Rechallenge in idiosyncratic drug-induced liver injury: An analysis of cases in two large prospective registries according to existing definitions.

INTRODUCTION: Data on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. METHODS: Cases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. RESULTS: Of 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. CONCLUSIONS: Episodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

Gene expression changes related to immune processes associate with cognitive endophenotypes of schizophrenia.

Schizophrenia is a heterogeneous disorder characterized by a spectrum of symptoms and many different underlying causes. Thus, instead of using the broad diagnosis, intermediate phenotypes can be used to possibly decrease the underlying complexity of the disorder. Alongside the classical symptoms of delusions and hallucinations, cognitive deficits are a core feature of schizophrenia. To increase our understanding of the biological processes related to these cognitive deficits, we performed a genome-wide gene expression analysis. A battery of 14 neuropsychological tests was administered to 844 individuals from a Finnish familial schizophrenia cohort. We grouped the applied neuropsychological tests into five factors for further analysis. Cognitive endophenotypes, whole blood mRNA, genotype, and medication use data were studied from 47 individuals. Expression level of several RNA probes were significantly associated with cognitive performance. The factor representing Verbal Working Memory was associated with altered expression levels of 11 probes, of which one probe was also associated with a specific sub-measure of this factor (WMS-R Digit span backward). While, the factor Processing speed was related to one probe, which additionally associated among 55 probes with a specific sub-measure of this factor (WAIS-R Digit symbol). Two probes were associated with the measure recognition memory performance. Enrichment analysis of these differentially expressed probes highlighted immunological processes. Our findings are in line with genome-wide genetic discoveries made in schizophrenia, suggesting that immunological processes may be of biological interest for future drug design towards schizophrenia and the cognitive dysfunctions that underlie it.

A randomized controlled trial on the effects of combined aerobic-resistance exercise on muscle strength and fatigue, glycemic control and health-related quality of life of type 2 diabetes patients.

AIM: to evaluate the effects of a 12--weeks combined aerobic--resistance exercise therapy on fatigue and isokinetic muscle strength, glycemic control and health--related quality of life (HRQoL) in moderately affected type 2 diabetes (T2DM) patients. METHODS: a randomized controlled trial design was employed. Forty--three T2DM patients were assigned to an exercise group (n = 22), performing 3 weekly sessions of 60 minutes of combined aerobic--resistance exercise for 12--weeks; or a no exercise control group (n = 21). Both groups were evaluated at a baseline and after 12--weeks of exercise therapy for: 1) muscle strength and fatigue by isokinetic dynamometry; 2) plasma glycated hemoglobin A1C (HbA1C); and 3) HRQoL utilizing the SF--36 questionnaire. RESULTS: the exercise therapy led to improvements in muscle fatigue in knee extensors (--55%) and increased muscle strength in knee flexors and extensors (+15 to +30%), while HbA1C decreased (--18%). In addition, the exercising patients showed sizeable improvements in HRQoL: physical function (+53%), vitality (+21%) and mental health (+40%). CONCLUSION: 12--weeks of combined aerobic--resistance exercise was highly effective to improve muscle strength and fatigue, glycemic control and several aspects of HRQoL in T2DM patients. These data encourage the use of aerobic and resistance exercise in the good clinical care of T2DM.

Distinct phenotype of hepatotoxicity associated with illicit use of anabolic androgenic steroids.

BACKGROUND: We have observed an increase in hepatotoxicity (DILI) reporting related to the use of anabolic androgenic steroids (AAS) for bodybuilding. AIM: To characterise phenotype presentation, outcome and severity of AAS DILI. METHODS: Data on 25 cases of AAS DILI reported to the Spanish (20) and Latin-American (5) DILI Registries were collated and compared with previously published cases. RESULTS: AAS DILI increased from representing less than 1% of the total cases in the Spanish DILI Registry in the period 2001-2009 to 8% in 2010-2013. Young men (mean age 32 years), requiring hospitalisation, hepatocellular injury and jaundice were predominating features among the AAS cases. AAS DILI caused significantly higher bilirubin values independent of type of damage when compared to other drug classes (P = 0.001). Furthermore, the cholestatic AAS cases presented significantly higher mean peak bilirubin (P = 0.029) and serum creatinine values (P = 0.0002), compared to the hepatocellular cases. In a logistic regression model, the interaction between peak bilirubin values and cholestatic damage was associated with the development of AAS-induced acute kidney impairment (AKI) [OR 1.26 (95% CI: 1.035-1.526); P = 0.021], with 21.5 ×ULN being the best bilirubin cut-off point for predicting AKI risk (AUCROC 0.92). No fatalities occurred. CONCLUSIONS: Illicit recreational AAS use is a growing cause of reported DILI that can lead to severe hepatic and renal injury. AAS DILI is associated with a distinct phenotype, characterised by considerable bilirubin elevations independent of type of damage. Although hepatocellular injury predominates, acute kidney injury develops in cholestatic cases with pronounced jaundice.

Genetic influences on adult body mass index followed over 29 years and their effects on late-life mobility: a study of twin sisters.

BACKGROUND: The rise in body mass index (BMI) during adulthood increases the risk for metabolic disorders, functional limitations and disability in old age. This twin study examined prospectively whether genetic and environmental influences on women's BMI also account for mobility 29 years later. METHODS: The sample consisted of 103 monozygotic and 114 dizygotic pairs of twin sisters reared together. Body mass index was initially evaluated in 1975, when the women were aged 42.6+/-3.4 years, and was followed-up in 1981, 1990, 2001 and 2004. Mobility was evaluated using the standardised 6-minute walking test in 2001, when the women were aged 68.6+/-3.2 years, and followed-up 3 years later. An investigation was made into how genetic and environmental influences on adult BMI accounted for mobility in old age using a genetic latent growth modelling approach. RESULTS: During the follow-up period, BMI increased by 17%. Midlife BMI was a significant predictor of mobility 29 years later. Genetic influences on BMI level and its rate-of-change accounted for 37% and 25% respectively, of the genetic influences on mobility later in life. The corresponding environmental influences on BMI level and its rate-of-change were 35% and 22%. CONCLUSION: Genes predisposing to higher BMI across middle age increase the risk for poorer mobility in old age. Identifying those genes could lead to interventions targeted at preventing obesity and mobility loss later in life. However, modification of environmental factors, eg exercise and nutrition, remain the most feasible ways of influencing BMI and mobility across the life span.

Longitudinal changes in genetic and environmental influences on older women's walking ability.

This study examined the stability and change over time in genetic and environmental influences on walking ability among older women. Maximal walking speed over 10 m and 6-min walking endurance test were measured under standard conditions at baseline and 3 years later. At both times, 63 monozygotic (MZ) and 67 dizygotic (DZ) twin pairs were measured for walking speed and 58 MZ and 56 DZ pairs for walking endurance. Participants were twin sisters reared together and aged 63-75 years at baseline. Genetic and environmental influences were examined using longitudinal genetic modelling. The results showed that walking speed was preserved from baseline to follow-up. Genetic influences on walking speed were also similar at baseline (56%) and follow-up (60%). Walking endurance declined from baseline to follow-up, while genetic influences for walking endurance increased from baseline (40%) to follow-up (60%). Most of the genetic influences identified at baseline were also present at follow-up for walking speed (r(g)=0.72) and endurance (r(g)=0.71). In conclusion, among relatively healthy older women, genetic influences on walking speed and endurance were moderate at baseline, while at 3-year follow-up a moderate increment was observed in walking endurance. Newly expressed genetic influences were recognized at follow-up.

Exercise in waist-high warm water decreases pain and improves health-related quality of life and strength in the lower extremities in women with fibromyalgia.

OBJECTIVE: To evaluate the short- and long-term efficacy of exercise therapy in a warm, waist-high pool in women with fibromyalgia. METHODS: Thirty-four women (mean +/- SD tender points 17 +/- 1) were randomly assigned to either an exercise group (n = 17) to perform 3 weekly sessions of training including aerobic, proprioceptive, and strengthening exercises during 12 weeks, or to a control group (n = 17). Maximal unilateral isokinetic strength was measured in the knee extensors and flexors in concentric and eccentric actions at 60 degrees /second and 210 degrees /second, and in the shoulder abductors and adductors in concentric contractions. Health-related quality of life (HRQOL) was assessed using the EQ-5D questionnaire; pain was assessed on a visual analog scale. All were measured at baseline, posttreatment, and after 6 months. RESULTS: The strength of the knee extensors in concentric actions increased by 20% in both limbs after the training period, and these improvements were maintained after the de-training period in the exercise group. The strength of other muscle actions measured did not change. HRQOL improved by 93% (P = 0.007) and pain was reduced by 29% (P = 0.012) in the exercise group during the training, but pain returned close to the pretraining level during the subsequent de-training. However, there were no changes in the control group during the entire period. CONCLUSION: The therapy relieved pain and improved HRQOL and muscle strength in the lower limbs at low velocity in patients with initial low muscle strength and high number of tender points. Most of these improvements were maintained long term.