Systemic Effects Induced by Hyperoxia in a Preclinical Model of Intra-abdominal Sepsis

Supplemental oxygen is a supportive treatment in patients with sepsis to balance tissue oxygen delivery and demand in the tissues. However, hyperoxia may induce some pathological effects. We sought to assess organ damage associated with hyperoxia and its correlation with the production of reactive oxygen species (ROS) in a preclinical model of intra-abdominal sepsis. For this purpose, sepsis was induced in male, Sprague-Dawley rats by cecal ligation and puncture (CLP). We randomly assigned experimental animals to three groups: control (healthy animals), septic (CLP), and sham-septic (surgical intervention without CLP). At 18 h after CLP, septic (n = 39), sham-septic (n = 16), and healthy (n = 24) animals were placed within a sealed Plexiglas cage and randomly distributed into four groups for continuous treatment with 21%, 40%, 60%, or 100% oxygen for 24 h. At the end of the experimental period, we evaluated serum levels of cytokines, organ damage biomarkers, histological examination of brain and lung tissue, and ROS production in each surviving animal. We found that high oxygen concentrations increased IL-6 and biomarkers of organ damage levels in septic animals, although no relevant histopathological lung or brain damage was observed. Healthy rats had an increase in IL-6 and aspartate aminotransferase at high oxygen concentration. IL-6 levels, but not ROS levels, are correlated with markers of organ damage. In our study, the use of high oxygen concentrations in a clinically relevant model of intra-abdominal sepsis was associated with enhanced inflammation and organ damage. These findings were unrelated to ROS release into circulation. Hyperoxia could exacerbate sepsis-induced inflammation, and it could be by itself detrimental. Our study highlights the need of developing safer thresholds for oxygen therapy

Psychiatric comorbidities in Asperger syndrome are related with polygenic overlap and differ from other Autism subtypes

There is great phenotypic heterogeneity within autism spectrum disorders (ASD), which has led to question their classification into a single diagnostic category. The study of the common genetic variation in ASD has suggested a greater contribution of other psychiatric conditions in Asperger syndrome (AS) than in the rest of the DSM-IV ASD subtypes (Non_AS). Here, using available genetic data from previously performed genome-wide association studies (GWAS), we aimed to study the genetic overlap between five of the most related disorders (schizophrenia (SCZ), major depression disorder (MDD), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorders (OCD) and anxiety (ANX)), and AS, comparing it with the overlap in Non_AS subtypes. A Spanish cohort of autism trios (N = 371) was exome sequenced as part of the Autism Sequencing Consortium (ASC) and 241 trios were extensively characterized to be diagnosed with AS following DSM-IV and Gillberg's criteria (N = 39) or not (N = 202). Following exome imputation, polygenic risk scores (PRS) were calculated for ASD, SCZ, ADHD, MDD, ANX, and OCD (from available summary data from Psychiatric Genomic Consortium (PGC) repository) in the Spanish trios' cohort. By using polygenic transmission disequilibrium test (pTDT), we reported that risk for SCZ (Pscz = 0.008, corrected-PSCZ = 0.0409), ADHD (PADHD = 0.021, corrected-PADHD = 0.0301), and MDD (PMDD = 0.039, corrected-PMDD = 0.0501) is over-transmitted to children with AS but not to Non_AS. Indeed, agnostic clustering procedure with deviation values from pTDT tests suggested two differentiated clusters of subjects, one of which is significantly enriched in AS (P = 0.025). Subsequent analysis with S-Predixcan, a recently developed software to predict gene expression from genotype data, revealed a clear pattern of correlation between cortical gene expression in ADHD and AS (P < 0.001) and a similar strong correlation pattern between MDD and AS, but also extendable to another non-brain tissue such as lung (P < 0.001). Altogether, these results support the idea of AS being qualitatively distinct from Non_AS autism and consistently evidence the genetic overlap between AS and ADHD, MDD, or SCZ

Temperature but not leptin prevents semi-starvation induced hyperactivity in rats: implications for anorexia nervosa treatment

The hypothesis linking hyperactivity with weight loss associated hypoleptinemia in anorexia nervosa gained momentum after a study showing that leptin suppressed semi-starvation induced hyperactivity in rats. Alternatively, ambient temperature is a key modulating factor of activity in semi-starved rats. The aim of the study is to compare the efficacy of leptin with increased ambient temperature in the prevention of hyperactivity in semi-starved rats. 74 Sprague-Dawley male rats were employed in two experiments with the difference residing in the length of baseline. After an extended (28 days), or shorter (14 days) baseline with free access to food and the running wheel, housed at 21 degrees C, animals were either ad-lib feed or food restricted (60% of food ingested during previous week) and infused with same amount of leptin at 21 degrees C, 25 degrees C, or vehicle at 21 degrees C, 25 degrees C and 32 degrees C for a week. Animals housed at 32 degrees C significantly reduced wheel running and weight loss during food restriction while animals given leptin did not yield no differences in activity or weight loss. Moreover, unlike animals housed at 32 degrees C, body temperature of leptin infused animals housed at 21 degrees C was significantly reduced during food restriction. Furthermore, leptin treated rats without a preceding stable pattern of activity displayed a severe dysregulation of circadian rhythm in activity and a collapse of body temperature. Housing temperature plays a more critical role than leptin in the regulation of semi-starvation induced hyperactivity in rats, which may be of relevance for the management of hyperactivity in anorexia nervosa

The social return on investment of a new approach to heart failure in the Spanish National Health System

AIMS: We aim to agree on a set of proposals to improve the current management of heart failure (HF) within the Spanish National Health System (SNHS) and apply the social return on investment (SROI) method to measure the social impact that these proposals would generate. METHODS AND RESULTS: A multidisciplinary working team of 16 experts was set up, with representation from the main stakeholders regarding HF: medical specialists (cardiologists, internal medicine physicians, general practitioners, and geriatric physicians), nursing professionals, health management professionals, patients, and informal caregivers. This team established a set of proposals to improve the management of HF according to the main areas of HF care: emergency and hospitalization, primary care, cardiology, and internal medicine. A forecast-type SROI method, with a 1-year time frame, was applied to measure the social impact resulting from the implementation of these proposals. The required investment and social return were estimated and summarized into a ratio indicating how much social return could be generated for each euro invested. Intangible returns were included and quantified through financial proxies. The approach to improve the management of HF consisted of 28 proposals, including the implementation of a case management nurse network, standardization of operational protocols, psychological support, availability of echocardiography machines at emergency departments, stationary units and primary care, early specialist visits after hospital discharge, and cardiac rehabilitation units, among others. These proposals would benefit not only patients and their informal caregivers but also the SNHS. Regarding patients, proposals would increase their autonomy in everyday activities, decrease anxiety, increase psychological and physical well-being, improve pharmacological adherence and self-care, enhance understanding of the disease, delay disease progression, expedite medical assessment, and prevent the decrease in work productivity associated with HF management. Regarding informal caregivers, proposals would increase their quality of life; improve their social, economic, and emotional well-being; and reduce their care burden. The SNHS would benefit from shorter stays of HF patients at intensive care units and reduction of hospitalizations and admissions to emergency departments. The investment needed to implement these proposals would amount to euro548m and yield a social return of euro1932m, that is, euro3.52 for each euro invested. CONCLUSIONS: The current management of HF could be improved by a set of proposals that resulted in an overall positive social return, varying between areas of analysis. This may guide the allocation of healthcare resources and improve the quality of life of patients with HF

Points to consider in cardiovascular disease risk management among patients with rheumatoid arthritis living in South Africa, an unequal middle income country

Background: It is plausible that optimal cardiovascular disease (CVD) risk management differs in patients with rheumatoid arthritis (RA) from low or middle income compared to high income populations. This study aimed at producing evidence-based points to consider for CVD prevention in South African RA patients. Methods: Five rheumatologists, one cardiologist and one epidemiologist with experience in CVD risk management in RA patients, as well as two patient representatives, two health professionals and one radiologist, one rheumatology fellow and 11 rheumatologists that treat RA patients regularly contributed. Systematic literature searches were performed and the level of evidence was determined according to standard guidelines. Results: Eighteen points to consider were formulated. These were grouped into 6 categories that comprised overall CVD risk assessment and management (n = 4), and specific interventions aimed at reducing CVD risk including RA control with disease modifying anti-rheumatic drugs, glucocorticoids and non-steroidal anti-inflammatory drugs (n = 3), lipid lowering agents (n = 8), antihypertensive drugs (n = 1), low dose aspirin (n = 1) and lifestyle modification (n = 1). Each point to consider differs partially or completely from recommendations previously reported for CVD risk management in RA patients from high income populations. Currently recommended CVD risk calculators do not reliably identify South African black RA patients with very high-risk atherosclerosis as represented by carotid artery plaque presence on ultrasound. Conclusions: Our findings indicate that optimal cardiovascular risk management likely differs substantially in RA patients from low or middle income compared to high income populations. There is an urgent need for future multicentre longitudinal studies on CVD risk in black African patients with RA

COVID-19 and Sick Leave: An Analysis of the Ibermutua Cohort of Over 1,651,305 Spanish Workers in the First Trimester of 2020

Objectives: The worldwide SARS-COV2 pandemic has impacted the health of workers and companies. The aim is to quantify it according to sick leave. Methods: Using ICD-9 codes, we analyzed Ibermutua records of all sick leaves during the first trimester of 2020, compared to during the same months of 2017, 2018, and 2019. We stratified the analysis by causes, patient sex, activity sectors, and regional data. All sick leaves were adjusted by the number of Ibermutua-affiliated persons in each period. Results: In March 2020, there was an unprecedented (116%) increase in total sick leaves, mainly due to infectious and respiratory diseases. Men and women were equally affected. All activity sectors were impacted, with the highest increase (457%) observed among health-related workers, especially due to contagious disease. The incidences of sick leaves were heterogeneous among different regions. Cost-analysis of sick leaves during the first trimester of 2020 compared with in previous years showed 40.3% increment (mean 2,813 vs. 2,005 euro per 100 affiliated workers). Conclusions: The SARS-COV2 pandemic is having a huge impact on workers' health, as shown by data regarding sick leaves in March 2020. This is associated with greater economic burden for companies, both due to the cost associated with sick leaves and the losses in productivity due to confinement

XPO1 Gene Therapy Attenuates Cardiac Dysfunction in Rats with Chronic Induced Myocardial Infarction

Transcriptomic signature of XPO1 was highly expressed and inversely related to left ventricular function in ischemic cardiomyopathy patients. We hypothesized that treatment with AAV9-shXPO1 attenuates left ventricular dysfunction and remodeling in a myocardial infarction rat model. We induced myocardial infarction by coronary ligation in Sprague-Dawley rats (n = 10), which received AAV9-shXPO1 (n = 5) or placebo AAV9-scramble (n = 5) treatment. Serial echocardiographic assessment was performed throughout the study. After myocardial infarction, AAV9-shXPO1-treated rats showed partial recovery of left ventricular fractional shortening (16.8 +/- 2.8 vs 24.6 +/- 4.1%, P < 0.05) and a maintained left ventricular dimension (6.17 +/- 0.95 vs 4.70 +/- 0.93 mm, P < 0.05), which was not observed in non-treated rats. Furthermore, lower levels of EXP-1 (P < 0.05) and lower collagen fibers and fibrosis in cardiac tissue were observed. However, no differences were found in the IL-6 or TNFR1 plasma levels of the myocardium of AAV9-shXPO1 rats. AAV9-shXPO1 administration attenuates cardiac dysfunction and remodeling in rats after myocardial infarction, producing the gene silencing of XPO1

Inositol 1,3,4,5,6-pentakisphosphate 2-kinase is a distant IPK member with a singular inositide binding site for axial 2-OH recognition

Inositol phosphates (InsPs) are signaling molecules with multiple roles in cells. In particular Graphic (InsP6) is involved in mRNA export and editing or chromatin remodeling among other events. InsP6 accumulates as mixed salts (phytate) in storage tissues of plants and plays a key role in their physiology. Human diets that are exclusively grain-based provide an excess of InsP6 that, through chelation of metal ions, may have a detrimental effect on human health. Ins(1,3,4,5,6)P5 2-kinase (InsP5 2-kinase or Ipk1) catalyses the synthesis of InsP6 from InsP5 and ATP, and is the only enzyme that transfers a phosphate group to the axial 2-OH of the myo-inositide. We present the first structure for an InsP5 2-kinase in complex with both substrates and products. This enzyme presents a singular structural region for inositide binding that encompasses almost half of the protein. The key residues in substrate binding are identified, with Asp368 being responsible for recognition of the axial 2-OH. This study sheds light on the unique molecular mechanism for the synthesis of the precursor of inositol pyrophosphates

Bioelectronics-on-a-chip for cardio myoblast proliferation enhancement using electric field stimulation

Background: Cardio myoblast generation from conventional approaches is laborious and time-consuming. We present a bioelectronics on-a-chip for stimulating cells cardio myoblast proliferation during culture. Method: The bioelectronics chip fabrication methodology involves two different process. In the first step, an aluminum layer of 200 nm is deposited over a soda-lime glass substrate using physical vapor deposition and selectively removed using a Q-switched Nd:YVO4 laser to create the electric tracks. To perform the experiments, we developed a biochip composed of a cell culture chamber fabricated with polydimethylsiloxane (PDMS) with a glass coverslip or a cell culture dish placed over the electric circuit tracks. By using such a glass cover slip or cell culture dish we avoid any toxic reactions caused by electrodes in the culture or may be degraded by electrochemical reactions with the cell medium, which is crucial to determine the effective cell-device coupling. Results: The chip was used to study the effect of electric field stimulation of Rat ventricular cardiomyoblasts cells (H9c2). Results shows a remarkable increase in the number of H9c2 cells for the stimulated samples, where after 72 h the cell density double the cell density of control samples. Conclusions: Cell proliferation of Rat ventricular cardiomyoblasts cells (H9c2) using the bioelectronics-on-a-chip was enhanced upon the electrical stimulation. The dependence on the geometrical characteristics of the electric circuit on the peak value and homogeneity of the electric field generated are analyzed and proper parameters to ensure a homogeneous electric field at the cell culture chamber are obtained. It can also be observed a high dependence of the electric field on the geometry of the electrostimulator circuit tracks and envisage the potential applications on electrophysiology studies, monitoring and modulate cellular behavior through the application of electric fields

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

AIMS: The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin-kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (>/=1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. METHODS AND RESULTS: Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77-0.99; P = 0.032) and Type 2 (0.77, 0.61-0.97; P = 0.025), but not Type 4 MI. CONCLUSION: After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types