Engineering cell platforms for myocardial regeneration

INTRODUCTION: Various engineered 'cell-platforms' have been reported in recent years for the possible treatment of myocardial infarction (MI) and end-stage heart failure. These engineered platforms rely on two key factors: cells and/or biomaterial scaffolds for the regeneration of the infarcted heart tissue. AREAS COVERED: Two major cell-platform approaches are described and broadly categorized as 'injectable cell platforms' and 'patch-based cell platforms'. The recent advancements in these cell-platforms in terms of their relative successes in-vivo as well as their clinical feasibility are summarized. Natural as well as synthetic scaffolds, with or without the cellular component, are compared with cell based therapy alone. This review focuses on achievements, as well as the gaps that are presently checking any progress towards producing clinically relevant panacea for myocardial regeneration. EXPERT OPINION: Cardiac and induced pluripotent stem cells will probably be the focus of future research. The combined cell-biomaterial scaffold therapy is superior to cell therapy alone. Nevertheless, encouraging pre-clinical successes have limited translation into clinical practice due to limited cell survival post transplantation, inadequate construct thicknesses for human-sized hearts and the traditional use of 'flat (2D) tissue culture' techniques. The development of complementary dynamic 3D cultivation platforms will probably lead to improved outcomes and enable fast screening of various therapeutic approaches.     

P wave dispersion in familial Mediterranean fever

Familial Mediterranean fever (FMF) is a hereditary disease characterized by recurrent and self-terminated attacks of fever and polyserositis. A recent study found that FMF patients had an abnormally high P wave duration and P wave dispersion, markers for supraventricular arrhythmogenicity. The aim of our study was to further evaluate atrial dispersion in FMF patients. The study group consisted of 26 patients with uncomplicated FMF and age- and sex-matched control subjects. All participants underwent 12-lead electrocardiography under strict standards. P wave length and P wave dispersion were computed from a randomly selected beat and from an averaged beat constructed from 7 to 12 beats, included in a 10-s ECG. No statistically significant differences were found between the groups in minimal, maximal, and average P wave duration and P wave dispersion calculated either from a random beat or averaged beats. During 6 months of follow-up, no supraventricular arrhythmias were documented in either group. FMF patients who are continuously treated with colchicine and do not develop amyloidosis have normal atrial conduction parameters and therefore seemingly do not have an increased electrocardiographic risk of atrial fibrillation.     

Self-report of illicit benzodiazepine use on the Addiction Severity Index predicts treatment outcome

The relationship between pre-treatment illicit benzodiazepine use (days of use in the last 30) assessed on the Addiction Severity Index (ASI) and treatment outcome was investigated by retrospective analysis of data from two controlled clinical trials in 361 methadone maintained cocaine/opiate users randomly assigned to 12-week voucher- or prize-based contingency management (CM) or control interventions. Based on screening ASI, participants were identified as non-users (BZD-N; 0 days of use) or users (BZD-U; >0 days of use). Outcome measures were: urine drug screens (thrice weekly); quality of life and self-reported HIV-risk behaviors (every 2 weeks); and current DSM-IV diagnosis of cocaine and heroin dependence (study exit). In the CM group, BZD-U had significantly worse outcomes on in-treatment cocaine use, quality-of-life scores, needle-sharing behaviors, and current heroin dependence diagnoses at study exit compared to BZD-N. In the control group, BZD-U had significantly higher in-treatment cocaine use but did not differ from BZD-N on psychosocial measures. Thus, in a sample of non-dependent BZD users, self-reported illicit BZD use on the ASI, even at low levels, predicted worse outcome on cocaine use and blunted response to CM.     

Effects of valproic acid on the placental barrier in the pregnant mouse: Optical imaging and transporter expression studies

Our aim was to evaluate the effects of valproic acid (VPA) on the function of the placental barrier in vivo, in pregnant mice. Studies were conducted on gestational days 12.5 (mid‐gestation) or 17.5 (late gestation), following intraperitoneal treatment with 200 mg/kg VPA or the vehicle. Indocyanine green (ICG; 0.167 mg, i.v.) was used as a marker for the placental barrier permeability. Transporter expression was evaluated by quantitative ‐PCR. VPA treatment was associated with a 40% increase (p < 0.05) in accumulation of ICG in maternal liver in mid‐pregnancy and a decrease by one fifth (p < 0.05) in late pregnancy. Ex vivo, VPA treatment led to a 20% increase (p < 0.05) in fetal ICG emission in mid‐pregnancy. Also in mid‐pregnancy, the placental expression of the L ‐type amino acid transporter, the organic anion–transporting polypeptide (Oatp)4a1 (thyroid hormone transporter), and the reduced folate carrier was lower in VPA‐treated mice (p < 0.05). In late pregnancy, hepatic Oatp4a1 levels were 40% less than in controls (p > 0.05). The observed changes in placental transporter expression and function support further research into the potential role of the placenta in the adverse pregnancy outcomes of VPA. Near‐infrared imaging provides a noninvasive, nonradioactive tool for future studies on the effects of epilepsy and antiepileptic drugs on tissue transport functions.     

Clonidine blocks stress-induced craving in cocaine users

Rationale  

Reactivity to stressors and environmental cues, a putative cause of relapse in addiction, may be a useful target for relapse-prevention medication. In rodents, alpha-2 adrenergic agonists such as clonidine block stress-induced reinstatement of drug seeking, but not drug cue-induced reinstatement.     

Expression of activated type I receptor tyrosine kinases in early breast cancer

Overexpression of EGFR, HER2 and HER3 are known to be associated with poor outcome in breast cancer. Few studies have examined the clinical impact of activation of these proteins. In the present study, we evaluated EGFR, HER2 and HER3 and the activated (phosphorylated) forms of these proteins in patients with early breast cancer. EGFR, HER2, HER3, pEGFR, pHER2 and pHER3 expression was determined by immunohistochemical analysis of tissue microarrays constructed from tumours within the Edinburgh Breast Conservation Series (BCS). The BCS represents a fully-documented consecutive cohort of 1,812 patients treated by breast conservation surgery in a single institution. Our results demonstrate overexpression of HER2 and pHER2 to be associated with a significant reduction in overall survival (OS) (HR: 1.66, 95 % CI 1.22-2.26, p = 0.001 and HR: 1.57, 95 % CI 1.22-2.03, p = 0.001, respectively) and distant relapse-free survival (DRFS) (HR: 1.63, 95 % CI 1.23-2.18, p = 0.001 and HR: 1.55, 95 % CI 1.23-1.97, p = 0.0002, respectively). Paradoxically, expression of pEGFR was associated with a significantly improved OS (HR: 0.67 95 % CI 0.50-0.91, p = 0.01) and DRFS (HR: 0.73, 95 % CI 0.56-0.96, p = 0.025). Expression of activated EGFR/HER2 provides additional information on ER positive breast cancer patients and suggests alternative treatment for those in this subgroup.     

Design considerations for a study to evaluate the impact of smoking cessation treatment on stimulant use outcomes in stimulant-dependent individuals

Cigarette smoking is prevalent in cocaine/methamphetamine-dependent patients and associated with significant morbidity and mortality, yet, the provision of smoking cessation treatment in conjunction with substance use disorder (SUD) treatment is not standard practice. This is due, in part, to clinician concern that combining smoking cessation treatment with SUD treatment could lead to poorer SUD outcomes. The NIDA Clinical Trials Network is conducting a 10-week, two-group, randomized trial to evaluate the impact of providing smoking cessation treatment (SCT) with SUD treatment as usual (TAU), compared to TAU alone, in smokers who are in outpatient treatment for cocaine or methamphetamine dependence. Approximately 528 participants, recruited from 12 community treatment programs, will be randomized into the trial. The present paper describes key design decisions made during protocol development. The trial is designed to evaluate the relationship between cigarette smoking and stimulant use, which prior research suggests is linked, and should contribute to our understanding of how best to address the co-occurring problems of nicotine dependence and cocaine/methamphetamine-dependence. Unique aspects of the trial include the primary question of interest, which concerns the impact of providing SCT on SUD outcomes rather than on smoking outcomes, and the intensity of the SCT chosen, which includes bupropion, nicotine replacement, and two psychosocial interventions.