Urinary soluble CD163 is a putative non-invasive biomarker for primary sclerosing cholangitis.

Soluble CD163 (sCD163) is a selective marker of macrophages whose circulating levels have been found to be induced in patients with active inflammatory bowel disease (IBD). Urinary proteins are emerging as non-invasive diagnostic biomarkers, and here, sCD163 levels were measured in the urine of 18 controls and 63 patients with IBD by enzyme-linked immunosorbent assay. Urinary sCD163 levels did, however, not differentiate IBD patients from controls. Analysis of sCD163 in the serum of 51 of these patients did not show higher levels in IBD. Primary sclerosing cholangitis (PSC) is often associated with IBD, and sCD163 was higher in the urine of the 21 patients and in the serum of the 13 patients with PSC compared to patients with IBD. Of clinical relevance, urinary sCD163 levels were higher in PSC patients compared to those with other chronic liver diseases (n = 16), while serum sCD163 levels were comparable between the two groups. Serum sCD163 of IBD and PSC patients positively correlated with serum C-reactive protein. Serum creatinine and glomerular filtration rate, surrogate markers for renal function, did not significantly correlate with urinary or serum sCD163 levels in IBD or PSC patients. Moreover, urinary sCD163 was not related to fecal calprotectin levels whereas serum sCD163 of IBD patients showed a positive trend. PSC associated with IBD and PSC without underlying IBD had similar levels of urinary sCD163 while serum sCD163 tended to be higher in the latter group. In PSC patients, urinary sCD163 did not correlate with serum aminotransferase levels, gamma glutamyl transferase, alkaline phosphatase, bilirubin or the Model for End Stage Liver Disease score. Ursodeoxycholic acid was prescribed to our PSC patients and fecal levels of ursodeoxycholic acid and its conjugated forms were increased in PSC compared to IBD patients. Otherwise, fecal bile acid levels of IBD and PSC patients were almost identical, and were not correlated with urinary and serum sCD163 in PSC. In summary, our study identified urinary sCD163 as a potential biomarker for PSC.

Unraveling the Role of Reactive Oxygen Species in T Lymphocyte Signaling.

Reactive oxygen species (ROS) are central to inter- and intracellular signaling. Their localized and transient effects are due to their short half-life, especially when generated in controlled amounts. Upon T cell receptor (TCR) activation, regulated ROS signaling is primarily initiated by complexes I and III of the electron transport chain (ETC). Subsequent ROS production triggers the activation of nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2), prolonging the oxidative signal. This signal then engages kinase signaling cascades such as the mitogen-activated protein kinase (MAPK) pathway and increases the activity of REDOX-sensitive transcription factors such as nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). To limit ROS overproduction and prevent oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant proteins such as superoxide dismutases (SODs) finely regulate signal intensity and are capable of terminating the oxidative signal when needed. Thus, oxidative signals, such as T cell activation, are well-controlled and critical for cellular communication.

Rising Lysophosphatidylcholine Levels Post-Hepatitis C Clearance.

Hepatitis C virus (HCV) infection alters lysophosphatidylcholine (LPC) metabolism, enhancing viral infectivity and replication. Direct-acting antivirals (DAAs) effectively treat HCV and rapidly normalize serum cholesterol. In serum, LPC species are primarily albumin-bound but are also present in lipoprotein particles. This study aims to assess the impact of HCV eradication on serum LPC species levels in patients infected with HCV. Therefore, 12 different LPC species were measured by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the sera of 178 patients with chronic HCV infections at baseline, and in 176 of these patients after therapy with DAAs. All LPC species increased at 4 and 12 weeks post-initiation of DAA therapy. The serum profiles of the LPC species were similar before and after the viral cure. Patients with HCV and liver cirrhosis exhibited lower serum levels of all LPC species, except LPC 16:1, both before and after DAA treatment. Percentages of LPC 18:1 (relative to the total LPC level) were higher, and % LPC 22:5 and 22:6 were lower in cirrhotic compared to non-cirrhotic patients at baseline and at the end of therapy. LPC species levels inversely correlated with the model of end-stage liver disease score and directly with baseline and post-therapy albumin levels. Receiver operating characteristic curve analysis indicated an area under the curve of 0.773 and 0.720 for % LPC 18:1 (relative to total LPC levels) for classifying fibrosis at baseline and post-therapy, respectively. In summary, HCV elimination was found to increase all LPC species and elevated LPC 18:1 relative to total LPC levels may have pathological significance in HCV-related liver cirrhosis.

Serum Galectin-3 as a Non-Invasive Marker for Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a serious liver disease associated with inflammatory bowel disease (IBD). Galectin-3, an inflammatory and fibrotic molecule, has elevated circulating levels in patients with chronic liver disease and inflammatory bowel disease (IBD). This study aims to clarify whether galectin-3 can differentiate between patients with IBD, PSC, and PSC-IBD. Our study measured serum galectin-3 levels in 38 healthy controls, 55 patients with IBD, and 22 patients with PSC (11 patients had underlying IBD and 11 patients did not), alongside the urinary galectin-3 of these patients and 18 controls. Serum and urinary galectin-3 levels in IBD patients were comparable to those in controls. Among IBD patients, those with high fecal calprotectin, indicating severe disease, exhibited lower serum and elevated urinary galectin-3 levels compared to those with low calprotectin levels. Serum galectin-3 levels were inversely correlated with C-reactive protein levels. PSC patients displayed higher serum and urinary galectin-3 levels than IBD patients, with the highest serum levels observed in PSC patients with coexisting IBD. There was no correlation between serum and urinary galectin-3 levels and laboratory indicators of liver injury in both IBD and PSC patients. In conclusion, this study demonstrates that serum and urinary galectin-3 levels can distinguish IBD from PSC patients, and also reveals higher serum galectin-3 levels in PSC-IBD patients compared to those with isolated PSC.

Soluble CD137 is a novel serum marker of liver cirrhosis in patients with hepatitis C and alcohol-associated disease etiology.

Defective T-cell functions play a role in the persistence of HCV infection. Activated T cells express CD137, which costimulates antivirus T-cell responses, and this activity is antagonized by soluble CD137 (sCD137). Here, we show that in sera of 81 patients with chronic HCV, sCD137 levels did not correlate with measures of viral infection, and did not decline after virus eradication using direct-acting antivirals. Thus, serum sCD137 was similar in patients infected with HCV and in uninfected controls. Of note, in HCV patients with liver cirrhosis and patients with mostly alcohol-associated liver cirrhosis, sCD137 was increased. A negative association of sCD137 and albumin existed in both cohorts. sCD137 concentrations were similar in hepatic and portal vein blood excluding the liver as the origin of higher levels. Recombinant sCD137 reduced Th1 and Th2 but not Th17 cell polarization in vitro, and accordingly lowered IFN-γ, TNF, and IL-13 in cell media. Serum sCD137 is associated with inflammatory states, and positively correlated with serum TNF in cirrhotic HCV patients following virus eradication. Our study argues against a role of sCD137 in HCV infection and suggests a function of sCD137 in liver cirrhosis, which yet has to be defined.

Partial splenic embolization as a rescue and emergency treatment for portal hypertension and gastroesophageal variceal hemorrhage.

BACKGROUND: Partial splenic embolization (PSE) is a non-surgical procedure which was initially used to treat hypersplenism. Furthermore, partial splenic embolization can be used for the treatment of different conditions, including gastroesophageal variceal hemorrhage. Here, we evaluated the safety and efficacy of emergency and non-emergency PSE in patients with gastroesophageal variceal hemorrhage and recurrent portal hypertensive gastropathy bleeding due to cirrhotic (CPH) and non-cirrhotic portal hypertension (NCPH). METHODS: From December 2014 to July 2022, twenty-five patients with persistent esophageal variceal hemorrhage (EVH) and gastric variceal hemorrhage (GVH), recurrent EVH and GVH, controlled EVH with a high risk of recurrent bleeding, controlled GVH with a high risk of rebleeding, and portal hypertensive gastropathy due to CPH and NCPH underwent emergency and non-emergency PSE. PSE for treatment of persistent EVH and GVH was defined as emergency PSE. In all patients pharmacological and endoscopic treatment alone had not been sufficient to control variceal bleeding, and the placement of a transjugular intrahepatic portosystemic shunt (TIPS) was contraindicated, not reasonable due to portal hemodynamics, or TIPS failure with recurrent esophageal bleeding had occurred. The patients were followed-up for six months. RESULTS: All twenty-five patients, 12 with CPH and 13 with NCPH were successfully treated with PSE. In 13 out of 25 (52%) patients, PSE was performed under emergency conditions due to persistent EVH and GVH, clearly stopping the bleeding. Follow-up gastroscopy showed a significant regression of esophageal and gastric varices, classified as grade II or lower according to Paquet's classification after PSE in comparison to grade III to IV before PSE. During the follow-up period, no variceal re-bleeding occurred, neither in patients who were treated under emergency conditions nor in patients with non-emergency PSE. Furthermore, platelet count increased starting from day one after PSE, and after one week, thrombocyte levels had improved significantly. After six months, there was a sustained increase in the thrombocyte count at significantly higher levels. Fever, abdominal pain, and an increase in leucocyte count were transient side effects of the procedure. Severe complications were not observed. CONCLUSION: This is the first study analyzing the efficacy of emergency and non-emergency PSE for the treatment of gastroesophageal hemorrhage and recurrent portal hypertensive gastropathy bleeding in patients with CPH and NCPH. We show that PSE is a successful rescue therapy for patients in whom pharmacological and endoscopic treatment options fail and the placement of a TIPS is contraindicated. In critically ill CPH and NCPH patients with fulminant gastroesophageal variceal bleeding, PSE showed good results and is therefore an effective tool for the rescue and emergency management of gastroesophageal hemorrhage.

Therapeutic Plasma Exchange in ICU Patients with Acute Hypertriglyceridemia-Induced Pancreatitis Improves Patient Outcomes.

BACKGROUND: Acute severe pancreatitis is associated with high morbidity and mortality. Hypertriglyceridemia is the third most common cause of acute pancreatitis and higher triglyceride levels increase the risk for severe acute pancreatitis. Plasma exchange is an effective treatment method to lower triglycerides. Our study aimed to investigate the efficiency of plasma exchange as a treatment option for acute hypertriglyceridemia-induced pancreatitis (HTGP), the impact on mortality assessed by the SOFA, SAPS II, BISAP Score, Ranson's, and Glasgow-Imrie Criteria, as well as the overall length of stay in hospital and ICU. METHODS: In this retrospective single-center cohort study, triglycerides before and after plasma exchange were compared. SOFA and SAPS II were taken on ICU admission and at discharge. To further characterize the patient cohort, BISAP Score (on admission), Ranson's Criteria (on admission and after 48 h), and the Glasgow-Imrie Criteria (48 h after admission) were calculated. RESULTS: The study included 11 patients (91% male; median age 45 years). Triglycerides were reduced from 4,266 ± 3,560.6 to 842 ± 575.9 mg/dL during plasmapheresis (p < 0.001). The median ICU length of stay was 3 ± 4.2 days. In-hospital mortality was 0%. The SOFA score was significantly reduced from 4 ± 3.4 points on admission to 2 ± 2.1 points at discharge (p = 0.017). Triglycerides and cholesterol decreased from 3,126 ± 3,665 to 531 ± 273 mg/dL (p = 0.003) and from 438 ± 137.9 to 222 ± 59.5 mg/dL (p = 0.028), respectively. The BISAP Score on admission was 3 ± 0.5 points, Ranson's Criteria were 3 ± 1.5 points (48 h after admission, cumulative), and Glasgow-Imrie Criteria 3 ± 1.3 points (48 h after admission). CONCLUSION: Plasmapheresis is an efficient and safe treatment method for ICU patients with acute HTGP and significantly reduces triglycerides. Furthermore, plasmapheresis significantly improves the clinical outcomes of patients with HTGP.

Fecal short chain fatty acids and urinary 3-indoxyl sulfate do not discriminate between patients with Crohn´s disease and ulcerative colitis and are not of diagnostic utility for predicting disease severity.

BACKGROUND: Urinary 3-indoxyl sulfate levels as well as fecal short chain fatty acid (SCFA) concentrations are surrogate markers for gut microbiota diversity. Patients with inflammatory bowel diseases (IBDs) and patients with primary sclerosing cholangitis (PSC), a disease closely associated with IBD, have decreased microbiome diversity. In this paper, the fecal SCFAs propionate, acetate, butyrate and isobutyrate of patients with IBD and patients with PSC-IBD and urinary 3-indoxyl sulfate of IBD patients were determined to study associations with disease etiology and severity. METHODS: SCFA levels in feces of 64 IBD patients and 20 PSC-IBD patients were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Urinary 3-indoxyl sulfate levels of 45 of these IBD patients were analysed by means of reversed-phase liquid chromatography-electrospray ionization-tandem mass spectrometry. Feces of 17 healthy controls and urine of 13 of these controls were analyzed in parallel. These cohorts had comparable sex distribution and age. RESULTS: Urinary 3-indoxyl sulfate concentrations (normalized to urinary creatinine levels) was increased (P = 0.030) and fecal isobutyrate levels (normalized to dry weight of the stool sample) of IBD patients were decreased (P = 0.035) in comparison to healthy controls. None of the analyzed metabolites differed between patients with Crohn´s disease (CD) and patients with ulcerative colitis (UC). Fecal acetate and butyrate positively correlated with fecal calprotectin (P = 0.040 and P = 0.005, respectively) and serum C-reactive protein (P = 0.024 and P = 0.025, respectively) in UC but not CD patients. UC patients with fecal calprotectin levels above 150 µg/g, indicating intestinal inflammatory activity, had higher fecal acetate (P = 0.016), butyrate (P = 0.007) and propionate (P = 0.046) in comparison to patients with fecal calprotectin levels < 50 µg/g. Fecal SCFA levels of PSC-IBD and IBD patients were comparable. CONCLUSIONS: Current findings suggest that analysis of urinary 3-indoxyl-sulfate as well as fecal SCFAs has no diagnostic value for IBD and PSC-IBD diagnosis or monitoring of disease severity.

Altered fecal bile acid composition in active ulcerative colitis.

BACKGROUND: Disturbed bile acid homeostasis associated with a rise of primary and a decline of secondary bile acids is a consistent finding in inflammatory bowel diseases (IBDs). Whether fecal bile acids may emerge as biomarkers for IBD diagnosis and disease severity is less clear. Our study aimed to identify associations of 18 fecal bile acid species with IBD entity and disease activity. METHODS: Stool samples of 62 IBD patients and 17 controls were collected. Eighteen fecal bile acid species were quantified by LC-MS/MS using stable isotope dilution. Lipid levels normalized to a dry weight of the fecal homogenates and ratios of single bile acid species to total bile acid levels were used for calculations. RESULTS: IBD patients exhibited altered primary and secondary bile acid ratios in stool, with notable distinctions between ulcerative colitis (UC) compared to Crohn's disease (CD) and healthy controls. Fecal calprotectin was negatively correlated with glycolithocholic acid (GLCA) and hyodeoxycholic acid (HDCA) in UC. These bile acids were reduced in stool of UC patients with fecal calprotectin levels > 500 µg/g compared to UC patients with low calprotectin levels. Moreover, negative associations of six secondary bile acids with C-reactive protein (CRP) existed in UC. In CD patients, fecal bile acids did not correlate with CRP or fecal calprotectin. Diarrhoea is common in IBD, and UC patients with diarrhoea had reduced deoxycholic acid (DCA), glycine conjugated DCA (GDCA) and lithocholic acid in stool in contrast to patients with normal stool consistency. Fecal bile acid levels were not associated with diarrhoea in CD patients. UC patients treated with mesalazine had increased levels of fecal GDCA whereas no such changes were observed in CD patients. Bile acid levels of CD and UC patients treated with biologicals or corticosteroids did not change. Relative levels of GHDCA (specificity: 79%, sensitivity: 67%) and glycochenodeoxycholic acid (specificity: 74%, sensitivity: 63%) were the most specific to distinguish UC from CD. CONCLUSION: Disrupted fecal bile acid homeostasis is associated with disease severity and disease symptoms in UC but not in CD, potentially aiding in distinguishing IBD subtypes and classifying the pathophysiology of diarrhoea in UC.

Gender-Specific Differences in Serum Sphingomyelin Species in Patients with Hepatitis C Virus Infection-Sphingomyelin Species Are Related to the Model of End-Stage Liver Disease (MELD) Score in Male Patients.

Hepatitis C virus (HCV) replication depends on cellular sphingomyelin (SM), but serum SM composition in chronic HCV infection has been hardly analyzed. In this work, 18 SM species could be quantified in the serum of 178 patients with chronic HCV infection before therapy with direct-acting antivirals (DAAs) and 12 weeks later, when therapy was completed. Six SM species were higher in the serum of females than males before therapy and nine at the end of therapy; thus, sex-specific analysis was performed. Type 2 diabetes was associated with lower serum levels of SM 36:2;O2 and 38:2;O2 in men. Serum SM species did not correlate with the viral load in both sexes. Of note, three SM species were lower in males infected with HCV genotype 3 in comparison to genotype 1 infection. These SM species normalized after viral cure. SM 38:1;O2, 40:1;O2, 41:1;O2, and 42:1;O2 (and, thus, total SM levels) were higher in the serum of both sexes at the end of therapy. In males, SM 39:1;O2 was induced in addition, and higher levels of all of these SM species were already detected at 4 weeks after therapy has been started. Serum lipids are related to liver disease severity, and in females 15 serum SM species were low in patients with liver cirrhosis before initiation of and after treatment with DAAs. The serum SM species did not correlate with the model of end-stage liver disease (MELD) score in the cirrhosis and the non-cirrhosis subgroups in females. In HCV-infected male patients, nine SM species were lower in the serum of patients with cirrhosis before DAA treatment and eleven at the end of the study. Most of the SM species showed strong negative correlations with the MELD score in the male cirrhosis patients before DAA treatment and at the end of therapy. Associations of SM species with the MELD score were not detected in the non-cirrhosis male subgroup. In summary, the current analysis identified sex-specific differences in the serum levels of SM species in HCV infection, in liver cirrhosis, and during DAA therapy. Correlations of SM species with the MELD score in male but not in female patients indicate a much closer association between SM metabolism and liver function in male patients.

Soluble CD137: A Potential Prognostic Biomarker in Critically Ill Patients.

T cell depletion and functional impairment are characteristics of sepsis. CD137 is a costimulatory receptor on activated T cells, while soluble CD137 (sCD137) inhibits CD137 signaling. This study found elevated sCD137 levels in the plasma of patients with systemic inflammatory response syndrome (SIRS), sepsis, or septic shock compared to healthy controls. The sCD137 levels negatively correlated with the C-reactive protein and positively with procalcitonin and interleukin-6. There was no difference in sCD137 levels based on ventilation, dialysis, or vasopressor treatment. Patients with SARS-CoV-2, Gram-positive, or Gram-negative bacterial infections had similar sCD137 levels as noninfected individuals. Notably, higher plasma sCD137 levels were observed in non-survivors compared to survivors in both the SIRS/sepsis group and the SARS-CoV-2 subgroup. In conclusion, plasma sCD137 levels are associated with severe illness and survival in critically ill patients.

Serum Metabolomic Profiling of Patients with Lipedema.

Lipedema is a chronic condition characterized by disproportionate and symmetrical enlargement of adipose tissue, predominantly affecting the lower limbs of women. This study investigated the use of metabolomics in lipedema research, with the objective of identifying complex metabolic disturbances and potential biomarkers for early detection, prognosis, and treatment strategies. The study group (n = 25) comprised women diagnosed with lipedema. The controls were 25 lean women and 25 obese females, both matched for age. In the patients with lipedema, there were notable changes in the metabolite parameters. Specifically, lower levels of histidine and phenylalanine were observed, whereas pyruvic acid was elevated compared with the weight controls. The receiver operating characteristic (ROC) curves for the diagnostic accuracy of histidine, phenylalanine, and pyruvic acid concentrations in distinguishing between patients with lipedema and those with obesity but without lipedema revealed good diagnostic ability for all parameters, with pyruvic acid being the most promising (area under the curve (AUC): 0.9992). Subgroup analysis within matched body mass index (BMI) ranges (30.0 to 39.9 kg/m2) further revealed that differences in pyruvic acid, phenylalanine, and histidine levels are likely linked to lipedema pathology rather than BMI variations. Changes in low-density lipoprotein (LDL)-6 TG levels and significant reductions in various LDL-2-carried lipids of patients with lipedema, compared with the lean controls, were observed. However, these lipids were similar between the lipedema patients and the obese controls, suggesting that these alterations are related to adiposity. Metabolomics is a valuable tool for investigating lipedema, offering a comprehensive view of metabolic changes and insights into lipedema's underlying mechanisms.

Bacterial Infection of an Alveolar Echinococcus Cyst from C. perfringens Septicemia: A Case Report and Review of the Literature.

Background and Objectives: Alveolar echinococcosis (AE) is a highly variable disease able to present as structurally diverse cysts in different organs based on the host's immunological state as well as the time between diagnosis and the primary infection. Bacterial superinfections, especially with anaerobic pathogens from the Clostridiaceae genus, can further alter the radiological findings due to pneumobilia, newly formed abscess formations, and inflammatory changes. Materials and Methods: We present a case of a 71-year-old Caucasian male admitted to our intensive care unit with septic shock, pneumobilia, and a complex cyst of the liver with calcification, as shown by an initial CT. Because of the septic shock, the patient was started on broad-band antibiotics. Clostridiaceae infection was considered an important differential diagnosis due to the presence of pneumobilia observed in the initial CT, without a history of previous endoscopy. Furthermore, serology for echinococcus was positive, and blood cultures showed growth of C. perfringens. Therefore, the patient was additionally treated with albendazole. After recovery, further staging was conducted, showing complete remission of the cyst and a left-over lesion classified as Alveolar Echinococcosis Ulm Classification (AEUC) V. In summary, the patient had a pre-existing, controlled AE infection that became superinfected with C. perfringens, likely attributable to the anaerobic necrotic tissue, leading to septicemia. Results: The anaerobic tissue within the AE cyst provided an ideal medium for C. perfringens to replicate, leading to cyst infection, which subsequently caused septic shock and pneumobilia. The initial findings from CT and MRI were confounded by the superinfection, demonstrating the diagnostic challenges of AE, especially when presenting with complications. Conclusions: Diagnosing AE remains a demanding task, even with the excellent tools available through serology, coupled with CT, FDG-PET-CT, and MRI. Notably, older superinfected cysts can pose difficulties when integrated into the appropriate diagnostic context. Prompt diagnosis is critical for the accurate treatment of echinococcosis and its complications, such as bacterial superinfections. From a clinical perspective, septicemia from Clostridiaceae and infections with C. perfringens-pathogens capable of inducing pneumobilia-should be regarded as significant differential diagnoses for pneumobilia in the absence of a recent history of endoscopy.

Contribution of High Viral Loads, Detection of Viral Antigen and Seroconversion to Severe Acute Respiratory Syndrome Coronavirus 2 Infectivity.

BACKGROUND: From a public health perspective, effective containment strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be balanced with individual liberties. METHODS: We collected 79 respiratory samples from 59 patients monitored in an outpatient center or in the intensive care unit of the University Hospital Regensburg. We analyzed viral load by quantitative real-time polymerase chain reaction, viral antigen by point-of-care assay, time since onset of symptoms, and the presence of SARS-CoV-2 immunoglobulin G (IgG) antibodies in the context of virus isolation from respiratory specimens. RESULTS: The odds ratio for virus isolation increased 1.9-fold for each log10 level of SARS-CoV-2 RNA and 7.4-fold with detection of viral antigen, while it decreased 6.3-fold beyond 10 days of symptoms and 20.0-fold with the presence of SARS-CoV-2 antibodies. The latter was confirmed for B.1.1.7 strains. The positive predictive value for virus isolation was 60.0% for viral loads >107 RNA copies/mL and 50.0% for the presence of viral antigen. Symptom onset before 10 days and seroconversion predicted lack of infectivity with negative predictive values of 93.8% and 96.0%. CONCLUSIONS: Our data support quarantining patients with high viral load and detection of viral antigen and lifting restrictive measures with increasing time to symptom onset and seroconversion. Delay of antibody formation may prolong infectivity.

Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases.

OBJECTIVE: Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis with a 1-year mortality of 66%. Bacterial translocation (BT) from the intestine to the mesenteric lymph nodes is crucial for the pathogenesis of SBP. DESIGN: Since BT presupposes a leaky intestinal epithelium, the integrity of mucus and epithelial cell junctions (E-cadherin and occludin) was examined in colonic biopsies from patients with liver cirrhosis and controls. SBP-inducing Escherichia coli (E. coli) and Proteus mirabilis (P. mirabilis) were isolated from ascites of patients with liver cirrhosis and co-cultured with Caco-2 cells to characterise bacteria-to-cell effects. RESULTS: SBP-derived E. coli and P. mirabilis led to a marked reduction of cell-to-cell junctions in a dose-dependent and time-dependent manner. This effect was enhanced by a direct interaction of live bacteria with epithelial cells. Degradation of occludin is mediated via increased ubiquitination by the proteasome. Remarkably, a novel bacterial protease activity is of pivotal importance for the cleavage of E-cadherin. CONCLUSION: Patients with liver cirrhosis show a reduced thickness of colonic mucus, which allows bacteria-to-epithelial cell contact. Intestinal bacteria induce degradation of occludin by exploiting the proteasome of epithelial cells. We identified a novel bacterial protease activity of patient-derived SBP-inducing bacteria, which is responsible for the cleavage of E-cadherin structures. Inhibition of this protease activity leads to stabilisation of cell junctions. Thus, targeting these mechanisms by blocking the ubiquitin-proteasome system and/or the bacterial protease activity might interfere with BT and constitute a novel innovative therapeutic strategy to prevent SBP in patients with liver cirrhosis.

Sex-specific changes in triglyceride profiles in liver cirrhosis and hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with serum lipid abnormalities, which partly normalize following direct-acting antiviral (DAA) therapy. Here, associations of serum triglycerides (TGs) with viral genotype and markers of liver disease severity were evaluated in patients with chronic HCV.  METHODS: The study included the serum of 177 patients with chronic HCV. TGs were quantified by flow injection analysis Fourier transform mass spectrometry. Laboratory values and noninvasive scores for liver fibrosis assessment were determined. The nonparametric Kruskal‒Wallis test, one-way ANOVA, multiple linear regression and Student's t test were used as appropriate. P values were adjusted for multiple comparisons. RESULTS: HCV-infected women had lower serum TGs than men, and thus, a sex-specific analysis was performed. None of the 46 TG species analyzed differed in the serum of female patients with and without liver cirrhosis. In contrast, in the serum of male patients with liver cirrhosis, TGs with 53, 56 and 58 carbon atoms and three to eight double bonds were diminished. These polyunsaturated TGs were also low in males with a high fibrosis-4 score. TGs with 7 or 8 double bonds negatively correlated with the model of end-stage liver disease score in males. In addition, TGs with 49, 51 and 53 carbon atoms were reduced in male patients infected with genotype 3a in comparison to genotype 1a. TGs with 56 carbon atoms were lower in genotype 3a-infected males than in genotype 1b-infected males. TGs did not differ in females by genotype. Genotype 3-related changes disappeared at the end of therapy with DAAs. Overall, the levels of serum TGs did not change during DAA therapy in either sex. Consequently, the serum TGs of males with liver cirrhosis were lower than those of males without cirrhosis at the end of therapy. Such a difference was not apparent in females. CONCLUSIONS: The decline in TGs observed only in male patients with liver cirrhosis and male patients infected with genotype 3 illustrates sex-specific changes in lipid metabolism in chronic HCV.

Hereditary Diffuse Gastric Cancer: Molecular Genetics, Biological Mechanisms and Current Therapeutic Approaches.

Hereditary diffuse gastric cancer is an autosomal dominant syndrome characterized by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is caused by inactivating mutations in the tumor suppressor gene CDH1. Genetic testing technologies have become more efficient over the years, also enabling the discovery of other susceptibility genes for gastric cancer, such as CTNNA1 among the most important genes. The diagnosis of pathogenic variant carriers with an increased risk of developing gastric cancer is a selection process involving a multidisciplinary team. To achieve optimal long-term results, it requires shared decision-making in risk management. In this review, we present a synopsis of the molecular changes and current therapeutic approaches in HDGC based on the current literature.

Serum Ceramide Species Are Associated with Liver Cirrhosis and Viral Genotype in Patients with Hepatitis C Infection.

Hepatitis C virus (HCV) infection affects ceramide metabolism, and, here, we have evaluated associations of eight serum ceramide species with viral load, viral genotype, and disease markers in 178 patients with chronic HCV. In this cohort, ceramide d18:1;O2/16:0 was higher in the serum of the 20 diabetic patients compared to the patients without this complication. Moreover, ceramide d18:1;O2/24:0 was negatively correlated with age. Of note, all but ceramide d18:1;O2/16:0 and 26:0 were diminished in the serum of patients with liver cirrhosis and, with the exception of ceramide d18:1;O2/16:0, were negatively correlated with the model for end-stage liver disease (MELD) score. Most of the serum ceramides are carried in low-density lipoprotein (LDL), which rises following effective direct-acting antiviral (DAA) therapy. Ceramide d18:1;O2/24:0 recovered in parallel with LDL, whereas ceramide d18:1;O2/18:0 declined. Genotype-3-infected patients had the lowest ceramide levels, which were comparable to other genotypes after DAA treatment. Notably, ceramide d18:1;O2/23:0 and 24:0 were negatively correlated with the MELD score in patients with liver cirrhosis at the end of DAA therapy. Long-chain (LC) ceramides show adverse effects, whereas very-long-chain (VL) species have protective functions in the liver. The ratio of VL/LC ceramides was higher in non-cirrhosis patients than cirrhosis patients and further increased at the end of therapy in this subgroup. In summary, our study shows that serum ceramide levels are related to liver cirrhosis and viral genotype. Whether the more favorable serum ceramide profile in non-cirrhosis patients, before and after DAA therapy, is of pathophysiological importance needs further investigation.

Monkeypox in a Patient with Controlled HIV Infection Initially Presenting with Fever, Painful Pharyngitis, and Tonsillitis.

Background and Objectives: With more and more cases emerging outside central and west African countries, where the disease is endemic, the World Health Organization (WHO) has recently declared human monkeypox a Public Health Emergency of International Concern. Typical symptoms of the disease include fever, myalgia, and lymphadenopathy followed by a rash, but other symptoms may occur. Immunocompromised patients, including patients with uncontrolled Human Immunodeficiency Virus (HIV) infection, may be at risk for more severe courses. Case presentation: We present the case of a 30-year-old male patient of Brazilian descent with monkeypox. Initial symptoms were fever and general discomfort, with painful pharyngitis and tonsillitis and finally a papular rash of the anogenital area as the disease progressed. The presumed date of infection was a sexual contact with an unknown male eight days before the first symptoms occurred. The patient had a known and controlled HIV infection. The main reason for the initial presentation at the hospital was painful pharyngitis and tonsillitis, limiting food intake. Monkeypox infection was confirmed via PCR testing from a swab sample of cutaneous lesions. Adequate systemic and local analgesia enabled oral food uptake again. Antiviral therapy with Tecovirimat was not administered due to the stable immune status of the patient and the mild clinical symptoms. To cover a possible bacterial superinfection or Syphilis infection of the tonsil, antibiotic therapy with Ceftriaxone was added. Several days after presentation, the inflammation of the pharynx resolved and was followed by non-painful mucosal peeling. The patient was followed up with telephone calls and reported a complete recovery. The skin lesions were completely dried out 18 days after the first symptoms. Conclusions: Painful pharyngitis and tonsillitis can be rare early symptoms of monkeypox, which is highly relevant in everyday clinical practice. Particularly in patients with risk factors for monkeypox infection, further clinical and microbiologic testing for monkeypox should be performed if there is a clinical presentation with pharyngitis and tonsillitis.

A highly specific and sensitive serological assay detects SARS-CoV-2 antibody levels in COVID-19 patients that correlate with neutralization.

OBJECTIVE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic challenges national health systems and the global economy. Monitoring of infection rates and seroprevalence can guide public health measures to combat the pandemic. This depends on reliable tests on active and former infections. Here, we set out to develop and validate a specific and sensitive enzyme linked immunosorbent assay (ELISA) for detection of anti-SARS-CoV-2 antibody levels. METHODS: In our ELISA, we used SARS-CoV-2 receptor-binding domain (RBD) and a stabilized version of the spike (S) ectodomain as antigens. We assessed sera from patients infected with seasonal coronaviruses, SARS-CoV-2 and controls. We determined and monitored IgM-, IgA- and IgG-antibody responses towards these antigens. In addition, for a panel of 22 sera, virus neutralization and ELISA parameters were measured and correlated. RESULTS: The RBD-based ELISA detected SARS-CoV-2-directed antibodies, did not cross-react with seasonal coronavirus antibodies and correlated with virus neutralization (R2 = 0.89). Seroconversion started at 5 days after symptom onset and led to robust antibody levels at 10 days after symptom onset. We demonstrate high specificity (99.3%; N = 1000) and sensitivity (92% for IgA, 96% for IgG and 98% for IgM; > 10 days after PCR-proven infection; N = 53) in serum. CONCLUSIONS: With the described RBD-based ELISA protocol, we provide a reliable test for seroepidemiological surveys. Due to high specificity and strong correlation with virus neutralization, the RBD ELISA holds great potential to become a preferred tool to assess thresholds of protective immunity after infection and vaccination.