mayaffect the ultimate assessment of radon as a carcinogen, at low domestic and workplaceradon levels, in particular the Bystander Effect (BE) and the Adaptive Response radio-protection(AR). We analyzed the microbeam and broadbeam alpha particle data of Miller etal. (1995, 1999), Zhou et al. (2001, 2003, 2004), Nagasawa and Little (1999, 2002), Hei etal. (1999), Sawant et al. (2001a) and found that the shape of the cellular response toalphas is relatively independent of cell species and LET of the alphas. The same alpha particletraversal dose response behavior should be true for human lung tissue exposure toradon progeny alpha particles. In the Bystander Damage Region of the alpha particleresponse, there is a variation of RBE from about 10 to 35. There is a transition regionbetween the Bystander Damage Region and Direct Damage Region of between one andtwo microdose alpha particle traversals indicating that perhaps two alpha particle "hits"are necessary to produce the direct damage. Extrapolation of underground miners lungcancer risks to human risks at domestic and workplace levels may not be valid. © 2011 University of Massachusetts.

Giglia T.M.,Children's Hospital of Philadelphia | Witmer C.,Children's Hospital of Philadelphia | Procaccini D.E.,Johns Hopkins Medical Center | Byrnes J.W.,University of Cincinnati
Pediatric Critical Care Medicine | Year: 2016

Objective: Thrombotic complications are increasingly being recognized as a significant cause of morbidity and mortality in pediatric and congenital heart disease. The objective of this article is to review the medications currently available to prevent and treat such complications. Data Sources: Online searches were conducted using PubMed. Study Selection: Studies were selected for inclusion based on their scientific merit and applicability to the pediatric cardiac population. Data Extraction: Pertinent information from each selected study or scientific review was extracted for inclusion. Data Synthesis: Four classes of medications were identified as potentially beneficial in this patient group: anticoagulants, antiplatelet agents, thrombolytic agents, and novel oral anticoagulants. Data on each class of medication were synthesized into the follow sections: mechanism of action, pharmacokinetics, dosing, monitoring, reversal, considerations for use, and evidence to support. Conclusions: Anticoagulants, antiplatelet agents, and thrombolytic agents are routinely used successfully in the pediatric patient with heart disease for the prevention and treatment of a wide range of thrombotic complications. Although the novel oral anticoagulants have been approved for a limited number of indications in adults, studies on the safety and efficacy of these agents in children are pending. © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

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