Egr-1 functions as a master switch regulator of remote ischemic preconditioning-induced cardioprotection.

Despite improved treatment options myocardial infarction (MI) is still a leading cause of mortality and morbidity worldwide. Remote ischemic preconditioning (RIPC) is a mechanistic process that reduces myocardial infarction size and protects against ischemia reperfusion (I/R) injury. The zinc finger transcription factor early growth response-1 (Egr-1) is integral to the biological response to I/R, as its upregulation mediates the increased expression of inflammatory and prothrombotic processes. We aimed to determine the association and/or role of Egr-1 expression with the molecular mechanisms controlling the cardioprotective effects of RIPC. This study used H9C2 cells in vitro and a rat model of cardiac ischemia reperfusion (I/R) injury. We silenced Egr-1 with DNAzyme (ED5) in vitro and in vivo, before three cycles of RIPC consisting of alternating 5 min hypoxia and normoxia in cells or hind-limb ligation and release in the rat, followed by hypoxic challenge in vitro and I/R injury in vivo. Post-procedure, ED5 administration led to a significant increase in infarct size compared to controls (65.90 ± 2.38% vs. 41.00 ± 2.83%, p < 0.0001) following administration prior to RIPC in vivo, concurrent with decreased plasma IL-6 levels (118.30 ± 4.30 pg/ml vs. 130.50 ± 1.29 pg/ml, p < 0.05), downregulation of the cardioprotective JAK-STAT pathway, and elevated myocardial endothelial dysfunction. In vitro, ED5 administration abrogated IL-6 mRNA expression in H9C2 cells subjected to RIPC (0.95 ± 0.20 vs. 6.08 ± 1.40-fold relative to the control group, p < 0.05), resulting in increase in apoptosis (4.76 ± 0.70% vs. 2.23 ± 0.34%, p < 0.05) and loss of mitochondrial membrane potential (0.57 ± 0.11% vs. 1.0 ± 0.14%-fold relative to control, p < 0.05) in recipient cells receiving preconditioned media from the DNAzyme treated donor cells. This study suggests that Egr-1 functions as a master regulator of remote preconditioning inducing a protective effect against myocardial I/R injury through IL-6-dependent JAK-STAT signaling.

Using an Integrated -Omics Approach to Identify Key Cellular Processes That Are Disturbed in the Kidney After Brain Death.

In an era where we are becoming more reliant on vulnerable kidneys for transplantation from older donors, there is an urgent need to understand how brain death leads to kidney dysfunction and, hence, how this can be prevented. Using a rodent model of hemorrhagic stroke and next-generation proteomic and metabolomic technologies, we aimed to delineate which key cellular processes are perturbed in the kidney after brain death. Pathway analysis of the proteomic signature of kidneys from brain-dead donors revealed large-scale changes in mitochondrial proteins that were associated with altered mitochondrial activity and morphological evidence of mitochondrial injury. We identified an increase in a number of glycolytic proteins and lactate production, suggesting a shift toward anaerobic metabolism. Higher amounts of succinate were found in the brain death group, in conjunction with increased markers of oxidative stress. We characterized the responsiveness of hypoxia inducible factors and found this correlated with post-brain death mean arterial pressures. Brain death leads to metabolic disturbances in the kidney and alterations in mitochondrial function and reactive oxygen species generation. This metabolic disturbance and alteration in mitochondrial function may lead to further cellular injury. Conditioning the brain-dead organ donor by altering metabolism could be a novel approach to ameliorate this brain death-induced kidney injury.

Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma.

Paediatric and adult astrocytomas are notably different, where clinical treatments used for adults are not as effective on children with the same form of cancer and these treatments lead to adverse long-term health concerns. Integrative omics-based studies have shown the pathology and fundamental molecular characteristics differ significantly and cannot be extrapolated from the more widely studied adult disease. Recent clinical advances in our understanding of paediatric astrocytomas, with the aid of next-generation sequencing and epigenome-wide profiling, have led to the identification of key canonical mutations that vary based on the tumour location and age of onset. These driver mutations, in particular the identification of the recurrent histone H3 mutations in high-grade tumours, have confirmed the important role epigenetic dysregulations play in cancer progression. This review summarises the current updates of the classification, epidemiology, pathogenesis and clinical management of paediatric astrocytoma based on their grades and the ongoing clinical trials. It also provides novel insights on genetic and epigenetic alterations as diagnostic biomarkers, highlighting the potential of targeting these pathways as therapeutics for this devastating childhood cancer.

Prevalence and characteristics of anemia in patients with diabetes mellitus aged 50 or older in health unit area of Cadiz (Spain).

BACKGROUND: Anemia is a common comorbidity in patients with diabetes mellitus (DM), particularly in older adults. However, there is a lack of data on the prevalence and the characteristics of anemia in this population in Spain. OBJECTIVE: To describe the prevalence and the characteristics of anemia in patients with DM aged 50 or older (PDM50) in a healthcare district in the province of Cádiz. METHODS: A retrospective cross-sectional study was conducted that included outpatient's laboratory tests (OLT) performed over 30 months at PDM50. RESULTS: The prevalence of anemia was 29.9% (95% CI: 28.7%-31.1%), predominating in women (33.3% vs 26.7%; P < 0.01), in older people stratified by decades (61.7% in 9th decade vs 12% in 5th decade; P < 0.01), and in those with kidney disease (44.7% vs 28%; P < 0.01). Most cases were mild (68.3%), normocytic (78.7%), and hypochromic (52%). Similarly, moderate-to-severe anemia was more frequent in women (39% vs 23%), their prevalence increased with age (45% in the 9th decade vs 24% in the 5th decade), and with the progression of kidney damage, either measured by a decreased glomerular filtration rate (GFR) (49% in G4 vs 25% in G1), or the presence of albuminuria (P < 0.01). No association was found between DM control, based on glycated hemoglobin (HbA1c), and anemia in either sex (P = 0.887). CONCLUSION: This study describes a high prevalence of anemia in PDM50, particularly in women, in the most advantageous people and in the presence of kidney disease, even in early stages, highlighting the clinical importance of this coexistence.

Measuring tissue water potential in marine macroalgae via an updated Chardakov method.

Regulation of tissue water potential is a key mechanism in macroalgal osmotic responses to changing external osmotic conditions, which are common in tidally influenced estuarine and intertidal systems. Nevertheless, significant knowledge gaps exist in our understanding of osmotic responses in macroalgae because few methods measure osmotic potential within macroalgal tissues. Leaf psychrometers have furthered understanding of osmotic potentials in terrestrial plant water relations, yet these have not been developed to measure the range of highly negative potential values found in marine macroalgae. To address these gaps, we present an effective, updated version of the Chardakov method to measure tissue water potential in macroalgae. Here, we present a case study examining macroalgal response in tissue water potential by two morphologically and evolutionarily distinct species, Ulva lactuca (Chlorophyta) and Hypnea musciformis (Rhodophyta) to four paired salinity and nutrient treatments at two temperatures. These treatments simulate a gradient from full coastal ocean conditions to brackish submarine groundwater discharge, an ecosystem type found on basaltic shorelines. Both algae demonstrated plasticity in osmotic response to submarine groundwater discharge with significant positive correlations between tissue water potential and proportion of submarine groundwater discharge in the treatment. These results are the first to describe macroalgal response in tissue water potential, a first step to understanding algal physiological ecology in such complex coastal environments. This revised Chardakov method is a valuable tool to better understand species-specific osmotic responses to ecologically relevant conditions, and can augment the study of other tidal systems and ontogenetic stages.

Is the use of the new Chronic Kidney Disease Epidemiology Consortium (CKD-EPI 2021) formula appropriate for the Spanish population?

INTRODUCTION: United States nephrology societies recommend changing from the CKD-EPI 2009 equation to the new CKD-EPI 2021 equation, which does not include the race coefficient, for calculating estimated glomerular filtration rate (eGFR). It is unknown how this change might affect the distribution of kidney disease in the predominantly Caucasian Spanish population. METHODS: Two databases of adults from the province of Cádiz, DB-SIDICA (N=264,217) and DB-PANDEMIA (N=64,217), that had plasma creatinine measurements recorded between 2017 and 2021 were studied. Changes in eGFR and the consequent reclassification into different categories of the KDIGO 2012 classification resulting from substituting the CKD-EPI 2009 equation for the 2021 equation were calculated. RESULTS: Compared to the 2009 equation, CKD-EPI 2021 yielded a higher eGFR, with a median of 3.8mL/min/1.73m2 (IQR 2.98-4.48) in DB-SIDICA and 3.89mL/min/1.73m2 (IQR 3.05-4.55) in DB-PANDEMIA. The first consequence was that 15.3% of the total population in DB-SIDICA and 15.1% of the total population in DB-PANDEMIA were reclassified into a higher category of eGFR, as were 28.1% and 27.3%, respectively, of the population with CKD (G3-G5); no subjects were classified into the more severe category. The second consequence was that the prevalence of kidney disease decreased from 9% to 7.5% in both cohorts. CONCLUSIONS: Implementing the CKD-EPI 2021 equation in the Spanish population, which is predominantly Caucasian, would increase eGFR by a modest amount (greater in men and those who are older or have a higher GFR). A significant proportion of the population would be classified into a higher eGFR category, with a consequent decrease in the prevalence of kidney disease.

Detection of asinine gammaherpesviruses in association with pulmonary fibrosis in free-ranging donkeys.

A mortality event among recently captured feral donkeys (Equus asinus) occurred in south-central Utah in 2016. The deaths were sporadic, and clinical signs were indicative of respiratory disease, likely associated with an infectious etiology. Ten of 13 donkeys autopsied had moderate-to-severe interstitial fibrosing pneumonia, and one had pyogranulomatous pneumonia. Consensus PCRs directed toward the DNA polymerase and DNA packaging terminase subunit 1 for herpesviruses were performed followed by sequencing of the PCR amplicons and phylogenetic analysis. Asinine herpesvirus 4 (AsHV4) and 5 (AsHV5) were consistently identified in lung tissues of affected donkeys. No other herpesviruses were identified, and herpesviral DNA was not detected in lung tissues of 2 donkeys without evidence of respiratory disease. The detection of asinine gammaherpesviruses may have been associated with the lesions described. AsHV4 and AsHV5 have been reported in previous studies as novel gammaherpesviruses based on sequences obtained from donkeys with interstitial pneumonia and marked syncytial cell formation. Our findings suggest that the association of asinine gammaherpesviruses with respiratory conditions in equids deserves further attention.

Unraveling the concepts of distress, burnout, and depression in type 1 diabetes: A scoping review.

BACKGROUND: Psychological complications are frequent in type 1 diabetes (T1D) but they might be difficult to distinguish one from the other in clinical practice. Our objective was to study the distinguishing characteristics, overlaps and their use in the literature between three concepts of T1D: depression, diabetes distress (DD) and diabetes burnout (DB). METHODS: A scoping review (PRISMA guidelines) performed in three databases (PubMed/MEDLINE, PsycInfo, Web of Science) with the keywords: T1D, depression, diabetes and burnout, from January 1990 to June 2021. We selected original studies with participants with T1D, which reported depression, DD, or DB. We extracted information about the concepts, their sub-concepts and screening tools. FINDINGS: Of the 4763 studies identified, 201 studies were included in the study. Seventy-three percent, 57% and 45% of sub-concepts do not overlap in depression, DD, and DB, respectively. We observed overlap between depression (27%)/DD (27%) and between DD (20%)/DB (50%). INTERPRETATION: A number of sub-concepts distinguish depression and DD. Overlaps between concepts suggest that a more precise definition is still lacking. DB is still a relatively new concept and more research is needed to better understand how it can present itself differently, in order to personalize care in comparison to those having DD.

Biomarkers of opiate use.

The interpretation of toxicological findings is critical for the thorough investigation of the use and abuse of psychoactive substances. A positive analytical result for a sample taken could usually result in criminal proceedings and a punitive outcome for the defendant whose sample was analysed. The detection of markers of illicit opiate misuse is important both in the management of substance misuse and in the postmortem identification of illicit opiate use. The aim of this study was to emphasise the role of opiate biomarkers available at the laboratory and in the clinical environment. Urine remains the biological tool of choice for qualitative detection of illicit drug use in a clinical setting, while quantitative accuracy remains strictly the domain of blood. Accurate interpretation of the screening tests within a clinical setting alongside other relevant information remains the key to the usefulness of any test. Moreover, the finding of a morphine/codeine concentration ratio in blood exceeding unity is a strong evidence that the person had used heroin, as opposed to having taken a prescription analgesic drug containing codeine.

Diagnosis of Bovine Respiratory Disease in feedlot cattle using blood 1H NMR metabolomics.

Current diagnosis methods for Bovine Respiratory Disease (BRD) in feedlots have a low diagnostic accuracy. The current study aimed to search for blood biomarkers of BRD using 1H NMR metabolomics and determine their accuracy in diagnosing BRD. Animals with visual signs of BRD (n = 149) and visually healthy (non-BRD; n = 148) were sampled for blood metabolomics analysis. Lung lesions indicative of BRD were scored at slaughter. Non-targeted 1H NMR metabolomics was used to develop predictive algorithms for disease classification using classification and regression trees. In the absence of a gold standard for BRD diagnosis, six reference diagnosis methods were used to define an animal as BRD or non-BRD. Sensitivity (Se) and specificity (Sp) were used to estimate diagnostic accuracy (Acc). Blood metabolomics demonstrated a high accuracy at diagnosing BRD when using visual signs of BRD (Acc = 0.85), however was less accurate at diagnosing BRD using rectal temperature (Acc = 0.65), lung auscultation score (Acc = 0.61) and lung lesions at slaughter as reference diagnosis methods (Acc = 0.71). Phenylalanine, lactate, hydroxybutyrate, tyrosine, citrate and leucine were identified as metabolites of importance in classifying animals as BRD or non-BRD. The blood metabolome classified BRD and non-BRD animals with high accuracy and shows potential for use as a BRD diagnosis tool.

[Concordance between the equations "Chronic Kidney Disease Epidemiological Collaboration" and "Modification of Diet in Renal Disease" with the "Berlin Initiative Study" to estimate renal function in the elderly]. / Concordancia entre las ecuaciones «Chronic Kidney Disease Epidemiological Collaboration¼ y «Modification of Diet in Renal Disease¼ con la «Berlin Initiative Study¼ para estimar la función renal en las personas mayores.

OBJECTIVE: Estimated glomerular filtration rate (eGFR) is calculated routinely using creatinine-based formulas, but their reliability in the elderly is limited. The aim of this study was to analyse the concordance between the BIS1 equation which is specific for the elderly, and the usual CKD-EPI and MDRD-IDMS in a large population over 70 years of age. MATERIAL AND METHODS: Retrospective cross-sectional study in which the eGFR was calculated using BIS1, CKD-EPI and MDRD-IDMS equations based on gender, age, and creatinine data of 85,089 subjects (58.5% women, mean age 78 years [IQR 73-83]).The following statistics were carried out: Wilcoxon test, Bland-Altman graphic analysis, study of the concordance using the intraclass correlation coefficient (ICC), and comparison tables for the classification of CKD. RESULTS: The median of the eGFRs using BIS1 was 58mL/min/1.73m2 (IQR 48-70), using CKD-EPI was 68mL/min/1.73m2 (IQR 53-84), and using MDRD it was 68mL/min/1.73m2 (IQR 53-82). The concordance between BIS1 and CKD-EPI (intraclass correlation coefficient =0.87) was found to be acceptable. It was lower with MDRD (intraclass correlation coefficient =0.81). A mean difference of 8mL/min/1.73m2 (SD 2.6-18) was found BIS1 vs. CKD-EPI, and 10mL/min/1.73m2 (SD 6-27) with BIS1 vs. MDRD, which was maintained when stratifying by gender and age groups. CONCLUSIONS: Despite the acceptable statistical agreement, the eGFR obtained with the BIS1 equation is not interchangeable with CKD-EPI or with MDRD-IDMS. The BIS1 equation gives lower values than CKD-EPI, and classifies patients into a higher level of CKD, mainly when the eGFR is above 30mL/min/1.73 m2.

Prevalence of diabetes, use of antidiabetic drugs and degree of glycaemic control in the province of Cadiz (2014-2016): A population-based study. / Prevalencia de diabetes, utilización de antidiabéticos y grado de control glucémico en la provincia de Cádiz (2014-2016): un estudio de base poblacional.

BACKGROUND AND OBJECTIVE: The aim of the study was to assess the prevalence of diabetes mellitus treated pharmacologically, analyse the prescription patterns of antidiabetic drugs and assess the degree of control over the disease in the province of Cadiz. PATIENTS AND METHODS: An observational retrospective study was conducted with the databases of the public health system of the Andalusian Health Service between 2014 and 2016, inclusive. Adults with treated diabetes (ATD) were considered those older than 14 years who had consumed at least 1 package of medication from the A10 group during the corresponding year covered by the study. RESULTS: The prevalence of ATD varied between 8.65% and 8.83% from 2014 to 2016, respectively. Seventy-one percent of the ATD were treated with only noninsulin drugs, 11% were treated with insulin, and 18% were treated with a combination of both. For approximately one-third of the ATD, an HbA1c reading was not performed during each year. Sixty-nine percent of the assessed ATD in 2016 had an appropriate degree of control according to RedGDPS criteria (based on HbA1c and age). CONCLUSION: The prevalence of pharmacologically treated diabetes in the province of Cadiz is high and appears to be increasing. The patients presented limited glycaemic control, to which inadequate follow-up in almost a third of the patients could be the major contributor.

Labile haemoglobin as a glycaemic biomarker for patient-specific monitoring of diabetes: mathematical modelling approach.

Diabetes mellitus constitutes a major health problem and its clinical presentation and progression may vary considerably. A number of standardized diagnostic and monitoring tests are currently used for diabetes. They are based on measuring either plasma glucose, glycated haemoglobin or both. Their main goal is to assess the average blood glucose concentration. There are several sources of interference that can lead to discordances between measured plasma glucose and glycated haemoglobin levels. These include haemoglobinopathies, conditions associated with increased red blood cell turnover or the administration of some therapies, to name a few. Therefore, there is a need to provide new diagnostic tools for diabetes that employ clinically accessible biomarkers which, at the same time, can offer additional information allowing us to detect possible conflicting cases and to yield more reliable evaluations of the average blood glucose level concentration. We put forward a biomathematical model to describe the kinetics of two patient-specific glycaemic biomarkers to track the emergence and evolution of diabetes: glycated haemoglobin and its labile fraction. Our method incorporates erythrocyte age distribution and utilizes a large cohort of clinical data from blood tests to support its usefulness for diabetes monitoring.

Remote ischemic preconditioning attenuates EGR-1 expression following myocardial ischemia reperfusion injury through activation of the JAK-STAT pathway.

BACKGROUND/OBJECTIVES: Remote ischemic preconditioning (RIPC) protects the myocardium from ischemia/reperfusion (I/R) injury however the molecular pathways involved in cardioprotection are yet to be fully delineated. Transcription factor Early growth response-1 (Egr-1) is a key upstream activator in a variety of cardiovascular diseases. In this study, we elucidated the role of RIPC in modulating the regulation of Egr-1. METHODS: This study subjected rats to transient blockade of the left anterior descending (LAD) coronary artery with or without prior RIPC of the hind-limb muscle and thereafter excised the heart 24h following surgical intervention. In vitro, rat cardiac myoblast H9c2 cells were exposed to ischemic preconditioning by subjecting them to 3cycles of alternating nitrogen-flushed hypoxia and normoxia. These preconditioned media were added to recipient H9c2 cells which were then subjected to 30min of hypoxia followed by 30min of normoxia to simulate myocardial I/R injury. Thereafter, the effects of RIPC on cell viability, apoptosis and inflammatory markers were assessed. RESULTS: We showed reduced infarct size and suppressed Egr-1 in the heart of rats when RIPC was administered to the hind leg. In vitro, we showed that RIPC improved cell viability, reduced apoptosis and attenuated Egr-1 in recipient cells. CONCLUSIONS: Selective inhibition of intracellular signaling pathways confirmed that RIPC increased production of intracellular nitric oxide (NO) and reactive oxygen species (ROS) via activation of the JAK-STAT pathway which then inactivated I/R-induced ERK 1/2 signaling pathways, ultimately leading to the suppression of Egr-1.

Adverse effects of anabolic steroids in athletes. A constant threat.

Anabolic-androgenic steroids (AAS) are used as ergogenic aids by athletes and non-athletes to enhance performance by augmenting muscular development and strength. AAS administration is often associated with various adverse effects that are generally dose related. High and multi-doses of AAS used for athletic enhancement can lead to serious and irreversible organ damage. Among the most common adverse effects of AAS are some degree of reduced fertility and gynecomastia in males and masculinization in women and children. Other adverse effects include hypertension and atherosclerosis, blood clotting, jaundice, hepatic neoplasms and carcinoma, tendon damage, psychiatric and behavioral disorders. More specifically, this article reviews the reproductive, hepatic, cardiovascular, hematological, cerebrovascular, musculoskeletal, endocrine, renal, immunologic and psychologic effects. Drug-prevention counseling to athletes is highlighted and the use of anabolic steroids is must be avoided, emphasizing that sports goals may be met within the framework of honest competition, free of doping substances.

Dominant components of the Thoroughbred metabolome characterised by (1) H-nuclear magnetic resonance spectroscopy: A metabolite atlas of common biofluids.

REASONS FOR PERFORMING STUDY: Metabonomics is emerging as a powerful tool for disease screening and investigating mammalian metabolism. This study aims to create a metabolic framework by producing a preliminary reference guide for the normal equine metabolic milieu. OBJECTIVES: To metabolically profile plasma, urine and faecal water from healthy racehorses using high resolution (1) H-nuclear magnetic resonance (NMR) spectroscopy and to provide a list of dominant metabolites present in each biofluid for the benefit of future research in this area. STUDY DESIGN: This study was performed using 7 Thoroughbreds in race training at a single time point. Urine and faecal samples were collected noninvasively and plasma was obtained from samples taken for routine clinical chemistry purposes. METHODS: Biofluids were analysed using (1) H-NMR spectroscopy. Metabolite assignment was achieved via a range of one- and 2-dimensional experiments. RESULTS: A total of 102 metabolites were assigned across the 3 biological matrices. A core metabonome of 14 metabolites was ubiquitous across all biofluids. All biological matrices provided a unique window on different aspects of systematic metabolism. Urine was the most populated metabolite matrix with 65 identified metabolites, 39 of which were unique to this biological compartment. A number of these were related to gut microbial host cometabolism. Faecal samples were the most metabolically variable between animals; acetate was responsible for the majority (28%) of this variation. Short-chain fatty acids were the predominant features identified within this biofluid by (1) H-NMR spectroscopy. CONCLUSIONS: Metabonomics provides a platform for investigating complex and dynamic interactions between the host and its consortium of gut microbes and has the potential to uncover markers for health and disease in a variety of biofluids. Inherent variation in faecal extracts along with the relative abundance of microbial-mammalian metabolites in urine and invasive nature of plasma sampling, infers that urine is the most appropriate biofluid for the purposes of metabonomic analysis.