Combined systemic administration of the glycine/NMDA receptor antagonist, (+)-HA966 and morphine attenuates pain-related behaviour in a rat model of trigeminal neuropathic pain

Chronic constriction injury to the infraorbital nerve (CCI-ION) by loose ligatures may represent a useful model for some trigeminal neuropathic pain disorders. Activation of the N-methyl-D-aspartate (NMDA) receptor is involved in the induction and maintenance of neuropathic pain and may contribute to the poor opioid sensitivity of this syndrome. We evaluated the effect of combined systemic administration of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, (+)-(1-Hydroxy-3-aminopyrrolodine-2-one) ((+)-HA966) with morphine on mechanical allodynia-like behaviour in CCI-ION rats. Two weeks after surgery rats with a CCI-ION displayed mechanical hyperresponsiveness to von Frey filament stimulation of the vibrissal pad with a median at 0.217 g (95% confidence limits, 0. 217-0.224) versus > or = 12.5 g pre-operative. Administration of either (+)-HA966 (2.5 mg/kg s.c.) alone or morphine (1 mg/kg i.v.) alone was devoid of effects on the mechanical hyperresponsiveness. By contrast, combined administration of (+)-HA966 and morphine (0.25, 0. 5 and 1 mg/kg i.v.) dose-dependently increased the mechanical response thresholds (peak-effects 0.745 g (0.745-0.745), 4.64 (3.3-8. 7) and 12.5 g (8.4-12.5), respectively). This effect was prevented and reversed by naloxone (0.1 mg/kg i.v.). The drug combination produced no motor deficits in animals using the rotarod test. The present results indicate that combination therapy with NMDA/glycine receptor antagonists and morphine may be a useful approach for the clinical management of trigeminal neuropathic pain disorders.     

Fibronectin, laminin, and collagen IV as modulators of cell behavior during adrenal gland development in the human fetus

The specific development of the human fetal adrenal gland requires cell proliferation, migration, apoptosis, and zone-specific steroidogenic activity. The present work was designed to determine the physiological significance of the previously identified spatial distribution of extracellular matrix components in the fetal gland. Primary cultures of human fetal adrenal cells grown on collagen IV, laminin, or fibronectin revealed that cell morphology was affected by environmental cues. Matrices also modulated the profile of steroid secretion by the fetal cells. Collagen IV favored cortisol secretion after ACTH or angiotensin II stimulation and increased dehydroepiandrosterone production when the AT(2) receptor of angiotensin II was specifically stimulated. These effects were correlated by changes in the mRNA levels of 3beta-hydroxysteroid dehydrogenase and cytochrome P450C17. In contrast, fibronectin and laminin decreased cell responsiveness to ACTH in terms of cortisol secretion, but enhanced ACTH-stimulated androgen secretion. Finally, extracellular matrices were able to orchestrate cell behavior. Collagen IV and laminin enhanced cell proliferation, and fibronectin increased cell death. This study is the first to demonstrate that the nature of extracellular matrix coordinates specific steroidogenic pathways and cell turnover in the developing human fetal adrenal gland.     

HealthKick: a nutrition and physical activity intervention for primary schools in low-income settings

Background  

The burden of non-communicable diseases, including type 2 diabetes, is growing in South Africa. This country has a complex mix of over- and under-nutrition, especially in low-income communities, and concerning levels of physical inactivity in children and youth. This paper describes HealthKick, a school-based nutrition and physical activity intervention in primary schools in these settings aimed at reducing diabetes risk factors.     

Unscheduled expression of CDC25B in S-phase leads to replicative stress and DNA damage

Background  

CDC25B phosphatase is a cell cycle regulator that plays a critical role in checkpoint control. Up-regulation of CDC25B expression has been documented in a variety of human cancers, however, the relationships with the alteration of the molecular mechanisms that lead to oncogenesis still remain unclear. To address this issue we have investigated, in model cell lines, the consequences of unscheduled and elevated CDC25B levels.