Regulation of p21rac activation in human neutrophils.

The small guanosine triphosphate (GTPase) p21rac is highly expressed in human neutrophils where it is thought to play a role in cytoskeletal reorganization and superoxide production. Using the p21rac binding domain of PAK (PAK-RBD) as an activation-specific probe, we have investigated agonist-stimulated activation of p21rac. Stimulation of neutrophils with the chemoattractants fMet-Leu-Phe (fMLP) or platelet-activating factor (PAF) induced an extremely rapid and transient p21rac activation, being optimal within 5 seconds. This activation correlates with the rapid changes of intracellular free Ca(2+) ([Ca(2+)](i)) stimulated by fMLP; however, changes in [Ca(2+)](i) were neither sufficient nor required for p21rac activation. Furthermore, fMLP-induced p21rac activation was not inhibited by broad tyrosine kinase inhibitors or specific inhibitors of ERK, p38 mitogen activated protein kinase, Src, or phosphatidylinositol 3-kinases. Surprisingly, the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha did not cause p21rac activation or modulate fMLP-induced p21rac activation. AlF(-), a potent activator of heterotrimeric G-protein alpha-subunits, however, was found to activate p21rac. Stimulation of neutrophils with phorbol myristate acetate (PMA) strongly activated the respiratory burst, but did not induce p21rac activation, suggesting that superoxide production per se can occur independently of p21rac activation. These data suggest that in human granulocytes, G-protein coupled receptors, but not cytokine receptors, activate p21rac via a rapid, novel exchange-mechanism independently of changes in [Ca(2+)](i), tyrosine phosphorylation, or PI3K.     

Diffusion-weighted MRI of ischemic stroke at 3T: Value of synthetic b-values

Objectives:Diffusion-weighted imaging (DWI) plays a crucial role in the diagnosis of ischemic stroke. We assessed the value of computed and acquired high b-value DWI in comparison with conventional b = 1000 s mm⁻² DWI for ischemic stroke at 3T.Methods:We included 36 patients with acute ischemic stroke who presented with diffusion abnormalities on DWI performed within 24 h of symptom onset. B-values of 0, 500, 1000 and 2000 s mm⁻² were acquired. Synthetic images with b-values of 1000, 1500, 2000 and 2500 s mm⁻² were computed. Two readers compared synthetic (syn) and acquired (acq) b = 2000 s mm⁻² images with acquired b = 1000 s mm⁻² images in terms of lesion detection rate, image quality, presence of uncertain hyperintensities and lesion conspicuity. Readers also selected their preferred b-value. Contrast ratio (CR) measurements were performed. Non-parametrical statistical tests and weighted Cohens’ κ tests were computed.Results:Syn1000 and syn1500 matched acq1000 images in terms of lesion detection rate, image quality and presence of uncertain hyperintensities but presented with significantly improved lesion conspicuity (p < 0.01) and were frequently selected as preferred b-values. Acq2000 images exhibited a similar lesion detection rate and improved lesion conspicuity (p < 0.01) but worse image quality (p < 0.01) than acq1000 images. Syn2000 and syn2500 images performed significantly worse (p < 0.01) than acq1000 images in most or all categories. CR significantly increased with increasing b-values.Conclusion:Synthetic images at b = 1000 and 1500 s mm⁻² and acquired DWI images at b = 2000 s mm⁻² may be of clinical value due to improved lesion conspicuity.Advances in knowledge:Synthetic b-values enable improved lesion conspicuity for DWI of ischemic stroke.     

Alternaria infectoria phaeohyphomycosis in a renal transplant patient.

A male renal transplant patient developed a tumor on the dorsum of his right hand. After excision, histological examination of the tumor showed hyphal structures, but growth developed very slowly. Therapy consisted of surgery alone. A definitive identification of Alternaria infectoria was only possible with molecular techniques.     

Population Pharmacokinetics of Mycophenolic Acid

Clinical Pharmacokinetics - Objective: The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated...     

Tolerizing effects of co-stimulation blockade rest on functional dominance of CD4+CD25+ regulatory T cells

BACKGROUND: Clinical tolerance is the net result of regulatory and effector functions. In this article, the authors show that tolerance induction by co-stimulation blockade preferentially works through CD4CD25 regulatory T-cell-mediated suppression that is effectively achieved by selective reduction of the effector T-cell load. Anti-CD86 and anti-CD40L monoclonal antibody treatment during in vitro mixed lymphocyte reaction (MLR) typically results in the induction of a suppressive polyclonal T-cell population. This induced suppressive capacity was found to be dependent on the presence of CD4CD25 T cells at the start of MLR. METHODS: Using a CFSE-based strategy, the authors show that within the polyclonal T-cell population, the suppressive effect was exerted by a nondividing CD4CD25 T-cell subset. RESULTS: The cells exclusively originated from preexisting CD4CD25 regulatory T cells and proved anergic and highly suppressive on isolation. They carried the CD45RB and CD62L phenotype and expressed GITR. There was no indication of de novo induction of regulatory T cells by co-stimulation blockers. Instead, the authors observed, both in vitro and in vivo, that co-stimulation blockade shifted the ratio between alloreactive effectors and regulatory T cells in favor of the latter. CONCLUSION: The authors therefore conclude that co-stimulation blockade contributes to functional dominance of regulatory T cells by preventing expansion of alloreactive effector T cells. Tolerance-inducing protocols should ideally facilitate this phenomenon.     

Worksite health promotion programs with environmental changes: a systematic review

BACKGROUND: It is now widely believed that health promotion strategies should go beyond education or communication to achieve significant behavioral changes among the target population. Environmental modifications are thought to be an important addition to a worksite health promotion program (WHPP). This review aimed to systematically assess the effectiveness of WHPPs with environmental modifications, on physical activity, dietary intake, and health risk indicators. METHODS: Online searches were performed for articles published up to January 2004 using the following inclusion criteria: (1) (randomized) controlled trial (RCT/CT); (2) intervention should include environmental modifications; (3) main outcome must include physical activity, dietary intake, and health risk indicators; and (4) healthy working population. Methodologic quality was assessed using a checklist derived from the methodologic guidelines for systematic reviews (Cochrane Back Review Group), and conclusions on the effectiveness were based on a rating system of five levels of evidence. RESULTS: Thirteen relevant, mostly multicenter, trials were included. All studies aimed to stimulate healthy dietary intake, and three trials focused on physical activity. Follow-up measurements of most studies took place after an average 1-year period. Methodologic quality of most included trials was rated as poor. However, strong evidence was found for an effect on dietary intake, inconclusive evidence for an effect on physical activity, and no evidence for an effect on health risk indicators. CONCLUSIONS: It is difficult to draw general conclusions based on the small number of studies included in this review. However, evidence exists that WHPPs that include environmental modifications can influence dietary intake. More controlled studies of high methodologic quality need to be initiated that investigate the effects of environmental interventions on dietary intake and especially on physical activity in an occupational setting.     

Remote iliac artery endarterectomy: seven-year results of a less invasive technique for iliac artery occlusive disease

OBJECTIVE: Remote endarterectomy of external and common iliac artery occlusions through a single, groin incision under fluoroscopic guidance is a relative unknown surgical procedure. This prospective single center cohort study describes this less invasive endovascular technique with the ring strip cutter and its early complications. The results at midterm follow-up are presented. PATIENTS AND METHODS: From April 1994 to July 2001, 49 remote-endarterectomies of the external or common iliac artery were performed in a retrograde manner from a single, groin incision in 48 patients (30 men, 31 procedures). The median age was 66 years (39 to 82 years). Indications for operation were as follows: severe claudication in 28 (57%), rest pain in 13 (27%), and gangrene in 8 (16%) procedures. Follow-up included clinical evaluation, ankle-brachial index, and duplex scanning at 6 weeks, 3 months, and yearly thereafter. RESULTS: Intraoperative technical success was achieved in 43 (88%) procedures. A retroperitoneal incision was necessary in three patients for an additional arteriotomy in the iliac artery and in three others for a bypass procedure. The mean follow-up was 20 months (2 to 77 months). Three-year cumulative primary patency rate by means of life table analysis was 60.2% +/- 12.0 (SE). During follow-up, percutaneous transluminal balloon angioplasty with and without stenting was performed in six and two patients, respectively, resulting in a 3-year primary-assisted patency rate of 85.7% +/- 9.56. Three-year secondary patency was 94.2% +/- 5.50. CONCLUSIONS: Remote endarterectomy in external and common iliac arterial occlusive disease is a feasible endovascular procedure with a low complication rate. The midterm primary-assisted patency rate is good.     

Understanding the effect of socio-economic characteristics and psychosocial factors on household water treatment practices in rural Nepal using Bayesian Belief Networks

About 20 Million (73%) people in Nepal still do not have access to safely managed drinking water service and 22 million (79%) do not treat their drinking water before consumption. Few studies have addressed the combination of socio-economic characteristics and psychosocial factors that explain such behaviour in a probabilistic manner. In this paper we present a novel approach to assess the usage of household water treatment (HWT), using data from 451 households in mid and far-western rural Nepal. We developed a Bayesian belief network model that integrates socio-economic characteristics and five psychosocial factors. The socio-economic characteristics of households included presence of young children, having been exposed to HWT promotion in the past, level of education, type of water source used, access to technology and wealth level. The five psychosocial factors capture households’ perceptions of incidence and severity of water-borne infections, attitudes towards the impact of poor water quality on health, water treatment norms and the knowledge level for performing HWT. We found that the adoption of technology was influenced by the psychosocial factors norms, followed by the knowledge level for operating the technology. Education, wealth level, and being exposed to the promotion of HWT were the most influential socio-economic characteristics. Interestingly, households who were connected to a piped water scheme have a higher probability of HWT adoption compared to other types of water sources. The scenario analysis revealed that interventions that only target single socio-economic characteristics do not effectively boost the probability of HWT practice. However, interventions addressing several socio-economic characteristics increase the probability of HWT adoption among the target groups.