A teratologist to extinction. Ad Hoc Committee on Grant Funding.
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Congenital Abnormalities↗
Biomedical subjects
C Harris
Publications and source records attributed to C Harris.
Use of fluorescent in situ hybridization to detect aneuploidy in cervical dysplasia.
Fluorescent in situ hybridization (FISH) with alpha satellite DNA probes for chromosomes 11 and X were applied to normal, atypical, and dysplastic cervical-vaginal cytology smears to evaluate the detection of hyperploidy in suspected abnormal cells. Forty-six cases were obtained from fixed archival material. Eight cases with a morphological diagnosis of within normal limits (WNL) were directly selected to use as controls. The other 38 cases were blinded as study cases. These included five WNL, six ASCUS, six SIL-LG, 16 SIL-HG, four invasive squamous cell carcinomas, and one case of adenocarcinoma of the cervix. Cells with chromosome copy numbers suggesting hyperploidy (3-4 signals per chromosome specific probe) were found more often in higher grade dysplasia (Bethesda class SIL-HG) cases and less often in lower grade lesions (SIL-LG). All cases morphologically diagnosed as WNL were found to have normal copy number except for one control case which was hyperploid and, upon reexamination of the original slides, was upgraded from normal to atypical squamous cells of undetermined significance (ASCUS). Our FISH results are similar to those of previous studies involving flow cytometry and morphometric cytometry in which changes in ploidy correlated with progression toward higher grade lesions. However, FISH with enumeration probes offers a higher resolution view of the genome than is possible with flow cytometry or morphometry by allowing detection of specific chromosome changes in small numbers of affected cells in a routine cervical smear, and it may have the capacity to detect those cases in which progression toward high grade dysplasias is more likely.
Adenocarcinoma↗
Balanced interaction of growth factors and taurine regulate energy metabolism, neuronal survival, and function of cultured mouse cerebellar cells under depolarizing conditions.
The development of neuronal cells in a given cellular environment requires mechanisms that dynamically regulate the balanced interactions of multiple factors which are known to control maintenance and plasticity in function of neurons throughout constantly changing extracellular conditions. Periodic release of excitatory amino acids from both developing glial and neuronal cells into the extracellular environment and their uptake has been shown to stimulate neuronal function in concert with growth factors that control the degree of depolarization and, therefore, neuronal function. This study attempts to characterize the critical concentrations of these factors either alone or together in relation to energy metabolism, cell survival and function. We demonstrate a close correlation between energy metabolism of neuronal cells, controlled by the combination of growth-factors (beta FGF, BDNF), and glutamate-taurine as well as K+ in depolarizing concentrations (10-25 mM), during the balancing act of neuronal survival or death, and neuronal function. These functions depend on medium conditions (energy sources, ion composition), the ratio of glial cells versus neurons and cell density. Granule cell migration as a measure of developmental neuronal function was analyzed in the presence of various combinations of growth factors and taurine under various depolarizing conditions (glutamate, K+). We found that K+ concentrations > 7 mM in BME and 10% horse serum blocked migration in less than 30 min. Taurine did not prevent this effect. However, in the presence of HEPES as well as in F12-medium with HEPES, taurine restored granule cell migration. On the other hand, glutamate-or NMDA-mediated depolarization stopped migrating granule cells while NMDA antagonists extended the period of migration. Taurine amplified the stop-signal in the presence of glutamate agonists but increased the number of migrating cells in the absence of glutamate. Thus, the mechanisms of glutamate receptor mediated excitotoxicity, possibly by reducing Ca2+ influx under depolarizing conditions, but amplifies the stop-signal, Ca2+ levels may not control granule cell migration.
2-Amino-5-phosphonovalerate↗
The molecular identity of Ca channel alpha 1-subunits expressed in rat sympathetic neurons.
Much of our understanding of the mechanisms of the gating, modulation, and function of neuronal Ca channels has its origins in investigations of sympathetic neurons. In this article, we use molecular analyses to identify the three Ca channel alpha 1-subunits that are the likely counterparts to the pharmacologically defined: omega-Conotoxin GVIA-sensitive N-type; dihydropyridine-sensitive L-type, and omega-Conotoxin GVIA-insensitive, dihydropyridine-insensitive Ca channel currents observed in sympathetic neurons. With a combination of degenerate and exact primers, small regions of Ca channel alpha 1-subunit sequences were amplified by the polymerase chain reaction (PCR). Although all five Ca channel alpha 1-subunit genes were expressed in rat sympathetic ganglia, alpha 1B-, alpha 1D-, and alpha 1E-derived cDNAs were the dominant species. No novel Ca channel alpha 1-sequences were identified in the regions selected for amplification, and we conclude that alpha 1B, alpha 1D, and alpha 1E likely encode, respectively, N-type, L-type, and non-N/non-L-type channel currents of rat sympathetic neurons. In addition, we show that Ca channel beta 2-, beta 3-, and beta 4-subunit sequences are strongly represented in sympathetic ganglia. The results of this study also suggest that alpha 1D, and not alpha 1C, regulates Ca influx through dihydropyridine-sensitive Ca channel currents.
Amino Acid Sequence↗
Oral and dental health in the alcohol misuser.
This review explores the relationship between oral and dental health and disease in substance misusers. Although it focuses on oral cancer, we also examine the relationship of misuse with dental caries and periodontal diseases. It is difficult to separate out the inter-related aetiological factors such as the use of alcohol and tobacco (smoked and chewed). They probably act in a synergistic manner.
Journal Article↗
Serum cryptococcal antigen in patients with AIDS.
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Acquired Immunodeficiency Syndrome↗
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↗