Microglial responses to amyloid β peptide opsonization and indomethacin treatment

BACKGROUND: Recent studies have suggested that passive or active immunization with anti-amyloid β peptide (Aβ) antibodies may enhance microglial clearance of Aβ deposits from the brain. However, in a human clinical trial, several patients developed secondary inflammatory responses in brain that were sufficient to halt the study. METHODS: We have used an in vitro culture system to model the responses of microglia, derived from rapid autopsies of Alzheimer's disease patients, to Aβ deposits. RESULTS: Opsonization of the deposits with anti-Aβ IgG 6E10 enhanced microglial chemotaxis to and phagocytosis of Aβ, as well as exacerbated microglial secretion of the pro-inflammatory cytokines TNF-α and IL-6. Indomethacin, a common nonsteroidal anti-inflammatory drug (NSAID), had no effect on microglial chemotaxis or phagocytosis, but did significantly inhibit the enhanced production of IL-6 after Aβ opsonization. CONCLUSION: These results are consistent with well known, differential NSAID actions on immune cell functions, and suggest that concurrent NSAID administration might serve as a useful adjunct to Aβ immunization, permitting unfettered clearance of Aβ while dampening secondary, inflammation-related adverse events

Shoreline Situation Report Cities of Chesapeake, Norfolk, and Portsmouth

It i s the objective of this report to supply an assessment, and at least a partial integration, of those important shoreland parameters and characteristics which will aid the planners and the managers of the shorelands in making the best decisions for the utilization of this limited and very valuable resource. The report gives particular attention to the problem of shore erosion and to recommendations concerning the alleviation of the impact of this problem. In addition, we have tried to include in our assessment a discussion of those factors which might significantly limit development of the shoreline and, in some instances, a discussion of some of the potential or alternate uses of the shoreline, particularly with respect to recreational use, since such information could aid potential users in the perception of a segment of the shoreline

Pentobarbital and picrotoxin have reciprocal actions on single GABAA receptor channels

Pentobarbital (PB) and picrotoxin (PIC) bind to allosterically coupled sites on the GABAA receptor complex but have opposite effects on GABA receptor currents. PB, an anesthetic/anticonvulsant, enhances, and PIC, a convulsant, inhibits GABA receptor currents. PB and PIC also had opposite effects on single main conductance channel GABA receptor currents recorded from excised outside-out patches from mouse spinal neurons in culture. PB prolonged bursts of channel openings by increasing mean duration and number of intraburst openings. PIC shortened bursts by reducing mean duration and number of intraburst openings. The results demonstrate the reciprocal regulation of GABA receptor channels by PB and PIC and suggest that their allosterically coupled binding sites are coupled to the chloride channel in an opposite manner.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28094/1/0000541.pd

Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway

Palmitoylation is postulated to regulate Ras signaling by modulating its intracellular trafficking and membrane microenvironment. The mechanisms by which palmitoylation contributes to these events are poorly understood. Here, we show that dynamic turnover of palmitate regulates the intracellular trafficking of HRas and NRas to and from the Golgi complex by shifting the protein between vesicular and nonvesicular modes of transport. A combination of time-lapse microscopy and photobleaching techniques reveal that in the absence of palmitoylation, GFP-tagged HRas and NRas undergo rapid exchange between the cytosol and ER/Golgi membranes, and that wild-type GFP-HRas and GFP-NRas are recycled to the Golgi complex by a nonvesicular mechanism. Our findings support a model where palmitoylation kinetically traps Ras on membranes, enabling the protein to undergo vesicular transport. We propose that a cycle of depalmitoylation and repalmitoylation regulates the time course and sites of Ras signaling by allowing the protein to be released from the cell surface and rapidly redistributed to intracellular membranes

Maternal Characteristics and Clinical Diagnoses Influence Obstetrical Outcomes in Indonesia

This Indonesian study evaluates associations between near-miss status/death with maternal demographic, health care characteristics, and obstetrical complications, comparing results using retrospective and prospective data. The main outcome measures were obstetric conditions and socio-economic factors to predict near-miss/death. We abstracted all obstetric admissions (1,358 retrospective and 1,240 prospective) from two district hospitals in East Java, Indonesia between 4/1/2009 and 5/15/2010. Prospective data added socio-economic status, access to care and referral patterns. Reduced logistic models were constructed, and multivariate analyses used to assess association of risk variables to outcome. Using multivariate analysis, variables associated with risk of near-miss/death include postpartum hemorrhage (retrospective AOR 5.41, 95 % CI 2.64–11.08; prospective AOR 10.45, 95 % CI 5.59–19.52) and severe preeclampsia/ eclampsia (retrospective AOR 1.94, 95 % CI 1.05–3.57; prospective AOR 3.26, 95 % CI 1.79–5.94). Associations with near-miss/death were seen for antepartum hemorrhage in retrospective data (AOR 9.34, 95 % CI 4.34–20.13), and prospectively for poverty (AOR 2.17, 95 % CI 1.33–3.54) and delivering outside the hospital (AOR 2.04, 95 % CI 1.08–3.82). Postpartum hemorrhage and severe preeclampsia/ eclampsia are leading causes of near-miss/death in Indonesia. Poverty and delivery outside the hospital are significant risk factors. Prompt recognition of complications, timely referrals, standardized care protocols, prompt hospital triage, and structured provider education may reduce obstetric mortality and morbidity. Retrospective data were reliable, but prospective data provided valuable information about barriers to care and referral patterns

From theory to 'measurement' in complex interventions: methodological lessons from the development of an e-health normalisation instrument

<b>Background</b> Although empirical and theoretical understanding of processes of implementation in health care is advancing, translation of theory into structured measures that capture the complex interplay between interventions, individuals and context remain limited. This paper aimed to (1) describe the process and outcome of a project to develop a theory-based instrument for measuring implementation processes relating to e-health interventions; and (2) identify key issues and methodological challenges for advancing work in this field.<p></p> <b>Methods</b> A 30-item instrument (Technology Adoption Readiness Scale (TARS)) for measuring normalisation processes in the context of e-health service interventions was developed on the basis on Normalization Process Theory (NPT). NPT focuses on how new practices become routinely embedded within social contexts. The instrument was pre-tested in two health care settings in which e-health (electronic facilitation of healthcare decision-making and practice) was used by health care professionals.<p></p> <b>Results</b> The developed instrument was pre-tested in two professional samples (N = 46; N = 231). Ratings of items representing normalisation 'processes' were significantly related to staff members' perceptions of whether or not e-health had become 'routine'. Key methodological challenges are discussed in relation to: translating multi-component theoretical constructs into simple questions; developing and choosing appropriate outcome measures; conducting multiple-stakeholder assessments; instrument and question framing; and more general issues for instrument development in practice contexts.<p></p> <b>Conclusions</b> To develop theory-derived measures of implementation process for progressing research in this field, four key recommendations are made relating to (1) greater attention to underlying theoretical assumptions and extent of translation work required; (2) the need for appropriate but flexible approaches to outcomes measurement; (3) representation of multiple perspectives and collaborative nature of work; and (4) emphasis on generic measurement approaches that can be flexibly tailored to particular contexts of study