Analysis of human transcriptomes.
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Biomedical subjects
Publications and source records attributed to B Mathews.
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BACKGROUND: Traditional approaches to community health initiatives provide guidance on community mobilization, health assessment, planning, and intervention. Yet direction in how to frame the action steps to implement and measure results is often missing. Many community health initiatives find implementation overwhelming and ineffectual. FRAMEWORK FOR COMMUNITY HEALTH-THE CLINICAL IMPROVEMENT MODEL: The process--outcome methodology of continuous quality improvement (CQI) can translate large community aims into manageable projects. The sequential application of the clinical improvement model and the Community Health Value Compass for measuring outcomes-in state of health, quality of life, satisfaction, and costs-provides a link between data and action, thereby producing accountability for the community health initiative. USING THE CLINICAL IMPROVEMENT MODEL IN TWIN FALLS: Healthy Magic Valley (Twin Falls, Idaho) is the vision for long-term improvement in health status and reduction of health risks for the Southcentral Idaho Health Network. Since 1996 the Twin Falls Community Health Collaborative and SAFE KIDS Coalition have used the Value Compass model and CQI methods to decrease the rate of motor vehicle collisions, serious injuries, and deaths involving teens, while reducing the health, educational, legal, and financial consequences associated with teen-involved motor vehicle collisions. In 1993 the Twin Falls collaborative convened to apply CQI methods to the health of the community. The team has since met periodically to address the issues of community health, using the Dartmouth value compass model since 1996. Each sequential application of the process-outcome CQI framework exposes a blueprint for action and the unfolding of a health improvement strategy. The interventions should affect one or more dimensions of the value compass for teenage driving and motor vehicle collisions. CASE STUDY OF THE CLINICAL IMPROVEMENT MODEL: The motor vehicle death in October 1997 of a high school football player, who was not wearing a seat belt, led to a call to action for injury prevention. Implementation of a local community health initiative on seat belt use started in 1998. A strategy was developed to address implementation of the project among high school teens (for immediate impact) and elementary school children (for long-term impact) and to promote collaboration between the school and the rest of the community. RESULTS: Observed use of seat belts increased from January to September 1998. Data on fatality rates; injury rates; percentages of teens in crashes, of teens injured, and of teen collisions involving use of alcohol; and comprehensive costs are also monitored. DISCUSSION: Once coalitions are built and priorities set, the Dartmouth clinical improvement model presents a method that emphasizes measuring the benefits to the individual members of the community. A portfolio composed of a value compass for each health improvement initiative provides ongoing feedback for guiding subsequent strategic planning by the governing community health network.
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Rifapentine is a cyclopentyl derivative of rifampin under development for the treatment of Mycobacterium tuberculosis and Mycobacterium avium complex infections. These studies were designed to investigate the disposition and biotransformation of single iv and oral doses of 14C-rifapentine in mice, bile duct-cannulated and uncannulated rats, and monkeys. Mass balance studies included 14C analyses of urine, feces, bile, cage wash, carcasses, and cage air collected for up to 120 hr postdose. Separation of radioactive compounds extracted from urine, bile, and feces was conducted using high-performance liquid chromatography and radioisotope detection. The mass spectra of selected chromatographic peaks were obtained. Disposition results were similar for all three species. Less than 5% of the radioactive dose of 14C-rifapentine was recovered in urine, indicating that renal excretion is a minor route of elimination in these species. The major route of elimination of radioactivity was into the feces, where more than 75% of the radioactivity was recovered. Biliary excretion was the major route of elimination of radioactivity in bile duct-cannulated rats dosed either po or IV. Radiochromatograms were similar for fecal samples from animals dosed by IV or orally. Ten regions of radioactivity were observed in mouse and rat fecal sample radiochromatograms, and seven regions of radioactivity were observed in monkey fecal sample radiochromatograms. The most abundant compound identified in feces was usually intact rifapentine (27%-41% of dose in mouse, 3%-35% of dose in rat, and 17%-29% of dose in monkey). Other peaks identified or characterized in feces based on liquid chromatography/ultraviolet/14C and/or liquid chromatography/mass spectrometry methods included 25-desacetyl-rifapentine, 3-formyl-25-desacetyl-rifapentine, and 3-formyl-rifapentine. The compounds rifapentine, 25-desacetyl-rifapentine, and 3-formyl-rifapentine were present in rat bile samples. These studies show that the metabolism and disposition of rifapentine in mice, rats, and monkeys were similar.
Human nasopharyngeal carriage of Streptococcus pneumoniae constitutes the major natural reservoir of pneumococci and is thought to be the prelude to virtually all pneumococcal disease. If carriage could be greatly reduced, pneumococcal transmission and disease could be largely eliminated. To facilitate the studies of mechanisms important in carriage and to identify immunogens that can elicit protection against carriage, we characterized an adult mouse model of nasopharyngeal carriage. Non-anaesthetized mice were inoculated intranasally with pneumococci in 10 microl of fluid. Nasopharyngeal carriage was observed with strains of capsular types 3, 4, 6A, 6B, 14, 19, and 23. Carriage was stable over time, and the numbers of pneumococci carried were relatively independent of inoculation dose; findings which indicate that the recovery of pneumococci from 1 day to 2 weeks post inoculation was dependent on colonization, rather than just temporary contamination. To ensure carriage in the largest percentage of mice, without causing sepsis or death, inoculations of 10(7) colony forming units (cfu) should be used. In this model, carriage was generally observed without concomitant bacteremia or sepsis and carriage was observed even with strains that were avirulent when injected i.v. The model should be useful for the identification of protection-eliciting antigens, since intranasal immunization with heat-killed pneumococci or lysates of pneumococci protected against carriage.
As small business employers, physician group practices will be subject to provisions of the Health Insurance Portability and Accountability Act of 1996 related to coverage guarantees. The act prevents currently insured individuals from losing coverage if they change jobs, limits insurance exclusions related to preexisting conditions, and requires insurers that offer small group coverage to make such policies available to all small employers. While the act's coverage guarantees may help group practices to attract good employees who formerly feared losing their coverage if they changed jobs, it also is likely to increase administrative costs, lead to premium increases, and limit to the choices for practices that must shop for health plans. Practices planning to purchase health insurance can ensure that they receive the best coverage possible by carefully comparing policy features and the claims services potential insurers provide.
To obtain information about the evolution of the cholinesterases, we investigated the cholinesterase activity of an agnathan vertebrate, the hagfish Myxine glutinosa. On the basis of evidence from enzymology, pharmacology, and molecular biology, we conclude that the cholinesterase activity is due to acetylcholinesterase (AChE). The enzyme hydrolyzes acetylthiocholine preferentially and exhibits substrate inhibition. The hydrolysis of both acetylthiocholine and butyrylthiocholine are inhibited in parallel by cholinesterase inhibitors, with the AChE-specific drug BW284c51 being the most potent; however, this drug and propidium, a peripheral anionic site ligand, are much weaker inhibitors of the hagfish enzyme than of Torpedo AChE. We used sequential extraction, collagenase digestion, and velocity sedimentation on sucrose gradients to determine that the AChE from the skeletal muscle of the hagfish is present in both globular and asymmetric forms. We also used the polymerase chain reaction with degenerate oligonucleotide probes and genomic DNA to obtain a 1 kb gene fragment for hagfish AChE. The enzyme has an acyl binding site typical of other vertebrate AChE, but lacks two aromatic residues implicated in the function of the peripheral anionic subsite. We discuss the relevance of our findings to the evolution of the cholinesterases in the vertebrates.
Oxidized low density lipoprotein (oxLDL) is known to be toxic to a variety of cell types, but relatively little is known about the toxic effects of oxLDL on vascular smooth muscle cells (SMC). We found that LDL oxidized by incubation with 5 microM cupric ions was toxic to cultured porcine SMC when administered at concentrations of 25 micrograms protein/ml and higher. The toxicity was demonstrated whether cells were proliferating or not, and was more evident in the presence of 0.4% lipoprotein-deficient serum than in 10%. Because of recent evidence that 7-ketocholesterol and 7-hydroxycholesterol are toxic species in copper-oxidized LDL, inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase was hypothesized as a mechanism of toxicity. However, mevalonic acid, the product of this enzyme, failed to protect against the toxicity of either oxLDL or the pure oxysterols. Alpha-tocopherol, alpha-tocopherol acetate, probucol, butylated hydroxytoluene, and deferoxamine provided partial protection to SMC exposed to oxLDL. These results suggested a toxic role for newly initiated lipid peroxidation, either in cells or in media oxLDL. Cellular lipid peroxidation appeared more likely, since no further oxidation of media oxLDL was demonstrated in the presence or absence of antioxidants. Overall, the results suggest that toxicity of copper-oxidized LDL for SMC is multifactorial and differs from the previously described toxicity of iron-oxidized LDL for fibroblasts.
The cytotoxicity of oxidized low-density lipoprotein (Ox-LDL) to arterial smooth muscle cells (SMCs) may contribute to atherogenesis by causing cell death in core regions of plaques. The aim of the present study was to identify the components of copper-oxidized LDL responsible for its toxicity to porcine aortic SMCs. Toxicity to SMCs was assessed as the decrease in viable cell counts after 3-day cell incubation. Extracts of LDL were tested for toxicity at concentrations equivalent to that derived from 100 micrograms LDL protein per milliliter. Lipid extracts of Ox-LDL but not native-LDL were toxic to SMCs. When separated into neutral and polar lipid classes, only the neutral lipids were toxic (89.7 +/- 0.7% cell loss). The neutral lipids were fractionated further by use of solid-phase extraction and high-performance liquid chromatography (HPLC). Two toxic fractions, causing 93.3% and 60.3% cell loss, were isolated from HPLC and analyzed by gas chromatography/mass spectrometry. The most toxic of these fractions contained 7-ketocholesterol, and the other contained 7 alpha- and 7 beta-hydroxycholesterol. Quantification of these unesterified oxysterols in LDL extracts and comparison with the toxicity of authentic standards indicate that 7-ketocholesterol and 7-hydroxycholesterol are present in Ox-LDL at levels sufficient to account for its toxicity to SMCs.
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The use of self by the therapist, generally referred to as therapist self-disclosure, and its potential impact on the therapeutic process, continues to be an important and contentious area of interest and inquiry. In contrast to most research in our field, which concentrates on the patient, in this investigation it was the therapist, and her/his beliefs, attitudes, and reported behaviors that served as the primary focus. The literature shows quite a few studies regarding the theoretical aspects of therapist self-disclosure but studies concerning actual psychotherapy are rare. The intent of this article is to focus on the practice of psychotherapy in an attempt to comprehend more fully one aspect of it: therapist self-disclosure.
A double-blind controlled study was undertaken to examine the value of phosphatidylcholine as a treatment for tardive dyskinesia (TD) in 19 psychiatric patients. All patients were maintained on their usual psychotropic medication throughout the entire study. In addition, they were given either phosphatidylcholine (30 g/day) or placebo for 6 weeks. Thirteen of the patients received the crossover treatment for 6 weeks, after which 10 of the 13 were continued on the crossover medication for an additional 6 weeks. At the end of the study, 5 patients had received phosphatidylcholine for 12 weeks and another 12 patients had received the drug for only 6 weeks. Plasma and red blood cell choline levels were monitored every 3 weeks as a measure of compliance. Although some patients showed clinical improvement of their TD, the results did not differ significantly between active drug and placebo. This was in spite of a marked elevation of plasma and red blood cell choline (up to 300% for the Lafayette Clinic patients and up to 400% for the patients from the Ypsilanti Regional Psychiatric Hospital) during treatment with phosphatidylcholine. Side effects of the drug included occasional gastrointestinal upsets and diarrhea but, in general, the medication was tolerated very well. The results indicate that large doses of phosphatidylcholine of soya origin are of no clinical value in treating symptoms of TD in spite of very large increases in blood choline.
The purification of NADP-linked isocitrate dehydrogenase from ox heart mitochondria is described. The molecular weight from gel filtration, sedimentation equilibrium and gel electrophoresis is 90000+/-4000, and there are two subunits in the molecule each of which binds NADPH with enhancement of the coenzyme fluorescence. The amino-acid composition is reported, and the absorption coefficient, A1/280%, estimated from dry weight measurements is 11.8 cm-1.
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