Role of tumour necrosis factor-alpha receptor p75 in cigarette smoke-induced pulmonary inflammation and emphysema.

Chronic obstructive pulmonary disease (COPD) is characterised by a local pulmonary inflammatory response to respiratory pollutants and by systemic inflammation. Tumour necrosis factor (TNF)-alpha has been implicated in systemic effects of COPD and operates by binding the p55 (R1) and p75 (R2) TNF-alpha receptors. To investigate the contribution of each TNF-alpha receptor in the pathogenesis of COPD, the present study examined the effects of chronic air or cigarette smoke (CS) exposure in TNF-alpha R1 knockout (KO) mice, TNF-alpha R2 KO mice and wild type (WT) mice. CS was found to significantly increase the protein levels of soluble TNF-alpha R1 (by four-fold) and TNF-alpha R2 (by 10-fold) in the bronchoalveolar lavage of WT mice. After 3 months, CS induced a prominent pulmonary inflammatory cell influx in WT and TNF-alpha R1 KO mice. In TNF-alpha R2 KO mice, CS-induced pulmonary inflammation was clearly attenuated. After 6 months, no emphysema was observed in CS-exposed TNF-alpha R2 KO mice in contrast to WT and TNF-alpha R1 KO mice. CS-exposed WT and TNF-alpha R1 KO mice failed to gain weight, whereas the body mass of TNF-alpha R2 KO mice was not affected. These current findings suggest that both tumour necrosis factor-alpha receptors contribute to the pathogenesis of chronic obstructive pulmonary disease, but tumour necrosis factor-alpha receptor-2 is the most active receptor in the development of inflammation, emphysema and systemic weight loss in this murine model of chronic obstructive pulmonary disease.     

How neurosecretory vesicles release their cargo.

Neurons and related cell types often contain two major classes of neurosecretory vesicles, synaptic vesicles (SVs) and dense-core granules (DCGs), which store and release distinct cargo. SVs store and release classic neurotransmitters, which facilitate propagation of action potentials across the synaptic cleft, whereas DCGs transport, store, and release hormones, proteins, and neuropeptides, which facilitate neuronal survival, synaptic transmission, and learning. Over the past few years, there has been a major surge in our understanding of many of the key molecular mechanisms underlying cargo release from SVs and DCGs. This surge has been driven largely by the use of fluorescence microscopy (especially total internal reflection fluorescence microscopy) to visualize SVs or DCGs in living cells. This review highlights some of the recent insights into cargo release from neurosecretory vesicles provided by fluorescence microscopy, with emphasis on DCGs.     

Effects of poor glucose handling on arterial stiffness and left ventricular mass in normal children.

AIM: Cardiovascular risk factors can be present in children and young adults. We previously found abnormal microvascular function in children who had glucose intolerance and insulin resistance. The aim of the present study was to investigate whether they also have abnormalities in left ventricular mass (LVM) and arterial stiffness. METHODS: We measured heart dimensions and LVM using echocardiography, and arterial stiffness using pulse wave analysis in 23 children with good glucose handling (postfeeding glucose: 3.9 to 5 mmol/L) and 21 with poor glucose handling (7.7 to 11.4 mmol/L). RESULTS: The time to pulse reflection was slightly shorter in the poorer glucose handlers (mean+/-SD: 143+/-10 vs 153+/-20 ms, P=0.04), suggestive of increased arterial stiffness. Also in this group, there were significant relationships between intraventricular septal thickness, blood pressure and body mass index, but not in the normal glucose handlers. CONCLUSIONS: We have found that normal children who are in the lowest quintile of glucose tolerance in comparison with their peers are exhibiting the first signs of arterial stiffening. In addition, we have seen the beginnings of a relationship between blood pressure, body mass index and left ventricular enlargement in this group. While these changes may not yet be clinically significant, their emergence might be further evidence of early predisposition to cardiovascular disease.     

Evaluation of a strict protocol approach in managing women with severe disease due to abortion.

AIM: To evaluate whether the introduction of a strict protocol approach based on the systemic evaluation of critically ill pregnant women with complications of abortion affected outcome. SETTING: Indigent South Africans managed in the regional and tertiary hospitals of the Pretoria Academic Complex. METHOD: Since 1997 a standard definition of severe acute maternal morbidity (SAMM) has been used in the Pretoria Academic Complex. All cases of SAMM and maternal deaths were entered on the Maternal Morbidity and Mortality Audit System programme. A comparison of outcome of severely ill women who had complications of abortion was made between 1997-1998 (original protocol) and 2002-2004 (strict protocol). OUTCOME MEASURES: The mortality index and prevalence of organ system failure or dysfunction. RESULTS: In 1997-1998 there were 43 women with SAMM who survived and a further 10 maternal deaths due to complications of abortion, compared with 107 women with SAMM and 7 maternal deaths during 2002-2004. The mortality index declined from 18.9% in 1997-1998 to 6.1% in 2002-2004 (p = 0.02, odds ratio 0.28, 95% confidence limits 0.10 - 0.79). Significantly more women had hypovolaemic shock in 2002-2004 compared with 1997-1998 (54.4% v. 35.8%, p = 0.04), but fewer women had immune system failure including septic shock (18.4% v. 47.2%, p = 0.0002) and metabolic dysfunction (0 v. 5.7%, p = 0.03) and there was a trend to less renal failure (10.5% v. 22.6%, p = 0.06) and cardiac failure (4.4% v. 13.2%, p = 0.08). CONCLUSION: The strict protocol approach based on systemic evaluation in managing critically ill pregnant women with complications of abortion, coupled with an intensive, regular feedback mechanism, has been associated with a reduction in the mortality index.