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.     

Characteristics and outcome of patients with active pulmonary tuberculosis requiring intensive care.

Severe tuberculosis (TB) requiring intensive care unit (ICU) care is rare but commonly known to be of markedly bad prognosis. The present study aimed to describe this condition and to determine the mortality rate and risk factors associated with mortality. Patients with confirmed TB admitted to ICU between 1990 and 2001 were retrospectively identified and enrolled. Clinical, radiological and bacteriological data at admission and during hospital stay were recorded. A multivariate analysis was performed to identify the predictive factors for mortality. A total of 58 TB patients (12 females, mean age 48 yrs) admitted to ICU were included. Mean Acute Physiology and Chronic Health Evaluation (APACHE) II score at admission was 13.1+/-5.6 and 22 of 58 (37.9%) patients required mechanical ventilation. The in-hospital mortality was 15 of 58 (25.9%); 13 (22.4%) patients died in the ICU. The mean survival of patients who died was 53.6 days (range 1-229), with 50% of the patients dying within the first 32 days. The factors independently associated with mortality were: acute renal failure, need for mechanical ventilation, chronic pancreatitis, sepsis, acute respiratory distress syndrome, and nosocomial pneumonia. These data indicate a high mortality of patients with tuberculosis requiring intensive care unit care and identifies new independently associated risk factors.     

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.     

Psoriasis confined strictly to vitiligo areas – a Koebner‐like phenomenon?

Vitiligo and psoriasis are both common skin disorders. However, psoriasis strictly confined to pre-existing vitiligo areas is rare and suggests a causal relationship. We report here on two patients with a strict anatomical colocalization of vitiligo and psoriasis. The histopathological examinations showed typical changes for both diseases together with a dense infiltrate of CD4+ and CD8+ T cells. By immunohistochemistry, intracytoplasmatic granzyme B and tumour necrosis factor alpha (TNF-alpha) were detected within the T-cell population, suggesting the functional activity of these cells and the creation of a local T helper 1 (Th1)-cytokine milieu. Additionally, in one patient we could identify anti-melanocytic T cells by tetramer staining and enzyme-linked immunospot (ELISPOT) analysis. These skin-infiltrating lymphocytes might trigger, by the local production of Th-1 cytokines such as TNF-alpha and interferon-gamma (IFN-gamma), the eruption of psoriatic plaques in patients with a genetic predisposition for psoriasis.     

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.