Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy.

Hypomorphic mutations in the DNA repair enzyme RNase H2 cause the neuroinflammatory autoimmune disorder Aicardi-Goutières syndrome (AGS). Endogenous nucleic acids are believed to accumulate in patient cells and instigate pathogenic type I interferon expression. However, the underlying nucleic acid species amassing in the absence of RNase H2 has not been established yet. Here, we report that murine RNase H2 knockout cells accumulated cytosolic DNA aggregates virtually indistinguishable from micronuclei. RNase H2-dependent micronuclei were surrounded by nuclear lamina and most of them contained damaged DNA. Importantly, they induced expression of interferon-stimulated genes (ISGs) and co-localized with the nucleic acid sensor cGAS. Moreover, micronuclei associated with RNase H2 deficiency were cleared by autophagy. Consequently, induction of autophagy by pharmacological mTOR inhibition resulted in a significant reduction of cytosolic DNA and the accompanied interferon signature. Autophagy induction might therefore represent a viable therapeutic option for RNase H2-dependent disease. Endogenous retroelements have previously been proposed as a source of self-nucleic acids triggering inappropriate activation of the immune system in AGS. We used human RNase H2-knockout cells generated by CRISPR/Cas9 to investigate the impact of RNase H2 on retroelement propagation. Surprisingly, replication of LINE-1 and Alu elements was blunted in cells lacking RNase H2, establishing RNase H2 as essential host factor for the mobilisation of endogenous retrotransposons.

miR-155 Predicts Long-Term Mortality in Critically Ill Patients Younger than 65 Years.

INTRODUCTION: Alterations in miR-155 serum levels have been described in inflammatory and infectious diseases. Moreover, a role for miR-155 in aging and age-related diseases was recently suggested. We therefore analyzed a potential age-dependent prognostic value of circulating miR-155 as a serum-based marker in critical illness. METHODS: Concentrations of circulating miR-155 were determined in 218 critically ill patients and 76 healthy controls. RESULTS: By using qPCR, we demonstrate that miR-155 serum levels are elevated in patients with critical illness when compared to controls. Notably, levels of circulating miR-155 were independent on the severity of disease, the disease etiology, or the presence of sepsis. In the total cohort, miR-155 was not an indicator for patient survival. Intriguingly, when patients were subdivided according to their age upon admission to the ICU into those younger than 65 years, lower levels of miR-155 turned out as a strong marker, indicating patient mortality with a similar accuracy than other markers frequently used to evaluate critically ill patients on a medical ICU. CONCLUSION: In summary, the data provided within this study suggest an age-specific role of miR-155 as a prognostic biomarker in patients younger than 65 years. Our study is the first to describe an age-dependent miRNA-based prognostic biomarker in human diseases.

Activin and TGFß use diverging mitogenic signaling in advanced colon cancer.

BACKGROUND: Understanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFß or activin-induced metastatic phenotype of colon cancer. METHOD: Mitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) -/- or wild type mice. Colon cancer cell lines (+/- SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays. RESULTS: In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFß/MEK/ERK pathway activation. Activin, but not TGFß, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFß increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFß induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling. CONCLUSION: Although activin and TGFß share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFß ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFß family receptors.

A functional methylome map of ulcerative colitis.

The etiology of inflammatory bowel diseases is only partially explained by the current genetic risk map. It is hypothesized that environmental factors modulate the epigenetic landscape and thus contribute to disease susceptibility, manifestation, and progression. To test this, we analyzed DNA methylation (DNAm), a fundamental mechanism of epigenetic long-term modulation of gene expression. We report a three-layer epigenome-wide association study (EWAS) using intestinal biopsies from 10 monozygotic twin pairs (n = 20 individuals) discordant for manifestation of ulcerative colitis (UC). Genome-wide expression scans were generated using Affymetrix UG 133 Plus 2.0 arrays (layer 1). Genome-wide DNAm scans were carried out using Illumina 27k Infinium Bead Arrays to identify methylation variable positions (MVPs, layer 2), and MeDIP-chip on Nimblegen custom 385k Tiling Arrays to identify differentially methylated regions (DMRs, layer 3). Identified MVPs and DMRs were validated in two independent patient populations by quantitative real-time PCR and bisulfite-pyrosequencing (n = 185). The EWAS identified 61 disease-associated loci harboring differential DNAm in cis of a differentially expressed transcript. All constitute novel candidate risk loci for UC not previously identified by GWAS. Among them are several that have been functionally implicated in inflammatory processes, e.g., complement factor CFI, the serine protease inhibitor SPINK4, and the adhesion molecule THY1 (also known as CD90). Our study design excludes nondisease inflammation as a cause of the identified changes in DNAm. This study represents the first replicated EWAS of UC integrated with transcriptional signatures in the affected tissue and demonstrates the power of EWAS to uncover unexplained disease risk and molecular events of disease manifestation.

Trp53 deficiency protects against acute intestinal inflammation.

The p53 protein has not only important tumor suppressor activity but also additional immunological and other functions, whose nature and extent are just beginning to be recognized. In this article, we show that p53 has a novel inflammation-promoting action in the intestinal tract, because loss of p53 or the upstream activating kinase, ATM, protects against acute intestinal inflammation in murine models. Mechanistically, deficiency in p53 leads to increased survival of epithelial cells and lamina propria macrophages, higher IL-6 expression owing to enhanced glucose-dependent NF-κB activation, and increased mucosal STAT3 activation. Blockade or loss of IL-6 signaling reverses the protective effects of p53 deficiency. Conversely, IL-6 treatment protects against acute colitis in a manner dependent on STAT3 signaling and induction of cytoprotective factors in epithelial cells. Together, these results indicate that p53 promotes inflammation in the intestinal tract through suppression of epithelium-protective factors, thus significantly expanding the spectrum of physiological and immunological p53 activities unrelated to cancer formation.

Whole genome and exome sequencing of monozygotic twins discordant for Crohn's disease.

BACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease caused by genetic and environmental factors. More than 160 susceptibility loci have been identified for IBD, yet a large part of the genetic variance remains unexplained. Recent studies have demonstrated genetic differences between monozygotic twins, who were long thought to be genetically completely identical. RESULTS: We aimed to test if somatic mutations play a role in CD etiology by sequencing the genomes and exomes of directly affected tissue from the bowel and blood samples of one and the blood-derived exomes of two further monozygotic discordant twin pairs. Our goal was the identification of mutations present only in the affected twins, pointing to novel candidates for CD susceptibility loci. We present a thorough genetic characterization of the sequenced individuals but detected no consistent differences within the twin pairs. An estimate of the CD susceptibility based on known CD loci however hinted at a higher mutational load in all three twin pairs compared to 1,920 healthy individuals. CONCLUSION: Somatic mosaicism does not seem to play a role in the discordance of monozygotic CD twins. Our study constitutes the first to perform whole genome sequencing for CD twins and therefore provides a valuable reference dataset for future studies. We present an example framework for mosaicism detection and point to the challenges in these types of analyses.

Low extracellular vesicle concentrations predict survival in patients with heart failure.

Background: Heart disease is of worldwide importance due to high morbidity and mortality. Extracellular vesicle (EV) concentration and size represent novel diagnostic and prognostic biomarkers, e.g. in patients with liver cancer, but data on their prognostic relevance in heart disease are lacking. Here, we investigated the role of EV concentration, size and zeta potential in patients with heart disease. Methods: Vesicle size distribution, concentration and zeta potential were measured by nanoparticle tracking analysis (NTA) in 28 intensive care unit (ICU) and 20 standard care (SC) patients and 20 healthy controls. Results: Patients with any disease had a lower zeta potential compared to the healthy controls. Vesicle size (X50) was significantly higher in ICU patients (245 nm) with heart disease as compared to those patients with heart disease receiving standard care (195 nm), or healthy controls (215 nm) (p = 0.001). Notably, EV concentration was lower in ICU patients with heart disease (4.68 × 1010 particles/ml) compared to SC patients with heart disease (7,62 × 1010 particles/ml) and healthy controls (1.50 × 1011 particles/ml) (p = 0.002). Extracellular vesicle concentration is prognostic for overall survival in patients with heart disease. Overall survival is significantly reduced when the vesicle concentration is below 5.55 × 1010 particles/ml. Median overall survival was only 140 days in patients with vesicle concentrations below 5.55 × 1010 particles/ml compared to 211 days in patients with vesicle concentrations above 5.55 × 1010 particles/ml (p = 0.032). Summary: Concentration of EVs is a novel prognostic marker in ICU and SC patients with heart disease.

Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis.

BACKGROUND & AIMS: Interactions between genetic and environmental factors are believed to be involved in onset and initiation of inflammatory bowel disease. We analyzed the interaction between gastrointestinal mucosal microbiota and host genes in twin pairs discordant for ulcerative colitis (UC) to study the functional interaction between microbiota and mucosal epithelium. METHODS: Biopsy were collected from sigmoid colon of UC patients and their healthy twins (discordant twin pairs) and from twins without UC. Microbiota profiles were determined from analysis of 16S ribosomal DNA libraries; messenger RNA profiles were determined by microarray analysis. RESULTS: Patients with UC had dysbiotic microbiota, characterized by less bacterial diversity and more Actinobacteria and Proteobacteria than that of their healthy siblings; healthy siblings from discordant twins had more bacteria from the Lachnospiraceae and Ruminococcaceae families than twins who were both healthy. In twins who were both healthy, 34 mucosal transcripts correlated with bacterial genera, whereas only 25 and 11 correlated with bacteria genera in healthy individuals and their twins with UC, respectively. Transcripts related to oxidative and immune responses were differentially expressed between patients with UC and their healthy twins. CONCLUSIONS: The transcriptional profile of the mucosa appears to interact with the colonic microbiota; this interaction appears to be lost in colon of patients with UC. Bacterial functions, such as butyrate production, might affect mucosal gene expression. Patients with UC had different gene expression profiles and lower levels of biodiversity than their healthy twins, as well as unusual aerobic bacteria. Patients with UC had lower percentages of potentially protective bacterial species than their healthy twins.

Dataset of ileum bacterial diversity in mice after heart failure due to pressure overload.

We recently reported the correlation of gut bacterial diversity with heart failure using a mouse model of heart failure due to pressure overload induced by transverse aortic constriction (TAC). We found that gut the bacterial diversity is significantly altered and is directly correlated to the severity of heart failure (Heart Failure Severity Closely Correlates with Intestinal Dysbiosis and Subsequent Metabolomic Alterations (Spehlmann, 2022). In addition, stool samples that were collected for the gut microbial diversity analysis, we dissected ileum from the mice after 42 days of TAC. The total DNA was extracted to identify the bacterial diversity resided in ileum using 16S rRNA gene amplicon shotgun sequencing and downstream bioinformatics analysis to determine if it is correlated to the heart failure.

Heart Failure Severity Closely Correlates with Intestinal Dysbiosis and Subsequent Metabolomic Alterations.

Growing evidence suggests an altered gut microbiome in patients with heart failure (HF). However, the exact interrelationship between microbiota, HF, and its consequences on the metabolome are still unknown. We thus aimed here to decipher the association between the severity and progression of HF and the gut microbiome composition and circulating metabolites. Using a mouse model of transverse aortic constriction (TAC), gut bacterial diversity was found to be significantly lower in mice as early as day 7 post-TAC compared to Sham controls (p = 0.03), with a gradual progressive decrease in alpha-diversity on days 7, 14, and 42 (p = 0.014, p = 0.0016, p = 0.0021) compared to day 0, which coincided with compensated hypertrophy, maladaptive hypertrophy, and overtly failing hearts, respectively. Strikingly, segregated analysis based on the severity of the cardiac dysfunction (EF < 40% vs. EF 40−55%) manifested marked differences in the abundance and the grouping of several taxa. Multivariate analysis of plasma metabolites and bacterial diversity produced a strong correlation of metabolic alterations, such as reduced short-chain fatty acids and an increase in primary bile acids, with a differential abundance of distinct bacteria in HF. In conclusion, we showed that HF begets HF, likely via a vicious cycle of an altered microbiome and metabolic products.

Coordinate down-regulation of adenylyl cyclase isoforms and the stimulatory G protein (G(s)) in intestinal epithelial cell differentiation.

The intestinal epithelium is dynamic, with proliferation of undifferentiated crypt cells balanced by terminal differentiation and cell death at the colon surface or small intestinal villus tips. Cyclic AMP, induced by agonists such as prostaglandin E(2) and vasoactive intestinal polypeptide, promotes proliferation and ion secretion and suppresses apoptosis in intestinal epithelial cells. Here, we show that cell differentiation in a model intestinal epithelium leads to attenuation of cAMP production in response to G protein-coupled receptor and receptor-independent agonists. Concomitantly, key components of the cAMP cascade, the alpha subunit of the stimulatory G protein, G(s), and adenylyl cyclase (AC) isoforms 3, 4, 6, and 7 are down-regulated. By contrast, AC1, AC2, AC8, and AC9, and the receptors for prostaglandin E(2) and vasoactive intestinal polypeptide, are not expressed or not affected by differentiation. We confirmed key findings in normal murine colon epithelium, in which the major AC isoforms and G(s)alpha are markedly down-regulated in differentiated surface cells. Suppression of AC isoforms and G(s)alpha is functionally important, because their constitutive expression completely reverses differentiation-induced cAMP attenuation. Thus, down-regulation of AC isoforms and G(s)alpha is an integral part of the intestinal epithelial differentiation program, perhaps serving to release cells from cAMP-promoted anti-apoptosis as a prerequisite for cell death upon terminal differentiation.

CXCR2-dependent mucosal neutrophil influx protects against colitis-associated diarrhea caused by an attaching/effacing lesion-forming bacterial pathogen.

Enteropathogenic Escherichia coli (EPEC) is a major cause of diarrheal disease in young children, yet symptoms and duration are highly variable for unknown reasons. Citrobacter rodentium, a murine model pathogen that shares important functional features with EPEC, colonizes mice in colon and cecum and causes inflammation, but typically little or no diarrhea. We conducted genome-wide microarray studies to define mechanisms of host defense and disease in C. rodentium infection. A significant fraction of the genes most highly induced in the colon by infection encoded CXC chemokines, particularly CXCL1/2/5 and CXCL9/10, which are ligands for the chemokine receptors CXCR2 and CXCR3, respectively. CD11b(+) dendritic cells were the major producers of CXCL1, CXCL5, and CXCL9, while CXCL2 was mainly induced in macrophages. Infection of gene-targeted mice revealed that CXCR3 had a significant but modest role in defense against C. rodentium, whereas CXCR2 had a major and indispensable function. CXCR2 was required for normal mucosal influx of neutrophils, which act as direct antibacterial effectors. Moreover, CXCR2 loss led to severe diarrhea and failure to express critical components of normal ion and fluid transport, including ATPase beta(2)-subunit, CFTR, and DRA. The antidiarrheal functions were unique to CXCR2, since other immune defects leading to increased bacterial load and inflammation did not cause diarrhea. Thus, CXCR2-dependent processes, particularly mucosal neutrophil influx, not only contribute to host defense against C. rodentium, but provide protection against infection-associated diarrhea.

Certolizumab pegol in patients with moderate to severe Crohn's disease and secondary failure to infliximab.

BACKGROUND & AIMS: Patients with moderate to severe Crohn's disease who receive infliximab may experience secondary failure (loss of response and/or hypersensitivity). Data on the utility of switching to certolizumab pegol in these patients are limited. METHODS: A total of 539 patients with active Crohn's disease and secondary failure to infliximab were enrolled in a 26-week trial. Patients received open-label induction with subcutaneous certolizumab pegol 400 mg at weeks 0, 2, and 4. Those in clinical response at week 6 were randomized to certolizumab pegol 400 mg every 2 or every 4 weeks through week 24. The primary end point was response at week 6. Secondary end points included remission at week 6 and response and remission at week 26. RESULTS: At week 6, 334 of 539 patients (62.0%) achieved response and 212 of 539 (39.3%) achieved remission. A total of 329 patients were randomized and received maintenance therapy. At week 26, 39.9% (67 of 168) and 36.6% (59 of 161) of patients in the every-4-weeks and every-2-weeks groups were in clinical response, respectively (P = .55). Corresponding remission rates at week 26 were 29.2% and 30.4%, respectively (P = .81). Serious infections occurred in 9 of 539 (1.7%) and 12 of 373 (3.2%) of patients during induction and maintenance, respectively. A single malignancy (skin carcinoma) occurred in a patient receiving every-4-weeks maintenance therapy. CONCLUSIONS: Response to open-label induction therapy with certolizumab pegol was achieved by 62% of patients with moderate to severely active Crohn's disease and secondary failure to infliximab. Among these patients, certolizumab pegol 400 mg every 4 weeks showed similar efficacy to every-2-weeks dosing for maintenance of response and remission.

Identification of Disease-associated Traits and Clonotypes in the T Cell Receptor Repertoire of Monozygotic Twins Affected by Inflammatory Bowel Diseases.

BACKGROUND AND AIMS: Intestinal inflammation in inflammatory bowel diseases [IBD] is thought to be T cell mediated and therefore dependent on the interaction between the T cell receptor [TCR] and human leukocyte antigen [HLA] proteins expressed on antigen presenting cells. The collection of all TCRs in one individual, known as the TCR repertoire, is characterised by enormous diversity and inter-individual variability. It was shown that healthy monozygotic [MZ] twins are more similar in their TCR repertoire than unrelated individuals. Therefore MZ twins, concordant or discordant for IBD, may be useful to identify disease-related and non-genetic factors in the TCR repertoire which could potentially be used as disease biomarkers. METHODS: Employing unique molecular barcoding that can distinguish between polymerase chain reaction [PCR] artefacts and true sequence variation, we performed deep TCRα and TCRß repertoire profiling of the peripheral blood of 28 MZ twin pairs from Denmark and Germany, 24 of whom were discordant and four concordant for IBD. RESULTS: We observed disease- and smoking-associated traits such as sharing, diversity and abundance of specific clonotypes in the TCR repertoire of IBD patients, and particularly in patients with active disease, compared with their healthy twins. CONCLUSIONS: Our findings identified TCR repertoire features specific for smokers and IBD patients, particularly when signs of disease activity were present. These findings are a first step towards the application of TCR repertoire analyses as a valuable tool to characterise inflammatory bowel diseases and to identify potential biomarkers and true disease causes.

Genetic control of global gene expression levels in the intestinal mucosa: a human twin study.

Phenotypic variation between individuals, such as different mRNA expression levels, is influenced by genetic and nongenetic factors. Although several studies have addressed the interplay between genotypes and expression profiles in various model organisms in the recent years, the detailed and relative contributions of genetic and nongenetic factors in regulating plasticity of gene expression in barrier organs (e.g., skin, gut), which are exposed to continuous environmental challenge, are still poorly understood. Here we systematically monitored the level of genetic control over genomewide mRNA expression profiles in the healthy intestinal mucosa of 10 monozygotic and 10 dizygotic human twin pairs with microarray analyses. Our results, which are supported by real-time PCR and analysis of molecular phylogenetic conservation, indicate that genes associated with energy metabolism and cell and tissue regeneration pathways are under strong genetic control. Conversely, genes associated with immune response seem to be mainly controlled by exogenous factors. Further insights into the relative extent of genetic and nongenetic determinants of transcriptomal profiles and their influence on physiological and pathophysiological mechanisms are crucial to understanding the key role played by gene-environment interactions in health and disease.

Nuclear factor-kappa B in intestinal protection and destruction.

PURPOSE OF REVIEW: Nuclear factor-kappa B (NF-kappaB) is a key transcriptional regulator of innate and adaptive immunity. This review highlights new insights into the functions of NF-kappaB in normal homeostasis and specific disease processes in the intestinal tract. RECENT FINDINGS: Inflammatory bowel disease and experimental intestinal inflammation are characterized by NF-kappaB activation and increased expression of proinflammatory NF-kappaB target genes. Accordingly, NF-kappaB inhibition protects against chronic intestinal inflammation and necrotizing enterocolitis in animal models. However, recent findings suggest that NF-kappaB has not only proinflammatory but also tissue-protective functions. Thus, genetic ablation of the regulatory subunit, IkappaB kinase (IKK)gamma, of the central kinase complex required for NF-kappaB activation, IKK, or of both kinase subunits, IKKalpha and IKKbeta, in intestinal epithelial cells causes spontaneous murine colitis. Pharmacological inhibition of IKKbeta, and loss of IKKbeta or NF-kappaB p65 in the epithelium, sensitizes mice to acute inflammatory and injurious challenges. Deficiency in Toll-like receptor 5, a strong activator of NF-kappaB, results in spontaneous colitis and exacerbates mucosal inflammatory responses to Salmonella infection. Conversely, Toll-like receptor 5 stimulation confers radioprotection in the intestine. SUMMARY: NF-kappaB has multiple, often opposing functions in the intestine. Antiapoptotic actions of NF-kappaB in intestinal epithelial cells dominate tissue responses to many acute inflammatory and injurious challenges, whereas proinflammatory and cell survival functions of NF-kappaB in macrophages and T cells govern chronic intestinal inflammation.

Progress in heart failure treatment in Germany.

Acute and chronic heart failure is still a major cause of morbidity and mortality in Europe. Nevertheless, significant progress has been made in diagnosis and treatment of heart failure as well as in unraveling its molecular causes. Here, we focus on some relevant contributions to these achievements by German cardiovascular clinicians and scientists.

Cardio-toxicity of checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have started revolutionizing the treatment of numerous advanced oncological diseases by restoring immune resistance against cancer cells. ICI-associated cardiac adverse effects are rare, but severe. About 50% of cardiac complications comprise myocarditis with variable clinical presentation and a high rate of fatality. The pathomechanism is incompletely understood and may involve preexisting autoimmunity such as autoantibodies or common epitopes shared by cardiomyocytes and tumor cells. Especially patients at risk might be followed up by serial troponin measurements in order to allow an early identification of ICI-associated myocarditis. Therapeutic options are limited and consist of early discontinuation of ICI treatment and initiation of an immunosuppression. Further studies are necessary to elucidate the mechanism, define diagnostic criteria, improve surveillance of patients at risk, and finally refine therapy.

Radial access protects from contrast media induced nephropathy after cardiac catheterization procedures.

OBJECTIVES: To assess, whether cardiac catheterization via radial access prevents contrast-induced nephropathy. BACKGROUND: Contrast-induced nephropathy (CIN) is a major clinical problem which accounts for more than 10% of acute kidney injury cases in hospitalized patients. Protective measures such as the infusion of isotonic saline solution or acetylcysteine have not consistently been proven to prevent acute kidney injury (AKI). However, there is growing evidence that radial access for coronary angiography and coronary intervention is associated with a lower incidence of AKI compared to femoral access. METHODS AND RESULTS: In a retrospective monocentric analysis, 2937 patients that had undergone cardiac catheterization were examined. Up to 2013, coronary intervention was performed primarily via the femoral artery in our hospital; thereafter, interventions were primarily done via the radial artery. In the cohort under study, 1141 patients had received catheterization using the radial access while 1796 were examined via the femoral artery. No significant differences were found in the two groups regarding the amount of iodinated contrast medium applied [femoral group: 180 (120-260) ml; radial group: 180 (120-250) ml; P = 0.438]. A total of 400 (13.6%) patients developed acute kidney injury (AKI) after cardiac catheterization (85.3% AKI stage 1; 12.8% AKI stage 2; 2% AKI stage 3). AKI was significantly less frequent in patients that had received radial access compared to patients with femoral access (10.1 vs. 15.9%, P < 0.001). Multivariate regression analysis showed that patient age (1.03/year; 95% CI 1.02-1.04/year; P < 0.001), the amount of contrast media applied (OR 1.003/ml; 95% CI 1.002-1.004/ml; P < 0.001), acute coronary syndrome (OR 2.01, 95% CI 1.52-2.66; P < 0.001), CKD (OR 1.62, 95% CI 1.50-1.70; P < 0.001), pre-existing heart failure (OR 1.27, 95% CI 1.00-1.42 P = 0.007), previous myocardial infarction (OR 1.34, 95% CI 1.15-1.49; P = 0.001), diabetes (OR 1.25, 95% CI 1.04-1.41; P = 0.020) and serum creatinine before the procedure (1.45/mg/dl; 95% CI 1.24-1.69/mg/dl; P < 0.001) were important risk factors for the occurrence of AKI. Our analysis points to a significant risk reduction using radial access (OR 0.65; 95% CI 0.51-0.83; P < 0.001). Interestingly, this reduction in risk was also evident in patients with CKD (OR 0.59; 95% CI 0.41-0.87; P = 0.007). The superiority of radial access was particularly obvious in the subgroup of patients with acute coronary syndrome (13.1% AKI in the radial access group vs. 23.6% AKI in the femoral access group, OR 0.52; 95% CI 0.34-0.81; P = 0.003). CONCLUSION: Our study shows that cardiac catheterization using radial access bears significantly lower risk of AKI than cardiac catheterization via femoral access. The advantage of radial access in acute coronary syndrome regarding morbidity and mortality could partly be explained by the here demonstrated reduced risk for AKI. Thus, radial access should be preferred in patients at risk for AKI.

Serum levels of kisspeptin are elevated in critically ill patients.

INTRODUCTION: Members of the adipokine family such as resistin, adiponectin and omentin have recently been described as novel biomarkers with a diagnostic and prognostic role in the context of critically ill patients during intensive care unit (ICU) treatment. Kisspeptin represent another member of this family and has been shown to be closely correlated to different members of the adipokine family in manifold diseases. However, its role in critical illness and sepsis is currently unknown. MATERIALS AND METHODS: Kisspeptin serum concentrations were measured in 133 ICU patients admitted to the medical ICU. Results were compared with 36 healthy controls. RESULTS: Kisspeptin serum levels were elevated in the serum of critically ill patients at admission to the ICU, when compared to healthy controls, and remained increased after 72 hours of ICU treatment. Notably, kisspeptin levels were independent of the presence of sepsis and etiology of critical illness. In line, serum concentrations of kisspeptin were not correlated to concentrations of inflammatory cytokines or established sepsis markers. Serum kisspeptin correlated inversely with the glomerular filtration rate. In contrast to the reported role of other members of the adipokine family, serum levels of kisspeptin were neither predictive for short term survival during ICU treatment nor for patients' overall survival. Kisspeptin levels did not correlate with other adipokines measured in serum, including leptin, resistin, ghrelin, or adiponectin. CONCLUSIONS: Although circulating kisspeptin levels were strongly elevated in ICU-patients, elevated kisspeptin levels were not predictive for an impaired patients' survival.