Stem cell-derived hepatocytes as a predictive model for drug-induced liver injury: are we there yet?

Amongst the different types of adverse drug reactions, drug-induced liver injury is the most prominent cause of patient morbidity and mortality. However, the current available hepatic model systems developed for evaluating safety have limited utility and relevance as they do not fully recapitulate a fully functional hepatocyte, and do not sufficiently represent the genetic polymorphisms present in the population. The rapidly advancing research in stem cells raises the possibility of using human pluripotent stem cells in bridging this gap. The generation of human induced pluripotent stem cells via reprogramming of mature human somatic cells may also allow for disease modelling in vitro for the purposes of assessing drug safety and toxicology. This would also allow for better understanding of disease processes and thus facilitate in the potential identification of novel therapeutic targets. This review will focus on the current state of effort to derive hepatocytes from human pluripotent stem cells for potential use in hepatotoxicity evaluation and aims to provide an insight as to where the future of the field may lie.     

Smoking, nutrition, alcohol and physical activity interventions targeting Indigenous Australians: rigorous evaluations and new directions needed

Objective: To describe and critique methodological aspects of interventions targeting reductions in smoking, poor nutrition, alcohol misuse and physical inactivity (SNAP risk factors) among Indigenous Australians. Methods: An electronic search of eight databases and a manual search of reference lists of literature reviews and reference libraries for Indigenous‐specific intervention studies published in peer‐reviewed journals (January 1990 to August 2007) were undertaken. Alcohol, smoking, nutrition or physical activity needed to be the primary focus of the study and the intervention needed to specifically target Indigenous Australians. Results: Twenty studies were selected for inclusion in the review. Methodologically, few studies employed randomisation or a control group, most omitted important details (e.g. costs), some did not report process measures (e.g. attrition rates), and some did not use validated measures. Two‐thirds of interventions were implemented at the community level and employed multiple strategies. Conclusion: There is a need for more rigorous evaluations of interventions targeting reductions in SNAP risk factors among Indigenous Australians, and to establish the reliability and validity of measures to quantify their effect. Implications: It may be beneficial for future Indigenous‐specific intervention research to focus on the evaluation of secondary prevention to complement the current concentration of effort targeting primary prevention. Community‐wide interventions, combining strategies of greater intensity for high risk individuals with those of less intensity targeting lower risk individuals, might also offer considerable promise.     

Nurse-Led Behavioral Management of Diabetes and Hypertension in Community Practices: A Randomized Trial

Background

Several trials have demonstrated the efficacy of nurse telephone case management for diabetes (DM) and hypertension (HTN) in academic or vertically integrated systems. Little is known about the real-world potency of these interventions.

Objective

To assess the effectiveness of nurse behavioral management of DM and HTN in community practices among patients with both diseases.

Design

The study was designed as a patient-level randomized controlled trial.

Participants

Participants included adult patients with both type 2 DM and HTN who were receiving care at one of nine community fee-for-service practices. Subjects were required to have inadequately controlled DM (hemoglobin A1c [A1c] ≥ 7.5 %) but could have well-controlled HTN.

Interventions

All patients received a call from a nurse experienced in DM and HTN management once every two months over a period of two years, for a total of 12 calls. Intervention patients received tailored DM- and HTN- focused behavioral content; control patients received non-tailored, non-interactive information regarding health issues unrelated to DM and HTN (e.g., skin cancer prevention).

Main Outcomes and Measures

Systolic blood pressure (SBP) and A1c were co-primary outcomes, measured at 6, 12, and 24 months; 24 months was the primary time point.

Results

Three hundred seventy-seven subjects were enrolled; 193 were randomized to intervention, 184 to control. Subjects were 55 % female and 50 % white; the mean baseline A1c was 9.1 % (SD = 1 %) and mean SBP was 142 mmHg (SD = 20). Eighty-two percent of scheduled interviews were conducted; 69 % of intervention patients and 70 % of control patients reached the 24-month time point. Expressing model estimated differences as (intervention – control), at 24 months, intervention patients had similar A1c [diff = 0.1 %, 95 % CI (−0.3, 0.5), p = 0.51] and SBP [diff = −0.9 mmH g, 95% CI (−5.4, 3.5), p = 0.68] values compared to control patients. Likewise, DBP (diff = 0.4 mmHg, p = 0.76), weight (diff = 0.3 kg, p = 0.80), and physical activity levels (diff = 153 MET-min/week, p = 0.41) were similar between control and intervention patients. Results were also similar at the 6- and 12-month time points.

Conclusions

In nine community fee-for-service practices, telephonic nurse case management did not lead to improvement in A1c or SBP. Gains seen in telephonic behavioral self-management interventions in optimal settings may not translate to the wider range of primary care settings.KEY WORDS: Diabetes, Hypertension, Implementation     

Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

Case reports: sudden worsening of cluster headache: A signal of aneurysmal thrombosis and enlargement

We report a 55-year-old man presenting with symptoms of cluster headache, including throbbing pain behind the left eye, tearing, and rhinorrhea. Magnetic resonance imaging and magnetic resonance angiography revealed no abnormalities. Two days of intravenous dihydroergotamine resolved his pain. His headaches were somewhat relieved with a treatment regimen of 100 mg of imipramine each night, 40 mg of propranolol twice a day, 250 mg of divalproex three times a day, and dihydroergotamine nasal spray for breakthrough headaches. Two months later, the severity of his pain increased dramatically. Repeat imaging revealed a large thrombosed left posterior communicating artery aneurysm. Following obliterative surgery, his headaches are infrequent and mild and resemble tension headaches. Dramatic changes in headache characteristics can be an indicator of aneurysmal enlargement and thrombosis. This case illustrates the importance of repeat imaging when a patient's headache significantly worsens.     

Anti‐envelope antibody responses in highly exposed seronegative individuals may be associated with protection from HCV infection

In rare cases, individuals with a history of long‐term injecting drug use remain seronegative and aviraemic, despite prolonged and likely repeated exposure to Hepatitis C virus (HCV) through high‐risk behaviour. We describe anti‐HCV Envelope (E) antibody responses in a prospective cohort of carefully defined highly exposed but uninfected subjects (HESN) and comparison subjects who were also high risk and uninfected, but rapidly became HCV infected (Incident). Longitudinally collected samples from HESN cases (n = 22) were compared to Incident controls (n = 22). IgG, IgM and IgA from sera were tested by ELISA to genotype 1a and 3a E glycoproteins, and recombinant genotype 1a E2 antigen. IgG subclass isotyping was performed for those positive for IgG. Virus‐neutralizing activity was assessed on HCV pseudoparticles, and HCV E–specific B cells analysed using flow cytometry. A significant minority of HESN cases (n = 10; 45%) had anti‐E, predominantly in the IgG2 subclass, which was not found in the pre‐infection time point of the Incident cases (n = 1; 5%). A subset of the HESN subjects also had neutralizing activity and HCV‐specific B cells detected significantly more than Incident cases pre‐infection. In conclusion, the HESN phenotype is associated with IgG2 anti‐E antibodies, neutralization activity and HCV E–specific memory B cells. These findings suggest that HESN subjects may be resistant to HCV infection through humoral immune‐mediated mechanisms.     

Initiative for Early Lung Cancer Research on Treatment: Development of Study Design and Pilot Implementation

Introduction

To maximize the benefits of computed tomographic screening for lung cancer, optimal treatment for small, early lung cancers is needed. Limiting the extent of surgery spares lung tissue, preserves pulmonary function, and decreases operative time, complications, and morbidities. It also increases the likelihood of resecting future new primary lung cancers. The goal is to assess alternative treatments in a timely manner.