Endotoxin preconditioning protects against the cytotoxic effects of TNFalpha after stroke: a novel role for TNFalpha in LPS-ischemic tolerance.

Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-alpha (TNFalpha) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFalpha in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFalpha are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFalpha before middle cerebral artery occlusion in mice and show that TNFalpha is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFalpha are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFalpha (approximately threefold) and the proximal TNFalpha signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (approximately 2.5-fold), which may neutralize the effect of TNFalpha and reduce TNFalpha-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFalpha after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFalpha in the setting of ischemia. Our studies suggest that TNFalpha is a twin-edged sword in the setting of stroke: TNFalpha upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFalpha signaling during ischemia confers neuroprotection after LPS preconditioning.     

Finding temporary relief: strategy for nursing recruitment in northern aboriginal communities.

To address a recurring shortage of nurses in the aboriginal communities of Northwestern Ontario, the First Nations and Inuit Health Branch, Health Canada, commissioned a study to explore the viability of establishing a relief pool among nurses from nearby small industrial towns. An open/close-ended survey completed by a random sample of 237 nurses from the target population documented levels of awareness, willingness, and preparedness for northern practice, as well as recruitment incentives and disincentives. Findings demonstrate an awareness of the overlap between the professional and personal dimensions characteristic of such practices, and suggest support for innovative rotations that would cut across federal/provincial/community jurisdictions. Although complex, given time and willingness, a regional relief system seems viable.     

Child,family, and system outcomes of intensive case management in New York State

New York State’s Children and Youth Intensive Case Management (CYICM) was implemented in 1988 as one of several community-based initiatives for children with serious emotional disturbance (SED). Underlying this program is the goal of maintaining children with SED in the least restrictive environment appropriate to their needs. This paper presents CYICM child, family, and system outcomes over six years, describes program refinements, and explores continuing research efforts. Data are supportive of the positive outcomes associated with intensive case management for children with SED. Associated with enrollment in CYICM are a decrease in symptoms, improvement in functioning, and fewer hospitalizations in state-operated psychiatric centers, which translates into cost savings and a possible reduction in hospital beds.     

Genetic segregation analysis of red blood cell (RBC) histamine N-methyltransferase (HNMT) activity

Methylation is an important pathway in the biotransformation of many drugs, neurotransmitters, and xenobiotic compounds. Histamine N-methyltransferase (HNMT) catalyzes the Nτ-methylation of histamine and structurally related compounds. Measurement of HNMT activity in the RBC makes it possible to access variation in the enzyme activity that may reflect differences in less accessible tissues such as brain. Previously reported high family correlations for RBC HNMT activity suggested that genetic inheritance plays a major role in the regulation of variation in this enzyme. In the present study we completed complex segregation analyses of RBC HNMT activity of 241 individuals in 51 nuclear families that were randomly ascertained through children in the Rochester, Minnesota public school system in order to characterize the mode of inheritance of this important enzyme. We found evidence for major gene influence on the regulation of RBC HNMT activity. Both transformed and untransformed data support the presence of Mendelian major gene segregation, but the gene frequency differences do not indicate a direct correspondence between genotypes inferred from the two sets of analyses. Analyses of the skewed untransformed data indicated the presence of a relatively rare (Q = 0.121) additive major gene for high activity, with the three overlapping genotype distributions representing 77, 21, and 2 % of individuals. Analyses of the normalized transformed data indicated the presence of a common (Q = 0.71) additive major gene for high activity, with the three overlapping genotype distributions accounting for 9, 41, and 50 % of individuals. The analyses of transformed data give the best fit as well as the most parsimonious Mendelian major gene model. However, we cannot rule out the possibility of multiple alleles, and analyses of untransformed data provide some support for a third allele. Molecular studies will be needed to validate and characterize the alleles that regulate RBC HNMT activity levels in humans. © 1993 Wiley-Liss. Inc.     

The effects of self-generated comparison targets, BMI, and social comparison tendencies on body image appraisal

Previous studies examining the association between social comparison processes and body image dissatisfaction have yielded inconsistent findings. This study examined whether such discrepancies are due to either the use of identical comparison targets for all subjects or variability in body mass. Specifically, 216 subjects were randomly assigned to one of three experimental conditions: self-generated upward comparison group, self-generated downward comparison group, or control group. Dependent variables were measures of body image. Results indicated that increasing body mass and trait comparison tendencies were associated with increased body dissatisfaction. However, the experimental manipulation did not affect body image ratings. Results suggest that social comparison processes may operate similarly over a range of body mass index (BMI) values.     

Optimizing Suicide Gene Therapy for Head and Neck Cancer

An effective “suicide gene” therapy strategy in experimental studies has been the use of the herpes simplex virus thymidine kinase gene(HSV-tk) to sensitize tumors to the cytotoxic effects of ganciclovir administration. Previous studies using this model have focused on utilizing maximal viral titers and high levels of ganciclovir that are not compatible with human dosing. Because of the high ganciclovir doses and the maximal viral titers, this strategy has limited application to actual clinical scenarios. In the following studies the authors investigate tumor regression in an oral squamous cell carcinoma animal model as a function of variable adenoviral titers and more physiologic ganciclovir dosing. Using adenoviral titers ranging from 1 × 10⁸ to 2 × 10⁹ plaque forming units(pfu) to treat oral tumors, they found no statistical difference in tumor regression among the different viral doses, despite differences in mitotic activity. Each treatment group, however, demonstrated a significant effect on tumor regression when compared with controls. Furthermore, the authors were able to reduce the level of ganciclovir administration to 10 mg/kg twice daily from established levels of 100 to 150 mg/kg twice daily while maintaining significant tumor responses to the HSV-tk therapy. Mean survival of animals treated with this lower ganciclovir dose was significantly higher than in controls and was equal to established means based on previous studies using higher ganciclovir doses. The optimization of this suicide gene therapy strategy is imperative in order to minimize theoretical and known viral and ganciclovir toxicities while establishing a foundation upon which to design appropriate and effective clinical trials.     

A phase II study of sulofenur,a novel sulfonylurea,in recurrent epithelial ovarian cancer

Summary A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in antitumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted.