Crohn’s disease (CD) is associated with a multitude of genetic defects, many of which likely affect Paneth cell function. Paneth cells reside in the small intestine and produce antimicrobial peptides ...essential for the host barrier, principally human α-defensin 5 (HD5) and HD6. Patients with CD of the ileum are characterized by reduced constitutive expression of these peptides and, accordingly, compromised antimicrobial barrier function. Here, we present a previously unidentified regulatory mechanism of Paneth cell defensins. Using cultures of human ileal tissue, we showed that the secretome of peripheral blood mononuclear cells (PBMCs) from healthy controls restored the attenuated Paneth cell α-defensin expression characteristic of patients with ileal CD. Analysis of the Wnt pathway in both cultured biopsies and intestinal epithelial cells implicated Wnt ligands driving the PBMC effect, whereas various tested cytokines were ineffective. We further detected another defect in patients with ileal CD, because the PBMC secretomes derived from patients with CD were unable to restore the reduced HD5/HD6 expression. Accordingly, analysis of PBMC subtypes showed that monocytes of patients with CD express significantly lower levels of canonical Wnt ligands, including Wnt3, Wnt3a, Wnt1, and wntless Wnt ligand secretion mediator (Evi/Wls). These studies reveal an important cross-talk between bone marrow-derived cells and epithelial secretory Paneth cells. Defective Paneth cell-mediated innate immunity due to inadequate Wnt ligand stimulation by monocytes provides an additional mechanism in CD. Because defects of Paneth cell function stemming from various etiologies are overcome by Wnt ligands, this mechanism is a potential therapeutic target for this disease.
AIM To gather data on the antiviral efficacy and safety of second generation direct acting antiviral(DAA) treatment with respect to sustained virological response(SVR) 12 wk after conclusion of ...treatment, and to determine predictors of SVR12 in this setting.METHODS Two hundred and sixty patients treated with SOF combination partners PR(n = 51), R(n = 10), SMV(n = 30), DCV(n = 81), LDV(n = 73), or 3D(n = 15).144/260 were pre-treated, 89/260 had liver cirrhosis, 56/260 had portal hypertension with platelets < 100/nL, 25/260 had a MELD score ≥ 10 and 17/260 were postliver transplantation patients. 194/260 had HCV GT1, 44/260 HCV GT3.RESULTS Two hundred and forty/256(93.7%) patients achieved SVR12(m ITT); 4/260 were lost to follow-up. SVR12 rates for subgroups were: 92% for SOF/DCV, 93% for each SOF/SMV, SOF/PR, 94% for SOF/LDV, 100% for 3D, 94% for pretreated, 87% for liver cirrhosis, 82% for patients with platelets < 100/n L, 88% post-liver transplantation, 95% for GT1 a, 93% for GT1 b, 90% for GT3, 100% for GT2, 4, and 6. 12 patients suffered from relapse, 6 prematurely discontinued treatment, of which 4 died. Negative predictors of SVR12 were a platelet count < 100/nL, MELD score ≥ 10(P < 0.0001), liver cirrhosis(P = 0.005) at baseline. In Interferonfree treatment GT3 had significantly lower SVR rates than GT1(P = 0.016). Side effects were mild. CONCLUSION Excellent SVR12 rates and the favorable side-effect profile of DAA-combination therapy can be well translated into 'real-world'. Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/n L and patients with GT3 are in special need for further research efforts to overcome comparatively higher rates of virological failure.
Defensins represents an integral part of the innate immune system serving to ward off potential pathogens and to protect the intestinal barrier from microbial encroachment. In addition to their ...antimicrobial activities, defensins in general, and human β-defensin 2 (hBD2) in particular, also exhibit immunomodulatory capabilities. In this report, we assessed the therapeutic efficacy of systemically administered recombinant hBD2 to ameliorate intestinal inflammation in three distinct animal models of inflammatory bowel disease; i.e., chemically induced mucosal injury (DSS), loss of mucosal tolerance (TNBS), and T-cell transfer into immunodeficient recipient mice. Treatment efficacy was confirmed in all tested models, where systemically administered hBD2 mitigated inflammation, improved disease activity index, and hindered colitis-induced body weight loss on par with anti-TNF-α and steroids. Treatment of lipopolysaccharide (LPS)-activated human peripheral blood mononuclear cells with rhBD2 confirmed the immunomodulatory capacity in the circulatory compartment. Subsequent analyzes revealed dendritic cells (DCs) as the main target population. Suppression of LPS-induced inflammation was dependent on chemokine receptor 2 (CCR2) expression. Mechanistically, hBD2 engaged with CCR2 on its DC target cell to decrease NF-κB, and increase CREB phosphorylation, hence curbing inflammation. To our knowledge, this is the first study showing
efficacy of a systemically administered defensin in experimental disease.
The inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) are chronic diseases mostly affecting young patients. As they are diseases accompanying patients for their ...entire life, and the quality of life (QUOL) interacts with disease activity, improving QUOL should be one of the main goals of therapy. This study aims to identify factors contributing to good or impaired QUOL.
Questionnaires addressing health-related QUOL and other psychological and social features were positioned on our institutions' webpage and on the webpage of the largest self-help group for IBD in Germany. Patients were subdivided according to their QUOL score with a cutoff of <60. We used the Short Inflammatory Bowel Disease Questionnaire, the Assessment of the Demand for Additional Psychological Treatment, and the Fear of Progression Questionnaire Short Form.
High numbers of patients in both subgroups showed an impaired QUOL (87.34% in UC, 91.08% in CD). Active extraintestinal manifestations, smoking, high fear of progression and high demand for psychotherapy were associated with reduced QUOL. In addition, polypharmacological interventions did not result in a good QUOL, but ostomies are linked to improved QUOL especially in CD patients.
Scores used in clinical day-to-day-practice mainly focusing on somatic factors do not sufficiently address important aspects concerning QUOL. Most importantly, extraintestinal manifestations show a hitherto underestimated impact on QUOL.
Deregulated centrosome duplication can result in genetic instability and contribute to tumorigenesis. Here, we show that centrosome duplication is regulated by the activity of an E3-ubiquitin ligase ...that employs the F-box protein Fbxw5 (ref. ) as its targeting subunit. Depletion of endogenous Fbxw5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles. We identify the centriolar protein HsSAS-6 (refs , ) as a critical substrate of the SCF-Fbxw5 complex. Fbxw5 binds HsSAS-6 and promotes its ubiquitylation in vivo. The activity of SCF-Fbxw5 is in turn negatively regulated by Polo-like kinase 4 (Plk4), which phosphorylates Fbxw5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6. Fbxw5 is a cell-cycle-regulated protein with expression levels peaking at the G1/S transition. We show that Fbxw5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets Fbxw5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery. In summary, we show that a cell-cycle-regulated SCF complex is regulated by the kinase Plk4, and that this in turn restricts centrosome re-duplication through degradation of the centriolar protein HsSAS-6.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we ...aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall survival (OS) were studied by Kaplan-Meier analyses for clinical parameters using weighted log-rank testing. Next-generation sequencing (NGS) was performed in a subset of 15 patients. The objective response (OR) rate was 19% median OS (mOS)16.7 months. Forty-one percent reached a PFS > 6 months; these patients had a significantly longer mOS (32.0 vs. 8.5 months). Child-Pugh (CP) A and B patients showed a mOS of 22.1 and 12.1 months, respectively. Ten of thirty CP-B patients reached PFS > 6 months, including 3 patients with an OR. Tumor mutational burden (TMB) could not predict responders. Of note, antibiotic treatment within 30 days around ICI initiation was associated with significantly shorter mOS (8.5 vs. 17.4 months). Taken together, this study shows favorable outcomes for OS with low AFP, OR, and PFS > 6 months. No specific genetic pattern, including TMB, could identify responders. Antibiotics around treatment initiation were associated with worse outcome, suggesting an influence of the host microbiome on therapy success.
Background Cohorts of hospitalized COVID-19 patients have been studied in several countries since the beginning of the pandemic. So far, there is no complete survey of older patients in a German ...district that includes both outpatients and inpatients. In this retrospective observational cohort study, we aimed to investigate risk factors, mortality, and functional outcomes of all patients with COVID-19 aged 70 and older living in the district of Tübingen in the southwest of Germany. Methods We retrospectively analysed all 256 patients who tested positive for SARS-CoV-2 in one of the earliest affected German districts during the first wave of the disease from February to April 2020. To ensure inclusion of all infected patients, we analysed reported data from the public health department as well as the results of a comprehensive screening intervention in all nursing homes of the district (n = 1169). Furthermore, we examined clinical data of all hospitalized patients with COVID-19 (n = 109). Results The all-cause mortality was 18%. Screening in nursing homes showed a point-prevalence of 4.6%. 39% of residents showed no COVID-specific symptoms according to the official definition at that time. The most important predictors of mortality were the need for inpatient treatment (odds ratio (OR): 3.95 95%-confidence interval (CI): 2.00-7.86, p<0.001) and care needs before infection (non-hospitalized patients: OR: 3.79 95%-CI: 1.01-14.27, p = 0.037, hospitalized patients: OR: 2.89 95%-CI 1.21-6.92, p = 0.015). Newly emerged care needs were a relevant complication of COVID-19: 27% of previously self-sufficient patients who survived the disease were not able to return to their home environment after discharge from the hospital. Conclusion Our findings demonstrate the importance of a differentiated view of risk groups and long-term effects within the older population. These findings should be included in the political and social debate during the ongoing pandemic to evaluate the true effect of COVID-19 on healthcare systems and individual functional status.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Endoscopic negative pressure therapy is an effective treatment strategy for various defects of the gastrointestinal tract. The functional principle is based on an open-pore element, which is ...placed around a perforated drainage tube and connected to a vacuum source. The resulting open-pore suction device can undergo endoluminal or intracavitary placement. Different open-pore suction devices are used for endoscopic negative pressure therapy of upper gastrointestinal tract defects. Comparative analyses for features and properties of these devices are still lacking. Eight different (six hand-made devices and two commercial devices) open-pore suction devices for endoscopic negative pressure therapy of the upper gastrointestinal tract were used, amount fluid removed was evaluated. The evaluation parameters included the time to reach the target pressure, the time required to remove 100 ml of water, and the material resistance of the device. All open-pore suction devices are able to aspirate the target volume of fluids. The time to reach the target volume varied considerably. Target negative pressure was not achieved with all open-pore suction devices during the aspiration of fluids; however, there was no negative effect on suction efficiency. Of the measurement data, material resistance could be calculated for six open-pore elements. We present a simple experimental, nonphysiologically setup for open-pore suction devices used for endoscopic negative pressure therapy. The expected quantity of fluids secreted into the treated organs should affect open-pore suction device for endoscopic negative pressure therapy.
Iron deficiency or iron deficiency anemia (IDA) are some of the most common systemic complications of inflammatory bowel diseases (IBD). Symptoms such as fatigue, reduced ability to concentrate and ...reduced exercise tolerance can mimic common symptoms of IBD and can therefore easily be overseen. Furthermore, clinicians tend to see mild to moderate anemia as an inevitable accompaniment of IBD that is sufficiently explained by the underlying disease and does not require further workup. But in contrast to these clinical routines, current guidelines recommend that any degree of anemia in patients with IBD should be further evaluated and treated. Multiple studies have shown that anemia is a main factor for decreased quality of life (QoL) in patients with IBD. Correction of anemia, however, can significantly improve the QoL of patients with IBD. It is therefore recommended that every patient with IBD is regularly screened for iron deficiency and anemia. If detected, appropriate workup and treatment should be initiated. Over the last years, a number of new diagnostic tools and treatment options have been developed. Multiple studies have demonstrated the safety of newer formulations of intravenous iron in patients with IBD and have compared oral and intravenous iron in various situations. Treatment recommendations have changed and new evidence-based guidelines were developed. However, to date these guidelines are still not widely implemented in clinical practice. The aim of this review is to draw attention to the need for treatment for every level of anemia in patients with IBD and to provide some practical guidance for screening, diagnostics, treatment and follow up of IDA in patients with IBD following current international guidelines.
The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and ...advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively.
When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7-21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)).
Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up.
DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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