Systemic neutrophil intrinsic 5-lipoxygenase activity and CD 18 receptor expression linked to reperfusion injury

Objective: To determine if systemic neutrophil intrinsic 5-lipoxygenase (5-LO) inhibition correlates with decreased expression of surface adhesion molecules and attenuation of ischemia-reperfusion (i/r) injury in guinea pig island skin flaps. Methods: Eighty-one adult female Hartley guinea pigs were divided into one control group, three 2-hour ischemia groups, and four 10-hour ischemia groups. Island dorsal skin flaps were developed (except in the control group), and 2 hours before reperfusion, zileutin (a 5-LO inhibitor) or vehicle was administered orally. Postreperfusion systemic neutrophil receptor expression, neutrophil flap infiltration, and flap survival were measured. Neutrophils from whole blood were analyzed for CD 18 containing surface receptor expression using monoclonal antibodies and cell associated fluorescence. Neutrophil infiltration into a distal centimeter squared of flap tissue was assessed using myeloperoxidase antibodies, and flap survival was determined within 7 days postoperatively. Results: Flaps in the treated 2? and 10-hour ischemic groups survived totally intact, while the untreated 10-hour ischemic flaps underwent total necrosis. A significant main effect of the drug was detected using analysis of variance (ANOVA) (P =.0001). Surface receptor detection and neutrophil infiltration were significantly increased in the untreated animals. Conclusions: Zileuton, a 5-LO inhibitor, reduces adhesion receptor expression on systemic neutrophils and attenuates i/r injury. Systemic neutrophil intrinsic 5-LO activity and CD18 receptor expression are linked to reperfusion injury and may be fundamental events in its pathogenesis.     

Perceptions of social stigma and its effect on interpersonal relationships of young males who experience a psychotic disorder

Background:  People with psychotic disorders experience high levels of disability and impairment as a result of their illness. Difficulty in the area of social relationships poses a substantial problem with the majority of people with psychosis being socially isolated. Many of them experience an unmet need for services.
Methods:  A focus group was conducted with the aim of investigating the perceived experience of six young men who had a psychotic disorder to gain an understanding of the impact this had on interpersonal relationships.
Results:  The major themes identified were: (i) a significant decrease in the internal and external control of one's life at the onset of illness; (ii) the effects of labelling and stigma on interpersonal relationships; and (iii) the change in self perception that these effects bring.
Conclusion:  The implications of the findings for rehabilitation interventions are presented, specifically psychosocial group interventions addressing interpersonal relationships.     

Ocular pharmacokinetics of fluocinolone acetonide after Retisert intravitreal implantation in rabbits over a 1-year period.

PURPOSE: The present study was designed to examine the pharmacokinetics of a fluocinolone acetonide (FA) intravitreal implant in pigmented rabbits. METHODS: Pigmented rabbits were randomly assigned to receive either a 0.5 mg or 2.0 mg FA intravitreal implant (Retisert). Four animals were sacrificed per time point (2 hours; 2 weeks; and 3, 6, 9, and 12 months after implantation) for FA intraocular levels determination. RESULTS: In the vitreous, concentration of FA was relatively constant from the first time point, 2 hours, through 1 year, and dose-related, approximately seven- to eight-fold greater in the 2-mg implant. Concentrations of FA were generally higher in the vitreous (11-18 and 75-146 ng/g) and retina (42-87 and 224-489 ng/g) than in the aqueous humor (0.21-1.1 and 2.6-13.0 ng/g) for the 0.5- and 2-mg implants, respectively. Urine and plasma values were below the lower limit of quantitation (200 pg/mL) for all observations, indicating no evidence of systemic absorption. CONCLUSIONS: In this rabbit study, the Retisert provides relatively constant levels of FA in the posterior pole, which is consistent with previous reports of its clinical utility.     

Neuroprotective and symptomatological action of memantine relevant for alzheimer’s disease — a unified glutamatergic hypothesis on the mechanism of action

The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease is finding increasingly more acceptance in the scientific community. Central to this hypothesis is the assumption that in particular glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner. Such continuous mild activation leads under chronic conditions to neuronal damage. Moreover, one should consider that impairment of plasticity (learning) may result not only from neuronal damage per se but also from continuous activation of NMDA receptors. To investigate this possibility we tested whether overactivation of NMDA receptors using either non-toxic doses/concentrations of a direct NMDA agonist or through an indirect approach--decrease in magnesium concentration--produces deficits in plasticity. In fact NMDA both in vivo (passive avoidance test) and in vitro (LTP in CA1 region) impaired learning and synaptic plasticity. Under these conditions memantine which is an uncompetitive NMDA receptor antagonist with features of "improved magnesium" (voltage dependence, affinity) attenuated the deficit. The more direct proof that memantine can act as a surrogate for magnesium was obtained in LTP experiments under low magnesium conditions. In this case as well, impaired LTP was restored in the presence of therapeutically relevant concentrations of memantine (1 microM). In vivo, doses leading to similar brain/serum levels produce neuroprotection in animal models relevant for neurodegeneration in Alzheimer's disease such as neurotoxicity produced by inflammation in the NBM or beta-amyloid injection to the hippocampus. Hence, we postulate that if in Alzheimer's disease overactivation of NMDA receptors occurs indeed, memantine would be expected to improve both symptoms (cognition) and slow down disease progression because it takes over the physiological function of magnesium.     

Influence of the punch diameter and curvature on the yield pressure of MCC-compacts during Heckel analysis.

The volume reduction behaviour of powders has been quantified by means of the 'in-die' yield pressure (YP) using Heckel analysis. However, because different YPs are reported for the same material, the experimental conditions influencing this material-constant were investigated. Silicified microcrystalline cellulose was compressed into flat-faced and convex tablets using a compaction simulator instrumented with load and displacement transducers. During compression, upper and lower punch force and displacement data were recorded and corrected for punch deformation. A symmetrical triangle wave compression profile was used and the instantaneous punch velocity was kept constant (5mm/s). Individual tablet height and weight were used for Heckel analysis. The influence of the 'effective compression pressure' (P(EFF)) (ranging from 10 to 350 MPa), punch diameter (PD) (4, 9.5 and 12 mm) and filling depth (FD) (4.5, 7.5 and 10.5mm) on YP was statistically evaluated using Response Surface Modelling software. A quadratic surface response equation, describing the relationship between P(EFF), PD, FD and YP, was proposed for concave (Adj R(2): 0.8424; S.D.: 14.60 MPa) and flat-faced (Adj R(2): 0.8409; S.D.: 4.49 MPa) punches. YP and tensile strength were mainly determined by P(EFF), irrespective of punch curvature. FD and PD had only a minor influence on the YP, although more pronounced for the concave punches. The method used resulted in reproducible P(EFF) and tensile strength values and the flat-faced tablets showed less weight variation. Flat-faced punches are preferred over punches with a concave surface when investigating the volume reduction behaviour of a powder by means of Heckel analysis and the experimental parameters should be reported.     

Application of a statistical dynamic model investigating the short-term cellular kinetics induced by riddelliine, a hepatic endothelial carcinogen.

In recent studies, riddelliine, a pyrrolizidine alkaloid, was found to increase rates of replication and apoptosis and induce hemangiosarcoma in the liver of rats and mice. To analyze DNA replication and apoptosis data taken from the same animals, we have developed a predictive mathematical model for describing BrdU labeling and apoptotic processes. The model allows the incorporation of simple diurnal patterns in cellular kinetics and is applied to data on hepatocytes and endothelial cells taken from riddelliine exposed rats. Predictions from the model were used with multivariable nonlinear regression techniques to estimate replication and apoptotic rate constants for both cell types and all treatment groups. Hypothesis tests were used with the predicted rates to separate the competing effects of riddelliine on replication and apoptosis of hepatocytes and endothelial cells as well as compare replication rates between cell types. That estimated replication rates were found to be significantly higher for endothelial cells supports the supposition of induction of hemangiosarcoma by riddelliine in the liver.