Carvedilol for reducing portal pressure in primary prophylaxis of variceal bleeding: a dose-response study.

BACKGROUND: Sequential measurements of hepatic venous pressure gradient (HVPG) are used to assess the haemodynamic response to nonselective betablockers (NSBBs) in patients with portal hypertension. AIMS: To assess the rates of HVPG response to different doses of carvedilol. METHODS: Consecutive patients with cirrhosis undergoing HVPG-guided carvedilol therapy for primary prophylaxis of variceal bleeding between 08/2010 and 05/2015 were retrospectively included. After baseline HVPG measurement, carvedilol 6.25 mg/d was administered and HVPG response (HVPG-decrease ≥20% or to ≤12 mm Hg) was assessed after 3-4 weeks. In case of nonresponse, carvedilol dose was increased to 12.5 mg/d and a third HVPG-measurement was performed after 3-4 weeks. We also assessed HVPG-response rates according to the Baveno VI consensus (HVPG decrease ≥10% or to ≤12 mm Hg) and changes in systolic arterial pressure (SAP). RESULTS: Seventy-two patients (Child A, 37%; B, 35%; C, 28%) were included. 28 (39%) patients achieved a HVPG-decrease ≥ 20% with carvedilol 6.25 mg/d and another 10 (14%) with carvedilol 12.5 mg/d. Forty (56%) patients had a HVPG decrease ≥10% with carvedilol 6.25 mg/d and 24 (33%) with carvedilol 12.5 mg/d. Thus, in total, a HVPG-response of ≥20% and ≥10% and was achieved in 38 (53%) and 55 (76%) and of patients respectively. Notably, 6 patients (n = 4 with ascites) did not tolerate an increase to 12.5 mg/d due to hypotension/bradycardia. However, none of the other patients had a SAP < 90 mm Hg at the final HVPG measurement. CONCLUSION: Carvedilol 12.5 mg/d was more effective than 6.25 mg/d in decreasing HVPG in primary prophylaxis. A total of 76% of patients achieved a HVPG-response of ≥ 10% to carvedilol 12.5 mg/d, however, arterial hypotension might occur, especially in patients with ascites.

Randomised clinical study: the effects of oral taurine 6g/day vs placebo on portal hypertension.

BACKGROUND: The amino sulphonic acid taurine reduces oxidative endoplasmatic reticulum stress and inhibits hepatic stellate cell activation, which might lead to reduction of portal pressure in cirrhosis. AIM: To assess the haemodynamic effects of taurine supplementation in patients with cirrhosis and varices. METHODS: Patients with hepatic venous pressure gradient (HVPG) ≥12 mm Hg were included in this prospective proof of concept study. Concomitant nonselective beta-blockers therapy was not allowed. Patients received either 4 weeks of oral taurine (6 g/day), or placebo, prior to evaluation of HVPG response. RESULTS: Thirty patients were screened and 22 included in the efficacy analysis (12 taurine/10 placebo; 64% male, mean age: 52 ± 11 years, Child A: 9%, B:64%, C:27%, ascites:68%). In the taurine group, mean HVPG dropped from 20 mm Hg (±4) at baseline to 18 mm Hg (±4) on day 28 (mean relative change: -12%, P = .0093). In the placebo group, mean HVPG increased from 20 mm Hg (±5) at baseline to 21 mm Hg (±5) on day 28 (mean relative change:+2%, P = .4945). Taurine had no significant effects on systemic haemodynamics. Seven of 12 patients (58%) on taurine achieved a HVPG response >10%, compared to none in the placebo group (P = .0053). In a multivariate linear model, HVPG reduction was significantly larger in the taurine group compared to placebo group (P = .0091 and P = .0109 for absolute and relative change respectively). Treatment-related adverse events included gastrointestinal discomfort and fatigue, and were usually mild and comparable between treatment groups. CONCLUSION: Taurine is safe and may reduce portal pressure in cirrhotic patients. More studies on the underlying mechanisms of action and long-term effects of taurine supplementation are warranted.

[Urological aspects in patients with liver cirrhosis]. / Urologische Aspekte bei Patienten mit Leberzirrhose.

BACKGROUND: Patients with liver cirrhosis (LC) are multimorbid and have urological diseases that occur more often than in the general population. The short life expectancy and poor general health complicate diagnosis and treatment. Due to the rising prevalence of LC, the number of patients from this group will increasingly present to urological practices. TOPICS: There are only a few studies about urological diseases in LC which describe the diagnostic and therapeutic challenges in this patient group. LC patients have altered baseline PSA values, which must be considered in PSA monitoring as part of preventative prostate care. In addition, difficulties arise in diagnosis and treatment of bladder dysfunction, genitourinary infections/sepsis, hypogonadism, erectile dysfunction, and urological malignancies. The implementation of invasive/tumor surgical interventions depends on LC severity. The safest surgical approach possible should be used. CONCLUSION: The worldwide prevalence of LC continues to rise but urological diagnosis and therapy in affected patients is often complicated due to their poor performance status.

Interferon-free regimens for chronic hepatitis C overcome the effects of portal hypertension on virological responses.

BACKGROUND: Portal hypertension is the strongest predictor of virological response to pegylated interferon (IFN)/ribavirin in patients with chronic hepatitis C (CHC)-related cirrhosis. AIM: To investigate the effects of portal pressure assessed by hepatic venous pressure gradient (HVPG) measurement on virological responses in patients treated with IFN-free regimens outside of clinical trials. METHODS: Fifty-six patients with CHC and cirrhosis who underwent HVPG measurement before starting an IFN-free therapy were retrospectively studied. Patients were treated with sofosbuvir in combination with daclatasvir (n = 32), ribavirin (n = 12) or simeprevir (n = 11), or the combination of simeprevir/daclatasvir (n = 1), for 12-24 weeks. RESULTS: Hepatic venous pressure gradient values ≥10 mmHg and ≥16 mmHg were observed in 41 (73%) and 31 (55%) patients respectively. The distributions of treatment regimens and durations were comparable between patients with or without portal hypertension. Patients with portal hypertension had lower platelet counts and albumin levels, while bilirubin levels, INR, MELD and Child-Pugh scores were higher than in patients without portal hypertension. Importantly, rates of on-treatment virological response and viral kinetics, as well as the rates of sustained virological response 12 weeks after the end of therapy [96% (54/56)] were not affected by portal hypertension. Anti-viral therapy improved liver stiffness, platelet count, serum albumin and bilirubin levels, as well as prothrombin time. CONCLUSIONS: This is the first study to demonstrate that IFN-free regimens overcome the negative effect of portal hypertension on virological responses and viral kinetics. Improvements in liver stiffness and platelet count might reflect an anti-portal hypertensive effect of IFN-free treatments.

Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model.

Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-κB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM.

Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed-Sternberg cells.

A major pathogenetic mechanism in classical Hodgkin lymphoma (cHL) is constitutive activation of canonical nuclear factor-κB (NF-κB) p50/p65 signaling, controlling lymphoma cell proliferation and survival. Recently, we demonstrated that aberrant Notch1 activity is a negative regulator of the B cell program in B cell-derived Hodgkin and Reed-Sternberg (HRS) cells. Despite abundant evidence for a complex context-dependent cross talk between Notch and NF-κB signaling in hematopoietic cells, it is unknown whether these pathways interact in HRS cells. Here, we show that Notch-signaling inhibition in HRS cells by the γ-secretase inhibitor (GSI) XII results in decreased alternative p52/RelB NF-κB signaling, interfering with processing of the NF-κB2 gene product p100 into its active form p52. As a result, expression of Notch and NF-κB target genes is reduced, and survival of HRS cells is impaired. Stimulation of alternative NF-κB signaling in the Hodgkin cell line L540cy by activation of the CD30 receptor rescued GSI-mediated loss of cell viability and apoptosis induction. Our data reveal that Notch is an essential upstream regulator of alternative NF-κB signaling and indicate cross talk between both the pathways in HRS cells. Therefore, we suggest that targeting the Notch pathway is a promising therapeutic option in cHL.

Notch and NF-κB signaling pathways in the biology of classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is now recognized as a B-cell-derived lymphoma which is characterized by only about 1% malignant pathognomonic Hodgkin and Reed-Sternberg (HRS) cells and an abundant infiltrate of reactive bystander cells. HRS cells are unique with respect to their lost B-cell-specific gene expression pattern and recurrent genetic lesions. Aberrant activity of Notch signaling, a highly conserved developmental pathway, acts as a negative regulator of the B cell program in HRS cells and thereby contributes to their reprogramming. Another striking feature and the major pathogenetic mechanism in HRS cells is constitutive NF-κB activation. A number of aberrations that contribute to canonical NF-κB activity in HRS cells have been described such as genetic lesions, deregulated receptor signaling and Epstein-Barr virus (EBV) infection. The importance of Notch and NF-κB signaling for cHL pathogenesis, their potential cross-talk and implications for future therapeutic applications are being discussed.

Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis C.

We systematically reviewed the evidence for long-term effectiveness and cost-effectiveness of antiviral treatment in patients with chronic hepatitis C. We performed a systematic literature search on the long-term effectiveness and cost-effectiveness of AVT in hepatitis C (1990-March 2007), and included health technology assessment (HTA) reports, systematic reviews, long-term clinical trials, economic studies conducted alongside clinical trials and decision-analytic modelling studies. All costs were converted to 2005euro. Antiviral therapy with peginterferon plus ribavirin in treatment-naïve patients with chronic hepatitis C was the most effective (3.6-4.7 life years gained [LYG]) treatment and was reasonably cost-effective (cost-saving to 84 700euro/quality adjusted life years [QALY]) when compared to interferon plus ribavirin. Some results also suggest cost-effectiveness (below 8400euro/(QALY) of re-treatment in nonresponders/relapsers. Results for patients with persistently normal alanine aminotransferase (ALT) levels or with special co-morbidities (e.g. HIV) or risk profiles were rare. We conclude that antiviral therapy may prolong life, improve long-term health-related quality-of-life and be reasonably cost-effective in treatment-naïve patients with chronic hepatitis C as well as in former relapsers/nonresponders. Further research is needed in patients with specific co-morbidities or risk profiles.

Disentangling the relation between intentions, planning, and behaviour: a moderated mediation analysis.

Action planning is assumed to mediate between intentions and health behaviours. Moreover, intentions are assumed to moderate the planning-behaviour relation, because people with high intentions are more likely to enact their plans. The present studies extend these suppositions by integrating both assumptions to a novel and parsimonious model of moderated mediation: the mediation effect is hypothesised to be stronger in individuals who report higher intention levels. In two longitudinal studies on physical activity (N = 124) and interdental hygiene (N = 209), intentions and action planning were assessed at baseline, and behaviour was measured four (Study 1), and respectively, three (Study 2) months later. The moderated mediation hypothesis was tested with continuously measured intentions using regression analyses with non-parametric bootstrapping. Results from both studies suggest that levels of intentions moderate the mediation process: The strength of the mediated effect increased along with levels of intentions. Planning mediates the intention-behaviour relation, if individuals hold sufficient levels of intentions. Implications for theory advancement and intervention development are discussed.

Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma.

Plasticity of committed mouse B cells has been demonstrated by inactivation of the B-cell commitment transcription factor PAX5, resulting in loss of the B-cell phenotype and differentiation into various hematopoietic lineages. Furthermore, mature mouse B cells could be reprogrammed into macrophages by overexpression of myeloid-specific transcription factors. Here, we report that aberrant activity of the transmembrane receptor, Notch1, interferes with the B-lymphoid phenotype of mature human germinal center-derived B cells in Hodgkin lymphoma, so called Hodgkin and Reed-Sternberg cells. They have lost the B-cell phenotype despite their mature B-cell origin. Notch1 remodels the B-cell transcription factor network by antagonizing the key transcription factors E2A and early B-cell factor (EBF). Through this mechanism, B lineage-specific genes were suppressed and B lineage-inappropriate genes were induced. We provide evidence that absence of the Notch inhibitor Deltex1 contributes to deregulated Notch activity in Hodgkin and Reed-Sternberg cells. These data suggest that Notch activation interferes with dedifferentiation of neoplastic B cells in Hodgkin lymphoma.

Social-cognitive predictors of health behavior: action self-efficacy and coping self-efficacy.

The effects of social-cognitive variables on preventive nutrition and behavioral intentions were studied in 580 adults at 2 points in time. The authors hypothesized that optimistic self-beliefs operate in 2 phases and made a distinction between action self-efficacy (preintention) and coping self-efficacy (postintention). Risk perceptions, outcome expectancies, and action self-efficacy were specified as predictors of the intention at Wave 1. Behavioral intention and coping self-efficacy served as mediators linking the 3 predictors with low-fat and high-fiber dietary intake 6 months later at Wave 2. Covariance structure analysis yielded a good model fit for the total sample and 6 subsamples created by a median split of 3 moderators: gender, age, and body weight. Parameter estimates differed between samples; the importance of perceived self-efficacy increased with age and weight.

Substrate binding to 15beta-hydroxylase (CYP106A2) probed by FT infrared spectroscopic studies of the iron ligand CO stretch vibration.

CYP106A2 has been expressed in E. coli with a high yield of up to 130 mg per litre of culture, purified to electrophoretic homogenity and found to be active in 15beta-hydroxylation of deoxycorticosterone using the adrenal redox proteins adrenodoxin and adrenodoxin reductase. Inspite of catalytic activity no substrate binding was detectable by UV-Vis spectroscopy. In contrast, an effect of substrate binding has been detected using the CO stretch mode infrared spectrum indicating that deoxycorticosterone binds in the heme pocket near the iron ligand.

Self-regulatory Processes in the Adoption and Maintenance of Health Behaviors.

Specific psychological constructs and comprehensive models or theories have been designed to account for individual differences in the way people abstain from risk behaviors, adopt health behaviors, and succeed or fail in self-regulatory attempts. The present article traces the development of recent health behavior theories and relates them to research in the fields of motivation and self-regulation. Special emphasis is placed on optimism, both as a state and as a trait construct within self-regulatory processes. It is argued that optimistic self-beliefs may be phase-specific. For example, some individuals may have high confidence in their ability to set ambitious goals, whereas others may have high confidence in their ability to recover from setbacks. Moreover, a distinction is made between goal attainment processes and threat appraisal processes. Thus, emotions and behavior may differ when striving for superior health goals as opposed to coping with health threats. The present considerations are put forward to further elaborate the author's Health Action Process Approach (HAPA).

Psychosocial correlates of substance use: comparing high school students with incarcerated offenders in Hong Kong.

Drug use prevalence data were obtained from 969 adolescents, high school students and imprisoned offenders who reported use of cough medicine, organic solvents, cannabis, heroin, tranquilizers, and narcotics over the past six months. Incarcerated youths, in particular girls, had higher prevalence rates than students. Drug use frequencies were associated with psychosocial variables such as disinhibition, peer drug use, susceptibility to peer pressure, attitudes, encouragement by peers, and perceived availability of drugs. The psychosocial process of the initiation and maintenance of substance use was specified as a path model that considered 1) personality and social environment as distal precursors and 2) a drug-use predisposition and perceived availability as proximal precursors of three kinds of outcome variables: drug use, the intention to try illicit drugs if they were legal, and adverse outcomes of drug use. It was found that the same structural equation model fit the data of both samples of offenders and students, however, with very different weights assigned to the paths.

Predicting cardiac patients' quality of life from the characteristics of their spouses.

Recovery from surgery can be facilitated by personal and social resources such as perceived self-efficacy and social support. Moreover, the existence of a social network and the behavior of its members can also have a positive effect. Patients (N = 381; 302 men, 79 women) undergoing heart surgery were surveyed once before and twice after surgery. In addition, 114 social-network members (18 men, 96 women), most of them spouses, reported about their own perceived resources at Time 1. The patient-spouse dyad was chosen as the unit of analysis. It turned out that characteristics of spouses were related to those of patients. Recovery from surgery at Time 2 and readjustment to normal life after half a year (Time 3) could be partly predicted by spouses' perceived self-efficacy and social support as measured at Time 1.

The multidimensional nature of received social support in gay men at risk of HIV infection and AIDS.

This article concerns received social support in gay men at risk of HIV and AIDS. Distinctions are made between three types of support (informational, tangible, emotional), four sources of support (friends, relatives, partner, organizations), and three dimensions of support (amount, satisfaction, reciprocity). A 24-item inventory reflecting these distinctions was administered to a sample of 587 gay men at two points in time. The psychometric properties of the instrument were determined, and the factor structure of the items varying sources and types of social support were tested. This was done by exploratory as well as by confirmatory factor analyses. The hypothesized structure was confirmed in both waves separately. Results corroborated the assumption that enacted or received social support is a highly differentiated construct and requires assessment tools that are designed according. Descriptive results on the support perceptions in this sample are also presented. Implications for the study of support in men at risk of HIV and AIDS are discussed.