The acute inflammatory response to lipopolysaccharide in CNS parenchyma differs from that in other body tissues.

Acute inflammation is important for defence against infection, wound repair and the mediation of auto-immune tissue destruction. Myelomonocytic recruitment in acute inflammation is a stereotyped and non-specific response to tissue insult which begins within 2 h. In this study, lipopolysaccharide was injected into the murine CNS and other body sites of mice to compare the inflammatory responses. Doses of lipopolysaccharide which induced typical myelomonocytic recruitment in skin and the choroid plexus had no effect in CNS parenchyma, apart from the morphological activation of local resident microglia. The CNS parenchymal response proceeded independently of that in the choroid plexus-cerebral ventricles and had three distinct and unique phases. Initially there was minimal neutrophil exudation and a two-day delay before any increase in macrophage-microglial cell number. Next, there was a rapid increase in macrophage-microglial cell numbers during the third day, mainly due to recruitment of blood monocytes. During this phase, leukocyte recruitment was restricted to monocytes which rapidly adopted the arborized microglial phenotype. Monocytes migrated through an intact blood-brain barrier independent of changes in solute permeability. Finally, there was a florid myelomonocytic reaction predominantly in the white matter, one week after intracerebral injection of 2 micrograms lipopolysaccharide. At this time, the leukocyte reaction disrupted the blood-brain barrier, mononuclear phagocytes expressed macrophage morphology and abundant major histocompatibility complex Class II antigen, and T lymphocytes were present. Myelomonocytic entry into the CNS was partially inhibited by prior blockade of the type 3 complement receptor, known to mediate leukocyte adhesion to endothelium elsewhere. The processes which lead to rapid myelomonocytic recruitment in other tissues are absent in CNS parenchyma. Understanding the molecular mechanisms responsible could have considerable significance both for CNS pathophysiology as well as possible anti-inflammatory therapeutic application elsewhere in the body.     

Second-messenger pathways involved in the regulation of survival in germinal-centre B cells and in Burkitt lymphoma lines.

Spontaneous apoptosis in germinal-centre (GC) B cells can be prevented by treatment with anti-immunoglobulin (Ig). By contrast, susceptible group-I Burkitt lymphoma (BL) cells can be driven to apoptosis by anti-Ig. The second-messenger pathways involved in the regulation of apoptosis in GC B lymphocytes and in BL cell lines were studied using pharmacological agonists or inhibitors of intracellular calcium ([Ca2+]i) and protein kinase C (PKC). Anti-Ig was found to mobilize Ca2+ in group-I cells. Pre-incubation with the Ca2+ chelator EGTA partially reduced apoptosis induced by anti-Ig or by Ca2+ ionophore in group-I BL cells. Activation of PKC with phorbol ester reduced such Ca(2+)-driven programmed cell death (PCD) to control levels of apoptosis. Apoptosis in group-I BL cell lines could also be triggered by the kinase inhibitors staurosporine and Ro-31-8220 at concentrations selective for PKC activity. Expression of the bcl-2 protein in BL group-I cells following gene transfer affords protection from apoptosis induced by ionomycin or anti-Ig. In the present study, bcl-2 was additionally found to protect from apoptosis driven by staurosporine. The high levels of spontaneous apoptosis exhibited by normal GC B cells were reduced, but not abrogated, by co-culture with phorbol ester. These results indicate that, in group-I BL cells, imbalance in the phosphoinositide pathway of signalling, in favour of [Ca2+]i and away from PKC, results in apoptosis: constitutive phosphorylation of key proteins by PKC may therefore suppress apoptosis in BL as well as in GC B cells.     

The optimal technique for electrical cardioversion of atrial fibrillation

The optimal approach to electrical cardioversion of atrial fibrillation includes appropriate patient selection, anticoagulation, careful selection and monitoring of antiarrhythmic therapy, and proper electrical cardioversion technique. The optimal technique requires the use of metal electrodes, with one electrode of at least 8 cm in diameter placed in the anterior position, and the second of 12–13 cm diameter placed posteriorly just below the left scapulae, with generous amounts of the appropriate gel (such as Hewlett-Packard Redux Paste) as the electrode-skin interface and firm pressure to the paddle electrode with the patient in expiration. Thus the anterior-posterior chest diameter is decreased and less air between the electrodes is assured. The initial shock strength should be 200 J. The shock is synchronized with the electrocardiographic QRS complex. This report reviews the justification for these recommendations.     

Issues in selecting outcome measures to assess functional recovery after stroke

Most patients who survive a stroke experience some degree of physical recovery. Selecting the appropriate outcome measure to assess physical recovery is a difficult task, given the heterogeneity of stroke etiology, symptoms, severity, and even recovery itself. Despite these complexities, a number of strategies can facilitate the selection of functional outcome measures in stroke clinical trial research and practice. Clinical relevance in stroke outcome measures can be optimized by incorporating a framework of health and disability, such as the International Classification of Functioning, Disability, and Health (ICF). The ICF provides the conceptual basis for measurement and policy formulations for disability and health assessment. All outcome measures selected should also have sound psychometric properties. The essential psychometric properties are reliability, validity, responsiveness, sensibility, and established minimal clinically important difference. It is also important to establish the purpose of the measurement (discriminative, predictive, or evaluative) and to determine whether the purpose of the study is to evaluate the efficacy or effectiveness of an intervention. In addition, when selecting outcome measures and time of assessment, the natural history of stroke and stroke severity must be regarded. Finally, methods for acquiring data must also be considered. We present a comprehensive overview of the issues in selecting stroke outcome measures and characterize existing measures relative to these issues.     

Effects of the PPAR-gamma agonist rosiglitazone on renal haemodynamics and the renin-angiotensin system in diabetes.

BACKGROUND: Thiazolidinediones (TZD) have been reported to improve early stages of diabetic nephropathy independent of glycaemic control. Since blockade of the renin-angiotensin system (RAS) is known to reduce the risk of nephropathy, we hypothesised that the renal effect of TZDs might be related to a favourable effect on the intrarenal RAS. We aimed to determine if the TZD rosiglitazone could reduce RAS activation. METHODS: We studied adult type 2 diabetic patients and placed them on rosiglitazone for three months. We have previously used the renal haemodynamic response to angiotensin-converting enzyme (ACE) inhibition to demonstrate the state of RAS activation, and thus measured renal plasma flow (RPF) and glomerular filtration rate (GFR) before and after administration of captopril at 0 month and at three months. Plasma renin activity (PRA), active renin, aldosterone and natriuretic peptides were analysed. RESULTS: The RPF response to ACE inhibition was not altered. There was no change in GFR, PRA, active renin and aldosterone levels. Two patients developed oedema one had an elevated baseline active renin and another had an elevated baseline aldosterone level. CONCLUSION: The favourable effects of TZDs on diabetic nephropathy is likely not related to an influence on the RAS.     

Diversity in Clinical Psychology

Clinical psychology is not as diverse as society, and the generalizability of clinical psychology to diverse groups has largely been untested. Some progress has been made in increasing the number of ethnic minorities receiving PhD degrees in clinical psychology and in increasing ethnic minority representation in clinical trials. Nevertheless, clinical psychologists and clinical psychology research are not diverse. A stages of change model may be useful in motivating clinical psychologists to diversify. A future scenario involving inertia and a second involving change are offered.     

Corrosion potential variation of aged dental amalgam restorations over time.

OBJECTIVE: The corrosion potential of a dental amalgam restoration is generally determined using a single measurement, even though environmental factors and abrasion can continuously alter the surface state and reactivity of this alloy. It was, therefore, the purpose of this study to determine the maximum variability of the corrosion potential of aged dental amalgam restorations, for 28 days. METHODS: The corrosion potentials of 148 aged dental amalgam restorations in 12 human subjects were measured at t = 0 and 4 h, and 4, 7, 14, 21 and 28 days. Measurements were made with a high impedance voltmeter and a Ag/AgCl micro-reference electrode. The subjects were instructed not to alter their usual eating and oral hygiene routines. RESULTS: Corrosion potential changes occurred throughout the 28 days. They were both positive and negative for the same restoration, and were sometimes very large. Only 4 h after the initial measurement, the absolute value of the corrosion potential changes ranged between 18 and 287 mV for 50% of the restorations. The largest maximum absolute corrosion potential change for each subject's restorations ranged between 85 and 329 mV. Statistical analysis showed that the overall mean maximum absolute corrosion potential change for the subjects' restorations was 74 mV. SIGNIFICANCE: It was shown that the corrosion potential of aged dental amalgam restorations varies substantially over time, and that a single measurement is not representative of short- or long-term electrochemical behavior. This finding has implications regarding the corrosion rate of dental amalgam restorations, particularly those that are part of a galvanic couple.