Serum cryptococcal antigen in patients with AIDS.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
C Harris
Publications and source records attributed to C Harris.
Outpatient management of diabetes mellitus in five Arizona Medicare managed care plans.
We report findings on the outpatient management of diabetes mellitus in Medicare beneficiaries enrolled in five Arizona Medicare-managed care plans. These findings are the baseline of an ongoing collaboration between the Health Services Advisory Group, Inc., Arizona's Peer Review Organization (PRO), and the five plans whose object is improved care of diabetes patients. The purpose of the study was to determine congruity between quality indicators identified by the five plans and the care actually received by diabetes patients enrolled in the five plans. The five plans agreed on a common set of quality indicators, including 10 services and 10 measures of patient status. Each plan has identified its diabetic population, 75 of whom are randomly selected each quarter by the PRO for chart review and inclusion in the study. The findings in this report cover two quarters of data. Data from chart review were examined to determine the extent to which actual practice reflected the indicators. The mean patient age was 71.8, and for most patients onset occurred between 55 and 69 years of age. About 25% had a positive family history, and we estimate the annual incidence of diabetes in this population to be about 1.1%. Mean hemoglobin A1c (HbA1c) was 8.9 +/- 2.1%; 46% were hypertensive; 42% continued to smoke cigarettes; 36% had retinopathy; 20% had proteinuria; and only 22% were on some kind of exercise program. Thirty-two percent were hospitalized during the 1-year baseline period, and the average number of outpatient visits per patient was 11.1 +/- 7.4. When care provided to diabetes patients enrolled in the plans was compared with the 10 quality standards identified by the plans themselves, only two of these standards was attained in more than 60% of patients: blood pressure, 98.7%; and foot examination, 62.7%. Two standards were achieved less than one-third of the time: urine dipstick, 10.4%, and appropriate use of angiotensin-converting enzyme (ACE) inhibitors, 31.25%. The others were all between 40 and 55%. Of the 10 service standards, about one-third received 1-4, one-third received 5-6, and one-third received 7-10. Only 5% of patients received 9 or 10 services. Outpatient management of diabetes patients in managed-care plans is similar to that in fee-for-service. When compared with fee-for-service or another HMO, a higher proportion of Arizona-managed care patients had HbA1c, and a much lower proportion had a dipstick test for urine protein. Values for other variables were usually within 10 percentage points of each other. Regardless of payment scheme, diabetes care is characterized by inconsistencies, omissions, and a lower than desirable level of services. Although few patients received most of the indicator services, diabetes patients are nevertheless high utilizers of medical care, both in and out of the hospital. The hospitalization rate is twice that of Arizona Medicare beneficiaries as a whole, and the number of office visits is three or four times that reported in other studies. Further, it seems that many visits are required to achieve even these modest service levels. Had the average number of visits been six or less, HbA1c rates, for example, would have fallen to less than one-third in three of the five plans. We believe that these data are conservative because it is likely that some and perhaps most of these indicators are underreported. It should be emphasized that these are baseline data whose purpose is to provide a basis against which subsequent improvements many be measured.
Aged↗
A top-down approach to whole genome visualization.
The investigation of large DNA contigs like complete chromosomes or genomes requires novel methods of data visualization. The complex information contained in a genome, particularly the relation of its individual genetic elements, needs to be accessible in a comprehensive, intelligent and intelligible manner. The yeast genome is expected to contain more than 6,000 Open Reading Frames (ORFs). As yet, the function of many of these ORFs has not been characterized satisfactorily. Also, many ORFs are found to have redundant copies elsewhere in the genome that originated from common ancestors. Other genetic elements (e.g. Tss, delta-elements, t-RNAs) are present in multiple copies. To visualize these relationships, a top-down "genome browser" is introduced that enables inspection of genomic data at different levels of abstraction (e.g. chromosomes, coding/non-coding regions, high/low levels of similarity). This novel tool is a key component for the integrated services approach to biological sequence data management (Heumann et al. 1995) and is accessible through the world wide web (WWW). This work demonstrates how the genome browser visualizes the results of an all-against-all comparison of the elements in the yeast genome as a graph. Interactive navigational queries across yeast chromosomes along the lines of sequence similarity open versatile options for the detailed investigation of genome properties. For sequence comparison the hashed position tree HPT (Mewes & Heumann 1995) is applied. Sequence similarity relationships are represented using the genome similarity graph (GSG) (Heumann & Mewes 1996c).
Chromosomes, Fungal↗
Agouti structure and function: characterization of a potent alpha-melanocyte stimulating hormone receptor antagonist.
The murine agouti gene encodes for a novel 131 amino acid protein. The sequence includes a 22 residue putative secretion signal, an internal basic region, and a C-terminal domain containing 10 cysteines. Agouti has been found to antagonize the binding of certain pro-opiomelanocortin peptides, such as alpha-melanocyte stimulating hormone (alpha-MSH), to the murine melanocortin-1 receptor (MC1-R). We report the purification of a secreted murine agouti to homogeneity by a two-step procedure from baculovirus-infected Trichoplusia ni (T. ni). The protein is glycosylated and exhibits competitive, high-affinity antagonism (Ki = 0.8 nM) versus alpha-MSH in cell-based assays employing B16F10 cells. Association state analysis by analytical ultracentrifugation reveals that agouti exists in a monomer--dimer plus aggregate equilibrium at low micromolar concentrations. Data from secondary structure studies indicate that the protein is highly stable to thermal denaturation. Enzymatic digestion to probe disulfide bond arrangement yielded a discrete C-terminal (Val 83-Cys 131) domain. The isolated highly cysteine-rich C-terminal domain retains alpha-MSH antagonism equipotent with mature agouti. This bioactive domain contains all 10 cysteines which exhibit sequence homology when aligned with several conotoxins.
Agouti Signaling Protein↗
Four new cases of inverted terminal duplication: a modified hypothesis of mechanism of origin.
We present 4 recently diagnosed cases of inverted tandem duplication with involvement of the respective terminal band. Based on these 4 cases and review of the literature, the term "inverted terminal duplication" is proposed to designate specifically the type of inverted tandem duplication which involves the terminal band. A modification of the previous hypothesis of mechanism of origin is advanced. It is speculated further that a telomeric deletion of a meiotic chromosome followed by a U-type reunion of the chromatids, considered to be the first steps of the proposed mechanism of origin, may not be a rare gonadal event.
Abnormalities, Multiple↗
UICC Study Group on basic and clinical cancer research: apoptosis in normal and tumor cells.
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Animals↗
Inhibition of aberrant crypt growth by non-steroidal anti-inflammatory agents and differentiation agents in the rat colon.
Aberrant crypts are aggregates of single to multiple colonic crypts evidencing hallmarks of dysplasia and may be the earliest detectable pathological lesions for colon cancer. The aberrant crypt assay has been developed in 2 protocols. In one, putative chemoprevention agents are tested for inhibitory effects when administered concomitantly with a carcinogen. In the other, the objective of this study, aberrant crypts were induced in F344 rats by parenteral injection of the colon carcinogen azoxymethane (AOM) and allowed to develop for 4 weeks, when an average of 90-100 aberrant crypt foci per colon were found in the methylene blue-stained colon. Then, during the second 4 weeks of the experiment, aberrant crypts were allowed to further develop to a frequency of > 150 foci per colon, a time when multi-crypt foci were observed. During this time we tested the inhibitory effects of 4 analgesic drugs and 2 differentiation agents for effects of aberrant crypt growth and development. We found the non-steroidal anti-inflammatory drugs piroxicam, aspirin and ibuprofen, but not acetaminophen, to be effective in suppressing aberrant crypt formation or the progression to foci of multiple aberrant crypts. Treatment with chemosuppressing agents 13-cis-retinoic acid (13-cRA) and 4-hydroxyphenretinamide (4-HPR), known differentiating agents, however, did suppress expansion of aberrant crypt foci, with 13-cRA being the much more potent agent.
Acetaminophen↗
Proton nuclear magnetic resonance spectroscopic imaging of human temporal lobe epilepsy at 4.1 T.
We performed proton magnetic resonance spectroscopic imaging (MRSI) at high magnetic field (4.1 T) to study N-acetylaspartate, creatine, and choline levels in the brains of normal control subjects and patients with intractable temporal lobe epilepsy. We compared the results of MRSI to those of other presurgical techniques to determine the sensitivity of this method in the lateralization of the epileptic focus. The normal hippocampal creatine-N-acetylaspartate ratio was 0.71 +/- 0.14 with no differences between left and right. Using the mean control hippocampal creatine-N-acetylaspartate ratio plus 2 standard deviations to identify statistically significant changes, we found lateralizing metabolic abnormalities corresponding to the operated temporal lobe in all patients. Four patients (40%) had contralateral abnormalities, and 2 of them had bilateral independent seizure onset confirmed by intracranial electroencephalographic studies. Statistically significant increases in the choline-N-acetylaspartate ratio in comparison to healthy volunteers were observed in 8 of the 10 patients. With the creatine-N-acetylaspartate ratio, MRSI demonstrated a 100% sensitivity compared to magnetic resonance imaging, which identified pathology in 70% of the patients. These findings suggest that proton MRSI yields a distinctive metabolic profile in patients with temporal lobe epilepsy and is sensitive in detecting bilateral metabolic abnormalities in some patients. These preliminary findings suggest that MRSI is more sensitive than magnetic resonance imaging in the lateralization of epileptic foci in temporal lobe epilepsy.
Adult↗
Risk-adjusted analysis of surgeon performance: a 1-year study.
A 1-year prospective analysis was undertaken of all non-day-case general surgery in a district general hospital. Using the Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) scoring system 3004 patients were assessed. From the predictions of mortality and morbidity so obtained, a quality measure, the ratio of observed to expected numbers of deaths and complications (O:E ratio) was determined for each surgeon, both overall and within specialty zones. The present study demonstrates the serious hazard in using 'raw' uncorrected mortality and morbidity statistics to compare surgeon performance. Mortality rates varied from 1.0 to 4.9 per cent whereas O:E ratios ranged from 0.83 to 1.06; morbidity rates varied from 5.3 to 12.6 per cent with O:E ratios 0.86-1.02. Great misunderstanding may result from the publication of surgeon or hospital 'league tables'. The present study demonstrates a technique that might allow surgeon performance to be monitored adequately and accurately.
Day Care, Medical↗
Formation of protein-glutathione mixed disulfides in the developing rat conceptus following diamide treatment in vitro.
Protein-glutathione mixed disulfide (protein-S-SG) formation was investigated in developing rat conceptuses during early organogenesis (gestational day 10, GD 10) using the whole embryo culture system. Low levels of protein-S-SG (25.0 +/- 6.6 pmoles resolved GSH/conceptus) were found in conceptuses under normal culture conditions. Incubation of the conceptuses with 75-500 microM diamide (a thiol oxidant) resulted in rapid increases in protein-S-SG (to 2- to 16-fold that of control values) in a dose-dependent manner during 30 min of the culture period. Approximately 20% of the observed cytosolic glutathione (GSH) depletion following diamide (500 microM) could be accounted for as mixed disulfides of protein sulfhydryls, when determined in whole conceptual tissues after 15 min. The most extensive S-thiolation of protein sulfhydryls by GSH was observed in visceral yolk sac (VYS) when compared to embryo proper and ectoplacental cone. This result indicates that the most abundant, sensitive, or accessible protein sulfhydryls were found in the VYS. Inhibition of glutathione disulfide reductase activity by pretreatment of the conceptuses with 25 microM BCNU for 2 hr potentiated protein-S-SG formation elicited by 75 microM diamide. Reincubation of the conceptuses in fresh media, following the 15-min treatment with 500 microM diamide, reversed both the GSH depletion and the protein-S-SG formation in conceptal tissues. The reduction of the protein-S-SG was dependent on adequate intracellular GSH levels and was inhibited when GSH was rapidly depleted by subsequent addition of N-ethylmaleimide (NEM, 100 microM). Under the same experimental conditions, addition of 1 mM dithiothreitol (DTT) did not significantly enhance the GSH restoration rate nor the protein-S-SG reduction rate. The results also indicated that low levels of intracellular cysteine do not play an important role in the reduction of protein-S-SG. Protein-S-SG formation may be important for cellular regulation and in mediating the embryotoxicity elicited by diamide or other oxidative stresses.
Animals↗
Diamide-induced alterations of intracellular thiol status and the regulation of glucose metabolism in the developing rat conceptus in vitro.
Direct oxidation of embryonic reduced glutathione (GSH) by a thiol oxidant, diamide, has been demonstrated to result in increased glutathione disulfide (GSSG) and protein-glutathione mixed disulfide (protein-S-SG) formation, which is accompanied by embryotoxicity and reductions in amniotic fluid volume. The altered functions of critical proteins or enzymes caused by the formation of protein-S-SG perturb cellular metabolism and may be involved in the embryotoxicity produced by GSH oxidation. The present study investigates changes in the metabolism of glucose through glycolysis and the pentose phosphate shunt pathways (PPP) and their related enzymes under the oxidative conditions produced by diamide exposure in organogenesis-stage rat conceptus (gestational day 10) in vitro. The metabolism of glucose via the PPP, measured as amounts of CO2 production from D-[1-14C]-glucose, was significantly increased in the conceptus exposed to 100-500 microM diamide to levels 2.5-3-fold those of controls. It was found that these substantial increases in the PPP activity did not correlate well with a moderate activation of glucose 6-phosphate dehydrogenase (G6PD) activity, the key enzyme in the PPP pathway. Changes in glycolysis due to diamide treatment were also determined by measurements of lactate production from D-[U-14C]-glucose. Production of lactate by the conceptus exposed to 250-500 microM diamide for 60 min was reduced (to approximately 54% of control values) concomitantly with a significant inhibition of the glycolytic enzymes, glyceraldehyde 3-phosphate dehydrogenase (GPD) and phosphofructokinase (PFK), indicating an overall decrease in glycolysis. Diamide was found to produce a differential effect on the enzymatic activities determined in this study, with greater degrees of inhibition seen in the tissue supernatants from the visceral yolk sac (VYS) compared to those from the embryo. Activities of GPD and PFK were decreased to approximately 22% and 43% control values, respectively, when determined in the supernatants from the VYS of the conceptus exposed to 500 microM diamide for 60 min. In addition, more than 90% of the GPD activity in the VYS, but not the embryo, was rapidly inhibited by the thiol alkylating agent N-ethylmaleimide (NEM, 100 microM) within 15 min of the exposure. In contrast to diamide and NEM, no alterations in lactate production were seen in the conceptus treated with the GSH depletor L-buthionine-S,R-sulfoximine (1 mM) for 5 hr in the culture media. Further experiments demonstrated that the activity of the GPD, inhibited by a 30-min incubation with 500 microM diamide, can be reversed after removal of diamide and that this effect was potentiated by subsequent treatment with dithiothreitol (30 mM), a thiol reducing agent. These results indicated the involvement of thiol/disulfide status in regulation of the metabolism of glucose in the developing conceptus and support the hypothesis that GSH oxidation and protein-S-SG formation could be a critical event associated with mechanisms of embryotoxicity elicited by oxidative stress. It was suggested in this study that, under these experimental conditions, embryotoxicity induced by diamide is primarily mediated via altered VYS functions, including disrupted energy production (glycolysis).
Animals↗
Glutamate-mediated excitotoxic death of cultured striatal neurons is mediated by non-NMDA receptors.
Considerable interest has focused on the role of glutamate-mediated excitotoxicity in neurodegenerative disorders of the basal ganglia. The in vitro data on the receptor mechanisms involved in this process, however, have been inconclusive. Some studies have indicated that excitotoxins acting at NMDA receptors kill striatal neurons and others have indicated that NMDA receptor-mediated excitotoxic death of striatal neurons is minimal in the absence of cortex. In the present study, we used a pharmacological approach to carefully reexamine this issue in 2-week-old cultures of striatal neurons dissociated from E17 rat embryos. The sensitivity of these neurons to glutamate agonists and antagonists was determined by monitoring cell loss in identified regions of the growth dishes. We found that glutamate killed striatal neurons with an EC50 of 100 microM. This loss was not mediated by NMDA receptors, since it was not reduced by the NMDA receptor antagonist APV (0.1-1.0 mM). Consistent with this result, up to 50 mM NMDA receptor-specific excitotoxin quinolinic acid (QA) did not affect neuronal survival. Depolarizing the QA-exposed neurons with 35 mM potassium chloride to enhance NMDA receptor activation by QA also did not produce neuron loss. The metabotropic glutamate receptor antagonist AP3 (500 microM) also had no effect on the striatal neuron loss produced by 100 microM glutamate. In contrast, the non-NMDA antagonist GYKI 52466 (100 microM) did block the excitotoxic effect of glutamate (100 microM). Specific AMPA and KA receptor agonists and the non-NMDA antagonist GYKI 52466 revealed that the non-NMDA receptor-mediated excitotoxic effect of glutamate was mediated by KA receptors. These results suggest that cultured striatal neurons are directly vulnerable to non-NMDA glutamate agonists, but not to NMDA and metabotropic glutamate agonists. Thus, non-NMDA receptors may play a greater role in the excitotoxic death of striatal neurons in disease and experimental animal models than previously realized.
Animals↗
Real time microfiberoptic redox fluorometry: modulation of the pyridine nucleotide status of the organogenesis-stage rat visceral yolk sac with cyanide and alloxan.
The surface of rat visceral yolk sacs (VYS) of intact, viable rat conceptuses were continuously monitored with a microfiberoptic sensor optimized for detection of the reduced pyridine nucleotides, NADH and NADPH. Model chemical toxins, cyanide and alloxan, were used and evaluated on the basis of their differential ability to modulate NAD(H)- and NADP(H)-dependent cellular pathways, respectively. Exposure with 2 mM sodium cyanide for 5 min caused a reversible fluorescence increase of 325 arbitrary fluorescence units (AFU) and 225 AFU on Gestational Days (GD) 10 and 11, respectively. Exposure with 40 mM alloxan for 5 min resulted in a fluorescence decrease of 170 and 120 AFU on GD 10 and 11, respectively. Glutathione (GSH) levels in the VYS, as determined by HPLC, showed a marked decrease from 27.3 +/- 2.1 to 2.9 +/- 0.4 pmol/mg protein, within the 5-min alloxan exposure period on GD 10. No decrease in GSH levels was noted for the same exposure duration on GD 11. A 2-hr pretreatment with 25 microM BCNU [(1,3 bis(2-chloroethyl)-1-nitrosourea], to inhibit glutathione disulfide reductase (GSSG-Rd), resulted in an elimination of the fluorescence decrease, but still led to a significant drop in GSH levels as seen on both days of gestation. These results are consistent with overall changes in intracellular pyridine nucleotide concentrations, where the relative amounts of NADPH increase significantly and disproportionately from GD 10 to 11. The net oxidation of NADPH, through GSSG-Rd activity, appears to be responsible for the alloxan-induced decrease in surface fluorescence. Conversely, the cyanide-induced fluorescence increases appear to be the result of NAD+ reduction, mediated through the inhibition of the terminal cytochrome oxidase in the electron transport chain.
Abnormalities, Drug-Induced↗
Potential use of buccal smears for rapid diagnosis of autosomal trisomy or chromosomal sex in newborn infants using DNA probes.
Buccal smears from 3 women and 1 man were probed with alpha satellite DNA probes for chromosomes 8, 18, X, and Y. Buccal smears were also collected from an adolescent phenotypic female with uterine agenesis, as well as from newborn infants with suspected trisomy 18 and trisomy 21. The clinical cases were confirmed with conventional cytogenetic studies of peripheral lymphocytes. Overall probe efficiency at detecting expected chromosome number in interphase cells was found to be 71% +/- 6.8%. Higher than expected n-1 signal numbers may be due to karyopyknotic intermediate epithelial cells present in all collected samples. Overall probe efficiency was found to be consistent using alpha satellite and cosmid probes, both of which accurately reflected the modal copy number of the target chromosomes. False trisomy was less than 1%. This study suggests DNA probes can be used in buccal smears for rapid diagnosis of trisomies and chromosomal sex in newborns, but because of high rates of false hypoploid signals, probed buccal smear specimens may not be accurate at diagnosing mosaicism.
Adult↗
Laparoscopic cholecystectomy in surgical training.
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Cholecystectomy, Laparoscopic↗
Chloroquine accumulation and alterations of proteolysis and pinocytosis in the rat conceptus in vitro.
The teratogenicity of chloroquine (CQ) has been hypothesized to result from its effects on lysosomal function, specifically the ability of the visceral yolk sac (VYS) to capture and degrade external macromolecules. Using the rat whole embryo culture system, we evaluated the ability of CQ to accumulate in conceptual tissues and its effects on aspects of VYS function known to be important in the uptake and processing of nutrients. When CQ was added directly to the culture medium, it was found to accumulate rapidly in conceptual tissues, particularly the VYS. Tissue concentrations of CQ in the embryo proper reached approximately 10-fold those in the medium, whereas concentrations in the VYS exceeded by 100-fold the medium concentration within a 4-hr exposure on gestational day (GD) 10. Embryotoxic concentrations of CQ (10-30 microM) enhanced the activity of lysosomal cysteine proteinases measured in vitro under optimum pH conditions in both embryonic and VYS homogenates after a 26-hr treatment from GD 10-11. A different pattern of response in enzyme activity was observed between embryos and VYSs that could be attributed to the preferential accumulation of CQ in the VYS. Nonembryotoxic concentrations of CQ (1-7.5 microM) induced a concentration-dependent increase in VYS enzyme activity that peaked in conceptuses exposed to 20 microM CQ (an intermediate embryotoxic concentration). The enhanced cysteine proteinase activity was time dependent and appeared to increase gradually in conceptuses exposed to 10-20 microM CQ during the 26-hr culture period. This was in contrast to the rapid accumulation of CQ in conceptual tissues seen on gestational day 10. Protein content in the VYS was increased significantly after a 9-hr exposure of whole conceptuses to CQ (20 microM), indicating an inhibition of VYS proteolytic activity in situ. After 24 hr of exposure to 20 microM CQ, VYS protein content was not significantly different from control, but embryonic protein was reduced significantly by 20%. These observations are consistent with a model of reversible inhibition of VYS proteolysis by CQ followed by a compensatory increase in lysosomal proteinase activity. VYS fluid-phase pinocytosis was also assessed after CQ exposure and found to be inhibited only in the highest CQ concentration tested (30 microM). Lower concentrations of CQ that were still embryotoxic (10-20 microM) did not affect VYS fluid-phase pinocytosis, suggesting that inhibition of this activity is not primarily responsible for CQ embryotoxicity.
Animals↗