The nuclear factor of activated T cells 5 (NFAT5) contributes to the renal corticomedullary differences in gene expression.

The corticomedullary osmotic gradient between renal cortex and medulla induces a specific spatial gene expression pattern. The factors that controls these differences are not fully addressed. Adaptation to hypertonic environment is mediated by the actions of the nuclear factor of activated T-cells 5 (NFAT5). NFAT5 induces the expression of genes that lead to intracellular accumulation of organic osmolytes. However, a systematical analysis of the NFAT5-dependent gene expression in the kidneys was missing. We used primary cultivated inner medullary collecting duct (IMCD) cells from control and NFAT5 deficient mice as well as renal cortex and inner medulla from principal cell specific NFAT5 deficient mice for gene expression profiling. In primary NFAT5 deficient IMCD cells, hyperosmolality induced changes in gene expression were abolished. The majority of the hyperosmolality induced transcripts in primary IMCD culture were determined to have the greatest expression in the inner medulla. Loss of NFAT5 altered the expression of more than 3000 genes in the renal cortex and more than 5000 genes in the inner medulla. Gene enrichment analysis indicated that loss of NFAT5 is associated with renal inflammation and increased expression of kidney injury marker genes, like lipocalin-2 or kidney injury molecule-1. In conclusion we show that NFAT5 is a master regulator of gene expression in the kidney collecting duct and in vivo loss of NFAT function induces a kidney injury like phenotype.

Safety of early hospital discharge following admission with ST-elevation myocardial infarction treated with percutaneous coronary intervention: a nationwide cohort study.

BACKGROUND: The Second Primary Angioplasty in Myocardial Infarction (PAMI-II) risk score is recommended by guidelines to identify low-risk patients with ST-elevation myocardial infarction (STEMI) for an early discharge strategy. AIMS: We aimed to assess the safety of early discharge (≤2 days) for low-risk STEMI patients treated with primary percutaneous coronary intervention (PCI). METHODS: Using nationwide data from the SWEDEHEART registry, we identified patients with STEMI treated with primary PCI during the period 2009-2017, of whom 8,092 (26.4%) were identified as low risk with the PAMI-II score. Low-risk patients were stratified according to their length of hospital stay (≤2 days vs >2 days). The primary endpoint was major adverse cardiovascular events (MACE, including death, reinfarction treated with PCI, stroke or heart failure hospitalisation) at one year, assessed using a Cox proportional hazards model with propensity score as well as an inverse probability weighting propensity score of average treatment effect to adjust for confounders. RESULTS: A total of 1,449 (17.9%) patients were discharged ≤2 days from admission. After adjustment, the one-year MACE rate was not higher for patients discharged at >2 days from admission than for patients discharged ≤2 days (4.3% vs 3.2%; adjusted HR 1.31, 95% confidence interval [CI]: 0.92-1.87, p=0.14), and no difference was observed regarding any of the individual components of the main outcome. Results were consistent across all subgroups with no difference in MACE between early and late discharge patients. CONCLUSIONS: Nationwide observational data suggest that early discharge of low-risk patients with STEMI treated with PCI is not associated with an increase in one-year MACE.

Loss of RANBP3L leads to transformation of renal epithelial cells towards a renal clear cell carcinoma like phenotype.

BACKGROUND: Renal cell carcinomas (RCC) are characterized by the deregulation of several hundred hyperosmolality-responsive genes. High expression of a subset of these genes including the Ran binding protein 3 like (RANBP3L) is linked to a favorable prognostic outcome in RCC. However, the cellular function of RANBP3L remains largely unknown. METHODS: We used CRISPR/Cas9-mediated gene editing to generate functional deletions of the Ranbp3l and nuclear factor of activated T cells 5 (Nfat5) gene loci in a murine renal cell line. The NFAT5-KO cells were used to assess the regulation of Ranbp3l by NFAT5 using immunofluorescence, RNA-Seq and promoter assays. RANBP3L-deficient cells were analyzed for changes in cell morphology, proliferation, migration and colony-forming capacity using immunofluorescence and live cell imaging. RANPB3L-dependent changes in gene expression were identified by RNA-Seq. RESULTS: We show that NFAT5 directly regulates Ranpb3l under hyperosmotic conditions by binding its promoter. Functional analysis of RANBP3L-deficient cells revealed a loss of epithelial structure, an increased cell migration behavior and colony forming capacity, accompanied by massive alterations in gene expression, all of which are hallmarks for tumor cells. Strikingly, a RANBP3L dependent signature of 60 genes separated samples with clear cell carcinoma (KIRC) from papillary (KIRP), chromophobe renal carcinoma (KICH) and healthy tissue. CONCLUSIONS: Loss of RANBP3L induces a tumor like phenotype resembles RCC, especially KIRC, on the morphological and gene expression level and might promote tumor development and progression. Therapeutic reconstitution or elevation of osmoregulated RANBP3L expression might represent a novel treatment strategy for RCC or KIRC.

Drug therapy in cardiac arrest: a review of the literature.

The aim of this study was to review the literature on human studies of drug therapy in cardiac arrest during the last 25 years. In May 2015, a systematic literature search was performed in PubMed, Embase, the Cochrane Library, and CRD databases. Prospective interventional and observational studies evaluating a specified drug therapy in human cardiac arrest reporting a clinical endpoint [i.e. return of spontaneous circulation (ROSC) or survival] and published in English 1990 or later were included, whereas animal studies, case series and reports, studies of drug administration, drug pharmacology, non-specified drug therapies, preventive drug therapy, drug administration after ROSC, studies with primarily physiological endpoints, and studies of traumatic cardiac arrest were excluded. The literature search identified a total of 8936 articles. Eighty-eight articles met our inclusion criteria and were included in the review. We identified no human study in which drug therapy, compared with placebo, improved long-term survival. Regarding adrenaline and amiodarone, the drugs currently recommended in cardiac arrest, two prospective randomized placebo-controlled trials, were identified for adrenaline, and one for amiodarone, but they were all underpowered to detect differences in survival to hospital discharge. Of all reviewed studies, only one recent prospective study demonstrated improved neurological outcome with one therapy over another using a combination of vasopressin, steroids, and adrenaline as the intervention compared with standard adrenaline administration. The evidence base for drug therapy in cardiac arrest is scarce. However, many human studies on drug therapy in cardiac arrest have not been powered to identify differences in important clinical outcomes such as survival to hospital discharge and favourable neurological outcome. Efforts are needed to initiate large multicentre prospective randomized clinical trials to evaluate both currently recommended and future drug therapies.

Trends in Gender Differences in Cardiac Care and Outcome After Acute Myocardial Infarction in Western Sweden: A Report From the Swedish Web System for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART).

BACKGROUND: Cardiovascular disease is the most common cause of death for both genders. Debates are ongoing as to whether gender-specific differences in clinical course, diagnosis, and management of acute myocardial infarction (MI) exist. METHODS AND RESULTS: We compared all men and women who were treated for acute MI at cardiac care units in Västra Götaland, Sweden, between January 1995 and October 2014 by obtaining data from the prospective SWEDEHEART (Swedish Web-System for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry. We performed unadjusted and adjusted Cox proportional hazards and logistic regression analyses on complete case data and on imputed data sets. Overall, 48 118 patients (35.4% women) were diagnosed with acute MI. Women as a group had better age-adjusted prognosis than men, but this survival benefit was absent for younger women (aged <60 years) and for women with ST-segment elevation MI. Compared with men, younger women and women with ST-segment elevation MI were more likely to develop prehospital cardiogenic shock (adjusted odds ratio 1.67, 95% CI 1.30 to 2.16, P<0.001 and adjusted odds ratio 1.31, 95% CI 1.16 to 1.48, P<0.001) and were less likely to be prescribed evidence-based treatment at discharge (P<0.001 for ß-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, and P2Y12 antagonists). Differences in treatment between the genders did not decrease over the study period (P>0.1 for all treatments). CONCLUSIONS: Women on average have better adjusted prognosis than men after acute MI; however, younger women and women with ST-segment elevation MI have disproportionately poor prognosis and are less likely to be prescribed evidence-based treatment.

HCMV-specific T-cell therapy: do not forget supply of help.

Human cytomegalovirus infections have a major negative effect on morbidity and mortality of immunosuppressed allograft recipients and indirectly on graft function and survival. The adoptive antiviral T-cell therapy is a novel therapeutic tool to restore immune competence after solid organ transplantation. Till now, the antiviral T-cell products mainly focused on cytotoxic CD8(+) T cells, whereas CD4(+) T cells played a minor role. Here, we demonstrate the importance of CD4(+) T cells within T-cell lines specific for human cytomegalovirus besides its essential support for the quality of CD8(+) T-cell memory. Virus-specific CD4(+) T cells elicit profound functionality after rechallenge (multicytokine secretors, CD137, CD154, and CD107a expression and killing of infected target cells). The CD4(+) T cells show predominantly a Th1 phenotype with cytolytic properties that is mainly perforin-dependent. The data demonstrate the significance of CD4(+) T cells within T-cell products to achieve a successful adoption with enhanced efficacy.

Preferential expansion of human virus-specific multifunctional central memory T cells by partial targeting of the IL-2 receptor signaling pathway: the key role of CD4+ T cells.

Effector memory T cells are effective in controlling acute infections, but central memory T cells play a key role in long-lasting protection against viruses and tumors. In vivo/in vitro challenge by Ag commonly supports the generation of effector memory T cells with limited longevity. To our knowledge, this study demonstrates for the first time in the human system and under rechallenge conditions that targeting IL-2R by partial mammalian target of rapamycin inhibition or blocking IL-2Rα enriches human CD4(+)/CD8(+) central memory T cells within the virus-specific T cell product associated with enhanced functionality (i.e., multicytokine secretors, including IL-2; enhanced CD137 and CD107a expression on CD8(+) and CD4(+) T cells, respectively; and killing infected target cells). Remarkably, the effects on CD8(+) T cells are mainly mediated via the enhancement of CD4(+) T cell function. The data reveal new insights into the role of CD4(+) T cell support for the quality of CD8(+) T cell memory, even under rechallenge conditions. Moreover, our method offers a new approach to improve the long-lasting efficacy of adoptive T cell therapy in patients.

Physical activity, diet and behaviour modification in the treatment of overweight and obese adults: a systematic review.

AIM: The aim was to extend the body of knowledge through a systematic review that combines the strengths and partly fills the gaps from earlier reviews. The aim is to review randomized controlled trials of the long-term effectiveness of physical exercise/activity with or without diet and/or behaviour modification therapy in terms of training effect, weight loss and improvement of body composition in overweight and obese, healthy adults. METHODS: Data for systematic review was collected via a search of databases for literature published between 1995 and 2006. The search yielded 12 articles. RESULTS: The studies showed that training intensity should be moderate. The treatment of overweight and obese individuals with training alone cannot be expected to result in any substantial weight loss but should be combined with diet and behaviour modification therapy. However training can be an important factor in preventing further weight gain, or in helping individuals maintain a lowered body weight. CONCLUSION: According to this systematic review of randomized controlled trials, the treatment that produced the best weight loss results included a combination of training, behaviour therapy and diet.