Health policy. Time to turn the tide

The government should not increase funding to the NHS until it can be demonstrated that this will improve population health and that the money cannot be made available from reducing current inefficiencies. The absence of an information base in the NHS is one of the greatest challenges. The new administration needs to acquire a deeper understanding of how resources are being used. New untested organisational structures and policy stunts should be avoided. Waiting lists should be prioritised according to urgency and ability to benefit.     

Loligomers: design of de novo peptide-based intracellular vehicles.

Defined branched peptides (loligomers) incorporating cytoplasmic translocation signals, nuclear localization sequences, and fluorescent probes were designed and synthesized to demonstrate the feasibility and simplicity of creating novel classes of intracellular vehicles. Loligomers containing all the above signals were rapidly internalized by Chinese hamster ovary (CHO) cells and accumulated in their nucleus. At 4 degrees C, the interaction of peptide constructs with CHO cells was limited to membrane association. Loligomers entered cells at higher temperatures by adsorptive endocytosis. Inhibitors of ATP synthesis affected cytoplasmic import only weakly but abolished nuclear uptake. The peptide signals guided both cytoplasmic and nuclear localization events. The properties exhibited by loligomers suggest a strategy for the facile design of "guided" classes of intracellular agents.     

The DiSC assay. A cost-effective guide to treatment for chronic lymphocytic leukemia?

The differential staining cytotoxicity (DiSC) assay involves in vitro drug panel testing against patient tumor cells to identify optimal therapy. This observational study investigated whether DiSC assay guided treatment could improve outcome in patients with chronic lymphocytic leukemia. A cohort of 178 patients were categorized either as sensitive to drugs in vitro and receiving a sensitive drug in vivo, sensitive in vitro but not treated with a sensitive drug, or having disease resistant to all drugs tested in vitro. Response and survival for these patient categories were compared using multivariate regression techniques. Patients receiving a sensitive drug, compared with those who though having sensitivity did not, had a higher remission rate (odds ratio, 6.5; 95% CI, 2.91-14.53) and reduced death rate (hazard ratio, 0.29; 95% CI, 0.16-0.53). Having adjusted for all known confounding factors, the results suggest that in vitro drug sensitivity is an important independent prognostic variable to include in future trials, and that the DiSC assay may be a cost-effective use of health resources: the estimated incremental cost-effectiveness was 1,470 Pounds per life-year gained. A randomized controlled trial is required to confirm the benefit and estimate reliably the potential impact of assay-guided choice of therapy.     

Evaluation of the bias in using the time to the first event when the inter-event intervals have a Weibull distribution

Currently the analysis of clinical trials for treatment of paroxysmal atrial fibrillation (PAF) relies on the assumption that the events are distributed according to a Poisson distribution. We contend that the occurrence of PAF events are clearly not Poisson and tend to occur in clusters. A candidate parametric model of the inter-event interval, the Weibull distribution, is presented. When the events are distributed according to a Poisson distribution, the time to the first event (TFE) has the same distribution as the inter-event intervals (IEI) due to the 'memoryless' property of the Poisson distribution, hence the TFE can be used instead of the IEI. When the events do not form a Poisson distribution, the TFE does not have the same distribution as the IEI. We show that for the Weibull distribution, when the TFE is used to model the IEI, both the mean and the survivor distribution are biased. The bias in the survivor function is a function both of time and the parameters of the distribution. Therefore when two groups have different parameters for their distributions (as in the case of different treatment effects), the discrepancy between the survivor distribution of the IEI and the survivor distribution of the TFE is affected differentially. We demonstrate the low coverage probabilities of the mean and the survivor function which result when the underlying distribution is Weibull with shape parameter kappa < 1.0. It is likely that this problem will arise for other clustered event processes. This suggests that careful empirical investigation of the distribution of IEI for recurrent events is necessary before choosing to analyse the data using the TFE.     

The Janus principle

The leaders who guide health organizations into formal and informal alliances must serve their own organizations while meeting the demands of a larger environment. Those who recognize the need for change in leadership style are most likely to help their organizations to maintain their strengths within new structures. The authors examine several theories of leadership style, describe the developmental stages involved in forming an inter-institutional organization, and discuss the new leadership tasks and skills that collaboration mandates.     

Nitric oxide synthase activity and inhibition after neonatal hypoxia ischemia in the mouse brain

Despite the emergence of therapies for hypoxic-ischemic injury to the mature nervous system, there have been no proven efficacious therapies for the developing nervous system. Recent studies have shown that pharmacological blockade of neuronal nitric oxide synthase (nNOS) activity can ameliorate damage after ischemia in the mature rodent. We have previously shown that elimination of nNOS neurons, either by targeted disruption of the gene or by pharmacological depletion with intraparenchymal quisqualate, can decrease injury after hypoxia-ischemia. Using a simpler pharmacological approach, we studied the efficacy of a systemically administered NOS inhibitor, 7-nitroindazole, a relatively selective inhibitor of nNOS activity. Using multiple doses and concentrations administered after the insult, we found that there was only a trend for protection with higher doses of the drug. A significant decrease in NOS activity was seen at 18 h and 5 days in the cortex, and at 2 h and 18 h in the hippocampus after the hypoxia-ischemia. nNOS expression decreased and remained depressed for at least 18 h after the insult. When nNOS expression was normalized to MAP2 expression, a decrease was seen at 18 h in the cortex and at 2 and 18 h in the hippocampus. These data suggest that further inhibition of NOS activity at early timepoints may not provide substantial benefit. At 5 days after the insult, however, NOS activity and normalized nNOS expression returned to baseline or higher in the hippocampus, the region showing the most damage. These data suggest that delayed administration of nNOS inhibitor after hypoxic-ischemic injury might be beneficial.