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Biomedical subjects

S S Young

Publications and source records attributed to S S Young.

At least 19 recordsLinked to original sources
PubMed2003

The effects of body fat on pulmonary function and gas exchange in cynomolgus monkeys.

Obesity adversely affects lung function in humans often reducing arterial blood oxygenation. To determine if obesity adversely affects lung function in cynomolgus monkeys, which is a species that is often used for pulmonary research, pulmonary mechanics, ventilation, functional residual capacity (FRC), and arterial blood gases were measured using spontaneous respiration and on mechanical ventilation with room air or 100% O(2). Body fat percentage was measured by dual energy X-ray absorption. Blood leptin levels were measured by radioimmune assay. Obese monkeys breathed faster with lower tidal volume, but pulmonary resistance and dynamic lung compliance did not change with body fat. FRC and blood leptin were, respectively, negatively and positively correlated with percent body fat. FRC correlated moderately with ventilatory parameters and strongly with arterial oxygen tension, alveolar-arterial oxygen difference and venous admixture. Therefore, obesity in cynomolgus monkeys had marked, deleterious effects on FRC, ventilation and arterial oxygenation. Obesity may be an important confounding variable in lung function studies in primates.

Animals↗
PubMed2001

Genomic organization of the X-linked inhibitor of apoptosis and identification of a novel testis-specific transcript.

Here we report the genomic organization and mapping of the X-linked inhibitor of apoptosis gene (BIRC4, also known as XIAP and hILP) and the identification of a closely related transcript. BIRC4 is located on Xq25 and is composed of seven exons. The intron/exon structure is highly conserved between the mouse homologue and its human counterpart. Four bands cross-react with a BIRC4 coding region probe on a genomic Southern blot. One of these cross-reactive bands encodes an intronless gene that expresses a 2.2-kb transcript solely in the testis. This testis-specific transcript contains a putative open reading frame (ORF) that is homologous to the carboxy-terminal end of BIRC4; overexpression of this ORF shows protective effects against BAX-induced apoptosis.

Animals↗
PubMed2001

Cystic fibrosis screening in newborns: results from existing programs.

Newborn screening for cystic fibrosis (CF) provides early identification and initiation of treatment to infants with this fatal and often misdiagnosed genetic disease. Although reports of health benefits continue to mount from decade-old screening programs in Wisconsin, France, and Australia, newborn screening for CF is still a highly debated topic in genetic policy development. This article summarizes the literature published between May 2000 and April 2001 regarding the health benefits, risks, cost-effectiveness, and programmatic issues of newborn screening for CF. The literature consistently shows evidence of benefits and lack of harm from newborn screening for CF.

Cost-Benefit Analysis↗
PubMed2001

Statistical decoding of potent pools based on chemical structure.

Pooling experiments are used as a cost-effective approach for screening chemical compounds as part of the drug discovery process in pharmaceutical companies. When a biologically potent pool is found, the goal is to decode the pool, i.e., to determine which of the individual compounds are potent. We propose augmenting the data on pooled testing with information on the chemical structure of compounds in order to complete the decoding process. This proposal is based on the well-known relationship between biological potency of a compound and its chemical structure. Application to real data from a drug discovery process at GlaxoSmithKline reveals a 100% increase in hit rate, namely, the number of potent compounds identified divided by the number of tests required.

Biological Assay↗
PubMed2000

Assessment of visually lossless irreversible image compression: comparison of three methods by using an image-comparison workstation.

PURPOSE: To determine the degree of irreversible image compression detectable in conservative viewing conditions. MATERIALS AND METHODS: An image-comparison workstation, which alternately displayed two registered and magnified versions of an image, was used to study observer detection of image degradation introduced by irreversible compression. Five observers evaluated 20 16-bit posteroanterior digital chest radiographs compressed with Joint Photographic Experts Group (JPEG) or wavelet-based trellis-coded quantization (WTCQ) algorithms at compression ratios of 8:1-128:1 and x2 magnification by using (a) traditional two-alternative forced choice; (b) original-revealed two-alternative forced choice, in which the noncompressed image is identified to the observer; and (c) a resolution-metric method of matching test images to degraded reference images. RESULTS: The visually lossless threshold was between 8:1 and 16:1 for four observers. JPEG compression resulted in performance as good as that with WTCQ compression at these ratios. The original-revealed forced-choice method was faster and as sensitive as the two-alternative forced-choice method. The resolution-metric results were robust and provided information on performance above visually lossless levels. CONCLUSION: The image-comparison workstation is a versatile tool for comparative assessment of image quality. At x2 magnification, images compressed with either JPEG or WTCQ algorithms were indistinguishable from unaltered original images for most observers at compression ratios between 8:1 and 16:1, indicating that 10:1 compression is acceptable for primary image interpretation.

Algorithms↗
PubMed1999

Genomic organization and physical map of the human inhibitors of apoptosis: HIAP1 and HIAP2.

We report the genomic organization, mapping, and tissue distribution of the human inhibitors of apoptosis, HIAP1 and HIAP2. HIAP1 is 8.7 kb in length and is contained within eight coding and two non-coding (5'UTR) exons. The 4.5-kb HIAP2 message is contained within eight coding region exons and a single 5'UTR exon. The HIAP1 and HIAP2 genes lie in tandem on Chromosome (Chr) 11 (q22-23) with the intergenic distance being approximately 7 kb. The tissue distributions of HIAP1 and HIAP2 appear similar although the relative expression of HIAP1 is generally higher. Expression is highest in the kidney, small intestine, liver, and lung and lowest in tissues of the central nervous system.

5' Untranslated Regions↗
PubMed1999

Use of recursive partitioning in the sequential screening of G-protein-coupled receptors.

High-throughput screening (HTS) is changing as more compounds and better assay techniques become available. HTS is also generating a large amount of data. There is a need to rationalize the HTS process, because, in some cases, the screening of all available compounds is not economically feasible. In addition to the selection of promising compounds, there is a need to learn from the data that we collect. In this paper, we use a data-mining method, recursive partitioning, to help uncover and understand structure-activity relations and to help biology and chemistry experts make better decisions on which compounds to screen next and better characterize. The sequential-screening process is presented and the results of applying that process to 14 G-protein-coupled receptor assays are reported.

Animals↗
PubMed1999

Eotaxin and nitric oxide production as markers of inflammation in allergic cynomolgus monkeys.

BACKGROUND: Cynomolgus monkeys have a natural hypersensitivity to Ascaris suum antigen. Inhalation of antigen produces immediate and delayed allergic reactions and an influx of inflammatory cells into the lungs. This study investigated the production of nitric oxide (NO) and the chemokine eotaxin during this allergic response. The effect of bronchoscopy alone on lung inflammatory cells was also investigated along with the time course of the eosinophil influx into the lung. METHODS: Allergic cynomolgus monkeys were challenged with antigen. Bronchoalveolar lavage (BAL) was performed before and after challenge, and end-tidal NO was measured before and 24 h after challenge. Eotaxin was measured in the BAL fluid 6, 24 and 72 h after challenge. One group of animals was treated with dexamethasone before challenge to block the influx of cells into the lung. RESULTS: BLA alone induced an influx of neutrophils, but not eosinophils, into the lung 24 h later. A single antigen challenge produced a marked increase in BAL eosinophils that was apparent at 6 h but increased at 72 h after challenge. The increase at 6 h was largely blocked by dexamethasone. Three antigen challenges produced elevated BAL eosinophil levels that persisted for at least 8 weeks. Eotaxin levels rose dramatically 6 h after challenge and remained the same after 24 h. By 72 h, the eotaxin levels had returned to baseline. The increase in eotaxin at 6 h was nonsignificantly reduced by dexamethasone. Exhaled NO levels doubled 24 h after challenge and were not affected by dexamethasone. CONCLUSIONS: Eotaxin and NO production were increased after airway challenge in allergic monkeys. The rise in NO was not blocked by dexamethasone. The effects of bronchoscopy on the BAL can be avoided by using alternate lungs on consecutive occasions. Eosinophils persist in the BAL for many weeks after antigen challenge.

Animals↗
PubMed1999

Short duration anaesthesia with medetomidine and ketamine in cynomolgus monkeys.

Cynomolgus monkeys were anaesthetized with either intramuscular ketamine (10 mg/kg or intramuscular ketamine 2 mg/kg and medetomidine 50 microg/kg. Various physiological measurements were made once the animals were safe to handle and again 10 min later. Cardiovascular and respiratory function were well maintained with both regimens but the heart rate was lower and arterial-alveolar carbon dioxide gradient was higher in the animals that received medetomidine. In those animals that received medetomidine, atipamezole was given to reverse the medetomidine but there was no difference in recovery times between the two regimens. Anaesthesia was not entirely reliable with medetomidine/ketamine and we recommend caution when using this mixture.

Adrenergic alpha-Agonists↗
PubMed1999

Discovery 99: accelerate and improve the drug discovery process. 26-29 April 1999, San Diego, CA, USA.

The stated purpose of this conference was the examination of emerging technologies for drug discovery. The meeting was divided into numerous pre- and post-conferences and tracks. A pre-conference workshop examined enabling software and business strategies. Nine tracks covered natural products, high-throughput screening, bioinformatics, proteomics/functional genomics, pharmacogenomics, combichem, chemoinformatics and assay methods. A post-conference symposium covered ADME-toxicology screening. In short, the gamut of drug discovery.

Journal Article↗
PubMed1998

Using prior information to allocate significance levels for multiple endpoints.

We maximize power in a replicated clinical trial involving multiple endpoints by adjusting the individual significance levels for each hypothesis, using preliminary data to obtain the optimal adjustments. The levels are constrained to control the familywise error rate. Power is defined as the expected number of significances, where expectations are taken with respect to the posterior distributions of the non-centrality parameters under non-informative priors. Sample size requirements for the replicate study are given. Intuitive principles such as downweighting insignificant variables from a preliminary study and giving primary endpoints more emphasis are justifiable within the conceptual framework.

Analysis of Variance↗
PubMed1997

Life and death decisions: the role of the IAPs in modulating programmed cell death.

Multicellular organisms have evolved elaborate signal transduction pathways for maintaining homeostasis through the control of cell proliferation and death. The recent surge of interest in the regulation of programmed cell death has led to the rapid identification of many proteins involved in controlling and executing apoptosis. The inhibitors of apoptosis proteins (IAPs) constitute a family of highly conserved death suppressing proteins that were first identified in baculoviruses, and that has recently expanded to include at least two homologues in Drosophila melanogaster and four in rodents and humans. In this article we review the current state of IAP research. Two of the IAPs, HIAP-1 and HIAP-2, have been placed within the TNFalpha induced cell death pathway which involves two receptors for TNFalpha and multiple, overlapping signal transduction proteins. A third, X-linked gene termed XIAP, is ubiquitously expressed and appears to have a broad range of suppressor activity to a variety of apoptotic triggers. The fourth member, NAIP, has been identified as the protein product of a candidate gene for the inherited neuromuscular disorder, spinal muscular atrophy (SMA). The neuroprotective activity of NAIP in an in vivo model of cerebral ischemia has also been demonstrated.

Journal Article↗
PubMed1997

The comparative hypoxaemic effect of four alpha 2 adrenoceptor agonists (xylazine, romifidine, detomidine and medetomidine) in sheep.

In the present study, the hypoxaemic potential of four alpha 2 agonists possessing different selectivity for alpha 2 adrenoceptors and of a saline placebo was studied in five clinically healthy sheep using a randomized Latin square design and equipotent sedative doses. Baseline values for heart rate (HR), mean arterial pressure (MAP), arterial oxygen (PaO2)f and carbon dioxide (PaCO2) tensions, respiration rate and maximum change in pleural pressure (delta Ppl) were obtained, followed by the intravenous administration of either: xylazine (150 micrograms/kg); romifidine (50 micrograms/kg); detomidine (30 micrograms/kg); medetomidine (10 micrograms/kg) or placebo. Subsequent recordings were made up to 60 min after drug administration. No significant (P < or = 0.05) alterations in any variable occurred with placebo. All the alpha 2 agonists significantly (P < or = 0.05) decreased PaO2 levels without a significant (P < or = 0.05) change in PaCO2. The lowest PaO2 values were 29-42 mm Hg (3.9-5.5 kPa) with no significant difference between drugs. Respiratory rate and delta Ppl increased significantly within 2 min of drug administration; the duration of this effect varied with the alpha 2 agonist, lasting longest with romifidine. As compared to the saline treated group, a significant increase in MAP was observed up to 10 min after administration of romifidine and detomidine, however, a significant decrease was seen at 10 and 45 min after xylazine and medetomidine, respectively. The alpha 2 agonists studied induced a similar change in PaO2 at peak effect, despite their reported variable selectivity for alpha 2 vs. alpha 1 adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1997

Cardiopulmonary effects of clonidine, diazepam and the peripheral alpha 2 adrenoceptor agonist ST-91 in conscious sheep.

The cardiopulmonary effects of the intravenous administration of clonidine (15 micrograms/kg), ST-91 (30 micrograms/kg) and diazepam (0.4 mg/kg) were compared in five healthy sheep using a randomized cross-over design, to determine whether the hypoxaemic effects of alpha 2 adrenoceptor agonists are due to sedation, or to peripheral alpha 2 adrenoceptor stimulation. All three drugs significantly lowered arterial oxygen tension (PaO2) levels within 2 min of their administration; however, clonidine and ST-91 produced long lasting and severe hypoxaemia with mean PaO2 levels of approximately equal to 40 mm Hg and 50 mm Hg (5.3 kPa and 6.6 kPa), respectively. The fall in PaO2 was considerably less with diazepam (63 mm Hg or 8.4 kPa at 2 min) and by 15 min the values did not differ from placebo treated animals. None of the drugs increased arterial carbon dioxide tension (PaCO2) levels when compared to saline treatment and the acid base variables did not show any significant change. A significant increase was recorded in the packed cell volume of the ST-91 treated group throughout the study. Within 2 min of their administration, all drugs caused a significant increase in mean arterial pressure (MAP) as compared to the placebo treated group. The MAP remained significantly increased for 5 and 60 min after clonidine and ST-91 treatment, respectively. The study shows that ST-91 and clonidine produce a greater degree of hypoxaemia than occurs with diazepam sedation, and that the hypoxaemic effect of alpha 2 adrenoceptor agonists in sheep are mainly mediated by peripheral alpha 2 adrenoceptors.

Adjuvants, Anesthesia↗
PubMed1997

Frequency dependence of forced oscillatory respiratory mechanics in horses with heaves.

The effect of measurement frequency on respiratory mechanics was investigated in six horses with reversible allergic airway disease. Total respiratory impedance was measured at 1.5, 2.0, 3.0, and 5.0 Hz by using the forced oscillation technique with the horses in remission, after acute antigenic challenge producing clinical heaves, and with heaves but after the administration of 2 mg fenoterol by inhalation. The slopes of the magnitude (magnitude of Zrs) and real part (R) of total respiratory impedance over the frequency range 1.5-3 Hz changed significantly after antigenic challenge and fenoterol. The ratio of R at 2 Hz to R at 3 Hz, however, discriminated better among the three conditions. Compliance and resonant frequency (calculated by using a three-element model) changed significantly after antigenic challenge and fenoterol, but inertance did not. We concluded that horses with heaves showed frequency dependence of R and (magnitude of Zrs) at frequencies up to 3 Hz and that parameters derived from a three-element model were useful indicators of small airway obstruction in the horse.

Airway Resistance↗
PubMed1997

Modification of cardiopulmonary and intestinal motility effects of xylazine with glycopyrrolate in horses.

Xylazine (XYL) administration in horses is accompanied by significant cardiovascular depression characterized by a 25-35% decrease in cardiac output (CO) which is likely to compromise tissue oxygen delivery (DO2), and usually vagally mediated bradycardia is an important cause of this reduced cardiovascular performance. To examine the possible benefit of preventing the bradycardiac response, 6 healthy horses were treated with intravenous (IV) saline (SAL) or 2.5 micrograms/kg glycopyrrolate (GLY) in a blinded, randomized, crossover trial. Fifteen minutes later, 1 mg/kg XYL was administered IV and systolic, diastolic and mean blood pressures (SBP, DBP, and MBP, respectively), central venous pressure (CVP), mean pulmonary artery pressure, heart rate (HR), CO, and arterial and mixed venous blood gases were measured at the following times: baseline, 2, 5, and 10 min post-SAL or GLY; and 2, 5, 10, 15, 30, 45 and 60 min post-XYL. Determination of cardiac index (CI), stroke index (SI), left ventricular work, systemic vascular resistance (SVR), DO2, oxygen uptake, and oxygen extraction ratio were made at the same time. Gastrointestinal (GI) motility was evaluated by four-quadrant auscultation for 24 h post-XYL. Statistical analysis of continuous variables was carried out using ANOVA for repeated measures and Wilcoxon's rank-sum test for non-parametric data. In GLY treated horses, HR, SBP, MBP, DBP, CI, DO2 and mixed venous oxygen tension were significantly higher up to 30 min after XYL (P < or = 0.02) while CVP and SI were significantly lower 2 and 5 min post-XYL, respectively. In both groups, GI motility as assessed by auscultation was virtually abolished for an hour, with a non-significant tendency for the decrease in motility to last longer in the GLY/XYL group. None of the treated horses developed abdominal discomfort. No significant difference was observed in the other variables. The study shows that 2.5 micrograms/kg GLY premedication reduces the cardiovascular depression caused by 1 mg/kg XYL, without adversely affecting GI motility.

Adjuvants, Anesthesia↗
PubMed1996

Optimized target localization in stereotactic radiosurgery using real-time digital portal images.

This paper presents a method for optimized estimation of target localization in stereotactic radiosurgery using real-time digital portal images. The positions of the two radiation sources and the two projection planes in radiosurgery can be chosen arbitrarily. The reconstruction of the target is characterized as a non-linear multi-variable optimization problem, which minimizes the difference between the actual target and the reconstructed target. This optimization problem is solved by the Gaussian least square differential correction (GLSDC) method. Due to the digitized errors and input data errors, the algorithm defines an indirect reference factor (the shortest distance between two x-rays pointing onto the target) as an indication of the accuracy of the method. Our experimental results show that the reference factor is less than 1.0 mm for the correct data entry. The proposed algorithm provides a method that supports on-line target localization which can be done directly on the digital portal imaging device.

Algorithms↗