Background Cardiovascular disease (CVD) represents the leading cause of death worldwide. The identification of individuals at increased risk of CVD is essential to reduce its morbidity and mortality ...globally. Based on existing data on a potential association between the individual body height and the risk for CVD, we investigated this association in a large cohort of outpatients in Germany. Methods A total of 657,310 adult outpatients with available body height data from the Disease Analyzer (IQVIA) database were included in Germany between 2019 and 2021. The prevalence of common CVD diagnoses (hypertension, coronary heart disease, atrial fibrillation and flutter, heart failure, ischemic stroke, and venous thromboembolism) was evaluated as a function of the patients' body height stratified by age and sex. Results In both sexes, the prevalence of hypertension, coronary heart disease, heart failure, and ischemic stroke was higher among patients of smaller body height. In contrast, the prevalence of atrial fibrillation and venous thromboembolism was higher in taller patients. In age- and BMI-adjusted logistic regression analyses, an increased body height was negatively associated with coronary heart disease (OR = 0.91 in women and OR = 0.87 in men per 10-cm increase in height) and strongly positively associated with atrial fibrillation (OR = 1.25 in women and men) and venous thromboembolism (OR = 1.23 in women and OR = 1.24 in men). Conclusion We present the first data from a large cohort of outpatients in Germany providing strong evidence for an association between the body height and common CVD. These data should stimulate a discussion as to how far the body height should be implemented as a parameter in stratification tools to assess CVD risk in order to further reduce cardiovascular morbidity and mortality in the future. Keywords: Arterial hypertension, Atrial fibrillation, Myocardial infarction, Cardiovascular disease, Prevention
Liver fibrosis is defined as excessive extracellular matrix deposition and is based on complex interactions between matrix-producing hepatic stellate cells and an abundance of liver-resident and ...infiltrating cells. Investigation of these processes requires in vitro and in vivo experimental work in animals. However, the use of animals in translational research will be increasingly challenged, at least in countries of the European Union, because of the adoption of new animal welfare rules in 2013. These rules will create an urgent need for optimized standard operating procedures regarding animal experimentation and improved international communication in the liver fibrosis community. This review gives an update on current animal models, techniques and underlying pathomechanisms with the aim of fostering a critical discussion of the limitations and potential of up-to-date animal experimentation. We discuss potential complications in experimental liver fibrosis and provide examples of how the findings of studies in which these models are used can be translated to human disease and therapy. In this review, we want to motivate the international community to design more standardized animal models which might help to address the legally requested replacement, refinement and reduction of animals in fibrosis research.
Although pancreatic cancer is only the twelfth most common type of cancer in the world, it features a very unfavorable prognosis. The mortality rate almost equals the incidence rate, corroborating ...the very poor prognosis of pancreatic cancer. The 5-year survival rate for all stages of pancreatic ductal adenocarcinoma is only 7%. Surgical resection represents the only potentially curative treatment option for pancreatic ductal adenocarcinoma patients but is often not feasible due to the advanced stage of the disease upon diagnosis. For advanced disease, palliative chemotherapy is the treatment of choice although the regimens available to date are untargeted and have extensive side-effect profiles, making them unsuitable for patients with a low performance status. For this reason, early detection of pancreatic cancer is essential in order to provide patients with an optimal therapeutic approach. Up to the present day, carbohydrate antigen 19-9 is the only diagnostic marker approved by the U.S. Food and Drug Administration but its diagnostic potential is limited due to its restricted sensitivity and specificity, supporting the urgent need for novel biomarkers. In addition, prognostic and treatment-predictive biomarkers might provide essential information regarding personalized treatment decisions for individual patients. In this article, we aim to review current and future diagnostic, prognostic, and treatment-predictive biomarkers for pancreatic cancer.
Non-alcoholic fatty liver disease (NAFLD) is a major cause of morbidity and mortality in developed countries, resulting in steatohepatitis (NASH), fibrosis and eventually cirrhosis. Modulating ...inflammatory mediators such as chemokines may represent a novel therapeutic strategy for NAFLD. We recently demonstrated that the chemokine receptor CXCR6 promotes hepatic NKT cell accumulation, thereby controlling inflammation in experimental NAFLD. In this study, we first investigated human biopsies (n = 20), confirming that accumulation of inflammatory cells such as macrophages is a hallmark of progressive NAFLD. Moreover, CXCR6 gene expression correlated with the inflammatory activity (ALT levels) in human NAFLD. We then tested the hypothesis that pharmacological inhibition of CXCL16 might hold therapeutic potential in NAFLD, using mouse models of acute carbon tetrachloride (CCl4)- and chronic methionine-choline-deficient (MCD) diet-induced hepatic injury. Neutralizing CXCL16 by i.p. injection of anti-CXCL16 antibody inhibited the early intrahepatic NKT cell accumulation upon acute toxic injury in vivo. Weekly therapeutic anti-CXCL16 administrations during the last 3 weeks of 6 weeks MCD diet significantly decreased the infiltration of inflammatory macrophages into the liver and intrahepatic levels of inflammatory cytokines like TNF or MCP-1. Importantly, anti-CXCL16 treatment significantly reduced fatty liver degeneration upon MCD diet, as assessed by hepatic triglyceride levels, histological steatosis scoring and quantification of lipid droplets. Moreover, injured hepatocytes up-regulated CXCL16 expression, indicating that scavenging functions of CXCL16 might be additionally involved in the pathogenesis of NAFLD. Targeting CXCL16 might therefore represent a promising novel therapeutic approach for liver inflammation and steatohepatitis.
Background: The COVID-19 pandemic represents an unprecedented global challenge and implicates a wide range of burden on medical professionals. Here, we evaluated the perception of the COVID-19 ...pandemic among medical professionals in Germany.
Methods: A total of n = 2827 medical professionals participated in an online survey between 27 March and 11 April.
Results: While most participants stated that Germany was well prepared and rated the measures taken by their employer as positive, subgroup analyses revealed decisive differences. The preventive measures were rated significantly worse by nurses compared to doctors (p < 0.001) and by participants from ambulatory healthcare centres compared to participants from maximum-care hospitals (p < 0.001). Importantly, shortage of protective medical equipment was reported more commonly in the ambulatory sector (p < 0.001) and in East German federal states (p = 0.004). Moreover, the majority of health care professionals (72.4%) reported significant restrictions of daily work routine. Finally, over 60% of medical professionals had concerns regarding their own health, which were more pronounced among female participants (p = 0.024).
Conclusion: This survey may indicate starting points on how medical professionals could be supported in carrying out their important activities during the ongoing and future healthcare challenges.
Inflammation, particularly that mediated by bacterial components translocating from the gut to the liver and binding to toll-like receptors (TLRs), is central to cholestatic liver injury. The ...triggering receptor expressed on myeloid cells-2 (TREM-2) inhibits TLR-mediated signaling and exerts a protective role in hepatocellular injury and carcinogenesis. This study aims to evaluate the role of TREM-2 in cholestasis.
TREM-2 expression was analyzed in the livers of patients with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), and in mouse models of cholestasis. Wild-type (WT) and Trem-2 deficient (Trem-2-/-) mice were subjected to experimental cholestasis and gut sterilization. Primary cultured Kupffer cells were incubated with lipopolysaccharide and/or ursodeoxycholic acid (UDCA) and inflammatory responses were analyzed.
TREM-2 expression was upregulated in the livers of patients with PBC or PSC, and in murine models of cholestasis. Compared to WT, the response to bile duct ligation (BDL)-induced obstructive cholestasis or alpha-naphtylisothiocyanate (ANIT)-induced cholestasis was exacerbated in Trem-2-/- mice. This was characterized by enhanced necroptotic cell death, inflammatory responses and biliary expansion. Antibiotic treatment partially abrogated the effects observed in Trem-2-/- mice after BDL. Experimental overexpression of TREM-2 in the liver of WT mice downregulated ANIT-induced IL-33 expression and neutrophil recruitment. UDCA regulated Trem-1 and Trem-2 expression in primary cultured mouse Kupffer cells and dampened inflammatory gene transcription via a TREM-2-dependent mechanism.
TREM-2 acts as a negative regulator of inflammation during cholestasis, representing a novel potential therapeutic target.
Cholestasis (the reduction or cessation of bile flow) causes liver injury. This injury is exacerbated when gut-derived bacterial components interact with receptors (specifically Toll-like receptors or TLRs) on liver-resident immune cells, promoting inflammation. Herein, we show that the anti-inflammatory receptor TREM-2 dampens TLR-mediated signaling and hence protects against cholestasis-induced liver injury. Thus, TREM-2 could be a potential therapeutic target in cholestasis.
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•TREM-2 expression is upregulated in the livers of patients with PBC and PSC, and mice with cholestatic liver injury.•Trem-2-/- mice show an exacerbated inflammatory response to experimental cholestasis.•UDCA mediates anti-inflammatory effects in KCs via TREM-2.•TREM-2 arises as a novel therapeutic target for patients with cholestasis.
Cholangiocarcinoma (CCA) represents the second most common primary hepatic malignancy. Despite tremendous research activities, the prognosis for the majority of patients is still poor. Only in case ...of early diagnosis, liver resection might potentially lead to long-term survival. However, it is still unclear which patients benefit most from extensive liver surgery, highlighting the need for new diagnostic and prognostic stratification strategies.
Serum concentrations of a 4 miRNA panel (miR-122, miR-192, miR-29b and miR-155) were analyzed using semi-quantitative reverse-transcriptase PCR in serum samples from 94 patients with cholangiocarcinoma undergoing tumour resection and 40 healthy controls. Results were correlated with clinical data.
Serum concentrations of miR-122, miR-192, miR-29b and miR-155 were significantly elevated in patients with CCA compared to healthy controls or patients with primary sclerosing cholangitis without malignant transformation. Although preoperative levels of these miRNAs were unsuitable as a prognostic marker of survival, a strong postoperative decline of miR-122 serum levels was significantly associated with a favorable patients' prognosis.
Analysis of circulating miRNAs represents a promising tool for the diagnosis of even early stage CCA. A postoperative decline in miRNA serum concentrations might be indicative for a favorable patients' outcome and helpful to identify patients with a good prognosis after extended liver surgery.
Liver diseases contribute to the global mortality and morbidity and still represent a major health problem leading to the death of people worldwide. Although there are several treatment options ...available for Hepatitis C infections, for most liver disease the pharmacological options are still limited. Therefore, the development of new targets against liver diseases is of high interest. Non-coding RNA (ncRNA) such as microRNA (miRNA) or long ncRNA (lncRNA) have been shown to be deeply involved in the pathophysiology of almost all acute and chronic liver diseases. The emerging evidence showed the potential therapeutic use of miRNA associated with different steps of hepatic pathophysiology. In the present review, we summarize emerging insights of ncRNA in liver diseases. We also highlight example of ncRNAs participating in the pathogenesis of different forms of liver disease and how they can be used as potential therapeutic targets for novel treatment paradigms. Furthermore, we describe an overview of up-to-date clinical trials and discuss about its future in clinical applications. Finally, we highlight the role of circulating ncRNAs in diagnosis of liver diseases and discuss the challenges and drawbacks of the usage of ncRNAs in clinical setting.
Chemokines modulate inflammatory responses that are prerequisites for organ fibrosis upon liver injury. Monocyte‐derived hepatic macrophages are critical for the development, maintenance, and ...resolution of hepatic fibrosis. The specific role of monocyte‐associated chemokine (C‐X3‐C motif) receptor 1 (CX3CR1) and its cognate ligand fractalkine chemokine (C‐X3‐C motif) ligand 1) in liver inflammation and fibrosis is currently unknown. We examined 169 patients with chronic liver diseases and 84 healthy controls; we found that CX3CL1 is significantly up‐regulated in the circulation upon disease progression, whereas CX3CR1 is down‐regulated intrahepatically in patients with advanced liver fibrosis or cirrhosis. To analyze the functional relevance of this pathway, two models of experimental liver fibrosis were applied to wild‐type (WT) and CX3CR1‐deficient mice. Fractalkine expression was induced upon liver injury in mice, primarily in hepatocytes and hepatic stellate cells. CX3CR1−/− animals developed greater hepatic fibrosis than WT animals with carbon tetrachloride–induced and bile duct ligation–induced fibrosis. CX3CR1−/− mice displayed significantly increased numbers of monocyte‐derived macrophages within the injured liver. Chimeric animals that underwent bone marrow transplantation revealed that CX3CR1 restricts hepatic fibrosis progression and monocyte accumulation through mechanisms exerted by infiltrating immune cells. In the absence of CX3CR1, intrahepatic monocytes develop preferentially into proinflammatory tumor necrosis factor–producing and inducible nitric oxide synthase–producing macrophages. CX3CR1 represents an essential survival signal for hepatic monocyte–derived macrophages by activating antiapoptotic bcl2 expression. Monocytes/macrophages lacking CX3CR1 undergo increased cell death after liver injury, which then perpetuates inflammation, promotes prolonged inflammatory monocyte infiltration into the liver, and results in enhanced liver fibrosis. Conclusion: CX3CR1 limits liver fibrosis in vivo by controlling the differentiation and survival of intrahepatic monocytes. The opposing regulation of CX3CR1 and fractalkine in patients suggests that pharmacological augmentation of this pathway may represent a possible therapeutic antifibrotic strategy. (HEPATOLOGY 2010;52:1769‐1782)
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