Objective Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine, via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy targeting substance dependence. We sought to investigate N-acetylcysteine as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have limited efficacy. Method In this 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (age 15-21, N = 116) received N-acetylcysteine (1200 mg) or placebo twice daily, each added to a contingency management intervention and brief (≤10 minute) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid tests during treatment among participants receiving N-acetylcysteine versus placebo, via intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group. Results N-acetylcysteine was well tolerated with minimal adverse events. N-acetylcysteine participants had more than twice the odds, compared to placebo participants, of submitting negative urine cannabinoid tests during treatment (odds ratio = 2.4, [95% CI: 1.1-5.2], p = 0.029). Exploratory secondary abstinence outcomes numerically favored N-acetylcysteine, but were not statistically significant. Conclusions This is the first randomized trial of pharmacotherapy for cannabis dependence in any age group yielding a positive primary cessation outcome via intent-to-treat analysis. Findings support N-acetylcysteine as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents. Further research is needed to replicate these findings and explore the efficacy of N-acetylcysteine across a variety of treatment contexts and outcomes. Trial Registration clinicaltrials.gov identifier: NCT 01005810

Background Chronic pressure overload (such as arterial hypertension) may cause left ventricular (LV) remodeling, alterations in cardiac function, and the development of diastolic heart failure. Changes in the composition of the myocardial extracellular matrix (ECM) may contribute to the development of pressure-overload (PO) induced LV remodeling. We hypothesized that a specific pattern of plasma biomarker expression that reflected changes in these pathophysiologic mechanisms would have diagnostic application to identify: 1-patients who have developed LV hypertrophy and 2-patients with LV hypertrophy who have developed diastolic heart failure. Methods and Results Plasma concentration of 17 biomarkers (MMP-1, 2, 3, 7, 8, 9, TIMP-1, 2, 3, 4, NT-proBNP, cardiotrophin, osteopontin, sRAGE, CITP, PINP, PIIINP), an echocardiogram, and 6-minute hall walk were performed on 241 referent control subjects, 144 patients with LV hypertrophy (LVH) but no evidence of heart failure, and 61 patients with LV hypertrophy and diastolic heart failure (DHF). A plasma multi-biomarker panel consisting of increased MMP-7, MMP-9, TIMP-1, PIIINP, and NT-proBNP predicted the presence of LVH with an AUC of 0.80. A plasma multi-biomarker panel consisting of increased MMP-2, TIMP-4, PIIINP and decreased MMP-8 predicted the presence of DHF with an AUC of 0.79. These multi-biomarkers panels performed better than any single biomarker including NT-proBNP, and better than using clinical co-variates alone (AUC = 0.73 for LVH, 0.68 for DHF). Conclusions Plasma biomarkers reflecting changes in ECM fibrillar collagen homeostasis, combined into a multi-biomarker panel, have discriminative value in identifying the presence of structural remodeling (LVH) and clinical disease (DHF).

Background Cocaine dependence is a chronic relapsing disorder characterized by periods of abstinence and high rates of return to drug using behavior. Elevated levels of stress have been associated with relapse to cocaine; however, the nature of this association is not well understood. Methods The relationship between reactivity to three human laboratory provocations and relapse to cocaine was investigated. Participants were 53 cocaine-dependent individuals who were admitted for a 2-day inpatient stay during which a psychosocial provocation (i.e., the Trier Social Stress Task), a pharmacological provocation (i.e., administration of 1ųg/kg corticotrophin releasing hormone; CRH), and a drug cue exposure paradigm were completed. Adrenocorticotrophic hormone (ACTH), cortisol, heart rate, and subjective cocaine craving and stress were assessed at baseline and at multiple time points post-task. Participants’ cocaine use was monitored for approximately one month following testing. Results The majority (72.3%) of participants relapsed to cocaine during the follow-up period. In response to the CRH and drug cue exposure, elevated subjective craving and stress were significant predictors of cocaine use during follow-up. In response to the Trier, attenuated neuroendocrine responses were significant predictors of cocaine use. Conclusions The findings provide further evidence of the ability of laboratory paradigms to predict relapse. The observed associations between stress reactivity and subsequent cocaine use highlight the clinical importance of the findings. Predictors of relapse may vary based on the type of provocation utilized. Interventions aimed at normalizing stress response, as measured using laboratory paradigms, may prove useful in relapse prevention.

Object Based on continuous monitoring of the pressure reactivity index (PRx), the authors defined individualized intracranial pressure (ICP) thresholds by graphing the relationship between ICP and PRx. These investigators hypothesized that an “ICP dose” based on individually assessed ICP thresholds would correlate more closely with the 6-month outcome when compared with ICP doses derived by the recommended universal thresholds of 20 and 25 mm Hg. Methods This study was a retrospective analysis of prospectively collected data from 327 patients with severe traumatic brain injury. Results Individualized thresholds were visually identified from graphs of PRx versus ICP; PRx > 0.2 was the cutoff. Intracranial pressure doses were then computed as the cumulative area under the curve above the defined thresholds in graphing ICP versus time. The term “Dose 20” (D20) was used to refer to an ICP threshold of 20 mm Hg; the markers D25 and DPRx were calculated similarly. Separate logistic regression models were fit with death as the outcome and each dose as the predictor, both alone and adjusted for covariates. The discriminative ability of each dose for mortality was assessed by receiver operating characteristic AUC analysis in which 5-fold cross-validation was used. A clearly identifiable PRx-based threshold was possible in 224 patients (68%). The DPRx (AUC 0.81, 95% CI 0.74–0.87) was found to have the highest area under the curve (AUC) over both D20 (0.75, 95% CI 0.68–0.81) and D25 (0.77, 95% CI 0.70–0.83); in the cross-validation model, DPRx remained the best discriminator of mortality (DPRx: AUC 0.77 [95% CI 0.68–0.89]; D20: 0.72 [95% CI 0.66–0.81]; and D25: 0.65 [95% CI 0.56–0.73]). Conclusions The authors explored the importance of different ICP thresholds for outcome by calculating patient-specific ICP doses based on the continuous monitoring of cerebrovascular pressure reactivity. They found that these individualized doses of intracranial hypertension were stronger predictors of death than doses derived from the universal thresholds of 20 and 25 mm Hg. The PRx could offer a method that can be directed toward individualizing the ICP threshold.

Background MicroRNAs (miRs) are small noncoding RNAs that recognize and bind to mRNAs and inhibit protein translation or degrade mRNA. Studies in animal models have suggested that miRs play a translational or post-translational regulatory role in myocardial growth, fibrosis, viability, and remodeling. However, whether specific temporal changes in miRs occur in patients during the LV remodeling process that follows a myocardial infarction (post-MI) remains unknown. The purpose of the current pilot study was to test the hypothesis that plasma miRs could be reliably measured in post-MI patients and that there is the relationship between temporal changes in specific miRs and post-MI LV structural remodeling. Methods and Results LV end-diastolic volume (EDV, echocardiography) and plasma miR were measured in age matched referent controls (CTL n=12) and post-MI patients (n=12) from day 2 through day 90 post-MI. Selected miRs (miR-1, -21, -29a, 133a, 208) were measured using quantitative rt-PCR and normalized for endogenous snRNA U6. Following MI, LVEDV increased progressively compared to CTL; this was accompanied by time dependent changes in specific miRs. For example, miR-21 initially fell 2 days post-MI (0.3±0.1 fold vs. CTL, p< 0.05), increased 5 days post-MI (2±1 fold vs. CTL, p< 0.05), and returned to CTL values at later post-MI time points. In contrast, miR-29a increased 5 days post-MI (4±1 fold vs. CTL, p< 0.05) and then fell to CTL at later time points. miR-208 increased 5 days post-MI (3±1 fold vs. CTL, p< 0.05) and remained elevated up to 90 days post-MI. Conclusions A time-dependent change in miRs occurred in post-MI patients that included an early and robust rise in miRs that have been shown to affect myocardial growth, fibrosis and viability. Thus, serially profiling miRs in the plasma of post-MI patients may hold both mechanistic and prognostic significance.

There is evidence that women may be less successful when attempting to quit smoking than men. One potential contributory cause of this gender difference is differential craving and stress reactivity to smoking-and negative affect/stress-related cues. The present human laboratory study investigated the effects of gender on reactivity to smoking and negative affect/stress cues by exposing nicotine dependent women (n=37) and men (n=53) smokers to two active cue types, each with an associated control cue: 1) in vivo smoking cues and in vivo neutral control cues, and 2) imagery-based negative affect/stress script and a neutral/relaxing control script. Both before and after each cue/script, participants provided subjective reports of smoking-related craving and affective reactions. Heart rate (HR) and skin conductance (SC) responses were also measured. Results indicated that participants reported greater craving and SC in response to smoking vs. neutral cues and greater subjective stress in response to the negative affect/stress vs. neutral/relaxing script. With respect to gender differences, women evidenced greater craving, stress and arousal ratings and lower valence ratings (greater negative emotion) in response to the negative affect/stressful script. While there were no gender differences in responses to smoking cues, women trended towards higher arousal ratings. Implications of the findings for treatment and tobacco-related morbidity and mortality are discussed.

Objective A heightened inflammatory response occurs following cardiac surgery. The perioperative use of glucocorticoids has been advocated as a method to improve postoperative outcomes. Randomized prospective studies to quantify the effect of methylprednisolone on perioperative outcomes in neonatal cardiac surgery have not been performed. We sought to determine whether pre-operative methylprednisolone would improve postoperative recovery in neonates requiring cardiac surgery. Methods Neonates scheduled for cardiac surgery were randomly assigned to receive either Two Dose (8 hours preoperatively and operatively; n=39) or Single Dose (operatively; n=37) methylprednisolone (30 mg/kg/dose) in a double-blind, placebo-controlled trial. The primary outcome was the incidence of low cardiac output syndrome (standardized score) or death 36 hours postoperatively. Secondary outcomes were death at 30 days, interlukin-6 levels, inotropic score, fluid balance, serum creatinine, and ICU and hospital stay. Results Preoperative plasma levels of the inflammatory cytokine interlukin-6 were reduced by 2-fold (p<0.001) in the Two Dose methylprednisolone group, consistent with the anti-inflammatory effects of methylprednisolone. However, the incidence of low cardiac output syndrome was 46% (17/37) in the Single Dose and 38% (15/39) in the Two Dose methylprednisolone groups (p=0.51). Two Dose methylprednisolone was associated with a higher serum creatinine (0.61±0.18 vs. 0.53±0.12 mg/dL, p=0.03), and poorer postoperative diuresis (−96±49 mL, p=0.05). Inotropic requirement, duration of mechanical ventilation, ICU, and hospital stay did not differ between the 2 groups. Conclusions Combined preoperative and intraoperative use of glucocorticoids in neonatal cardiac surgery does not favorably affect early clinical outcomes, and may exacerbate perioperative renal dysfunction.

Objectives Elevated B-type natriuretic peptide (BNP) concentrations are associated with increased morbidity and mortality in ambulatory patients with congestive heart failure (CHF) or acute coronary syndromes. The value of BNP for predicting adverse cardiac surgical outcomes is less certain. We hypothesized that preoperative plasma BNP independently predicts in-hospital postoperative ventricular dysfunction (VnD), hospital length of stay (HLOS) and mortality up to 5 years after primary coronary artery bypass graft (CABG) surgery. Methods Prospective longitudinal study of 1023 patients undergoing primary CABG surgery with cardiopulmonary bypass (CPB) at two institutions. VnD was defined as a requirement either for ≥2 inotropes, or new intra-aortic balloon pump or ventricular assist device support after CABG surgery. Mortality was defined as all-cause death within 5 years after surgery. Multivariable analyses were performed to assess the independent role of preoperative BNP in predicting postoperative VnD, HLOS, and up to 5 year postoperative mortality, while controlling for patient demographics, perioperative risk factors, and medications. Results Preoperative plasma BNP concentration predicted VnD, HLOS and mortality in univariate and multivariable analyses. Logistic regression identified preoperative BNP as an independent predictor of VnD (odds ratio=1.92; 95% CI=1.12–3.29; P=0.018) after adjusting for preoperative left ventricular ejection fraction, CHF symptom severity and other clinical predictors. Multivariable Cox proportional hazards models identified preoperative BNP as an independent predictor of HLOS (hazard ratio=1.42; 95% CI=1.18–1.72; P=0.0002) and mortality (hazard ratio=1.89; 95% CI=1.08–3.33; P=0.026). Conclusions Preoperative plasma BNP concentration independently predicts in-hospital VnD, HLOS, and all-cause mortality up to 5 years after primary CABG surgery.