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Biomedical subjects

J D Young

Publications and source records attributed to J D Young.

At least 55 records · Page 3Linked to original sources
PubMed2000

Primary treatment choices for men with clinically localized prostate carcinoma detected by screening.

BACKGROUND: Increasingly, prostate carcinoma is diagnosed through screening. However, little is known regarding factors that influence a patient's decision concerning the treatment choices presented to him. METHODS: Subjects were prostate carcinoma patients detected through the Washington University PSA Prostate Cancer Screening Program between September 1989 and June 1998. The sources of data were the prostate specific antigen (PSA) screening database and follow-up questionnaire. RESULTS: Among 1809 study subjects, 79.2% chose radical prostatectomy (RP), 12.4% chose radiation therapy, and 8.4% chose watchful waiting (WW) as their decision regarding primary treatment. In bivariate analyses, education, income, age, indication for prostate biopsy, comorbidity score, serum PSA level, clinical stage, and pretreatment urinary and sexual function were associated significantly with treatment choice, but race, marital status, and Gleason grade were not. In a multivariate analysis, age, race, clinical stage, PSA level, and pretreatment urinary and sexual function were found to be associated significantly with treatment choice. For every 5-year decrease in age, the odds for choosing RP versus WW increased by 276%; for every 1-ng increase in PSA, the odds for choosing RP versus WW increased by 12%. Non-African-American patients were greater than four times more likely to select RP versus WW. Patients with T2 tumors and those with normal pretreatment urinary function were three times more likely and twice more likely to choose RP versus WW, respectively. CONCLUSIONS: In the current study, RP was the most widely used treatment in patients with screen-detected prostate carcinoma. Age, race, PSA level, clinical stage, and pretreatment urinary and sexual function were significant factors influencing treatment selection.

Aged↗
PubMed2000

Purine uptake and release in rat C6 glioma cells: nucleoside transport and purine metabolism under ATP-depleting conditions.

Adenosine, through activation of membrane-bound receptors, has been reported to have neuroprotective properties during strokes or seizures. The role of astrocytes in regulating brain interstitial adenosine levels has not been clearly defined. We have determined the nucleoside transporters present in rat C6 glioma cells. RT-PCR analysis, (3)H-nucleoside uptake experiments, and [(3)H]nitrobenzylthioinosine ([(3)H]NBMPR) binding assays indicated that the primary functional nucleoside transporter in C6 cells was rENT2, an equilibrative nucleoside transporter (ENT) that is relatively insensitive to inhibition by NBMPR. [(3)H]Formycin B, a poorly metabolized nucleoside analogue, was used to investigate nucleoside release processes, and rENT2 transporters mediated [(3)H]formycin B release from these cells. Adenosine release was investigated by first loading cells with [(3)H]adenine to label adenine nucleotide pools. Tritium release was initiated by inhibiting glycolytic and oxidative ATP generation and thus depleting ATP levels. Our results indicate that during ATP-depleting conditions, AMP catabolism progressed via the reactions AMP --> IMP --> inosine --> hypoxanthine, which accounted for >90% of the evoked tritium release. It was surprising that adenosine was not released during ATP-depleting conditions unless AMP deaminase and adenosine deaminase were inhibited. Inosine release was enhanced by inhibition of purine nucleoside phosphorylase; ENT2 transporters mediated the release of adenosine or inosine. However, inhibition of AMP deaminase/adenosine deaminase or purine nucleoside phosphorylase during ATP depletion produced release of adenosine or inosine, respectively, via the rENT2 transporter. This indicates that C6 glioma cells possess primarily rENT2 nucleoside transporters that function in adenosine uptake but that intracellular metabolism prevents the release of adenosine from these cells even during ATP-depleting conditions.

AMP Deaminase↗
PubMed2000

Severity scoring systems and the prediction of outcome from intensive care.

Severity scoring systems are tools that provide a predicted mortality for a group of intensive care unit patients on the basis of derangement of their physiology and some past medical history. This predicted mortality can then be compared with the actual mortality to give some indicator of the effectiveness of the package of care delivered by the intensive care unit, corrected for differences in case-mix. Thus, their primary use is in audit, and they are designed for use on large populations of patients and not on individuals. In spite of a large number of publications on the development, refinement and testing of scoring systems, papers describing their use in comparative audit are very rare. This may be partly due to limitations in their ability to predict mortality outside the population on which they were developed, and to the change in calibration of the system with time and advances in medical science. This review briefly addresses the limitations of severity scoring systems in light of recent publications.

Journal Article↗
PubMed2000

Sound transmission between 50 and 600 Hz in excised pig lungs filled with air and helium.

This study measured transit time (TT) and attenuation of sound transmitted through six pairs of excised pig lungs. Single-frequency sounds (50-600 Hz) were applied to the tracheal lumen, and the transmitted signals were monitored on the tracheal and lung surface using microphones. The effect of varying intrapulmonary pressure (Pip) between 5 and 25 cmH(2)O on TT and sound attenuation was studied using both air and helium (He) to inflate the lungs. From 50 to approximately 200 Hz, TT decreased from 4.5 ms at 50 Hz to 1 ms at 200 Hz (at 25 cmH(2)O). Between approximately 200 and 600 Hz, TT was relatively constant (1.1 ms at upper and 1.5 ms at lower sites). Gas density had very little effect on TT (air-to-He ratio of approximately 1.2 at upper sites and approximately 1 at lower sites at 25 cmH(2)O). Pip had marked effects (depending on gas and site) on TT between 50 and 200 Hz but no effect at higher frequencies. Attenuation was frequency dependent between 50 and 600 Hz, varying between -10 and -35 dB with air and -2 and -28 dB with He. Pip also had strong influence on attenuation, with a maximum sensitivity of 1.14 (air) and 0.64 dB/cmH(2)O (He) at 200 Hz. At 25 cmH(2)O and 200 Hz, attenuation with air was about three times higher than with He. This suggests that sound transmission through lungs may not be dominated by parenchyma but by the airways. The linear relationship between increasing Pip and increasing attenuation, which was found to be between 50 and approximately 100 Hz, was inverted above approximately 100 Hz. We suggest that this change is due to the transition of the parenchymal model from open to closed cell. These results indicate that acoustic propagation characteristics are a function of the density of the transmission media and, hence, may be used to locate collapsed lung tissue noninvasively.

Acoustics↗
PubMed2000

The technique of nasendoscopy in the evaluation of nasolacrimal duct obstruction in children.

Epiphora in infancy is most commonly the result of failure of canalisation of the nasolacrimal duct and most cases resolve spontaneously within 12 months. Lacrimal probing is the standard operative treatment when conservative expectant management fails. While this carries a high success rate, it does not reliably localise the site of obstruction, can create a false passage and may induce traumatic stenosis in the lacrimal passages. Nasendoscopy in conjunction with the lacrimal probing overcomes these problems as the procedure is performed under direct vision. The precise site of opening of the nasolacrimal duct is ascertained, the nature of obstruction established and the risks of false passage creation minimised. We report this technique of endoscopic assessment of lacrimal probing, and the outcome results of twenty such procedures performed on thirteen children.

Child, Preschool↗
PubMed2000

Outcome measures for adult critical care: a systematic review.

OBJECTIVES: 1. To identify generic and disease specific measures of impairment, functional status and health-related quality of life that have been used in adult critical care (intensive and high-dependency care) survivors. 2. To review the validity, reliability and responsiveness of the measures in adult critical care survivors. 3. To consider the implications for future policy and to make recommendations for further methodological research. 4. To review what is currently known of the outcome of adult critical care. METHODS DATA SOURCES: Searches of electronic databases (MEDLINE, EMBASE, CINAHL, PsycLIT, The Cochrane Library and SIGLE) from 1970 to August 1998. Manual searches of five journals (1985-98) not indexed in electronic databases and relevant conference proceedings (1993-98). Reference lists of six existing reviews, plus snowballing from reference lists of all relevant articles identified. STUDY SELECTION: Randomised trials, non-randomised trials (cohort studies) and case series that included data on outcomes after discharge from adult (16 years and over) critical care. DATA EXTRACTION AND SYNTHESIS: If reported, the following data were extracted from each paper: patient characteristics (age, gender, severity of illness, diagnostic category) number of patients eligible for study, follow-up period, number of deaths before follow-up, number and proportion of survivors included in follow-up method of presentation of outcome data - proportion normal as defined by reference values, or aggregate value (e.g. mean or median), or aggregate values plus an indication of variance (e.g. standard deviation or inter-quartile range). Evidence for three measurement properties was sought for each outcome measure that had been used in at least two studies - their validity, reliability and responsiveness in adult critical care. If the authors did not report these aspects explicitly, an attempt was made to use the data provided to provide these measurement properties. For measures that were used in at least ten studies, information on actual reported outcomes were also extracted. RESULTS: MEASURES USED IN CRITICAL CARE: Measures of impairment were largely confined to the respiratory system so are almost certainly not appropriate for many critical care survivors. They can be categorised as respiratory volumes (e.g. vital capacity), gas flow within the respiratory system (e.g. forced expiratory volume in 1 second (FEV1)), pulmonary diffusing capacity (e.g. carbon monoxide diffusing capacity) and visualisation of the upper airway (e.g. bronchoscopy). Multiple tests are often performed. Eight measures of physical functional status were used, five generic and three disease-specific. The most frequently used generic measures were multi-item scales. Two single-item global measures attempted to capture a person's overall activity level or functional status. Five multi-item measures of mental functional status were used, four generic and one specific to trauma patients. The generic measures were either confined to assessing depressive symptoms or also encompassed a measure of anxiety. Measures of neuropsychological functioning relate to a person's cognition, attention, ability to process information and memory. Apart from one single-item measure, which focused on communication level, six multi-item measures were used with critical care survivors. Such measures are particularly appropriate for use with survivors of head injury or other neurological insult and, in that sense, they are disease-specific rather than generic measures. Single item measures of recovery were frequently used but researchers often invented their own, so there was little consistency in the wording. These measures had five principal foci - return to work, return to own home, degree of recovery, productivity and chronic health status. One multi-item scale was also used. (ABSTRACT TRUNCATED)

Adult↗
PubMed1999

Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters.

BACKGROUND: Gemcitabine, a pyrimidine analogue of deoxycytidine, is an anticancer nucleoside drug that requires functional plasma membrane nucleoside transporter proteins to reach its intracellular targets and cause cytotoxicity. Because of technical difficulties inherent in studying nucleoside transport in human cells, we rigorously defined gemcitabine membrane transportability by producing each of the available human (h) and rat (r) recombinant nucleoside transporters (NTs) individually in Xenopus laevis oocytes. METHODS: Oocytes were microinjected with in vitro-transcribed RNAs derived from complementary DNAs encoding (C = concentrative) rCNT1, rCNT2, hCNT1, hCNT2, (E = equilibrative) rENT1, rENT2, hENT1, and hENT2. Uptake of [(3)H]gemcitabine and [(14)C] uridine was measured 3 days after microinjection to determine kinetic constants. We also used the two-electrode, voltage-clamp technique to investigate the electrophysiology of hCNT1-mediated gemcitabine transport. RESULTS: Gemcitabine was transported by most of the tested proteins (the exceptions being the purine-selective rCNT2 and hCNT2), with the greatest uptake occurring in oocytes producing recombinant rCNT1 and hCNT1. Influxes of gemcitabine mediated by hCNT1, hENT1, and hENT2 were saturable and conformed to Michaelis-Menten kinetics with apparent K(m) values of 24, 160, and 740 microM, respectively. Gemcitabine had a limited ability to cross the lipid bilayer of oocyte membranes by simple diffusion. External application of gemcitabine to oocytes producing recombinant hCNT1 induced an inward current, which demonstrated that hCNT1 functions as a Na(+)/nucleoside co-transport protein and confirmed the transporter's ability to transport gemcitabine. CONCLUSIONS: Mammalian nucleoside transporters vary widely in their affinity and capacity to transport gemcitabine. Variation in the tumor and tissue distribution of plasma membrane nucleoside transporter proteins may contribute to the solid tumor activities and schedule-dependent toxic effects of gemcitabine.

Animals↗
PubMed1999

Identification of amino acid residues responsible for the pyrimidine and purine nucleoside specificities of human concentrative Na(+) nucleoside cotransporters hCNT1 and hCNT2.

hCNT1 and hCNT2 mediate concentrative (Na(+)-linked) cellular uptake of nucleosides and nucleoside drugs by human cells and tissues. The two proteins (650 and 658 residues, 71 kDa) are 72% identical in sequence and contain 13 putative transmembrane helices (TMs). When produced in Xenopus oocytes, recombinant hCNT1 is selective for pyrimidine nucleosides (system cit), whereas hCNT2 is selective for purine nucleosides (system cif). Both transport uridine. We have used (i) chimeric constructs between hCNT1 and hCNT2, (ii) sequence comparisons with a newly identified broad specificity concentrative nucleoside transporter (system cib) from Eptatretus stouti, the Pacific hagfish (hfCNT), and (iii) site-directed mutagenesis of hCNT1 to identify two sets of adjacent residues in TMs 7 and 8 of hCNT1 (Ser(319)/Gln(320) and Ser(353)/Leu(354)) that, when converted to the corresponding residues in hCNT2 (Gly(313)/Met(314) and Thr(347)/Val(348)), changed the specificity of the transporter from cit to cif. Mutation of Ser(319) in TM 7 of hCNT1 to Gly enabled transport of purine nucleosides, whereas concurrent mutation of Gln(320) to Met (which had no effect on its own) augmented this transport. The additional mutation of Ser(353) to Thr in TM 8 converted hCNT1/S319G/Q320M, from cib to cif, but with relatively low adenosine transport activity. Additional mutation of Leu(354) to Val (which had no effect on its own) increased the adenosine transport capability of hCNT1/S319G/Q320M/S353T, producing a full cif-type transporter phenotype. On its own, the S353T mutation converted hCNT1 into a transporter with novel uridine-selective transport properties. Helix modeling of hCNT1 placed Ser(319) (TM 7) and Ser(353) (TM 8) within the putative substrate translocation channel, whereas Gln(320) (TM 7) and Leu(354) (TM 8) may exert their effects through altered helix packing.

Adenosine↗
PubMed1999

Distribution of mRNA encoding a nitrobenzylthioinosine-insensitive nucleoside transporter (ENT2) in rat brain.

Nucleoside transporters may play a role in regulating levels of extracellular adenosine and adenosine receptor activity. Two members of the equilibrative nucleoside transporter family have recently been cloned. ENT1 is potently inhibited by nitrobenzylthioinosine (NBMPR) (K(i) approximately 1 nM) and was previously found to have a wide distribution in rat and human brain. ENT2 is insensitive to inhibition by NBMPR at low nanomolar concentrations and there is limited information describing its distribution in rat brain. The present study used RT-PCR, northern blot and in situ hybridization and detected rENT2 transcript in several brain regions including hippocampus, cortex, striatum and cerebellum. Our results indicate a wide cellular and regional distribution for ENT2 in rat brain, similar to ENT1, indicating that control of adenosine levels in brain is achieved by multiple transport processes.

Animals↗
PubMed1999

Functional production and reconstitution of the human equilibrative nucleoside transporter (hENT1) in Saccharomyces cerevisiae. Interaction of inhibitors of nucleoside transport with recombinant hENT1 and a glycosylation-defective derivative (hENT1/N48Q).

We have produced recombinant human equilibrative nucleoside transporter (hENT1) in the yeast Saccharomyces cerevisiae and have compared the binding of inhibitors of equilibrative nucleoside transport with the wild-type transporter and a N-glycosylation-defective mutant transporter. Equilibrium binding of 3H-labelled nitrobenzylmercaptopurine ribonucleoside {6-[(4-nitrobenzyl)thio]-9-beta-d-ribofuranosyl purine; NBMPR} to hENT1-producing yeast revealed a single class of high-affinity sites that were shown to be in membrane fractions by (1) equilibrium binding (means+/-S.D.) of [3H]NBMPR to intact yeast (Kd 1.2+/-0.2 nM; Bmax 5.0+/-0.5 pmol/mg of protein) and membranes (Kd 0.7+/-0.2 nM; Bmax 6.5+/-1 pmol/mg of protein), and (2) reconstitution of hENT1-mediated [3H]thymidine transport into proteoliposomes that was potently inhibited by NBMPR. Dilazep and dipyridamole inhibited NBMPR binding to hENT1 with IC50 values of 130+/-10 and 380+/-20 nM respectively. The role of N-linked glycosylation in the interaction of NBMPR with hENT1 was examined by the quantification of binding of [3H]NBMPR to yeast producing either wild-type hENT1 or a glycosylation-defective mutant (hENT1/N48Q) in which Asn-48 was converted into Gln. The Kd for binding of NBMPR to hENT1/N48Q was 10. 5+/-1.6 nM, indicating that the replacement of an Asn residue with Gln decreased the affinity of hENT1 for NBMPR. The decreased affinity of hENT1/N48Q for NBMPR was due to an increased rate of dissociation (koff) and a decreased rate of association (kon) of specifically bound [3H]NBMPR because the values for hENT1-producing and hENT1/N48Q-producing yeast were respectively 0.14+/-0.02 and 0. 36+/-0.05 min-1 for koff, and (1.2+/-0.1)x10(8) and (0.40+/-0. 04)x10(8) M-1.min-1 for kon. These results indicated that the conservative conversion of an Asn residue into Gln at position 48 of hENT1 and/or the loss of N-linked glycosylation capability altered the binding characteristics of the transporter for NBMPR, dilazep and dipyridamole.

Base Sequence↗
PubMed1999

Nucleoside transporters of mammalian cells.

In this review, we have summarized recent advances in our understanding of the biology of nucleoside transport arising from new insights provided by the isolation and functional expression of cDNAs encoding the major nucleoside transporters of mammalian cells. Nucleoside transporters are required for permeation of nucleosides across biological membranes and are present in the plasma membranes of most cell types. There is growing evidence that functional nucleoside transporters are required for translocation of nucleosides between intracellular compartments and thus are also present in organellar membranes. Functional studies during the 1980s established that nucleoside transport in mammalian cells occurs by two mechanistically distinct processes, facilitated diffusion and Na(+)-nucleoside cotransport. The determination of the primary amino acid sequences of the equilibrative and concentrative transporters of human and rat cells has provided a structural basis for the functional differences among the different transporter subtypes. Although nucleoside transporter proteins were first purified from human erythrocytes a decade ago, the low abundance of nucleoside transporter proteins in membranes of mammalian cells has hindered analysis of relationships between transporter structure and function. The molecular cloning of cDNAs encoding nucleoside transporters and the development of heterologous expression systems for production of recombinant nucleoside transporters, when combined with recombinant DNA technologies, provide powerful tools for characterization of functional domains within transporter proteins that are involved in nucleoside recognition and translocation. As relationships between molecular structure and function are determined, it should be possible to develop new approaches for optimizing the transportability of nucleoside drugs into diseased tissues, for development of new transport inhibitors, including reagents that are targeted to the concentrative transporters, and, eventually, for manipulation of transporter function through an understanding of the regulation of transport activity.

Animals↗
PubMed1999

Effect of inotrope withdrawal on morbidity and mortality in patients with chronic heart failure: results of the vesnarinone trial withdrawal substudy. Vest Withdrawal Substudy Group.

BACKGROUND: The use of inotropic agents in the therapy of patients with congestive heart failure (CHF) is controversial. One concern regarding inotropic therapy has been that drug withdrawal could be associated with a worsening of symptoms. METHODS AND RESULTS: We took advantage of the discontinuation of the recent trial of vesnarinone in the therapy of CHF to assess the effects of withdrawal of the inotropic agent, vesnarinone, in patients with chronic CHF who had been randomized to receive either placebo or 30 or 60 mg of vesnarinone. Contrary to our initial hypothesis, withdrawal of vesnarinone did not impact on either morbidity or mortality over a period of 6 months. CONCLUSION: Although these results suggest vesnarinone withdrawal is safe, the applicability of these results to other inotropic agents remains unclear.

Cardiotonic Agents↗
PubMed1999

Nucleoside transporters: molecular biology and implications for therapeutic development.

The uptake of nucleosides (or nucleobases) is essential for nucleic acid synthesis in many human cell types and in parasitic organisms that cannot synthesize nucleotides de novo. The transporters responsible are also the route of entry for many cytotoxic nucleoside analogues used in cancer and viral chemotherapy. Moreover, by regulating adenosine concentrations in the vicinity of its cell-surface receptors, nucleoside transporters profoundly affect neurotransmission, vascular tone and other processes. The recent molecular characterization of two families of human nucleoside transporters has provided new insights into the mechanisms of natural nucleoside and drug uptake and into future developments of improved therapies.

Animals↗
PubMed1999

Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids.

The possibility that glucocorticoids upregulate the expression of anti-inflammatory mediators is an exciting prospect for therapy in inflammatory diseases, because these molecules could give the therapeutic benefits of steroids without toxic side effects. Supernatants from monocytes and macrophages cultured in the presence of glucocorticoids increase the dispersion of neutrophils from a cell pellet in the capillary tube migration assay. This supernatant factor, unlike other neutrophil agonists, promotes dispersive locomotion of neutrophils at uniform concentration, lowers their adhesion to endothelial cells, inhibits their chemotactic response to fMLP and induces distinctive morphological changes. Here we show that thymosin beta4 sulfoxide is generated by monocytes in the presence of glucocorticoids and acts as a signal to inhibit an inflammatory response. In vitro, thymosin beta4 sulfoxide inhibited neutrophil chemotaxis, and in vivo, the oxidized peptide, but not the native form, was a potent inhibitor of carrageenin-induced edema in the mouse paw. Thymosin beta4 is unique, because oxidation attenuates its intracellular G-actin sequestering activity, but greatly enhances its extracellular signaling properties. This description of methionine oxidation conferring extracellular function on a cytosolic protein may have far-reaching implications for future strategies of anti-inflammatory therapy.

Amino Acid Sequence↗
PubMed1999

A comparison of ICU mortality prediction using the APACHE II scoring system and artificial neural networks.

The aim of this study was to compare the ability of artificial neural networks and the Acute Physiology and Chronic Health Evaluation II score to predict mortality in adult intensive care units. The same physiological variables were used in both predictive models to predict hospital mortality from a data set of 8796 patients collected from 26 adult intensive care units in the United Kingdom and Ireland as part of the Intensive Care Society study. The results from the two models were compared with the actual outcome. The overall prediction accuracy and the overall goodness-of-fit of all the models were assessed. Both predictive models showed similar goodness-of-fit and prediction discrimination. The overall predictive and classification performance of the artificial neural network developed matched and in some aspects was better than that of Acute Physiology and Chronic Health Evaluation II.

APACHE↗
PubMed1999

Distribution of equilibrative, nitrobenzylthioinosine-sensitive nucleoside transporters (ENT1) in brain.

Nucleoside transport processes may play a role in regulating endogenous levels of the inhibitory neuromodulator adenosine in brain. The cDNAs encoding species homologues of one member of the equilibrative nucleoside transporter (ENT) gene family have recently been isolated from rat (rENT1) and human (hENT1) tissues. The current study used RT-PCR, northern blot, in situ hybridization, and [3H]nitrobenzylthioinosine autoradiography to determine the distribution of mRNA and protein for ENT1 in rat and human brain. Northern blot analysis indicated that hENT1 mRNA is widely distributed in adult human brain. 35S-labeled sense and antisense riboprobes, transcribed from a 153-bp segment of rENT1, were hybridized to fresh frozen coronal sections from adult rat brain and revealed widespread rENT1 mRNA in pyramidal neurons of the hippocampus, granule neurons of the dentate gyrus, Purkinje and granule neurons of the cerebellum, and cortical and striatal neurons. Regional localization in rat brain was confirmed by RT-PCR. Thus, ENT1 mRNA has a wide cellular and regional distribution in brain, indicating that this nucleoside transporter subtype may be important in regulating intra- and extracellular levels of adenosine in brain.

Adenosine↗