MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Evaluating social and behavioural impacts of English smoke-free legislation in different ethnic and age groups: implications for reducing smoking-related health inequalities.

OBJECTIVE: To explore social and behavioural impacts of English smoke-free legislation (SFL) in different ethnic groups. DESIGN: A longitudinal, qualitative panel study of smokers using in-depth interviews conducted before and after introduction of SFL. PARTICIPANTS: A purposive sample of 32 smokers selected from three ethnic groups in deprived London neighbourhoods with approximately equal numbers of younger and older, male and female respondents. RESULTS: SFL has had positive impacts with half smoking less and three quitting. Although there were no apparent differences in smoking and quitting behaviours between groups, there were notable differences in the social impacts of SFL. The greatest negative impacts were in smokers over 60 years, potentially increasing their social isolation, and on young Somali women whose smoking was driven more underground. In contrast, most other young adult smokers felt relatively unaffected by SFL, describing unexpected social benefits. Although there was high compliance, reports of illegal smoking were more frequent among young, ethnic minority smokers, with descriptions of venues involved suggesting they are ethnically distinct and well hidden. Half of respondents reported stopping smoking in their own homes after SFL, but almost all were Somali or Turkish. White respondents tended to report increases in home smoking. DISCUSSION: Although our study suggests that SFL can lead to reductions in tobacco consumption, it also shows that impacts vary by ethnicity, age and sex. This study highlights the importance of understanding the meaning of smoking in different social contexts so future tobacco control interventions can be developed to reduce health and social inequalities.

Blocking Wnt5a signaling decreases CD36 expression and foam cell formation in atherosclerosis.

BACKGROUND AND AIMS: Wnt5a is a highly studied member of the Wnt family and recently has been implicated in the pathogenesis of atherosclerosis, but its precise role is unknown. Foam cell development is a critical process to atherosclerotic plaque formation. In the present study, we investigated the role of noncanonical Wnt5a signaling in the development of foam cells. METHODS: Human carotid atherosclerotic tissue and THP-1-derived macrophages were used to investigate the contribution of Wnt5a signaling in the formation of foam cells. Immunohistochemistry was used to evaluate protein expression of scavenger receptors and noncanonical Wnt5a receptors [frizzled 5 (Fz5) and receptor tyrosine kinase-like orphan receptor 2 (Ror2)] in human atherosclerotic macrophages/foam cells. Changes in protein expression in response to Wnt5a stimulation/inhibition were determined by Western blot, and lipid accumulation was evaluated by fluorescent lipid droplet staining. RESULTS: Wnt5a (P<.05), Fz5 (P<.01), and Ror2 (P<.01) were significantly expressed in advanced atherosclerotic lesions compared to less advanced lesions (N=10). Wnt5a, Fz5, and Ror2 were expressed in macrophages/foam cells within the plaque. In vitro studies revealed that Wnt5a significantly increased the expression of the lipid uptake receptor CD36 (P<.05) but not the lipid efflux receptor ATP-binding cassette transporter (P>.05). rWnt5a also significantly increased lipid accumulation in THP-1 macrophages (P<.05). Furthermore, inhibition of Wnt5a signaling with Box5 prevented lipid accumulation (P<.01) and prevented CD36 up-regulation (P<.01). CONCLUSIONS: These results suggest a direct role for Wnt5a signaling in the pathogenesis of atherosclerosis, specifically the accumulation of lipid in macrophages and the formation of foam cells.

Association of conventional and exertional coronary heart disease risk factors in 5,000 apparently healthy men.

BACKGROUND AND HYPOTHESIS: The aim of this study was to define the prevalence of previously undetected coronary heart disease among asymptomatic males, aged 30-65 years, by means of resting and exercise electrocardiography in conjunction with an analysis of conventional and exertional coronary risk factors. METHODS: Between January 1985 and December 1989 we examined 5,000 clinically asymptomatic subjects. A detailed case history was obtained for each individual, followed by a complete physical examination, comprehensive blood (including lipid) profile, lung function tests, chest x-ray, a resting 12-lead electrocardiogram (ECG), and a maximal treadmill exercise ECG. Whenever possible, on-line computerized respiratory analysis (Beckman Metabolic Measurement Cart) was carried out during the exercise tests. Conventional and exertional coronary heart disease risk factors were also recorded. RESULTS: A total of 162 persons (3.2%) showed abnormal S-T segment responses during the exercise or recovery period. Of these, 92 subjects underwent further investigations: coronary angiography (79), 201thallium scanning (13), 201thallium scanning followed by coronary angiography (7). Of the 86 patients who proceeded to coronary angiography, 19 (22%) had either normal coronary artery anatomy or only insignificant disease. Among the 67 (78%) of patients with significant angiographically demonstrable disease, 26 received coronary artery bypass grafting, 7 underwent coronary angioplasty, and the remainder continued on medical management. CONCLUSIONS: These results are discussed in relation to a variety of conventional and exertional coronary risk factors.

Evaluation of anastomoses of small intestine in dogs: crushing versus noncrushing suturing techniques.

Fifteen dogs were used to compare simple interrupted crushing and noncrushing single-layer small intestinal anastomoses. Groups of 5 dogs each were used to evaluate both techniques at 3 postsurgical times--days 4, 21, and 42. There were no significant differences between the 2 techniques at the evaluations. Grossly, there were marked adhesion formations at the 3 evaluation times. Luminal diameters at the anastomotic site indicated there may have been only slightly more stenosis with the noncrushing technique. Bursting pressure studies determined that the anastomotic strengths of the 2 techniques were not measurably different statistically. However, their bursting strengths had greatly increased from day 4 to day 21. There were also significant increases in bursting strengths of jejunal segments caudal to the anastomotic sites from day 4 to day 42. Subjective histopathologic evaluations of anastomotic sites revealed that the types and amounts of inflammation, collagen content, continuity of layers, and severity of peritonitis were not different within each time. It was concluded that both techniques for small intestinal anastomoses in the dog have equal value.

Plasma-fibrinogen and thromboemboli after myocardial infarction.

In 120 patients with myocardial infarction subsequent non-fatal thromboemboli occurred only in patients in whom plasma-fibrinogen had exceeded 750 mg/dl. It is suggested that patients at risk from thromboembolism after infarction can be identified by monitoring plasma-fibrinogen and that appropriate anticoagulation might reduce morbidity.

The effects of gossypol on the ultrastructure and function of tracheal ciliated cells.

Gossypol acetic acid inhibits rabbit tracheal ciliary function in a concentration dependent manner. At concentrations of both 10(-4)M and 5 X 10(-5), ciliary beat is reduced to less than 2 beats/sec in approximately 60 min. At 10(-5)M, reduction of frequency is more gradual, requiring 120 min or longer to approach inhibition. The primary site in the cell showing morphological alteration is the mitochondrion, although extended exposure at lower concentrations does seem to cause increase in the amount of endoplasmic reticulum and Golgi. At the time of inhibition of ciliary beat, mitochondria have a washed out matrix, disrupted cristae and extensive infolding of the outer membrane. Some indication of mitochondrial swelling is also evident. Demembranated axonemes exposed to gossypol show the same dose-dependent response as intact ciliated cells. At 10(-4)M gossypol, axonemes are completely inhibited from reactivation. Axonemes can be reactivated in the presence of 10(-5)M gossypol but are quickly inhibited. 10(-6)M gossypol has no inhibitory effect on demembranated axonemes or intact ciliated cells. Gossypol may be acting initially as a direct but reversible inhibitor of axonemal function while damage to mitochondria may be responsible for the long term, non-reversible inhibition of ciliary function.