Tracking consumers' reactions to the changing health care system: early indicators

A survey in fifteen communities and nationwide of consumers' opinions about changes in their local health care system reveals that Americans are surprisingly positive about recent changes in their personal access to and quality of care and consistently negative about changes in the cost of care. Although many consumers think that changes in the system are making things worse, they are optimistic about the trend toward managed care. Subgroup analysis shows that uninsured persons and persons with health problems reported high rates of concern about many of the health system issues we explored, while Medicaid recipients, Hispanics, and African Americans reported positive changes in their access to and quality of care.     

Critical islet mass for successful porcine islet autotransplantation

A major reason for the failure of clinical islet transplantations may be a limited islet mass. The aim of this study was to determine the critical islet mass necessary for normalization of glucose metabolism in a porcine model. Diabetes was induced by total pancreatectomy. The splenic lobe of the pancreas was intraductally distended with UW-solution containing 2.67-3.33 mg/ml collagenase, and the distended pancreas was digested in a continuous digestion filtration device. The islets were purified on a isoosmotic Ficoll-sodium-diatrizoate gradient. The survival period of the diabetic recipients in group 2 and 3 receiving, respectively, a low (2.14+/-0.39 microL/kg body weight) and a high (4.99+/-0.83 microL/kg body weight) islet mass was significantly prolonged compared to that of diabetic recipients in group 1 receiving no islet transplantation. However, the survival period of the recipients in group 2 was not significantly different to that in group 3. Three recipients of an islet mass of >5 microl/kg body weight became normoglycemic (fasting blood glucose <100 mg/dl) for more than two months. Furthermore, the glucose and insulin release reactions to the glucose challenge were comparable to that before pancreatectomy. Contrarily, another five diabetic recipients of an islet mass of <4 microL/kg body weight became a fasting blood glucose level of <200 mg/dl. The glucose and insulin release reactions to the glucose challenge were improved only, but not normalized compared to that before pancreatectomy. The data presented in this study demonstrate that metabolic normalization in pancreatectomized diabetic minipigs can be established by autotransplantation of an islet mass of >5 microl/kg body weight.     

Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy

The platelet P2T receptor plays a major role in platelet aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We have explored analogues of adenosine triphosphate (ATP), which is a weak, nonselective but competitive P2T receptor antagonist. Modification of the polyphosphate side chain to prevent breakdown to the agonist adenosine diphosphate (ADP) and substitution of the adenine moiety to enhance affinity and selectivity for the P2T receptor led to the identification of 10e (AR-C67085MX), having an IC50 of 2.5 nM against ADP-induced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P2T receptor, with a selectivity for that subtype of the P2 receptor family of >1000-fold. Further modification of the structure produced compound 10l (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at maximally effective antithrombotic doses, there is little prolongation of bleeding time (1.4-fold), which is in marked contrast to the 5-6-fold found with GPIIb/IIIa antagonists.     

Computer key switch force-displacement characteristics and short-term effects on localized fatigue

This study investigates the effects of key switch design parameters on short-term localized muscle fatigue in the forearm and hand. An experimental apparatus was utilized for simulating and controlling key switch make force and travel using leaf spring mechanisms, and provided direct measurement of applied key strike force using strain gauge load cells. Repetitive key tapping was performed as fast as possible using the dominant index finger for 500 s per condition (8.3 min) and a work-rest schedule consisting of 15 s of key tapping alternating with 10 s of rest. One combination of two make force levels (0.31 and 0.71 N) and two over travel distances (0.5 and 4.5 mm) was presented randomly on four different days. Nine subjects participated. Localized muscle fatigue in the hand and forearm was assessed subjectively using a 10 cm visual analogue scale, and objectively using surface electromyography (EMG). Average peak key strike force exerted was 0.35 N less for the smaller make force and 0.59 N less for the longer over travel distance. Fatigue occurred in all cases but no significant differences were observed between key switch parameters based on RMS EMG. Subjective reports of localized fatigue after 500 s were less when the key switch make force was less; however, a corresponding over travel effect was not observed despite the greatly reduced key strike force for the longer over travel distance. This discrepancy may be explained by the greater finger movement that was observed with increased over travel. Although there was no apparent improvement in short-term discomfort from fatigue when over travel was increased, this study did not consider the potential long-term health benefits from reduced key strike force.     

Protection against a lethal avian influenza A virus in a mammalian system

The question of how best to protect the human population against a potential influenza pandemic has been raised by the recent outbreak caused by an avian H5N1 virus in Hong Kong. The likely strategy would be to vaccinate with a less virulent, laboratory-adapted H5N1 strain isolated previously from birds. Little attention has been given, however, to dissecting the consequences of sequential exposure to serologically related influenza A viruses using contemporary immunology techniques. Such experiments with the H5N1 viruses are limited by the potential risk to humans. An extremely virulent H3N8 avian influenza A virus has been used to infect both immunoglobulin-expressing (Ig+/+) and Ig-/- mice primed previously with a laboratory-adapted H3N2 virus. The cross-reactive antibody response was very protective, while the recall of CD8(+) T-cell memory in the Ig-/- mice provided some small measure of resistance to a low-dose H3N8 challenge. The H3N8 virus also replicated in the respiratory tracts of the H3N2-primed Ig+/+ mice, generating secondary CD8(+) and CD4(+) T-cell responses that may contribute to recovery. The results indicate that the various components of immune memory operate together to provide optimal protection, and they support the idea that related viruses of nonhuman origin can be used as vaccines.     

The alpha-1,3-galactosyltransferase knockout mouse. Implications for xenotransplantation

BACKGROUND: A conformational change seems to represent the major difference between the scrapie prion protein (PrPSc) and its normal cellular isoform (PrPC). We recently proposed a set of four helix bundle models for the three-dimensional structure of PrPC that are consistent with a variety of spectroscopic and genetic data. RESULTS: We report a plausible model for the three-dimensional structure of a biologically important fragment of PrPSc. The model of residues 108-218 was constructed by an approach that combines computational techniques and experimental data. The proposed structures of this fragment of PrPSc display a four-stranded beta-sheet covered on one face by two alpha-helices. Residues implicated in the prion species barrier are found to cluster on the solvent-accessible surface of the beta-sheet of one of the models. This interface could provide a structural template that would assist the conversion of PrPC to PrPSc and hence direct prion propagation. CONCLUSIONS: Molecular models of the PrP isoforms should prove very useful in developing structural hypotheses about the process by which PrPC is transformed into PrPSc, the mechanisms by which PrP gene mutations give rise to the inherited human prion diseases, and the species barrier that seems to protect humans from animal prions. It seems likely that PrPC represents a kinetically trapped intermediate in PrP folding.     

Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of Multiple-Cause Mortality Data

BACKGROUND: Hemochromatosis, which can lead to serious chronic diseases resulting from iron overload, has an estimated prevalence of 50 to 80 cases per 10000 persons. However, little population-based information is available on the impact of hemochromatosis on morbidity and mortality. OBJECTIVE: To evaluate trends over 14 years in deaths and medical conditions associated with hemochromatosis in the United States. DESIGN: We searched Multiple-Cause Mortality Files compiled by the National Center for Health Statistics for the years 1979 to 1992 for all records listing hemochromatosis. We used these data to calculate age-adjusted and age-specific mortality rates, identify medical conditions associated with a known diagnosis of hemochromatosis at death, and calculate proportionate mortality ratios for these medical conditions. RESULTS: The listing of hemochromatosis on death certificates increased 60% from 1979 to 1992. Decedents with hemochromatosis were 23, 13, and 5 times more likely to have liver neoplasms, liver disease, and cardiomyopathy, respectively, than were decedents without hemochromatosis. Conversely, decedents with liver neoplasms, liver disease, and cardiomyopathy were 26, 14, and 5 times more likely, respectively, to have hemochromatosis than were decedents without these conditions. Hemochromatosis was 82 times more likely in persons with the combination of liver neoplasms and diabetes and 43 times more likely in those with the combination of liver disease and diabetes than in those without these conditions. CONCLUSIONS: Comparison of the reported prevalence of hemochromatosis among decedents with estimates of prevalence in the general U.S. population suggests that either the penetrance or the recognition of hemochromatosis, or both, is low. Nevertheless, substantial mortality resulting from liver disease, liver neoplasms, cardiomyopathy, and a combination of liver disease and diabetes in patients with hemochromatosis argues for the improved diagnosis and treatment of hemochromatosis in persons with these conditions.     

Introduction of the glutamate receptor subunit 1 into motor neurons in vitro and in vivo using a recombinant herpes simplex virus

We developed and characterized a recombinant herpes simplex virus vector and used it to introduce the complementary DNA encoding glutamate receptor subunit 1 flip into postmitotic motor neurons. Infection of purified motor neurons in vitro with this vector resulted in selective, high-level expression of glutamate receptor subunit 1 immunoreactivity in nearly 100% of the neurons. Patch-clamp experiments demonstrated that the protein product of the glutamate receptor subunit 1 flip transgene assembles into functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor channels. Herpes simplex virus-glutamate receptor subunit 1 flip was introduced into spinal cord cells by direct injection into the ventral horn and selectively into motor neurons by sciatic nerve injection. High levels of expression were sustained for at least one week and were accompanied by changes in the ionic permeability of AMPA receptors in transgene-expressing neurons. Throughout the first week of infection, there was little evidence for toxicity. Herpes simplex virus provides a versatile tool for manipulating the glutamate receptor phenotype of postmitotic neurons and will permit study of the role of individual glutamate receptor subunits in neuronal physiology and pathophysiology.