Social normative perceptions of alcohol use and episodic heavy drinking among Central and Eastern European adolescents

This study examined alcohol use and related social normative perceptions among a sample of 1,886 Central-Eastern European high school students. The youth represented in the study averaged 16.5 years of age and were from several localities in the countries of Hungary, Slovakia, Czech Republic, and Romania. Data for the study were collected through a school-based alcohol use survey that was completed in June 2005. Our results support the hypothesis that drinking was related to perception of the prevalence of alcohol use by schoolmates and by the number of friends who drink and/or engage in episodic heavy drinking. Specific implications of findings in terms of substance use prevention are discussed. In addition, the need for future research and the limitations of the current research are discussed. This study was largely financially supported through an international grant from the College of Health and Human Performance, Brigham Young University.     

Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases

A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.     

Conformationally constrained analogues of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716): design, synthesis, computational analysis, and biological evaluations

Structure-activity relationships (SARs) of 1 (SR141716) have been extensively documented, however, the conformational properties of this class have received less attention. In an attempt to better understand ligand conformations optimal for receptor recognition, we have designed and synthesized a number of derivatives of 1, including a four-carbon-bridged molecule (11), to constrain rotation of the diaryl rings. Computational analysis of 11 indicates approximately 20 kcal/mol energy barrier for rotation of the two aryl rings. NMR studies have determined the energy barrier to be approximately 18 kcal/mol and suggested atropisomers could exist. Receptor binding and functional studies with these compounds displayed reduced affinity and potency when compared to 1. This indicates that our structural modifications either constrain the ring systems in a suboptimal orientation for receptor interaction or the introduction of steric bulk leads to disfavored steric interactions with the receptor, and/or the relatively modest alterations in the molecular electrostatic potentials results in disfavored Coulombic interactions.     

Interrater reliability of the Antipsychotic Non-Neurological Side-Effects Rating Scale measured in patients treated with clozapine

The Antipsychotic Non-Neurological Side-Effects Rating Scale (ANNSERS) was developed to provide a comprehensive measure for rating non-neurological adverse drug reactions (ADRs) to antipsychotics. Although there were already available measures that adequately rated specific non-neurological ADRs, such as sexual side effects, a need was identified for a scale that comprehensively rated the full range of non-neurological ADRs commonly seen across the spectrum of first and second generation antipsychotic drugs, including metabolic and autonomic ADRs. This article reports on work to establish the interrater reliability of an early version and a later, more comprehensive version of the ANNSERS (versions 1 and 2, v1 and v2, respectively). The measures were administered in London centres to patients treated with clozapine. Trained clinicians rated the patients simultaneously and independently. Interrater reliability on the scores was calculated using the kappa coefficient method. The results (mean kappa coefficients of 0.77 and 0.72, respectively) indicate that substantial interrater reliability was achieved for both versions. Items for which the main basis for rating was laboratory investigations rather than patient interview were largely excluded from this study, and kappas were also not calculated for items with a low frequency (less than 10%) of endorsement. Samples of patients on other antipsychotics would be required to reliably calculate kappa coefficients for these items. In conclusion, the ANNSERS represents a clinically applicable research innovation, with good interrater reliability on clinician judged items, which is now available for the comprehensive assessment of non-neurological ADRs to antipsychotics, to aid the processes of clinical audit, research and drug discovery.     

Reduction in Mortality after Umbilical Cord Blood Transplantation in Children Over a 20-Year Period (1995-2014)

Infections and graft-versus-host disease (GVHD) have historically resulted in high mortality among children undergoing umbilical cord blood transplantation (UCBT). However, recent advances in clinical practice have likely improved outcomes of these patients. We conducted a retrospective cohort study of children (<18years of age) undergoing UCBT at Duke University between January 1, 1995 and December 31, 2014. We compared 2-year all-cause and cause-specific mortality during 3 time periods based on year of transplantation (1995 to 2001, 2002 to 2007, and 2008 to 2014). We used multivariable Cox regression to identify demographic and UCBT characteristics that were associated with all-cause mortality, transplantation-related mortality, and death from invasive aspergillosis after adjustment for time period. During the 20-year study period 824 children underwent UCBT. Two-year all-cause mortality declined from 48% in 1995 to 2001 to 30% in 2008 to 2014 (P?=?.0002). White race and nonmalignant UCBT indications were associated with lower mortality. Black children tended to have a higher risk of death for which GVHD (18% versus 11%; P?=?.06) or graft failure (9% versus 3%; P?=?.01) were contributory than white children. Comparing 2008 to 2014 with 1995 to 2001, more than half (59%) of the reduced mortality was attributable to a reduction in infectious mortality, with 45% specifically related to reduced mortality from invasive aspergillosis. Antifungal prophylaxis with voriconazole was associated with lower mortality from invasive aspergillosis than low-dose amphotericin B lipid complex (hazard ratio, .09; 95% confidence interval, .01 to .76). With the decline in mortality from invasive aspergillosis, adenovirus and cytomegalovirus have become the most frequentinfectious causes of death in children after UCBT. Advances in clinical practice over the past 20years improved survival of children after UCBT. Reduced mortality from infections, particularly invasive aspergillosis, accounted for the largest improvement in survival and was associated with use of voriconazole for antifungal prophylaxis.     

Modified constraint-induced therapy and botulinum toxin A: a promising combination

Modified constraint-induced therapy and chemodenervation with botulinum toxin A are each efficacious in managing stroke-induced motor disorders; however, the application of these two promising modalities in combination is yet to be examined. This case study describes a 44-yr-old man who experienced a right middle cerebral artery infarct 14 mo before participating in modified constraint-induced therapy. After modified constraint-induced therapy completion, the patient exhibited substantial improvement in affected upper limb use and function but retained difficulty with finger extension secondary to hypertonicity and spasticity in the forearm flexor muscles. Selective chemodenervation of these muscles with botulinum toxin A greatly improved the patient's self-reported hand function and his scores using objective measures. The authors of this paper present this case to raise the idea of increasing treatment efficacy by combining these two modalities.     

Outcome of transphenoidal surgery for acromegaly and its relationship to surgical experience

BACKGROUND: A number of surgical series have been reported on the treatment of acromegaly and their results vary widely. The acceptable definition of remission has changed in recent years and it is known, though in a small series, that growth hormone levels of > 5 mU/l are still associated with an increased mortality from the condition. We have analysed data at this centre and examined the outcome of transphenoidal surgery for acromegaly, compared our results with recently published series from other centres and also assessed factors which might effect outcome including whether there is any demonstrable effect of the experience of the surgeon on outcome. PATIENTS AND METHODS: We have analysed data from all of our 139 patients in whom follow up data are available who have undergone initial transphenoidal surgery for acromegaly by one surgeon at this centre, between 1974 and 1995. Follow up was for a median of 5 years (range 1 month to 17 years). RESULTS: 67% of patients achieved the criterion for remission (mean GH < 5 mU/l). Success was related to tumour size and preoperative growth hormone values. Thus 91% of patients with microadenomas were in remission postoperatively compared to 46% of patients with macroadenomas. Analysis of the results according to the year of operation showed an improvement in success rates with time. More than 15 years ago, the success rate according to the growth hormone criteria set was 48% and the failure rate 52%. In contrast in the last 5 years analysed, the overall success rate was 74% with a failure rate of 26% (P < 0.04). The success rate for microadenomas was 50% initially, then remained 100%. The case mix was analysed and no change was found. We have also demonstrated an improvement in pituitary function (including normalization of preoperative elevated prolactin) with time so that pre 1981 16% of patients' pituitary function improved perioperatively but 10 years later this figure had risen to 34% (P < 0.03). There was no change over time in the development of pituitary hypofunction, complication rate or recurrence rate. CONCLUSION: Surgical treatment is a safe and effective treatment for acromegaly and remains the first choice of treatment for most acromegalic patients. The results of this centre compare favourably with series from other centres. We have demonstrated improved results, both in terms of post operative growth hormone values and pituitary function tests with time and increasing neurosurgical experience. We conclude that outcome for the surgical treatment for acromegaly is best achieved with one surgeon specialising in pituitary surgery. Improved operative outcome thus achieved has major cost implications and avoids the necessity for consideration of postoperative radiotherapy and the use of expensive growth hormone suppressing drugs in the postoperative period.