Platelet adhesion to collagen types I through VIII under conditions of stasis and flow is mediated by GPIa/IIa (alpha 2 beta 1-integrin)

Platelet adhesion to fibrillar collagens (types I, II, III, and V) and nonfibrillar collagens (types IV, VI, VII, and VIII) was investigated in the presence of physiologic concentrations of divalent cations under conditions of stasis and flow. Under static conditions, platelet adhesion was observed to collagen types I through VII but not to type VIII. Under flow conditions, platelet adhesion to collagen types I, II, III, and IV was almost independent of shear rates above 300/s. Collagen type V was nonadhesive. Platelet adhesion to collagen type VI was shear rate-dependent and optimal at a rate of 300/s. Collagen types VII and VIII showed minor reactivity and supported platelet adhesion only between shear rates 100 to 1,000/s. Monoclonal antibody (MoAb) 176D7, directed against platelet membrane glycoprotein Ia (GPIa; very late antigen [VLA]-alpha 2 subunit), completely inhibited platelet adhesion to all collagens tested, under conditions of both stasis and flow. Platelet adhesion to collagen type III at shear rate 1,600/s was only inhibited for 85%. The concentration of antibody required for complete inhibition of platelet adhesion was dependent on the shear rate and the reactivity of the collagen. An MoAb directed against GPIIa (VLA-beta subunit) partially inhibited platelet adhesion to collagen. These results show that GPIa-IIa is a major and universal platelet receptor for eight unique types of collagen.     

Induction of apoptosis by the ginsenoside Rh2 by internalization of lipid rafts and caveolae and inactivation of Akt

Background and purpose:

Lipid rafts and caveolae are membrane microdomains with important roles in cell survival signalling involving the Akt pathway. Cholesterol is important for the structure and function of these microdomains. The ginsenoside Rh2 exhibits anti-tumour activity. Because Rh2 is structurally similar to cholesterol, we investigated the possibility that Rh2 exerted its anti-tumour effect by modulating rafts and caveolae.

Experimental approach:

A431 cells (human epidermoid carcinoma cell line) were treated with Rh2 and the effects on cell apoptosis, raft localization and Akt activation measured. We also examined the effects of over-expression of Akt and active-Akt on Rh2-induced cell death.

Key results:

Rh2 induced apoptosis concentration- and time-dependently. Rh2 reduced the levels of rafts and caveolae in the plasma membrane and increased their internalization. Furthermore, Akt activity was decreased and consequently, Akt-dependent phosphorylation of Bad, a pro-survival protein, was decreased whereas the pro-apoptotic proteins, Bim and Bax, were increased upon Rh2 treatment. Unlike microdomain internalization induce by cholesterol depletion, Rh2-mediated internalization of rafts and caveolae was not reversed by cholesterol addition. Also, cholesterol addition did not restore Akt activation or rescue cells from Rh2-induced cell death. Rh2-induced cell death was attenuated in MDA-MB-231 cells over-expressing either wild-type or dominant-active Akt.

Conclusions and implications:

Rh2 induced internalization of rafts and caveolae, leading to Akt inactivation, and ultimately apoptosis. Because elevated levels of membrane rafts and caveolae, and Akt activation have been correlated with cancer development, internalization of these microdomains by Rh2 could potentially be used as an anti-cancer therapy.     

Maternal occupational exposure and congenital heart defects in offspring

Objectives:Congenital heart defects (CHD) are the most prevalent congenital anomalies. This study aims to examine the association between maternal occupational exposures to organic and mineral dust, solvents, pesticides, and metal dust and fumes and CHD in the offspring, assessing several subgroups of CHD.Methods:For this case–control study, we examined 1174 cases with CHD from EUROCAT Northern Netherlands and 5602 controls without congenital anomalies from the Lifelines cohort study. Information on maternal jobs held early in pregnancy was collected via self-administered questionnaires, and job titles were linked to occupational exposures using a job exposure matrix.Results:An association was found between organic dust exposure and coarctation of aorta [adjusted odds ratio (OR_adj) 1.90, 95% confidence interval (CI) 1.01–3.59] and pulmonary (valve) stenosis in combination with ventricular septal defect (OR_adj 2.68, 95% CI 1.07–6.73). Mineral dust exposure was associated with increased risk of coarctation of aorta (OR_adj 2.94, 95% CI 1.21–7.13) and pulmonary valve stenosis (OR_adj 1.99, 95% CI 1.10–3.62). Exposure to metal dust and fumes was infrequent but was associated with CHD in general (OR_adj 2.40, 95% CI 1.09–5.30). Exposure to both mineral dust and metal dust and fumes was associated with septal defects (OR_adj 3.23, 95% CI 1.14–9.11). Any maternal occupational exposure was associated with a lower risk of aortic stenosis (OR_adj 0.32, 95% CI 0.11–0.94).Conclusions:Women should take preventive measures or avoid exposure to mineral and organic dust as well as metal dust and fumes early in pregnancy as this could possibly affect foetal heart development.     

Dietary calcium, saturated fat, fiber and vitamin C as predictors of forearm cortical and trabecular bone mineral density in healthy children and adolescents

Diet, weight–bearing physical activity (WPA) and daylight hours spent outdoors (DE) were related to bone mineral density in the distal (BMDd) and ultradistal (BMDud) forearm of 495 healthy children (8–11 years) and adolescents (11–17 years). BMD was assessed by single photon absorptiometry. Using multiple regression, BMDd was predicted by saturated fat and BMDud by fiber in children. In adolescents, BMDd was predicted by saturated fat and vitamin C, and BMDud by calcium and vitamin C. WPA and DE were not related to BMD. In conclusion, our results showed that current intake of calcium, saturated fat, fiber and vitamin C were positively associated with forearm BMD in children and adolescents. These associations depended on age and bone type. If our findings are verified, dietary recommendations, especially when aimed at young people, may have to be reconsidered.