The Image and Its Pot

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Prevention Strategies of Traumatic Brain Injury in Football Players

In this project, we study the effects of the impact angle during a helmet-to-helmet collision on stress distribution and deacceleration values of the brain tissue in efforts to reduce brain injuries for football players. The overall goal is to provide sufficient information to improve the design of helmet technology. In addition, our study will be able to inform the athletes to avoid a helmet-to-helmet collision, such that, they can be trained to shift their heads in the horizontal direction to create a “glancing blow” effect. It is suggested that by avoiding a helmet-to-helmet collision, both rotational acceleration and stress can be reduced leading to a lower probability of receiving concussions and subsequent brain injuries [1].Cockrell School of Engineerin

Pre- and postconditioning the heart with hydrogen sulfide (H2S) against ischemia/reperfusion injury in vivo: a systematic review and meta-analysis

Conditioning-like infarct limitation by enhanced level of hydrogen sulfide (H2S) has been demonstrated in many animal models of myocardial ischemia/reperfusion injury (MIRI) in vivo. We sought to evaluate the effect of H2S on myocardial infarction across in vivo pre-clinical studies of MIRI using a comprehensive systematic review followed by meta-analysis. Embase, Pubmed and Web of Science were searched for pre-clinical investigation of the effect of H2S on MIRI in vivo. Retained records (6031) were subjected to our pre-defined inclusion criteria then were objectively critiqued. Thirty-two reports were considered eligible to be included in this study and were grouped, based on the time of H2S application, into preconditioning and postconditioning groups. Data were pooled using random effect meta-analysis. We also investigated the possible impact of different experimental variables and the risk of bias on the observed effect size. Preconditioning with H2S (n = 23) caused a significant infarct limitation of − 20.25% (95% CI − 25.02, − 15.47). Similarly, postconditioning with H2S (n = 40) also limited infarct size by − 21.61% (95% CI − 24.17, − 19.05). This cardioprotection was also robust and consistent following sensitivity analyses where none of the pre-defined experimental variables had a significant effect on the observed infarct limitation. H2S shows a significant infarct limitation across in vivo pre-clinical studies of MIRI which include data from 825 animals. This infarct-sparing effect is robust and consistent when H2S is applied before ischemia or at reperfusion, independently on animal size or sulfide source. Validating this infarct limitation using large animals from standard medical therapy background and with co-morbidities should be the way forward

Nitric oxide treatments as adjuncts to reperfusion in acute myocardial infarction: a systematic review of experimental and clinical studies

Unmodified reperfusion therapy for acute myocardial infarction (AMI) is associated with irreversible myocardial injury beyond that sustained during ischemia. Studies in experimental models of ischemia/reperfusion and in humans undergoing reperfusion therapy for AMI have examined potential beneficial effects of nitric oxide (NO) supplemented at the time of reperfusion. Using a rigorous systematic search approach, we have identified and critically evaluated all the relevant experimental and clinical literature to assess whether exogenous NO given at reperfusion can limit infarct size. An inclusive search strategy was undertaken to identify all in vivo experimental animal and clinical human studies published in the period 1990–2014 where NO gas, nitrite, nitrate or NO donors were given to ameliorate reperfusion injury. Articles were screened at title and subsequently at abstract level, followed by objective full text analysis using a critical appraisal tool. In twenty-one animal studies, all NO treatments except nitroglycerin afforded protection against measures of reperfusion injury, including infarct size, creatinine kinase release, neutrophil accumulation and cardiac dysfunction. In three human AMI RCT’s, there was no consistent evidence of infarct limitation associated with NO treatment as an adjunct to reperfusion. Despite experimental evidence that most NO treatments can reduce infarct size when given as adjuncts to reperfusion, the value of these interventions in clinical AMI is unproven. Our study raises issues for the design of further clinical studies and emphasises the need for improved design of animal studies to reflect more accurately the comorbidities and other confounding factors seen in clinical AMI

Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137

Exogenous hydrogen sulfide (H2S) protects against myocardial ischemia/reperfusion injury but the mechanism of action is unclear. The present study investigated the effect of GYY4137, a slow-releasing H2S donor, on myocardial infarction given specifically at reperfusion and the signalling pathway involved. Thiobutabarbital-anesthetised rats were subjected to 30min of left coronary artery occlusion and 2h reperfusion. Infarct size was assessed by tetrazolium staining. In the first study, animals randomly received either no treatment or GYY4137 (26.6, 133 or 266μmolkg-1) by intravenous injection 10min before reperfusion. In a second series, involvement of PI3K and NO signalling were interrogated by concomitant administration of LY294002 or L-NAME respectively and the effects on the phosphorylation of Akt, eNOS, GSK-3β and ERK1/2 during early reperfusion were assessed by immunoblotting. GYY4137 266μmolkg-1 significantly limited infarct size by 47% compared to control hearts (P<0.01). In GYY4137-treated hearts, phosphorylation of Akt, eNOS and GSK-3β was increased 2.8, 2.2 and 2.2 fold respectively at early reperfusion. Co-administration of L-NAME and GYY4137 attenuated the cardioprotection afforded by GYY4137, associated with attenuated phosphorylation of eNOS. LY294002 totally abrogated the infarct-limiting effect of GYY4137 and inhibited Akt, eNOS and GSK-3β phosphorylation. These data are the first to demonstrate that GYY4137 protects the heart against lethal reperfusion injury through activation of PI3K/Akt signalling, with partial dependency on NO signalling and inhibition of GSK-3β during early reperfusion. H2S-based therapeutic approaches may have value as adjuncts to reperfusion in the treatment of acute myocardial infarction

Postconditioning signalling in the heart: mechanisms and translatability

The protective effect of ischaemic postconditioning (short cycles of reperfusion and reocclusion of a previously occluded vessel) was identified over a decade ago commanding intense interest as an approach for modifying reperfusion injury which contributes to infarct size in acute myocardial infarction. Elucidation of the major mechanisms of postconditioning has identified potential pharmacological targets for limitation of reperfusion injury. These include ligands for membrane-associated receptors, activators of phosphokinase survival signalling pathways and inhibitors of the mitochondrial permeability transition pore. In experimental models, numerous agents that target these mechanisms have shown promise as postconditioning mimetics. Nevertheless, clinical studies of ischaemic postconditioning and pharmacological postconditioning mimetics are equivocal. The majority of experimental research is conducted in animal models which do not fully portray the complexity of risk factors and comorbidities with which patients present and which we now know modify the signalling pathways recruited in postconditioning. Cohort size and power, patient selection, and deficiencies in clinical infarct size estimation may all represent major obstacles to assessing the therapeutic efficacy of postconditioning. Furthermore, chronic treatment of these patients with drugs like ACE inhibitors, statins and nitrates may modify signalling, inhibiting the protective effect of postconditioning mimetics, or conversely induce a maximally protected state wherein no further benefit can be demonstrated. Arguably, successful translation of postconditioning cannot occur until all of these issues are addressed, that is, experimental investigation requires more complex models that better reflect the clinical setting, while clinical investigation requires bigger trials with appropriate patient selection and standardization of clinical infarct size measurements

Effects of an Unusual Poison Identify a Lifespan Role for Topoisomerase 2 in Saccharomyces Cerevisiae

A progressive loss of genome maintenance has been implicated as both a cause and consequence of aging. Here we present evidence supporting the hypothesis that an age-associated decay in genome maintenance promotes aging in Saccharomyces cerevisiae (yeast) due to an inability to sense or repair DNA damage by topoisomerase 2 (yTop2). We describe the characterization of LS1, identified in a high throughput screen for small molecules that shorten the replicative lifespan of yeast. LS1 accelerates aging without affecting proliferative growth or viability. Genetic and biochemical criteria reveal LS1 to be a weak Top2 poison. Top2 poisons induce the accumulation of covalent Top2-linked DNA double strand breaks that, if left unrepaired, lead to genome instability and death. LS1 is toxic to cells deficient in homologous recombination, suggesting that the damage it induces is normally mitigated by genome maintenance systems. The essential roles of yTop2 in proliferating cells may come with a fitness trade-off in older cells that are less able to sense or repair yTop2-mediated DNA damage. Consistent with this idea, cells live longer when yTop2 expression levels are reduced. These results identify intrinsic yTop2-mediated DNA damage as a potentially manageable cause of aging

Novel approaches and opportunities for cardioprotective signaling through 3',5'-cyclic muanosine monophosphate manipulation

Limiting the injurious effects of myocardial ischemia-reperfusion is a desirable therapeutic target, which has been investigated extensively over the last three decades. Here we provide an up to date review of the literature documenting the experimental and clinical research demonstrating the effects of manipulating cGMP for the therapeutic targeting of the injurious effects of ischemic heart disease. Augmentation of the cyclic nucleotide cGMP plays a crucial role in many cardioprotective signaling pathways. There is an extensive body of literature which supports pharmacological targeting of cGMP or upstream activators in models of ischemia-reperfusion to limit injury. NO donors have long been utilised to manipulate cGMP, and more recently non-NO synthase derived NOx species have been investigated, resulting in their evaluation in clinical trials for the treatment of ischemic heart disease. Encouraging results demonstrate that natriuretic peptides are worthy candidates in manipulating cGMP and its downstream effectors to afford cytoprotection. Synthetic ligands have been designed which co-activate natriuretic peptide receptors to improve targeting this pathway. Advances have been made in targeting the soluble guanylyl cyclase which catalyzes the production of cGMP independently of the endogenous ligand NO using NO-independent stimulators and activators of sGC. These novel compounds show promise as a new class of drugs that target this signaling cascade specifically under pathological conditions when endogenous NO production may be compromised. Regulating the degradation of cGMP via phosphodiesterase inhibition also shows therapeutic potential. It is clear that production and regulation of cGMP is complex, indeed its spatial production and cellular distribution are only just emerging

Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning

Risc cardiovascular; Isquèmia/reperfusióCardiovascular risk; Ischemia/reperfusionRiesgo cardiovascular; Isquemia/reperfusiónPreconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and the potential to provide novel therapeutic paradigms for cardioprotection. While many signaling pathways leading to endogenous cardioprotection have been elucidated in experimental studies over the past 30 years, no cardioprotective drug is on the market yet for that indication. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic preclinical evaluation of promising cardioprotective therapies prior to their clinical evaluation, since ischemic heart disease in humans is a complex disorder caused by or associated with cardiovascular risk factors and comorbidities. These risk factors and comorbidities induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury and responses to cardioprotective interventions. Moreover, some of the medications used to treat these comorbidities may impact on cardioprotection by again modifying cellular signaling pathways. The aim of this article is to review the recent evidence that cardiovascular risk factors as well as comorbidities and their medications may modify the response to cardioprotective interventions. We emphasize the critical need for taking into account the presence of cardiovascular risk factors as well as comorbidities and their concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple comorbidities. Significance Statement Ischemic heart disease is a major cause of mortality; however, there are still no cardioprotective drugs on the market. Most studies on cardioprotection have been undertaken in animal models of ischemia/reperfusion in the absence of comorbidities; however, ischemic heart disease develops with other systemic disorders (e.g., hypertension, hyperlipidemia, diabetes, atherosclerosis). Here we focus on the preclinical and clinical evidence showing how these comorbidities and their routine medications affect ischemia/reperfusion injury and interfere with cardioprotective strategies.P.F. was supported by the National Research, Development and Innovation Office of Hungary (Research Excellence Program–TKP, National Heart Program NVKP 16-1-2016-0017) and by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Therapeutic Development thematic program of Semmelweis University. D.D. is supported by grants from National Institutes of Health National Heart, Lung, and Blood Institute [R01-HL136389, R01-HL131517, R01-HL089598, and R01-HL163277], the German Research Foundation [DFG, Do 769/4-1], the European Union (large-scale integrative project MAESTRIA, no. 965286). G.H. is supported by the German Research Foundation [SFB 1116 B8]. D.H. is supported by the Duke–NUS Signature Research Programme funded by the Ministry of Health, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist–Senior Investigator scheme [NMRC/CSA-SI/0011/2017], Centre Grant [CGAug16M006], and Collaborative Centre Grant scheme [NMRC/CGAug16C006]. I.A. is supported from Boehringer-Ingelheim for the investigation of the effects of empagliflozin on the myocardium and from the European Union (ERDF) and Greek national funds through the Operational Program “Competitiveness, Entrepreneurship and Innovation,” under the call “RESEARCH – CREATE – INNOVATE” (project code: 5048539). S.M.D. acknowledges the support of the British Heart Foundation [PG/19/51/34493 and PG/16/85/32471]. S.L. is supported by the South African National Research Foundation and received COST Seed funding from the Department of Science and Innovation in South Africa. M.R-M. is supported by the Instituto de Salud Carlos III of the Spanish Ministry of Health [FIS-PI19-01196] and a grant from the Spanish Society of Cardiology [SEC/FEC-INV-BAS 217003]. C.J.Z. is supported by a grant from European Foundation for the Study of Diabetes (EFSD), a research grant from Boehringer-Ingelheim and an institutional grant from Amsterdam UMC Cardiovascular Research. R.S. is supported by Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) [Project number 268555672—SFB 1213, Project B05]