Health information systems and the role of state government

State government entities have created a range of innovative electronic information systems to support their diverse and evolving roles in the health care system. Primary goals of these initiatives include improvement of traditional public health programs, meaningful oversight of providers, simplification of administrative procedures, and support of state purchasing decisions. We establish a taxonomy of state efforts, describing primary capabilities to (1) provide meaningful data to state decisionmakers; (2) disseminate information to purchasers and consumers; (3) coordinate and improve government services; (4) establish mechanisms for electronic transactions; and (5) support telemedicine services. Reductions in the costs of technology and use of the Internet have dramatically increased state capabilities in recent years. Both the successes and failures of existing programs offer important lessons for states that are initiating new electronic communication initiatives.     

Site-directed mutagenesis of dendrotoxin K reveals amino acids critical for its interaction with neuronal K+ channels

Dendrotoxin K (DTXK) is a 57-residue protein from mamba venom that blocks certain non-inactivating, voltage-activated K+ currents in neurones. In order to pinpoint the residues responsible for its specificity, structure-activity relations of DTX(K) were investigated by mutagenesis. A previously cloned gene encoding this toxin [Smith et al. (1993) Biochemistry 32, 5692-5697] was used to make single mutations; after expression in Escherichia coli as fusion proteins and enzymatic cleavage of the conjugates isolated from the periplasmic space, nine toxins were purified. Structural analysis of the native DTXK and representative mutants by circular dichroism showed that no significant differences were detectable in their folded structures. The biological activity of the mutants, which contained alterations of positively charged and other amino acids, was determined from their abilities to compete for the binding of 125I-labeled DTX(K) to K+ channels in synaptic plasma membranes from rat cerebral cortex. Mutants with residues substituted in the alpha-helix near the C-terminus (R52A or R53A) yielded binding parameters similar to those of wild-type and native DTX(K). In the case of the beta-turn (residues 24-28), however, altering single amino acids reduced binding to the high-affinity site of K+ channels, with the rank order of decreases being K26A > W25A > K24A = K28A. Also, substitutions made in the 3(10)-helix (residues 3-7), a region located close to the beta-turn, produced equivalent effects (K3A > K6A). Thus, it is deduced that residues in the distorted beta-turn and neighboring 3(10)-helix of DTX(K) are critical for its interaction with neuronal K+ channels.     

Importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity: an in vivo microdialysis study in the freely-moving guinea-pig

The importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity was investigated with the selective h5-HT1B receptor ligands SB 219085, SB 220272, SB 224289 and SB 216641. The studies employed measurement of compound affinity and efficacy in vitro and the measurement of extracellular 5-HT in the frontal cortex of the freely-moving guinea-pig using in vivo microdialysis. All compounds had high affinity and selectivity for the h5-HT1B receptor, with SB 224289 the most selective for h5-HT1B over h5-HT1D receptors. Compounds exhibited a range of efficacies at both receptors: SB 224289 and SB 219085 were inverse agonists, SB 220272 was an antagonist and SB 216641 was a partial agonist. SB 220272, SB 216641 and SB 224289 had no effect on extracellular 5-HT following systemic administration, however, SB 219085 produced a significant increase. The SB 219085-induced increase in extracellular 5-HT was attributed to the compounds non-specific releasing properties as it was also demonstrated to increase basal release of [3H]5-HT from pre-loaded guinea-pig cortical slices. The lack of effect of the above h5-HT1B receptor selective compounds and the decrease in extracellular 5-HT elicited by the non-selective compounds GR 127935, GR125743 and methiothepin suggest that antagonism of 5-HT1D receptors may mediate this decrease in 5-HT levels. It is plausible that blockade of 5-HT1D receptors increases 5-HT levels in the raphe, this activates 5-HTtA receptors which results in an overall decrease in terminal 5-HT release. Definitive proof now awaits elucidation of the action of a selective 5-HT1D receptor antagonist.     

Depressed Langerhans cell migration and reduced contact hypersensitivity response in mice lacking TNF receptor p75

Epidermal Langerhans cells (LC) belong to the dendritic cell family and represent the major APC within the skin. LC capture epicutaneous Ag, migrate into regional lymph nodes, and present Ag to T cells, thereby initiating primary immune response. The migratory properties of LC are an essential component of their function. The molecular mechanisms responsible for LC migration are far less defined. However, evidence has been accumulating to suggest that TNF-alpha, a major proinflammatory cytokine, plays an important role in promoting DC migration. To confirm the role of TNF-alpha in LC migration and to examine which type of TNF receptor signaling is involved in such an event, we utilized gene-targeted knockout mice lacking TNF receptor p55 or p75. The migration of LC was assessed by examining the frequency of hapten-bearing cells in draining lymph nodes following hapten FITC painting, and the accumulation of dendritic cells in draining lymph nodes after intradermal injection of TNF-alpha. While LC migration was normal in p55-deficient mice, the migration was markedly depressed in p75-deficient mice. Receptor p75-deficient mice also demonstrated a hyporesponsiveness in allergen-induced contact dermatitis, but a normal responsiveness in irritant-induced contact dermatitis. These results suggest that p75-dependent signaling plays a crucial role in the migration of LC and in the initiation of cutaneous immune responses.     

The pharmacokinetics of metoclopramide in man with observations in the dog

1 The pharmacokinetics of metoclopramide have been studied in eight normal male volunteers. 2 The mean plasma beta half-life was 156.7 min after i.v. administration of 10 mg metoclopramide. 3 After oral dosing of 10 mg the mean half-life was 196.6 min and after 20 mg 317.5 min (P less than 0.05). 4 Bioavailability of a 10 mg oral dose of metoclopramide varied between 32 and 97%. 5 A major urinary metabolite was metoclopramide-N-4-sulphate and the amounts of conjugates appearing in urine to 24 h correlated significantly with the bioavailability. 6 In the dog the metabolic fate of metoclopramide is different to man with conjugation being a minor metabolic pathway. The half-life in the dog does not appear to be dose dependent. 7 The wide differences in bioavailability of metoclopramide in man may contribute to the unpredictable occurrence of side effects.     

Weanling and adult rats differ in fatty acid and carnitine metabolism during sepsis

Increased oxidation of fat is an important host response to sepsis, and carnitine is essential for long-chain fatty acid oxidation. Because neonates have low levels of carnitine, their ability to respond to a septic insult may be impaired. The purpose of this study was to compare fatty acid and carnitine metabolism in septic weanling (60 to 85 g) and septic adult (285 to 310 g) rats. Sepsis was induced in weanling and adult male Sprague-Dawley rats by cecal ligation and puncture (CLP). The rats were killed 16 hours after CLP or sham operation, and serum glucose, lactate, beta-hydroxybutyrate, fatty acid, carnitine, liver fatty acid, and tissue carnitine levels were measured. The data suggest that during sepsis weanling rats may be more dependent on fatty acid oxidation than adult rats are, as evidenced by their elevated serum fatty acid and acylcarnitine levels, and relative hypoglycemia and hyperketonemia. In addition, although total serum carnitine levels were increased in both adult and weanling septic rats, tissue carnitine levels of weanling rats became significantly depleted during sepsis, unlike in adult rats. This study supports further investigation regarding the role of exogenous carnitine in newborn sepsis.