Controlling the rate in community rating--experts aren't sure how

What premiums states pay under community rating will be determined by how much they spend on health care. But it's not clear how spending is affected by prices, utilization, disease rates, and behavior. The answers will test Americans' commitment to one another.     

Influence of spatial and temporal manipulations on the anxiolytic efficacy of chlordiazepoxide in mice previously exposed to the elevated plus-maze

It has been widely reported that the anxiolytic efficacy of benzodiazepines in the elevated plus-maze test is abolished in subjects (rats or mice) that have been given a single prior undrugged experience of the test apparatus. The present series of experiments was designed to further characterise the key experiential determinants of this intriguing phenomenon in Swiss Webster mice. Using a standard 5 min test duration for both trials, Experiment 1 confirmed the anxiolytic efficacy of chlordiazepoxide (CDP; 5-20 mg/kg) in mice naive to the plus-maze, but a virtual elimination of drug effects in animals that had been pre-exposed to the maze 24 h earlier. Experiments 2 and 3 demonstrated that, while extending the duration of initial exposure to 10 min did not prevent the loss of CDP (10 mg/kg) efficacy in a standard-duration second trial, increasing the duration of both trials reinstated an anxiolytic profile for the compound. Finally, although trial 1 confinement to an open arm did not compromise CDP efficacy when animals were subsequently allowed to freely explore the maze (Experiment 4), closed arm confinement during initial exposure abolished the drug's anxiolytic action upon retest (Experiment 5). In contrast to previous findings in rats, these data suggest that the experientially induced loss of benzodiazepine efficacy in the mouse plus-maze depends rather critically upon prior discovery and exploration of relatively safe areas of the maze (i.e. closed arms). Results are discussed in relation to the hypothesis that the absence of an anxiolytic response to benzodiazepines in plus-maze-experienced subjects reflects the acquisition of an open arm phobia during trial 1.     

Olfactory bulbectomy increases prepro-enkephalin mRNA levels in the ventral striatum in rats

The effects of bilateral olfactory bulbectomy (OBX) on prepro-enkephalin, thyrotropin-releasing hormone, and D-2 receptor mRNA levels in the ventral striatum were examined by in situ hybridization histochemistry. Pre- pro-enkephalin mRNA levels were significantly increased in the olfactory tubercle (OT), but not in the nucleus accumbens, 14 days following bilateral OBX. Levels of D-2 receptor mRNA were also increased in the OT, though to a lesser degree. Prepro-thyrotropin-releasing hormone mRNA was unaffected by OBX. A separate experiment revealed no effect of OBX on enkephalin gene expression 7 days following surgery but a comparable elevation in pre- pro-enkephalin mRNA 14 and 28 days post-surgery. The findings are consistent with previously-reported effects of dopamine lesions on striatal gene expression, suggesting that the observed effects may be mediated by deafferentation-induced alterations in dopaminergic transmission in the OT. Altered dopaminergic function in the OT may be particularly relevant to the 'anhedonia' that has been associated with the olfactory bulbectomized rat model of depression.     

Induction of electrical excitability by NGF requires autocrine action of a CNTF-like factor

The overlapping expression of neurotrophin and neural cytokine receptors indicates that most neuronal populations are responsive to both classes of factors, yet relatively little is known about how these two trophic signaling systems interact to regulate neuronal phenotype. We report here that one hallmark of NGF's effects on target cells, the induction of membrane electrical excitability, requires the intermediary action of a CNTF-like factor. We found that NGF's regulation of voltage-gated potassium channels, unlike its regulation of voltage-gated sodium and calcium channels, involves a CNTF-like autocrine/paracrine loop. We showed that NGF induces secretion of a soluble factor that mimics the action of exogenous CNTF in regulating voltage-gated potassium channels and that NGF's ability to regulate this potassium channel is blocked by three independent reagents that inhibit the signaling of CNTF and/or related factors. The identity of this autocrine factor does not appear to be CNTF itself. Thus, a CNTF-like autocrine/paracrine factor is both necessary and sufficient for the regulation of potassium channels by NGF and is a key determinant of the type of electrical excitability that NGF induces in target cells.     

Lactic acidosis and mitochondrial dysfunction in two children with peroxisomal disorders

Summary Mitochondrial myopathies and defects in oxidative phosphorylation have been described in some patients with peroxisomal disorders. Although peroxisomes and mitochondria play a role in the -oxidation of fatty acids, the metabolic interactions between the two are not well defined. Defects in peroxisomal -oxidation are associated with extracellular accumulation of very long-chain fatty acids and may be accompanied by alterations in the intracellular pool of fatty acyl-CoAs, which are known to alter mitochondrial function. This study was initiated to examine alterations in the intracellular pool of acyl-CoAs and mitochondrial function in two children with generalized disorders of peroxisomal function and clinical lactic/pyruvic acidaemia. Fibroblasts were cultured from skin biopsies obtained from one child with neonatal adrenoleukodystrophy (NALD) and another with rhizomelic chondrodysplasia punctata (RCDP). Fibroblast lactate oxidation was significantly inhibited in NALD by 76% and RCDP by 92% compared to control values of 1.9±0.1 nmol/min per mg protein. Pyruvate dehydrogenase (PDH) (mean±SEM; activity nmol/min per mg protein) was: NALD 0.55±0.02 (p<0.01), RCDP 0.44±0.02 (p<0.01), and controls 0.83±0.02. The acid-insoluble (long-chain and very long-chain) acyl-CoA levels (mean±SEM; pmol/mg protein) were: NALD 129±69 (p<0.01), RCDP 65±15 (p<0.05), and control 45±7. These two patients with generalized peroxisomal disorders exhibited an increase in intracellular acyl-CoA species accompanied by decreased PDH activity and clinical lactic/pyruvic acidaemia.     

Group A meningococcal disease in the U.S. Pacific Northwest: epidemiology, clinical features, and effect of a vaccination control program

In 1975 an outbreak of group A meningococcal disease began in Seattle, Washington, and cases subsequently were recognized throughout the Pacific Northwest. Nearly one-half of the affected persons were Native Americans; two-thirds were alcohol abusers and/or habitués of skid road communities. In Seattle, group A meningococci colonized asymptomatic persons only if these individuals had contact with skid road (P = .006). The epidemic strain may have spread from American Indians in Manitoba, Canada. Traditional migration routes connect the two populations; asymptomatic American Indians on reservations in Washington carried group A meningococci. Vaccination programs were undertaken in four cities but only after cases occurred. In Seattle, vaccination reached 80% of the target population and was associated with a significant decrease in incidence of the disease, but cases recurred after the program ended. The social habits of skid road communities, combined with the "case-triggering" approach to, and premature termination of, vaccination programs, may have resulted in 56% of regional cases occurring after the start of the vaccination program in Seattle.