The role of bile acid retention and a common polymorphism in the ABCB11 gene as host factors affecting antiviral treatment response in chronic hepatitis C.

Summary.  The outcome of hepatitis C virus (HCV) infection and the likelihood of a sustained virological response (SVR) to antiviral therapy depends on both viral and host characteristics. In vitro studies demonstrated that bile acids (BA) interfere with antiviral interferon effects. We investigate the influence of plasma BA concentrations and an ABCB11 polymorphism associated with lower transporter expression on viral load and SVR. Four hundred and fifty-one Caucasian HCV-patients treated with PEG-interferon and ribavirin were included in the study. ABCB11 1331T>C was genotyped, and plasma BA levels were determined. The 1331C allele was slightly overrepresented in HCV-patients compared to controls. In HCV-patients, a significant difference between patients achieving SVR vs non-SVR was observed for HCV-2/3 (5 vs 9 μm; P = 0.0001), while median BA levels in HCV-1 were marginally elevated. Normal BA levels <8 μm were significantly associated with SVR (58.3%vs 36.3%; OR 2.48; P = 0.0001). This difference was significant for HCV-2/3 (90.7%vs 67.6%; P = 0.002) but marginal in HCV-1 (38.7%vs 27.8%; P = 0.058). SVR rates were equivalent between ABCB11 genotypes for HCV-1, but increased for HCV-2/3 (TT 100%vs CC 78%; OR 2.01; P = 0.043). IL28B genotype had no influence on these associations. No correlation between BA levels and HCV RNA was detected for any HCV genotype. The higher allelic frequency of ABCB11 1331C in HCV-patients compared to controls may indirectly link increased BA to HCV chronicity. Our data support a role for BA as host factor affecting therapy response in HCV-2/3 patients, whereas a weaker association was found for HCV-1.

Assistances ventriculaires gauches dans le choc cardiogène et l'insuffisance cardiaque terminate [Left ventricular assist devices in cardiogenic shock and chronic refractory heart failure].

Decompensated heart failure, either acute (cardiogenic shock) or chronic (terminal heart failure) may become refractory to conventional therapy, then requiring mechanical assistance of the failing heart to improve hemodynamics. In the acute setting, aortic balloon counterpulsation is used as first line therapy. In case of failure, other techniques include the extracorporal membrane oxygenator or a percutaneous left ventricular assist device, such as the TandemHeart or the Impella. In chronic heart failure, long-term left ventricular assist devices can be surgically implanted. The continuous flow devices give here the best results. The aim of the present review article is to present with some details the various methods of mechanical left ventricle assistance to which the intensivist may be confronted in his daily practice.

Sex, drugs and chronic illness: health behaviours among chronically ill youth.

BACKGROUND: A growing body of literature indicates that adolescents with chronic conditions are as likely, or more likely, to take risky behaviours than their healthy peers. The objective of this research was to assess whether adolescents with chronic illness in Catalonia differ from their healthy peers in risk-taking behaviour. METHODS: Data were drawn from the Catalonia Adolescent Health database, a survey including a random school-based sample of 6952 young people, aged 14-19 years. The index group (IG) included 665 adolescents (450 females) reporting several chronic conditions. The comparison group (CG) comprised 6287 healthy adolescents (3306 females). Personal, family and school-related variables were analysed to ensure comparability between groups. Sexual behaviour, drug use (tobacco, alcohol, cannabis, cocaine and synthetic drugs) and perception of drug use among peers and in school were compared. Analysis was carried out separately by gender. chi-square, Fisher's and Student's tests were used to compare categorical and continuous variables. RESULTS: The prevalence of chronic conditions was 9.6%, with females showing a higher prevalence than males. The IG showed similar or higher rates of sexual intercourse and risky sexual behaviour. For most studied drugs, IG males reported slightly lower rates of use than CG males, while IG females showed higher rates for every drug studied. No differences were found in the perceptions of drug use among peers or in their school. CONCLUSIONS: Similar to previous research, chronically ill adolescents in our sample are as likely, or more likely, to take risky behaviours than their healthy counterparts and should receive the same anticipatory guidance.

Targeting the intragraft microenvironment and the development of chronic allograft rejection.

In this review, we discuss a paradigm whereby changes in the intragraft microenvironment promote or sustain the development of chronic allograft rejection. A key feature of this model involves the microvasculature including (a) endothelial cell (EC) destruction, and (b) EC proliferation, both of which result from alloimmune leukocyte- and/or alloantibody-induced responses. These changes in the microvasculature likely create abnormal blood flow patterns and thus promote local tissue hypoxia. Another feature of the chronic rejection microenvironment involves the overexpression of vascular endothelial growth factor (VEGF). VEGF stimulates EC activation and proliferation and it has potential to sustain inflammation via direct interactions with leukocytes. In this manner, VEGF may promote ongoing tissue injury. Finally, we review how these events can be targeted therapeutically using mTOR inhibitors. EC activation and proliferation as well as VEGF-VEGFR interactions require PI-3K/Akt/mTOR intracellular signaling. Thus, agents that inhibit this signaling pathway within the graft may also target the progression of chronic rejection and thus promote long-term graft survival.

Inventory and perspectives of chronic disease management programs in Switzerland: an exploratory survey.

OBJECTIVE: To describe chronic disease management programs active in Switzerland in 2007, using an exploratory survey. METHODS: We searched the internet (Swiss official websites and Swiss web-pages, using Google), a medical electronic database (Medline), reference lists of pertinent articles, and contacted key informants. Programs met our operational definition of chronic disease management if their interventions targeted a chronic disease, included a multidisciplinary team (>/=2 healthcare professionals), lasted at least six months, and had already been implemented and were active in December 2007. We developed an extraction grid and collected data pertaining to eight domains (patient population, intervention recipient, intervention content, delivery personnel, method of communication, intensity and complexity, environment, clinical outcomes). RESULTS: We identified seven programs fulfilling our operational definition of chronic disease management. Programs targeted patients with diabetes, hypertension, heart failure, obesity, psychosis and breast cancer. Interventions were multifaceted; all included education and half considered planned follow-ups. The recipients of the interventions were patients, and healthcare professionals involved were physicians, nurses, social workers, psychologists and case managers of various backgrounds. CONCLUSIONS: In Switzerland, a country with universal healthcare insurance coverage and little incentive to develop new healthcare strategies, chronic disease management programs are scarce. For future developments, appropriate evaluations of existing programs, involvement of all healthcare stakeholders, strong leadership and political will are, at least, desirable.

Determinants and burden of chronic kidney disease in the population-based CoLaus study: a cross-sectional analysis.

BACKGROUND: Chronic kidney disease (CKD) represents an increasing health burden. We present the population-based prevalence of CKD and compare the CKD Epidemiology collaboration (CKD-EPI) and modification of diet in renal disease (MDRD) equations to estimate the glomerular filtration rate, using the revised CKD classification with three albuminuria classes. We also explore factors associated with CKD. METHODS: The Swiss population-based, cross-sectional CoLaus study conducted in Lausanne (2003-2006) included 2810 men and 3111 women aged 35-75. CKD prevalence was assessed using CKD-EPI and MDRD equations and albuminuria estimated by the albumin-to-creatinine ratio in spot morning urine. Multivariate logistic regression was used to analyse determinants of CKD. RESULTS: Prevalence [95% confidence interval (CI)] of all stages CKD was 10.0% (9.2-10.8%) with CKD-EPI and 13.8% (12.9-14.6%) with MDRD. Using the revised CKD classification, the prevalence of low-, medium-, high- and very high-risk groups was 90.0, 8.46, 1.18 and 0.35% with CKD-EPI, respectively. With MDRD, the corresponding values were 86.24, 11.86, 1.55 and 0.35%. Using the revised classification, CKD-EPI systematically reclassified people in a lower risk category than MDRD. Age and obesity were more strongly associated with CKD in men [odds ratio (95% CI): 2.23(1.95; 2.56) per 10 years and 3.05(2.08;4.47), respectively] than in women [1.46 (1.29; 1.65) and 1.78 (1.30;2.44), respectively]. Hypertension, type 2 diabetes, serum homocysteine and uric acid were positively independently associated with CKD in men and women. CONCLUSIONS: One in 10 adults suffers from CKD in the population of Lausanne. CKD-EPI systematically reclassifies people in a lower CKD risk category than MDRD. Serum homocysteine and uric acid levels are associated with CKD independently of classical risk factors such as age, hypertension and diabetes.

Prevention and treatment of protein energy wasting in chronic kidney disease patients: a consensus statement by the International Society of Renal Nutrition and Metabolism.

Protein energy wasting (PEW) is common in patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes, especially in individuals receiving maintenance dialysis therapy. A multitude of factors can affect the nutritional and metabolic status of CKD patients requiring a combination of therapeutic maneuvers to prevent or reverse protein and energy depletion. These include optimizing dietary nutrient intake, appropriate treatment of metabolic disturbances such as metabolic acidosis, systemic inflammation, and hormonal deficiencies, and prescribing optimized dialytic regimens. In patients where oral dietary intake from regular meals cannot maintain adequate nutritional status, nutritional supplementation, administered orally, enterally, or parenterally, is shown to be effective in replenishing protein and energy stores. In clinical practice, the advantages of oral nutritional supplements include proven efficacy, safety, and compliance. Anabolic strategies such as anabolic steroids, growth hormone, and exercise, in combination with nutritional supplementation or alone, have been shown to improve protein stores and represent potential additional approaches for the treatment of PEW. Appetite stimulants, anti-inflammatory interventions, and newer anabolic agents are emerging as novel therapies. While numerous epidemiological data suggest that an improvement in biomarkers of nutritional status is associated with improved survival, there are no large randomized clinical trials that have tested the effectiveness of nutritional interventions on mortality and morbidity.

Non-pharmacological interventions for chronic pain in people with spinal cord injury.

BACKGROUND: Chronic pain is frequent in persons living with spinal cord injury (SCI). Conventionally, the pain is treated pharmacologically, yet long-term pain medication is often refractory and associated with side effects. Non-pharmacological interventions are frequently advocated, although the benefit and harm profiles of these treatments are not well established, in part because of methodological weaknesses of available studies. OBJECTIVES: To critically appraise and synthesise available research evidence on the effects of non-pharmacological interventions for the treatment of chronic neuropathic and nociceptive pain in people living with SCI. SEARCH METHODS: The search was run on the 1st March 2011. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), four other databases and clinical trials registers. In addition, we manually searched the proceedings of three major scientific conferences on SCI. We updated this search in November 2014 but these results have not yet been incorporated. SELECTION CRITERIA: Randomised controlled trials of any intervention not involving intake of medication or other active substances to treat chronic pain in people with SCI. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in the included studies. The primary outcome was any measure of pain intensity or pain relief. Secondary outcomes included adverse events, anxiety, depression and quality of life. When possible, meta-analyses were performed to calculate standardised mean differences for each type of intervention. MAIN RESULTS: We identified 16 trials involving a total of 616 participants. Eight different types of interventions were studied. Eight trials investigated the effects of electrical brain stimulation (transcranial direct current stimulation (tDCS) and cranial electrotherapy stimulation (CES); five trials) or repetitive transcranial magnetic stimulation (rTMS; three trials). Interventions in the remaining studies included exercise programmes (three trials); acupuncture (two trials); self-hypnosis (one trial); transcutaneous electrical nerve stimulation (TENS) (one trial); and a cognitive behavioural programme (one trial). None of the included trials were considered to have low overall risk of bias. Twelve studies had high overall risk of bias, and in four studies risk of bias was unclear. The overall quality of the included studies was weak. Their validity was impaired by methodological weaknesses such as inappropriate choice of control groups. An additional search in November 2014 identified more recent studies that will be included in an update of this review.For tDCS the pooled mean difference between intervention and control groups in pain scores on an 11-point visual analogue scale (VAS) (0-10) was a reduction of -1.90 units (95% confidence interval (CI) -3.48 to -0.33; P value 0.02) in the short term and of -1.87 (95% CI -3.30 to -0.45; P value 0.01) in the mid term. Exercise programmes led to mean reductions in chronic shoulder pain of -1.9 score points for the Short Form (SF)-36 item for pain experience (95% CI -3.4 to -0.4; P value 0.01) and -2.8 pain VAS units (95% CI -3.77 to -1.83; P value < 0.00001); this represented the largest observed treatment effects in the included studies. Trials using rTMS, CES, acupuncture, self-hypnosis, TENS or a cognitive behavioural programme provided no evidence that these interventions reduce chronic pain. Ten trials examined study endpoints other than pain, including anxiety, depression and quality of life, but available data were too scarce for firm conclusions to be drawn. In four trials no side effects were reported with study interventions. Five trials reported transient mild side effects. Overall, a paucity of evidence was found on any serious or long-lasting side effects of the interventions. AUTHORS' CONCLUSIONS: Evidence is insufficient to suggest that non-pharmacological treatments are effective in reducing chronic pain in people living with SCI. The benefits and harms of commonly used non-pharmacological pain treatments should be investigated in randomised controlled trials with adequate sample size and study methodology.

Prefrailty and chronic morbidity in the youngest old: an insight from the Lausanne Cohort Lc65+.

OBJECTIVES: To estimate the prevalence of prefrailty, frailty, comorbidity, and disability in the youngest old and to identify chronic diseases associated with individual frailty criteria. DESIGN: Population-based cohort study of noninstitutionalized elderly adults at baseline; cross-sectional analysis. SETTING: Lausanne, Switzerland. PARTICIPANTS: One thousand two hundred eighty-three individuals with complete data on frailty, aged 65 to 70 (58.5% women). MEASUREMENTS: Frailty was assessed according to an adaptation of Fried's criteria (shrinking, weakness, exhaustion, slowness, and low activity, three criteria needed for the diagnosis of frailty, 1 to 2 for prefrailty). Other outcomes were diseases diagnosed by a doctor (≥ 2 chronic diseases: comorbidity) and limitations in activities of daily living (ADLs, basic and instrumental). RESULTS: At baseline, of 1,283 participants 71.1% were classified as nonfrail, 26.4% as prefrail, and 2.5% as frail. The proportion of women increased across these three groups (56.5%, 62.8%, and 71.9%, respectively; P = .01), as did the proportion of individuals with one or more chronic diseases (68.0%, 82.8%, and 90.6%, respectively; P < .001) and the proportion with basic or instrumental ADL disability (1.6%, 10.3%, and 59.4%, respectively; P < .001). Weakness (low grip strength) was the most frequent criterion (14.3%). Prefrail participants had significantly more comorbidity and ADL disability than nonfrail participants (P < .001). When present in isolation, weakness was associated with two to three times greater prevalence of coronary heart disease, other heart diseases, diabetes mellitus, and arthritis. Similarly, a significant association was identified between exhaustion and depression. CONCLUSION: Prefrailty is common in the youngest old. The most prevalent frailty criterion is weakness, which is associated with cardiovascular diseases. Longitudinal studies of the evolution of prefrailty should explore the role of potential interactions between individual frailty criteria and specific chronic diseases.

Chronic treatment of hypertensive patients with converting enzyme inhibitors.

It is widely accepted that pharmacologic reduction of the blood pressure of hypertensive patients reduces the risk of at least some of the major cardiovascular complications (1-5). All major studies were carried out before orally active converting enzyme inhibitors had become available. In other words, very effective antihypertensive drugs have been around for quite some time and have already proven their efficacy. Therefore, the considerable enthusiasm that has developed during the very recent years for the new converting enzyme inhibitors should be evaluated in the light of previously available antihypertensive drugs, the more so, as drugs cheaper than converting enzyme inhibiting agents are presently available. Thus, the increased expense when using this new class of antihypertensive compounds should be justified by a therapeutic gain. When evaluating a class of antihypertensive drugs such as converting enzyme inhibitors, there are basically three main considerations: What is their efficacy in long-term use? This includes the effect on blood pressure, on heart, on hemodynamics, and on blood flow distribution. What are the metabolic effects? What is the effect on sodium and potassium excretion? How are the serum lipids affected by its use? Are there any untoward effects related either to the chemical structure of the compound per se or rather to the approach? In particular, are there any central effects of the drug which can cause discomfort to the patient? The following discussion has the principal aim to review these aspects with chronic use of oral converting enzyme inhibiting agents without, however, even attempting to provide an exhaustive review of the subject.