Morphine-3-glucuronide's neuro-excitatory effects are mediated via indirect activation of N-methyl-D-aspartic acid receptors: Mechanistic studies in embryonic cultured hippocampal neurones

Indirect evidence indicates that morphine-3-glucuronide (M3G) may contribute significantly to the neuro-excitatory side effects (myoclonus and allodynia) of large-dose systemic morphine. To gain insight into the mechanism underlying M3G' s excitatory behaviors, We used fluo-3 fluorescence digital imaging techniques to assess the acute effects of M3G (5-500 muM) on the cytosolic calcium concentration ([Ca2+](CYT)) in cultured embryonic hippocampal neurones. Acute (3 min) exposure of neurones to M3G evoked [Ca2+](CYT) transients that were typically either (a) transient oscillatory responses characterized by a rapid increase in [Ca2+](CYT) oscillation amplitude that was sustained for at least similar to30 s or (b) a sustained increase in [Ca2+](CYT) that slowly recovered to baseline. Naloxone-pretreatment decreased the proportion of M3G-responsive neurones by 10%-25%, implicating a predominantly non-opioidergic mechanism. Although the naloxone-insensitive M3G-induced increases in [Ca2+](CYT) were completely blocked by N-methyl-D-aspartic acid (NMDA) antagonists and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (alphaamino-3-hydroxy-5-methyl-4-isoxazolepropiordc acid/ kainate antagonist), CNQX did not block the large increase in [Ca2+](CYT) evoked by NMDA (as expected), confirming that N13G indirectly activates the NMDA receptor. Additionally, tetrodotoxin (Na+ channel blocker), baclofen (gamma-aminobutyric acid, agonist), MVIIC (P/Q-type calcium channel blocker), and nifedipine (L-type calcium channel blocker) all abolished M3G-induced increases in [Ca2+](CYT), suggesting that M3G may produce its neuro-excitatory effects by modulating neurotransmitter release. However, additional characterization is required.

A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia

Based on the epidemiological finding that individuals with schizophrenia tend to be born in winter/spring when compared to the general population, we examined (1) the strength and timing of this effect in Northern Hemisphere sites, and (2) the correlation between the season of birth effect size and latitude. Studies were located via electronic data sources, published citations, and letters to authors. Inclusion criteria were that studies specify the diagnostic criteria used, that studies specify the counts of schizophrenia and general population births for each month, and that subjects and the general population be drawn from the same birth years and catchment area. We extracted data from eight studies based on 126,196 patients with schizophrenia and 86,605,807 general population births and drawn from 27 Northern Hemisphere sites. Comparing winter/spring versus summer/autumn births, we found a significant excess for winter/spring births (pooled odds ratio = 1.07; 95% confidence interval 1.05, 1.08; population attributable risk = 3.3%). There was a small but significant positive correlation between the odds ratios for the season of birth comparison and latitude (r = 0.271, p < 0.005). Furthermore, the shape of the seasonality in schizophrenia births varied by latitude band. These variations may encourage researchers to generate candidate seasonally fluctuating exposures.

What is the best size descriptor to use for pharmacokinetic studies in the obese?

The prevalence of obesity in the western world is dramatically rising, with many of these individuals requiring therapeutic intervention for a variety of disease states. Despite the growing prevalence of obesity there is a paucity of information describing how doses should be adjusted, or indeed whether they need to be adjusted, in the clinical setting. This review is aimed at identifying which descriptors of body size provide the most information about the relationship between dose and concentration in the obese. The size descriptors, weight, lean body weight, ideal body weight, body surface area, body mass index, fat-free mass, percent ideal body weight, adjusted body weight and predicted normal body weight were considered as potential size descriptors. We conducted an extensive review of the literature to identify studies that have assessed the quantitative relationship between the parameters clearance (CL) and volume of distribution (V) and these descriptors of body size. Surprisingly few studies have addressed the relationship between obesity and CL or V in a quantitative manner. Despite the lack of studies there were consistent findings: (i) most studies found total body weight to be the best descriptor of V. A further analysis of the studies that have addressed V found that total body weight or another descriptor that incorporated fat mass was the preferred descriptor for drugs that have high lipophilicity; (ii) in contrast, CL was best described by lean body mass and no apparent relationship between lipophilicity or clearance mechanism and preference for body size descriptor was found. In conclusion, no single descriptor described the influence of body size on both CL and V equally well. For drugs that are dosed chronically, and therefore CL is of primary concern, dosing for obese patients should not be based on their total weight. If a weight-based dose individualization is required then we would suggest that chronic drug dosing in the obese subject should be based on lean body weight, at least until a more robust size descriptor becomes available.

The five families of sucrose-phosphate synthase genes in Saccharum spp. are differentially expressed in leaves and stem

Sucrose-phosphate synthase (SPS) is a key enzyme in the pathway of sucrose synthesis. Five different gene families encoding SPS have been reported in the Poaceae [Castleden CK, Aoki N, Gillespie VJ, MacRae EA, Quick WP, Buchner P, Foyer CH, Furbank RT, Lunn JE (2004) Evolution and function of the sucrose-phosphate synthase gene families in wheat and othergrasses. PlantPhysiology 135, 1753-1764]. Expression of the five families in leaf and stem tissues of Saccharum spp. at different stages of development was determined by quantitative real-time PCR. The type B and C families of SPS genes were predominantly expressed in both immature and mature leaves, whereas the two subfamilies making up the type D family were expressed at similar levels in all tissues examined. In the type A family, expression was lowest in leaves and increased from the meristem region down to internode 7 of the stem.