Single‐ and Multiple‐Dose Randomized Studies of Blosozumab,a Monoclonal Antibody Against Sclerostin,in Healthy Postmenopausal Women

Two clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses (intravenous [iv] and subcutaneous [sc]) of blosozumab in postmenopausal women, including prior/current bisphosphonate (BP) users. In these phase 1, randomized, subject‐ and investigator‐blind, placebo‐controlled studies, subjects received escalating doses of blosozumab: single iv doses up to 750 mg, single sc doses of 150 mg, multiple iv doses up to 750 mg every 2 weeks (Q2W) for 8 weeks, multiple sc doses up to 270 mg Q2W for 8 weeks, or placebo. Six subjects were randomized to each dose in the single‐dose study (12 to placebo) and up to 12 subjects to each arm in the multiple‐dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose‐dependent responses were observed in sclerostin, N‐terminal propeptide of procollagen type 1, bone‐specific alkaline phosphatase, osteocalcin, C‐terminal fragment of type 1 collagen, and bone mineral density (BMD) after single and multiple (up to 5) administrations of blosozumab. There was up to a 3.41% (p = 0.002) and up to a 7.71% (p < 0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior BP use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. In summary, blosozumab was well tolerated and exhibited anabolic effects on bone. These findings support further investigation of blosozumab as a potential anabolic therapy for osteoporosis. © 2014 American Society for Bone and Mineral Research.     

Does colour say something about emotions?: Laypersons’ assessments of colour drawings

This study examines the use of colours in estimating psychological states. Sixteen artworks were produced by two different populations: clients with a psychological condition and psychologically healthy people. Their drawings were presented in pairs on screen either chromatically or achromatically. Two hundred and twenty-four subjects were asked to choose a picture which they thought had been produced by a psychologically unhealthy client. The rate of correct answers was higher for the chromatic condition. When artworks were presented achromatically, errors increased. Analysis of colour factors and post-inquiry indicated that the number of colours used, list of colours, and colour connotation might have affected choices. This study confirms that colour can be effective in estimating psychological states. Its implications and limitations are discussed and suggestions made for future study.     

Parkin Co-Regulated Gene (PACRG) is regulated by the ubiquitin-proteasomal system and is present in the pathological features of Parkinsonian diseases

Mutations in parkin are a common cause of early-onset autosomal recessive Parkinson's disease. Parkin Co-Regulated Gene (PACRG) is a novel gene that was discovered because of its close genetic proximity to parkin and the two genes were subsequently demonstrated to be regulated by a bi-directional promoter. However the role of PACRG has not been well characterized and the distribution of the protein in both normal and diseased brain is not known. Here, we report that like parkin, PACRG is regulated by the ubiquitin-proteasomal system. Immunohistochemistry identified PACRG in astrocytes throughout the brain and in pigmented noradrenergic neurons of the locus coeruleus. PACRG was also detected in Lewy bodies and glial cytoplasmic inclusions in patients with Parkinson's disease and Multiple System Atrophy, respectively. Together, these results demonstrate that PACRG is regulated by the ubiquitin-proteasomal system and may play a role in the pathogenesis of Parkinson's disease.     

Family therapy and dialectical behavior therapy with adolescents: Part I: Proposing a clinical synthesis

Although the practice of family therapy in dialectical behavior therapy (DBT) with multiproblem suicidal adolescents is common and generally indicated, a particular model has yet to be delineated with this age group. The purpose of this article is to propose a coherent clinical synthesis of the more individually oriented DBT strategies with a broader family-systems orientation that maintains the integrity of both theoretical approaches while addressing the treatment needs of adolescents and their families. First, the authors briefly review the literature. Second, they describe the core dialectic of DBT, balancing acceptance and change, and its relevance to family therapy. Finally, the authors propose several specific acceptance and change strategies useful when implementing DBT family therapy with multi-problem adolescents.     

Endogenous gonadal hormones modulate behavioral and neurochemical responses to acute and chronic cocaine administration

Recent evidence demonstrates that there are sex differences in behavioral responses to cocaine. Further, reproductive gonadal hormones (estrogen, progesterone and testosterone) have been further implicated in mediating some of the cocaine-induced alterations. To better understand sex differences and the role of gonadal hormones in cocaine-induced locomotor and stereotypic behavior, intact and gonadectomized male and female Fischer rats were randomly assigned to either chronic cocaine (15 mg/kg) or saline treatments for 14 days followed by a challenge administration (7 days after the last cocaine/saline administration). Locomotor (ambulatory and rearing) and stereotypic activities were measured on days 1, 7 and 14 as well as after withdrawal/challenge with cocaine. Overall, intact female rats consistently showed a rapid (acquired by day 7) and longer lasting (persistent through the challenge dose) sensitization for all locomotor behaviors than any of the other groups. In contrast, intact males developed sensitization of these locomotor activities only in response to chronic cocaine administration, and after withdrawal and drug challenge the sensitization to cocaine-induced locomotor activity was no longer present. In female rats, gonadectomy affected ambulatory activity but not total and rearing responses after acute, sub-acute, chronic and challenge response to cocaine. On the other hand, castrated male rats were affected in cocaine-induced ambulatory activity but not rearing activity. In intact male rats, cocaine-induced stereotypic activity was rapidly and persistently sensitized after 7 days of cocaine administration, where gonadectomized male rats developed sensitization to cocaine-induced stereotypic activity only after a challenge cocaine administration. Although cocaine induced stereotypic activity, no statistically significant differences were observed between intact and ovariectomized female rats or throughout the different lengths of cocaine administration. After a challenge of cocaine, corticosterone levels were induced in all experimental groups. Moreover, no differences in levels of benzoylecgonine, a cocaine metabolite, were observed. Similar to our previous observations after acute cocaine administration, after challenge of cocaine, an increase in progesterone and a decrease in testosterone levels were observed in intact females and males, respectively. In summary, endogenous hormones seem to be involved in the behavioral activation and development of sensitization to cocaine.     

Complete mapping of a novel HLA A*6801-restricted HIV-1 Tat epitope directly with a rapid modified enzyme-linked immunospot assay

We identified a novel HLA A*6801-restricted HIV-1 Tat-derived cytotoxic T lymphocyte (CTL) epitope using an adapted enzyme-linked immunospot assay that allows the rapid ex vivo identification of CTL epitopes together with their associated HLA Class I restriction elements. The optimal 11 amino acid residue Tat epitope efficiently stabilized the refolding of monomeric peptide-HLA A6801 complexes in vitro and fluorochrome-labelled, tetrameric peptide-HLA A6801 complexes stained CD8 T cells specific for this epitope directly ex vivo.     

Understandings of risk among HIV seroconverters in Sydney

This paper examines the risk discourses of Sydney gay men who had recently become HIV positive. 92 in depth interviews were conducted eliciting narratives about the incident in which they believed they became infected. The veracity of this narrative was negotiated between the interviewer and participant. Qualitative analysis was performed in order to distinguish different styles of thinking and acting in relation to risk. Two overarching discourses were distinguished that broadly related to the fields of public health, HIV prevention education, social theory and health policy. These we characterise as ‘quantifiable/objectivist’ and ‘social/subjectivist’. The first approach sees risk as objectively knowable through the application of scientific method or reasoned thinking. The second regards actors as culturally embedded in relation to risk, itself a cultural category. The fact that all men in this study became infected demonstrates the potential fallibility of both approaches. HIV prevention strategies need to take account of both the cultural aspects of risk, understanding the embedded quality of everyday cultural practices such as hygiene, and understand these assumptions are often inadequate for preventing HIV infection. Objectivist approaches also entail problems as many men using them felt HIV infection to be inevitable or unavoidable in some circumstances.