Comparing clinical characteristics of pediatric patients with pancreatic diabetes to patients with type 1 diabetes: A matched case-control study.

BACKGROUND: Only few studies have been conducted on pancreatic diabetes and data from large epidemiological studies are missing. Our main objective was to study the most important differences and similarities between pediatric individuals with pancreatic diabetes and type 1 diabetes (T1D). METHODS: Patients <20 years of age were identified from the diabetes patient follow-up registry (DPV). Data of the most recent treatment year between January 2000 and March 2018 were aggregated. Propensity score was used to match individuals with pancreatic diabetes to individuals with T1D. Matching was conducted one-to-one by sex, age, diabetes duration, body mass index SD score (BMI-SDS), and migration background. RESULTS: We studied 731 individuals with pancreatic diabetes and 74 460 with T1D. In the matched cohort of 631 pairs, HbA1c was significantly lower in pancreatic diabetes (7.4% [95% confidence interval: 7.2; 7.5%]) compared to T1D patients (8.7% [8.5; 8.8%]). Daily insulin dose (0.80 IU/kg [0.77; 0.84] vs 0.86 IU/kg [0.82; 0.90]) and insulin pump use (13.3% [10.7; 16.4] vs 22.1% [19.0; 25.6%]) were lower in patients with pancreatic diabetes. However, event rates of severe hypoglycemia were similar between pancreatic and T1D patients (8.8 [5.4; 14.2] vs 9.6 [5.9; 15.6] events per 100 patient years). CONCLUSIONS: With the use of robust epidemiological data, our study improves the knowledge on clinical characteristics in pediatric individuals with pancreatic diabetes. Moreover, our results serve as a basis to reconsider treatment options and for discussing clinical practice guidelines for patients with this rare medical condition.

Metabolic Endoscopy: Development and Perspectives.

BACKGROUND: Obesity and its metabolic sequelae are among the most serious challenges faced by health systems today and they are expected to pose a serious threat in the future as well. Therapy ranges from lifestyle modification to drug treatment to surgery. Metabolic endoscopy (ME) might close the gap between invasive "metabolic" surgery and conservative, less effective treatment. In recent years, several endoscopic approaches have emerged, promising a safe and effective approach to cope with obesity. Data on metabolic endpoints is scarce. This article will therefore highlight procedures with data on type 2 diabetes mellitus (T2DM) as the most prominent component of the metabolic syndrome. SUMMARY: Most procedures showed beneficial effects in terms of weight reduction. For gastric procedures, there were no systematic studies primarily addressing parameters of glucose metabolism or diabetes outcomes. Metabolic benefit, if there is any, is most likely a by-product of weight loss. By contrast, duodenal-jejunal bypass sleeve (DJBS) is conceptually an antidiabetic procedure. Although adverse events are frequent, recent data points to a positive benefit-risk ratio. Key Messages: ME has the potential to constitute a growing field in the treatment of obesity and associated T2DM. While data published on glycaemic parameters in restrictive approaches is not sufficient, there is strong evidence that malabsorptive DJBS has an antidiabetic "plus" effect. Further studies are necessary to define the role of ME within a lifelong concept of treating obesity and T2DM.

Regional differences in type 2 diabetes treatment and outcomes in Germany-An analysis of the German DPV and DIVE registries.

AIMS: On the basis of the Diabetes Versorgungs-Evaluation (DIVE) and Diabetes-Patienten-Verlaufsdokumentation (DPV) datasets, we aimed to explore the impact of differences in treatment modalities on outcomes in Germany and put these into a global context. METHODS: The 2014 to 2016 DIVE and DPV databases were combined, and a total of 127 838 patients 18 years and older was analysed with respect to demographics, cardiovascular risk factors, comorbidities, treatments, and outcomes, separately for each German state. Estimates were expressed as adjusted least squares means together with 95% confidence intervals. RESULTS: Saarland dataset recorded the lowest mean HbA1c (6.7%; 6.6%-6.8%; 50 mmol/mol, 49-51 mmol/mol), Saxony-Anhalt showed the highest (8.3%; 8.2%-8.3%; 67 mmol/mol, 66-67 mmol/mol). The highest percentage of hypoglycaemic events was reported in Mecklenburg-West Pomerania (MWP) (4.7%; 3.9%-5.7%), the lowest in Thuringia (0.9%; 0.2%-3.4%). Metformin and sulfonylurea accounted for 36.4% to 53.3% of anti-diabetic treatments across states; other antihyperglycaemic drugs such as DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 analogues were used most often in MWP (40.0%; 37.8%-42.1%) and least in Rhineland-Palatinate (13.6%; 13.0%-14.2%). Treatment with insulin (alone or in combination) was reported most often in MWP (78.2%; 76.4%-80.0%) and least in Thuringia (26.0%; 20.1%-32.9%). CONCLUSIONS: Federal states in Germany are heterogeneous concerning diabetes treatment and associated outcomes. These data should stimulate further discussion about how optimal diabetes care can be implemented in all areas of Germany, to achieve good treatment outcomes in all federal states.

A TNF-regulated recombinatorial macrophage immune receptor implicated in granuloma formation in tuberculosis.

Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) αß based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCRαß induces the release of CCL2 and modulates phagocytosis. TNF blockade suppresses macrophage-TCRαß expression. Infection of macrophages from healthy individuals with mycobacteria triggers formation of clusters that express restricted TCR Vß repertoires. In vivo, TCRαß bearing macrophages abundantly accumulate at the inner host-pathogen contact zone of caseous granulomas from patients with lung tuberculosis. In chimeric mouse models, deletion of the variable macrophage-TCRαß or TNF is associated with structurally compromised granulomas of pulmonary tuberculosis even in the presence of intact T cells. These results uncover a TNF-regulated recombinatorial immune receptor in monocytes/macrophages and demonstrate its implication in granuloma formation in tuberculosis.

Correlates of Food Addiction and Eating Behaviours in Patients with Morbid Obesity.

INTRODUCTION: Food addiction (FA) is a promising construct regarding the multifactorial aetiology of obesity and the search for therapeutic approaches. However, there is an ongoing debate regarding the overlap/differentiation with eating disorders and the classification as a substance- or behaviour-related addiction. Energy-dense foods, especially those combining carbohydrates and fat, are associated with addictive eating and suspected of playing a role in the genesis of FA. This study aims to further understand the clinical significance of FA and to identify possible therapeutic targets. A special focus is set on potentially addictive foods (combination of carbohydrates and fat). METHODS: Based on the Yale Food Addiction Scale 2.0, a cohort of 112 German adults with morbid obesity was divided into two sub-samples (patients with and without FA), which were examined for differences in the variables listed below. RESULTS: The prevalence of FA was 25%. Patients meeting criteria for FA showed higher degrees of hunger, emotional, binge, and night eating than patients without FA. In addition, hunger and disinhibition were found to be significant predictors of FA. FA was not associated with sex, age, body mass index (BMI), cognitive restraint, rigid and flexible control, prevalence of substance use, age of onset of obesity, stress level, level of social support, reduction of BMI during a weight loss programme, or programme withdrawal rate. There was no significant difference in the consumption of foods rich in both carbohydrates and fat, nor of fat or carbohydrates alone. CONCLUSION: FA can be considered as a sub-phenotype of obesity, occurring in approximately 25% of obesity cases. Dysfunctional emotional coping mechanisms associated with low distress tolerance showed to be significantly related to FA and should be targeted therapeutically. Behavioural interventions should include a bio-psycho-social model. Binge eating episodes were found to be characteristic for FA and the already stated overlap between FA and binge eating behaviour can be confirmed. The results do not support a decisive difference due to a substance-related component of FA. Despite this, the existence of FA as a distinct entity cannot be excluded, as not all patients with FA exhibit binges.

Free-Breathing Liver Fat, R2* and B0 Field Mapping Using Multi-Echo Radial FLASH and Regularized Model-Based Reconstruction.

This work introduced a stack-of-radial multi-echo asymmetric-echo MRI sequence for free-breathing liver volumetric acquisition. Regularized model-based reconstruction was implemented in Berkeley Advanced Reconstruction Toolbox (BART) to jointly estimate all physical parameter maps (water, fat, R2∗ , and B0 field inhomogeneity maps) and coil sensitivity maps from self-gated k -space data. Specifically, locally low rank and temporal total variation regularization were employed directly on physical parameter maps. The proposed free-breathing radial technique was tested on a water/fat & iron phantom, a young volunteer, and obesity/diabetes/hepatic steatosis patients. Quantitative fat fraction and R2∗ accuracy were confirmed by comparing our technique with the reference breath-hold Cartesian scan. The multi-echo radial sampling sequence achieves fast k -space coverage and is robust to motion. Moreover, the proposed motion-resolved model-based reconstruction allows for free-breathing liver fat and R2∗ quantification in multiple motion states. Overall, our proposed technique offers a convenient tool for non-invasive liver assessment with no breath holding requirement.

The anti-TNF-α antibody infliximab indirectly regulates PECAM-1 gene expression in two models of in vitro blood cell activation.

Chronic inflammatory bowel diseases can be successfully treated with antibodies against the acute phase mediator TNF-α. The process of activation and of extravasation of inflammatory cells from the blood into the 'stressed' tissue site is controlled by cytokines and chemokines, which attract leukocytes and by adhesion molecules, which mediate their attachment and transmigration toward the affected cell(s). The changes in the gene expression of adhesion molecules taking place in those cells before attachment have been less investigated. Changes of PECAM-1, ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) gene expression were studied in phytohaemagglutinin (PHA)- and lipolysaccharide (LPS)-treated human peripheral blood leukocytes (PBLs), granulocytes and the human monocyte cell line U-937. Cells were treated either with PHA or with LPS in the presence or absence of infliximab and incubated with TNF-α, IFN-γ and/or transforming growth factor beta (TGF-ß) and treated as above. Activation of PBLs by PHA or LPS treatment triggered a sharp upregulation of ICAM-1, VCAM-1 gene expression and a time-dependent downregulation of PECAM-1 gene expression reaching a minimum 4 h from start of the experiment. The anti-TNF-α antibody infliximab, by neutralizing TNF-α and IFN-γ production, completely reversed PECAM-1 mRNA downregulation and ICAM-1 and VCAM-1 upregulation. Immunostaining of PBLs cytospins with antibodies against PECAM-1 and ICAM-1 confirmed RT-PCR and western blot results. PBLs IFN-γ or TNF-α treatment downregulated PECAM-1 in parallel with the upregulation of ICAM-1 and VCAM-1 gene expression, whereas TGF-ß upregulated PECAM-1- and downregulated ICAM-1 and VCAM-1 gene expression counteracting the effect of TNF-α or IFN-γ. Similar results were obtained in human U937 cells and in granulocyte cultures by TNF-α or IFN-γ treatment. Taken together, these results suggest that infliximab, blocking TNF-α and IFN-γ production, exerts its anti-inflammatory effect through inhibiting downregulation of PECAM-1 gene expression and upregulation of ICAM-1 and VCAM-1 expression in leukocytes of the peripheral blood. These results also suggest that TGF-ß may thus be of therapeutic importance as an anti-inflammatory agent.

Melanocortin receptors in rat liver cells: change of gene expression and intracellular localization during acute-phase response.

MCRs are known to be expressed predominantly in the brain where they mediate metabolic and anti-inflammatory functions. Leptin plays an important role in appetite and energy regulation via signaling through melanocortin receptors (MCRs) in the brain. As serum levels of MCR ligands are elevated in a clinical situation [acute-phase response (APR)] to tissue damage, where the liver is responsible for the metabolic changes, we studied hepatic gene expression of MCRs in a model of muscle tissue damage induced by turpentine oil (TO) injection in rats. A significant increase in gene expression of all five MCRs (MC4R was the highest) in liver at the RNA and protein level was detected after TO injection. A similar pattern of increase was also found in the brain. Immunohistology showed MC4R in the cytoplasm, but also in the nucleus of parenchymal and non-parenchymal liver cells, whereas MC3R-positivity was mainly cytoplasmic. A time-dependent migration of MC4R protein from the cytoplasm into the nucleus was observed during APR, in parallel with an increase in α-MSH and leptin serum levels. An increase of MC4R was detected at the protein level in wild-type mice, while such an increase was not observed in IL-6ko mice during APR. Moreover, treatment of isolated liver cells with melanocortin agonists (α-MSH and THIQ) inhibited the endotoxin-induced upregulation of the acute-phase cytokine (IL-6, IL1ß and TNF-α) gene expression in Kupffer cells and of chemokine gene expression in hepatocytes. MCRs are expressed not only in the brain, but also in liver cells and their gene expression in liver and brain tissue is upregulated during APR. Due to the presence of specific ligands in the serum, they may mediate metabolic changes and exert a protective effect on liver cells.

Influence of food images with different macronutrient compositions on serum ghrelin levels: Analysis in healthy males.

Objective: Serum concentrations of the orexigenic hormone ghrelin fluctuate in anticipation of food intake. Moreover, presentation of food images causes an increase in serum ghrelin levels. Thus, the visual system may have a quantifiable role in the development of hunger via the endocrine system. The influence of macronutrient visualization on ghrelin has not yet been investigated. Methods: In four separate sessions, ghrelin concentrations, insulin, and glucose levels were compared before and after the presentation of different pictures to 14 male participants. Pictures included neutral, non-food-related items or isocaloric dishes whose macronutrient composition corresponded predominately to protein/fat, simple carbohydrates, or complex carbohydrates. Results: While pre/post ghrelin concentrations numerically increased in all sessions, significant increases were only observed following neutral and protein/fat pictures. The differences were not significant between food groups and compared to neutral images. Insulin levels decreased in all groups, but no significant differences were observed between sessions. The glucose concentrations were within the euglycemic range. Conclusion: The results did not reproduce the induction of ghrelin secretion in different food images. Therefore, it is unclear whether the visual perception of food influences ghrelin secretion or whether separation into macronutrients changes the hormone response. Further research is required to differentiate the interactions of sensory-specific satiety.

Influence of the Size of the Foveal Avascular Zone on Functional and Morphological Parameters in Patients with Early-Stage Diabetic Retinopathy.

Purpose: To correlate functional and morphological parameters with foveal avascular zone's (FAZ) size in diabetic patients with mild to moderate stage nonproliferative diabetic retinopathy. Methods: Monocentric and prospective study of a consecutive case series of diabetic patients. Medical history, best corrected visual acuity (BCVA), best corrected high/low contrast visual acuity (BChcVA/BClcVA), mean sensitivity (MS) and mean defect (MD) in central visual field testing, and FAZ size in fluorescein-angiography (FAG) were recorded. Macular thickness (central point thickness CPT, central subfield thickness CST) and volume measurements (central subfield volume CSV, total macular volume) were taken from SD-OCT (6x6mm ETDRS-grid). Groups were categorised as presenting FAZ sizes smaller (G1) or larger (G2) than 0.35mm2. Smallest (Q1) and largest quartiles (Q3) were also compared. Results: Thirty-six of 40 patients were included. MS differed significantly between G1 (n = 6) and G2 (n = 30), and BChcVA/BClcVA as well as TMV correlated significantly with FAZ size in correlation analysis. Mean HbA1c tended to be lower in G1 than G2. Patients in G1 were slightly older than in G2. Treatment period with insulin was shorter in G1/Q1 than in G2/Q3. CPT and TMV were lower in G1/Q1 than in G2/Q3. Our analysis of the FAZ in terms of patient age, HbA1c, disease duration and insulin therapy duration revealed no significance. That lack of significance also applies to BCVA, MS, MD, CPT, CST and CSV. Conclusion: As significantly associated, contrast sensitivity, central visual field parameters and potentially retinal thickness or volume seem to be suitable to detect early macular ischaemia. However, we failed to establish any correlation between FAZ and BCVA.

Comorbidities in Recent-Onset Adult Type 1 Diabetes: A Comparison of German Cohorts.

Aims: Restrictive exclusion criteria from different study populations may limit the generalizability of the observations. By comparing two differently designed German cohorts, we assessed the prevalence of cardiovascular risk factors and diabetes-related complications in recent-onset adult type 1 diabetes. Methods: This study evaluated 1511 persons with type 1 diabetes of the prospective diabetes follow-up registry (DPV) and 268 volunteers of the prospective observational German Diabetes Study (GDS) with a known diabetes duration <1 year. Participants had similar age (36 years), sex distribution (41% female) and BMI (26 kg/m2) in both cohorts. Results: The average HbA1c was 6.4 ± 0.8% in the GDS and 7.0 ± 1.1% in the DPV. Prevalence of hypertension (24%) was similar, while more DPV participants had dyslipidemia and lipid-lowering medication than GDS participants (77% vs. 41% and 7% vs. 2%, respectively; p<0.05). Prevalence of retinopathy and nephropathy was higher in DPV compared to GDS participants (10% vs. 3% and 18% vs. 7%, respectively; p<0.001). Conclusions: Diabetic nephropathy and retinopathy are the most frequent complications in type 1 diabetes, affecting up to every 10th patient within the first year after diagnosis, underlining the need for more stringent risk factor management already at the time of diagnosis of type 1 diabetes.

Endoscopic intragastric balloon: a gimmick or a viable option for obesity?

Worldwide, the prevalence of obesity has doubled since 1980 in 70 countries. More than one in three adults now suffer from overweight or obesity. Health problems related to obesity include orthopedic problems, psychiatric conditions, metabolic and cardiovascular diseases, and of increasing concern, cancer. Thus, obesity has an enormous impact on the individual's wellbeing as well as on society's workforce and health care expenses. Medical efforts are ongoing to find safe and effective treatment options for obesity and its metabolic implications. At present, available treatment options include lifestyle interventions, pharmacotherapy, endoscopic applications, and bariatric surgery. Within the range of endoscopic treatment options, the intragastric balloon is the most widely used device. The idea is simple: the gastric volume is reduced by a balloon that is in most cases implanted by an endoscopic procedure similar to a gastroscopy. During the past decades, different models have been developed, which we will briefly introduce in this review. We aim at reviewing the pathophysiology underlying the effect of endoscopic intragastric balloon on weight loss and metabolic changes. We will assess expected short-term and long-term benefits for the patient, and we will discuss common side effects as well as rare complications. We will compare endoscopic intragastric balloon to conservative treatment options with or without pharmacological support on the one hand and to the spectrum of bariatric surgery on the other hand. In most patients, obesity must be considered a chronic disease that requires a lifelong treatment concept. In view of current treatment options for obesity, we will discuss whether endoscopic intragastric balloon is a viable treatment option, and who may be the right patient to benefit from it.

Noninvasive assessment of liver fibrosis in a real-world cohort of patients with known or suspected chronic liver disease using 2D-shear wave elastography.

OBJECTIVES: We aimed to investigate the diagnostic accuracy of liver stiffness measurement (LSM) by 2D-shear wave elastography (2D-SWE, GE, Logiq E9) in patients with known or suspected chronic liver disease and to define cutoff values for the different stages of fibrosis. METHODS: First, we retrospectively enrolled 21 patients in a pilot study and validated the results in a prospective cohort of 70 patients between May 2017 and February 2019. In all patients, LSM and liver biopsy were performed. We analyzed the diagnostic accuracy of LSM for the different fibrosis stages and examined the impact of additional clinical parameters on LSM. RESULTS: The success rate of LSM was 88.6%. In the prospective cohort, optimal cutoff values for F ≥ 1, F ≥ 2, F ≥ 3 and F = 4 were 6.24, 7.86, 8.05 and 10.74 kPa [area under the receiver operating characteristic curve (AUROC) 0.831, 0.913, 0.996 and 0.954]. In both cohorts and in the subgroup of patients with nonalcoholic fatty liver disease (NAFLD) (n = 35), a cutoff value of 8.05 kPa differentiates patients with advanced fibrosis (F ≥ 3) and patients with no or mild fibrosis (F0-F2) with high diagnostic accuracy (AUROC 0.995-1.000). Parameters such as age, sex, BMI, bilirubin- and alanine aminotransferase-level had no significant impact on LSM. CONCLUSION: LSM by 2D-SWE is an excellent method to differentiate between patients with advanced fibrosis (F ≥ 3) and patients with no or mild fibrosis (F ≤ 2). We were able to show this also in a subgroup of patients with NAFLD.

The DIVE/DPV registries: evolution of empagliflozin use in clinical practice in Germany.

INTRODUCTION: Empagliflozin reduced morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) in clinical trials. A registry study was undertaken to describe evolution of patient characteristics and assess the real-world effectiveness/safety of empagliflozin. RESEARCH DESIGN AND METHODS: Data from the Diabetes Patienten Verlaufsdokumentation (DPV)/Diabetes Versorgungsevaluation (DIVE) registries on 9571 adults with T2DM (registered in 2014-2019) receiving empagliflozin were used. Patients were grouped according to the following: early users (group 1; n=505) received empagliflozin before the EMPA-REG OUTCOME study publication (mid-September 2015); intermediate users (group 2; n=2961) started empagliflozin after the EMPA-REG OUTCOME publication but before the European Medicines Agency label change (from mid-September 2015 to mid-January 2017); and late users (group 3; n=6105) started empagliflozin after mid-January 2017. Data on clinical and treatment characteristics were collected. RESULTS: Over time, the proportion of recipients aged <65 years decreased (71.1% vs 54.4% among early and late adopters), male patients increased (from 50.9% to 66.5%), body mass index (mean±SD) decreased (from 35.5±6.7 to 32.7±6.6 kg/m2), proportion with cardiovascular morbidities increased (from 20.4% to 26.4%), and mean estimated glomerular filtration rate decreased (from 83.2±19.5 to 78.5±21.1 mL/min/1.73 m2) (all p<0.001). Patients increasingly received empagliflozin in combination with metformin (60.8% vs 68.6% of early and late adopters; p<0.001), glucagon-like peptide-1 (GLP-1) agonists (11.0 vs 14.1%; p<0.001) or insulin (34.3% vs 49.9%; p<0.001). Empagliflozin was generally added to existing antidiabetic regimens. Six months after empagliflozin initiation, the mean glycated hemoglobin (HbA1c) decreased by 0.4%, the proportion of patients with HbA1c <6.5% increased (19.2% vs 12.8%), and the mean fasting plasma glucose decreased (155.8±49.7 vs 168.0±55.1 mg/dL) (all p<0.001). No significant changes in rates of severe hypoglycemia and no cases of diabetic ketoacidosis were seen. CONCLUSIONS: Over time, empagliflozin is being prescribed to a broader patient range in routine practice, is usually added to existing antidiabetic regimens, and is increasingly used in combination with metformin, GLP-1 agonists and/or insulin. Empagliflozin had a beneficial effect on glycemic control, with no increase in hypoglycemia.

Urine E-cadherin: A Marker for Early Detection of Kidney Injury in Diabetic Patients.

Diabetic nephropathy (DN) is the main reason for end-stage renal disease. Microalbuminuria as the non-invasive available diagnosis marker lacks specificity and gives high false positive rates. To identify and validate biomarkers for DN, we used in the present study urine samples from four patient groups: diabetes without nephropathy, diabetes with microalbuminuria, diabetes with macroalbuminuria and proteinuria without diabetes. For the longitudinal validation, we recruited 563 diabetic patients and collected 1363 urine samples with the clinical data during a follow-up of 6 years. Comparative urinary proteomics identified four proteins Apolipoprotein A-I (APOA1), Beta-2-microglobulin (B2M), E-cadherin (CDH1) and Lithostathine-1-alpha (REG1A), which differentiated with high statistical strength (p < 0.05) between DN patients and the other groups. Label-free mass spectrometric quantification of the candidates confirmed the discriminatory value of E-cadherin and Lithostathine-1-alpha (p < 0.05). Immunological validation highlighted E-cadherin as the only marker able to differentiate significantly between the different DN stages with an area under the curve (AUC) of 0.85 (95%-CI: [0.72, 0.97]). The analysis of the samples from the longitudinal study confirmed the prognostic value of E-cadherin, the critical increase in urinary E-cadherin level was measured 20 ± 12.5 months before the onset of microalbuminuria and correlated significantly (p < 0.05) with the glomerular filtration rate measured by estimated glomerular filtration rate (eGFR).

Favorable 90-Day Mortality in Obese Caucasian Patients with Septic Shock According to the Sepsis-3 Definition.

Septic shock is a frequent life-threatening condition and a leading cause of mortality in intensive care units (ICUs). Previous investigations have reported a potentially protective effect of obesity in septic shock patients. However, prior results have been inconsistent, focused on short-term in-hospital mortality and inadequately adjusted for confounders, and they have rarely applied the currently valid Sepsis-3 definition criteria for septic shock. This investigation examined the effect of obesity on 90-day mortality in patients with septic shock selected from a prospectively enrolled cohort of septic patients. A total of 352 patients who met the Sepsis-3 criteria for septic shock were enrolled in this study. Body-mass index (BMI) was used to divide the cohort into 24% obese (BMI ≥ 30 kg/m2) and 76% non-obese (BMI < 30 kg/m2) patients. Kaplan-Meier survival analysis revealed a significantly lower 90-day mortality (31% vs. 43%; p = 0.0436) in obese patients compared to non-obese patients. Additional analyses of baseline characteristics, disease severity, and microbiological findings outlined further statistically significant differences among the groups. Multivariate Cox regression analysis estimated a significant protective effect of obesity on 90-day mortality after adjustment for confounders. An understanding of the underlying physiologic mechanisms may improve therapeutic strategies and patient prognosis.

Negative inotropy of the gastric proton pump inhibitor pantoprazole in myocardium from humans and rabbits: evaluation of mechanisms.

BACKGROUND: Proton pump inhibitors are used extensively for acid-related gastrointestinal diseases. Their effect on cardiac contractility has not been assessed directly. METHODS AND RESULTS: Under physiological conditions (37 degrees C, pH 7.35, 1.25 mmol/L Ca2+), there was a dose-dependent decrease in contractile force in ventricular trabeculae isolated from end-stage failing human hearts superfused with pantoprazole. The concentration leading to 50% maximal response was 17.3+/-1.3 microg/mL. Similar observations were made in trabeculae from human atria, normal rabbit ventricles, and isolated rabbit ventricular myocytes. Real-time polymerase chain reaction demonstrated the expression of gastric H+/K+-adenosine triphosphatase in human and rabbit myocardium. However, measurements with BCECF-loaded rabbit trabeculae did not reveal any significant pantoprazole-dependent changes of pH(i). Ca2+ transients recorded from field-stimulated fluo 3-loaded myocytes (F/F0) were significantly depressed by 10.4+/-2.1% at 40 microg/mL. Intracellular Ca2+ fluxes were assessed in fura 2-loaded, voltage-clamped rabbit ventricular myocytes. Pantoprazole (40 microg/mL) caused an increase in diastolic [Ca2+]i by 33+/-12%, but peak systolic [Ca2+]i was unchanged, resulting in a decreased Ca2+ transient amplitude by 25+/-8%. The amplitude of the L-type Ca2+ current (I(Ca,L)) was reduced by 35+/-5%, and sarcoplasmic reticulum Ca2+ content was reduced by 18+/-6%. Measurements of oxalate-supported sarcoplasmic reticulum Ca2+ uptake in permeabilized cardiomyocytes indicated that pantoprazole decreased Ca2+ sensitivity (Kd) of sarcoplasmic reticulum Ca2+ adenosine triphosphatase: control, Kd=358+/-15 nmol/L; 40 microg/mL pantoprazole, Kd=395+/-12 nmol/L (P<0.05). Pantoprazole also acted on cardiac myofilaments to reduced Ca2+-activated force. CONCLUSIONS: Pantoprazole depresses cardiac contractility in vitro by depression of Ca2+ signaling and myofilament activity. In view of the extensive use of this agent, the effects should be evaluated in vivo.

Effect of radiation on gene expression of rat liver chemokines: in vivo and in vitro studies.

The aim of the study was to analyze the effect of a single irradiation on chemokine gene expression in the rat liver and in isolated rat hepatocytes. RNA extracted from livers and from hepatocytes within the first 48 h after irradiation was analyzed by real-time PCR and the Northern blot assay. The chemokine concentrations in the serum of irradiated rats were measured quantitatively by ELISA. A significant radiation-induced increase of CINC1, IP10, MCP1, MIP3alpha, MIP3beta, MIG and ITAC gene expression could be detected at the RNA level in the liver. CINC1, MCP1 and IP10 serum levels were significantly increased. In rat hepatocytes in vitro, only MIP3alpha showed a radiation-induced increase in expression, while CINC1, IP10, MIP3beta, MIG, MIP1alpha, ITAC and SDF1 RNA levels were significantly down-regulated. However, incubation of irradiated hepatocytes in vitro with either TNF-alpha, IL1beta, or IL6 plus TNF-alpha led to up-regulation of MCP1, IP10 and MCP1 or CINC1 and MIP3beta, respectively. Irradiation of the liver induces up-regulation of the genes of the main proinflammatory chemokines, probably through the action of locally synthesized proinflammatory cytokines. The reason for the lack of liver inflammation in this model has still to be clarified.

Isopropanolic extract of black cohosh stimulates osteoprotegerin production by human osteoblasts.

UNLABELLED: An isopropanolic extract (iCR) from the rhizomes of Cimicifuga racemosa (black cohosh) is used an alternative in the treatment of menopausal symptoms, and animal studies suggest positive skeletal effects. iCR stimulated osteoblastic OPG protein secretion by 3- to 5-fold as early as 12 h without affecting RANKL expression. The iCR effect, abrogated by the pure estrogen receptor antagonist ICI 182,780, also enhanced ALP activity (4-fold) and osteocalcin expression (3-fold), possibly contributing to the skeletal effects of black cohosh. INTRODUCTION: Despite its positive effects on the skeleton, estrogen replacement therapy is no longer recommended as first-line therapy for the prevention and treatment of postmenopausal osteoporosis because it increases cardiovascular, thromboembolic, and breast cancer risk. Recently, herbal therapeutics such as an isopropanolic extract (iCR) from the rhizomes of Cimicifuga (=Actaea) racemosa (black cohosh) are gaining interest as an alternative in the treatment of menopausal symptoms. Whereas animal studies in rats suggest positive skeletal effects, the mechanism of its actions on bone cells remain unclear. RANKL is essential for osteoclast formation and activation, while osteoprotegerin (OPG) neutralizes RANKL. MATERIALS AND METHODS: In this study, we assessed the effects of iCR on OPG and RANKL mRNA steady-state levels by semiquantitative RT-PCR and on protein production by an ELISA system in human osteoblasts (hOBs). RESULTS: Under serum-free conditions, treatment with iCR increased OPG mRNA levels and protein secretion of hOBs by 2- to 3-fold in a dose-dependent manner, with a maximum effect at a 10(6)-fold dilution of iCR (p < 0.001) after 24-48 h. Time-course experiments indicated a stimulatory effect of iCR on osteoblastic OPG protein secretion by 3- to 5-fold (p < 0.001) as early as 12 h, whereas RANKL expression was very low and was not found to be modulated by iCR. Of note, the stimulatory effect of iCR on OPG production was abrogated by the pure estrogen receptor antagonist ICI 182,780. Moreover, iCR enhanced two osteoblastic differentiation markers, bone-specific alkaline phosphatase activity and osteocalcin expression, by up to 4- and 3-fold, respectively (p < 0.001). CONCLUSIONS: Our data suggest that iCR enhances differentiation and increases the OPG-to-RANKL ratio of normal human osteoblasts. These effects may contribute to the positive skeletal effects of black cohosh.

Quantitative measurement of cytokine mRNA in inflammatory bowel disease: relation to clinical and endoscopic activity and outcome.

OBJECTIVE: The objective of this study was to quantitatively determine cytokine mRNA expression in inflammatory bowel disease under different clinical conditions including active disease, remission or an impaired response to a glucocorticoid (GC) therapy. METHODS: Mucosal biopsies were taken from 33 patients with ulcerative colitis (UC), 21 patients with Crohn's disease (CD) and 11 controls. Peripheral blood mononuclear cells (PBMNC) were isolated from 24 CU patients, 18 CD patients and 11 controls. Cytokine-mRNA [interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha)] expression was measured by quantitative reverse transcriptase-polymerase chain reaction in biopsies and PBMNC, and correlated to endoscopic findings, clinical activity and outcome after 6 months GC therapy. RESULTS: IL-1beta, IL-6 and TNF-alpha were the largely dominating cytokines. In contrast to IL-1beta and TNF-alpha-, IL-6 expression was restricted to inflamed mucosa and correlated with the clinical activity and C-reactive protein levels in cases of pancolitis ulcerosa. TNF-alpha was elevated in CD even in endoscopic normal tissue. IL-2 and IFN-gamma were downregulated in PBMNC from CD and UC. No Th1 or Th2 specificity could be detected. Cytokine mRNA levels did not correlate with the response to a GC therapy. CONCLUSION: IL-6 sharply distinguishes between inflamed and non-inflamed mucosa, and is therefore a suitable marker of intestinal inflammation. Its selective expression in the inflammatory site makes it an interesting target for future therapeutic strategies. TNF-alpha overexpression even in remission suggests a key role of this cytokine in CD pathogenesis and is possibly a feature that allows one to differentiate CD from UC.