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.     

Predictors of employment in substance-using male and female welfare recipients

This study examined predictors of employment among substance-using men and women enrolled in welfare-to-work programs. Participants were 394 welfare applicants assigned to either coordinated care management or usual care for treatment services and job training and followed up for 1 year to track employment outcomes. Common barriers to work were assessed at baseline in four key domains: disabilities, situational barriers, labor capital, and motivation. Results indicated substantial gender differences in the number and profile of work barriers. Among men, work experience and job motivation were the only significant predictors of employment; among women, multiple factors from each barrier domain predicted job acquisition even when controlling for all other significant predictors. Findings suggest that welfare-to-work programs should emphasize job training and job seeking during the early stages of welfare interventions for men and for many women.     

The ensemble-averaged impedance cardiogram: An evaluation of scoring methods and interrater reliability

The interrater reliability and concurrent validity of two methods of scoring the ensemble-averaged impedance cardiogram were evaluated. Impedance cardiographic and electrocardiographic signals were recorded from 40 undergraduate men and women during a baseline rest period and a vocal mental arithmetic task period. Recordings were scored by four raters using a conventional method, involving ensemble averaging after careful editing of beat-to-beat waveforms, and a streamlined method, involving ensemble averaging without beat-to-beat editing. Intraclass correlations for interrater reliability exceeded .92, whereas intraclass correlations for concurrent validity exceeded .97, indicating excellent agreement between raters and scoring methods for all cardiac measures. The streamlined method was significantly faster than the conventional method. The results indicate that variations in beat-to-beat editing do not constitute a serious source of error in the ensemble-averaged impedance cardiogram and support the interrater reliability and concurrent validity of the two scoring methods.     

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.     

Liver and intestine transplantation

The most significant development in liver transplantation in the USA over the past year was the full implementation of the MELD- and PELD-based allocation policy in March 2002, which shifted emphasis from waiting time within broad medical urgency status to prioritization by risk of waiting list death. The implementation of this system has led to a decrease in pretransplant mortality without increasing post-transplant mortality, despite a higher severity of illness at the time of transplant.
The trend over the last few years of rapidly increasing numbers of adult living donor liver transplants was reversed in 2002 by a decline of more than 30% in the number of these procedures. In 2002, a greater percentage of women received livers from living donors (43%) than deceased donors (34%), possibly because of size considerations.
From 1993 to 2001, the waiting list increased more than sixfold, from 2902 patients to 18 047 patients. For the first time since 1993, the waiting list size decreased in 2002, dropping 6% to 16 974 candidates. The percentage of temporarily inactive liver candidates also increased from 2001, thus the net decrease in the active waiting list for 2002 was 12%. This may reflect a trend toward less pre-emptive listing practices under MELD.
Intestine transplantation remains a low-volume procedure limited to a few transplant centers and is still accompanied by significant pre- and post-transplantation risks. As this procedure matures, its application may increase to include recipients at an earlier stage of their disease with better likelihood of success.