Opioid dependence treatment: options in pharmacotherapy.

The development of effective treatments for opioid dependence is of great importance given the devastating consequences of the disease. Pharmacotherapies for opioid addiction include opioid agonists, partial agonists, opioid antagonists, and alpha-2-adrenergic agonists, which are targeted toward either detoxification or long-term agonist maintenance. Agonist maintenance therapy is currently the recommended treatment for opioid dependence due to its superior outcomes relative to detoxification. Detoxification protocols have limited long-term efficacy, and patient discomfort remains a significant therapy challenge. Buprenorphine's effectiveness relative to methadone remains a controversy and may be most appropriate for patients in need of low doses of agonist treatment. Buprenorphine appears superior to alpha-2 agonists, however, and office-based treatment with buprenorphine in the USA is gaining support. Studies of sustained-release formulations of naltrexone suggest improved effectiveness for retention and sustained abstinence; however, randomized clinical trials are needed.

A randomized, double-blind, placebo-controlled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence.

BACKGROUND: Alcohol dependence is extremely common in patients with bipolar disorder and is associated with unfavorable outcomes including treatment nonadherence, violence, increased hospitalization, and decreased quality of life. While naltrexone is a standard treatment for alcohol dependence, no controlled trials have examined its use in patients with co-morbid bipolar disorder and alcohol dependence. In this pilot study, the efficacy of naltrexone in reducing alcohol use and on mood symptoms was assessed in bipolar disorder and alcohol dependence. METHODS: Fifty adult outpatients with bipolar I or II disorders and current alcohol dependence with active alcohol use were randomized to 12 weeks of naltrexone (50 mg/d) add-on therapy or placebo. Both groups received manual-driven cognitive behavioral therapy designed for patients with bipolar disorder and substance-use disorders. Drinking days and heavy drinking days, alcohol craving, liver enzymes, and manic and depressed mood symptoms were assessed. RESULTS: The 2 groups were similar in baseline and demographic characteristics. Naltrexone showed trends (p < 0.10) toward a greater decrease in drinking days (binary outcome), alcohol craving, and some liver enzyme levels than placebo. Side effects were similar in the 2 groups. Response to naltrexone was significantly related to medication adherence. CONCLUSIONS: Results suggest the potential value and acceptable tolerability of naltrexone for alcohol dependence in bipolar disorder patients. A larger trial is needed to establish efficacy.

Aggression, impulsivity and serotonin in drug dependence

Aggression, impulsivity, and central serotonergic function were evaluated in two groups of human volunteers; one group having a history of substance dependence (DRUG+) and another group with no drug use history (DRUG$-$). The hypothesis was that DRUG+ subjects would be more aggressive, more impulsive, and have attenuated serotonergic function. Results showed that DRUG+ subjects behaved more aggressively in a computer paradigm of aggression and also reported more aggression on questionnaires than DRUG$-$ subjects. In a computer paradigm of impulsivity, the DRUG+ group showed a lesser ability to delay gratification than the DRUG$-$ group in the last session of testing. The DRUG+ subjects also reported more venturesomeness and problems associated with low impulse control on questionnaires. Serotonergic function was measured through the neuroendocrine and hypothermic response to an orally administered serotonin (5-HT) agonist specific to the 5-HT$\rm\sb{1A}$ receptor subtype (ipsapirone). The neuroendocrine responses did not differ between DRUG$\pm$ groups, indicating no difference in the sensitivity of the presynaptic or postsynaptic 5-HT$\rm\sb{1A}$ receptors. An unexpected result was that the indicator hormone, cortisol, was at a lower baseline level in the DRUG+ group than the DRUG$-$ group. Lowered cortisol levels have been previously noted in children at high risk foul antisociality and future drug use. A principal components analysis including impulsivity, aggression, and serotonergic function measures produced three unique factors. The factors, Antisocial Tendency and Self-Control and Serotonergic Function combined to produce a significant regression equation explaining 36% of variability in the DRUG$\pm$ groups. These factors included measures of aggression, impulsivity, mood, and educational attainment. These results suggest that the current measures of aggression and impulsivity were predictive of a drug dependence disorder but that neuroendocrine function is not yet a useful indicator of drug dependence status. ^

Motivation as a predictor of drinking outcomes after residential treatment programs for alcohol dependence

OBJECTIVES: Patients' motivation to change their substance use is usually viewed as a crucial component of successful treatment. The objective of this study was to examine whether motivation contributes to drinking outcomes after residential treatment for alcohol dependence. METHODS: Our sample included 415 Swiss patients from 12 residential alcohol treatment programs. We statistically controlled for important predictors, such as sex, employment, alcohol consumption before admission, severity of alcohol dependence, severity of psychiatric symptoms at admission, and alcohol-related self-efficacy at discharge. Abstinence, alcohol consumption, and time to first drink were used as primary outcome measures and were assessed 1 year after discharge from treatment. RESULTS: Action-oriented motivation to change substance use had a modest impact on drinking outcomes. At the 1-year follow-up, only the Taking Steps subscale of the Stages of Change Readiness and Treatment Eagerness Scale and alcohol-related self-efficacy were found to be significant predictors of abstinence and the number of standard drinks. CONCLUSIONS: The impact of action-oriented motivation at admission to residential treatment is modest but still relevant, compared with other outcome predictors. It may be useful to focus treatment on improving action-oriented motivation to reduce substance use

The role of diameter versus volume as the best prognostic measurement of abdominal aortic aneurysms

Accurate measurement of abdominal aortic aneurysms is necessary to predict rupture risk and, more recently, to follow aneurysm sac behavior following endovascular repair. Up until this point, aneurysm diameter has been the most common measurement utilized for these purposes. Although aneurysm diameter is predictive of rupture, accurate measurement is hindered by such factors as aortic tortuosity and interobserver variability, and it does not account for variations in morphology such as saccular aneurysms. Additionally, decreases in aneurysm diameter do not completely describe the somewhat complex remodeling seen following endovascular repair of aortic aneurysms. Measurement of aneurysm volume has the advantage of describing aneurysm morphology in a multidimensional fashion, but it has not been readily available or easily measured until recently. This has changed with the introduction of commercially available software tools that permit quicker and easier to perform volume measurements. Whether it is time for volume to replace, or compliment, diameter is the subject of the current debate.

Part two: Against the motion. External diameter for AAA size

Aneurysm diameter measurement is quick and easy, but suffers from the pitfalls of being "too rough and ready". When semi-automated segmentation took 7-10 minutes to estimate volume, it was not a practical tool for busy, routine clinical practice. Today, the availability of automatic segmentation in seconds is bound to make volume measurement, along with 3D ultrasonography, the tools of the future. There can be no debate.

Dependence of Eemian Greenland temperature reconstructions on the ice sheet topography

The influence of a reduced Greenland Ice Sheet (GrIS) on Greenland's surface climate during the Eemian interglacial is studied using a set of simulations with different GrIS realizations performed with a comprehensive climate model. We find a distinct impact of changes in the GrIS topography on Greenland's surface air temperatures (SAT) even when correcting for changes in surface elevation, which influences SAT through the lapse rate effect. The resulting lapse-rate-corrected SAT anomalies are thermodynamically driven by changes in the local surface energy balance rather than dynamically caused through anomalous advection of warm/cold air masses. The large-scale circulation is indeed very stable among all sensitivity experiments and the Northern Hemisphere (NH) flow pattern does not depend on Greenland's topography in the Eemian. In contrast, Greenland's surface energy balance is clearly influenced by changes in the GrIS topography and this impact is seasonally diverse. In winter, the variable reacting strongest to changes in the topography is the sensible heat flux (SHF). The reason is its dependence on surface winds, which themselves are controlled to a large extent by the shape of the GrIS. Hence, regions where a receding GrIS causes higher surface wind velocities also experience anomalous warming through SHF. Vice-versa, regions that become flat and ice-free are characterized by low wind speeds, low SHF, and anomalous low winter temperatures. In summer, we find surface warming induced by a decrease in surface albedo in deglaciated areas and regions which experience surface melting. The Eemian temperature records derived from Greenland proxies, thus, likely include a temperature signal arising from changes in the GrIS topography. For the Eemian ice found in the NEEM core, our model suggests that up to 3.1 °C of the annual mean Eemian warming can be attributed to these topography-related processes and hence is not necessarily linked to large-scale climate variations.

Low-density lipoprotein particle diameter and mortality: the Ludwigshafen Risk and Cardiovascular Health Study.

AIMS The aim of the study was to examine whether differences in average diameter of low-density lipoprotein (LDL) particles were associated with total and cardiovascular mortality. METHODS AND RESULTS We studied 1643 subjects referred to coronary angiography, who did not receive lipid-lowering drugs. During a median follow-up of 9.9 years, 398 patients died, of these 246 from cardiovascular causes. We calculated average particle diameters of LDL from the composition of LDL obtained by β-quantification. When LDL with intermediate average diameters (16.5-16.8 nm) were used as reference category, the hazard ratios (HRs) adjusted for cardiovascular risk factors for death from any cause were 1.71 (95% CI: 1.31-2.25) and 1.24 (95% CI: 0.95-1.63) in patients with large (>16.8 nm) or small LDL (<16.5 nm), respectively. Adjusted HRs for death from cardiovascular causes were 1.89 (95% CI: 1.32-2.70) and 1.54 (95% CI: 1.06-2.12) in patients with large or small LDL, respectively. Patients with large LDL had higher concentrations of the inflammatory markers interleukin (IL)-6 and C-reactive protein than patients with small or intermediate LDL. Equilibrium density gradient ultracentrifugation revealed characteristic and distinct profiles of LDL particles in persons with large (approximately even distribution of intermediate-density lipoproteins and LDL-1 through LDL-6) intermediate (peak concentration at LDL-4) or small (peak concentration at LDL-6) average LDL particle diameters. CONCLUSIONS Calculated LDL particle diameters identify patients with different profiles of LDL subfractions. Both large and small LDL diameters are independently associated with increased risk mortality of all causes and, more so, due to cardiovascular causes compared with LDL of intermediate size.

Measurement of the jet radius and transverse momentum dependence of inclusive jet suppression in lead-lead collisions at sqrtsNN=2.76 TeV with the AT detector

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at root S-NN = 2.76 TeV corresponding to an integrated luminosity of approximately 7 mu b(-1), ATLAS has measured jets with a calorimeter system over the pseudorapidity interval vertical bar eta vertical bar < 2.1 and over the transverse momentum range 38 < pT <210 GeV. Jets were reconstructed using the anti-k(t) algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," R-CP. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. R-CP varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.

Measurement of the Azimuthal Angle Dependence of Inclusive Jet Yields in Pb+Pb Collisions at sqrts_NN= 2.76 TeV with the ATLAS detector

Measurements of the variation of inclusive jet suppression as a function of relative azimuthal angle, Delta phi, with respect to the elliptic event plane provide insight into the path-length dependence of jet quenching. ATLAS has measured the Delta phi dependence of jet yields in 0.14 nb(-1) of root s(NN) = 2.76 TeV Pb + Pb collisions at the LHC for jet transverse momenta p(T) > 45 GeV in different collision centrality bins using an underlying event subtraction procedure that accounts for elliptic flow. The variation of the jet yield with Delta phi was characterized by the parameter, nu(jet)(2), and the ratio of out-of-plane (Delta phi similar to pi/2) to in-plane (Delta phi similar to 0) yields. Nonzero nu(jet)(2) values were measured in all centrality bins for p(T) < 160 GeV. The jet yields are observed to vary by as much as 20% between in-plane and out-of-plane directions.

Interaction of Plectin with Keratins 5 and 14: Dependence on Several Plectin Domains and Keratin Quaternary Structure.

Plectin, a cytolinker of the plakin family, anchors the intermediate filament (IF) network formed by keratins 5 and 14 (K5/K14) to hemidesmosomes, junctional adhesion complexes in basal keratinocytes. Genetic alterations of these proteins cause epidermolysis bullosa simplex (EBS) characterized by disturbed cytoarchitecture and cell fragility. The mechanisms through which mutations located after the documented plectin IF-binding site, composed of the plakin-repeat domain (PRD) B5 and the linker, as well as mutations in K5 or K14, lead to EBS remain unclear. We investigated the interaction of plectin C terminus, encompassing four domains, the PRD B5, the linker, the PRD C, and the C extremity, with K5/K14 using different approaches, including a rapid and sensitive fluorescent protein-binding assay, based on enhanced green fluorescent protein-tagged proteins (FluoBACE). Our results demonstrate that all four plectin C-terminal domains contribute to its association with K5/K14 and act synergistically to ensure efficient IF binding. The plectin C terminus predominantly interacted with the K5/K14 coil 1 domain and bound more extensively to K5/K14 filaments compared with monomeric keratins or IF assembly intermediates. These findings indicate a multimodular association of plectin with K5/K14 filaments and give insights into the molecular basis of EBS associated with pathogenic mutations in plectin, K5, or K14 genes.Journal of Investigative Dermatology advance online publication, 10 July 2014; doi:10.1038/jid.2014.255.

Negative density dependence of seed dispersal and seedling recruitment in a Neotropical palm

Negative density dependence (NDD) of recruitment is pervasive in tropical tree species. We tested the hypotheses that seed dispersal is NDD, due to intraspecific competition for dispersers, and that this contributes to NDD of recruitment. We compared dispersal in the palm Attalea butyracea across a wide range of population density on Barro Colorado Island in Panama and assessed its consequences for seed distributions. We found that frugivore visitation, seed removal and dispersal distance all declined with population density of A. butyracea, demonstrating NDD of seed dispersal due to competition for dispersers. Furthermore, as population density increased, the distances of seeds from the nearest adult decreased, conspecific seed crowding increased and seedling recruitment success decreased, all patterns expected under poorer dispersal. Unexpectedly, however, our analyses showed that NDD of dispersal did not contribute substantially to these changes in the quality of the seed distribution; patterns with population density were dominated by effects due solely to increasing adult and seed density.

Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence

Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n = 95 group A, n = 103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.