Nuclear organization of orexinergic neurons in the hypothalamus of a lar gibbon and a chimpanzee.

Employing orexin-A immunohistochemical staining we describe the nuclear parcellation of orexinergic neurons in the hypothalami of a lar gibbon and a chimpanzee. The clustering of orexinergic neurons within the hypothalamus and the terminal networks follow the patterns generally observed in other mammals, including laboratory rodents, strepsirrhine primates and humans. The orexinergic neurons were found within three distinct clusters in the ape hypothalamus, which include the main cluster, zona incerta cluster and optic tract cluster. In addition, the orexinergic neurons of the optic tract cluster appear to extend to a more rostral and medial location than observed in other species, being observed in the tuberal region in the anterior ventromedial aspect of the hypothalamus. While orexinergic terminal networks were observed throughout the brain, high density terminal networks were observed within the hypothalamus, medial and intralaminar nuclei of the dorsal thalamus, and within the serotonergic and noradrenergic regions of the midbrain and pons, which is typical for mammals. The expanded distribution of orexinergic neurons into the tuberal region of the ape hypothalamus, is a feature that needs to be investigated in other primate species, but appears to correlate with orexin gene expression in the same region of the human hypothalamus, but these neurons are not revealed with immunohistochemical staining in humans. Thus, it appears that apes have a broader distribution of orexinergic neurons compared to other primate species, but that the neurons within this extension of the optic tract cluster in humans, while expressing the orexin gene, do not produce the neuropeptide.

A retrospective review of patients with Kaposi's sarcoma in Botswana.

BACKGROUND: Despite widespread antiretroviral coverage in Botswana, Kaposi's sarcoma (KS) remains among the most common malignancies. To date, adult KS in Botswana is not well characterized. The diagnosis relies on clinical suspicion that is often confirmed by histopathology given the implications of treatment; however, this poses a significant resource burden. METHODS: We conducted a retrospective review of the cohort of patients biopsied for possible KS at Princess Marina Hospital, the main dermatology referral site in Botswana, from September 2008 through June 2015 to describe the demographics, human immunodeficiency virus (HIV) characteristics, and clinical presentations of these patients. Histopathologic diagnoses were reviewed, and positive predictive value (PPV) was used to characterize the accuracy of clinical suspicion of KS. RESULTS: A total of 441 patients received 450 biopsies where KS was on the differential diagnosis, and 239 patients (54%) were ultimately diagnosed with KS. The KS cohort was more likely to be male (58% vs. 37%, P < 0.001), HIV positive (94% vs. 85%, P < 0.05), and have lower CD4 counts at the time of biopsy (274 cells/µl vs. 362 cells/µl, P < 0.05). The PPV of clinical suspicion of KS was 58%. When KS was not histopathologically diagnosed, clinically benign diseases were found in 17%, medically significant conditions requiring alternative therapies in 78%, and life-threatening diseases in 5%. DISCUSSION: Our study reinforces the risk factors in development of KS. The poor PPV supports the important role of histology in KS diagnosis to both ensure appropriate treatment and prevent overtreatment. Improved accessibility to biopsy and augmentation of local dermatopathologic services would likely improve diagnostic accuracy and treatment.

Healthy Start vitamins--a missed opportunity: findings of a multimethod study.

OBJECTIVE: To evaluate and provide a real-life view of the operation of the Healthy Start vitamins scheme. SETTING: The study took place in primary care and community settings that served rural, urban and ethnically diverse populations, in two sentinel sites: London, and Yorkshire and the Humber. An online consultation and stakeholder workshops elicited views from across England. PARTICIPANTS: 669 health and social care practitioners including health visitors, midwives, public health practitioners, general practitioners, paediatricians and support staff participated in focus group discussions (n=49) and an online consultation (n=620). 56 participants representing health and social care practitioners, policymakers, service commissioners, and voluntary and independent sectors took part in stakeholder workshops. METHODS: Three-phase multimethod study comprising focus group discussions, an online consultation and stakeholder workshops. Qualitative data were analysed thematically and quantitative data from the online survey were analysed using descriptive statistics. RESULTS: Study participants were concerned about the low uptake of Healthy Start vitamin supplements and the consequences of this for health outcomes for women and young children. They experienced Healthy Start vitamin distribution as logistically complex, requiring the time, resources and creative thinking of a range of local and regional practitioners from senior strategists to administrative support workers. In the light of this, many participants argued that moving to universal provision of vitamin supplements would be more cost-effective than the current system. CONCLUSIONS: There is consistency of views of health practitioners that the current targeted system of providing free vitamin supplements for low-income childbearing women and young children via the Healthy Start programme is not fulfilling its potential to address vitamin deficiencies. There is wide professional and voluntary sector support for moving from the current targeted system to provision of free vitamin supplements for all pregnant and new mothers, and children up to their fifth birthday.

Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors.

3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be a potent inhibitor of human DAAO, and its binding affinity was confirmed in a Biacore assay. Cocrystallization of 2 with the human DAAO enzyme defined the binding site and guided the design of new analogues. The SAR, pharmacokinetics, brain exposure, and effects on cerebellum D-serine are described. Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.