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Biomedical subjects

D A Young

Publications and source records attributed to D A Young.

At least 19 recordsLinked to original sources
PubMed2003

Metal-insulator transitions in an expanding metallic fluid: particle formation kinetics.

Core-level photoemission spectroscopy provides a local probe of expansion dynamics and associated transient chemical properties as a highly pressurized, metallic fluid expands into vacuum following impulsive heating of a semiconductor by an intense, ultrashort laser pulse. Transient photoemission peak shifts reveal that metal-insulator transitions occur rapidly following laser heating. These experiments probe constituents species and solidification kinetics occurring in the early moments of material ejection and provide insight into how particles arise in the current laser ablation regime.

Journal Article↗
PubMed2002

Effects of hippocampal lesions on patterned motor learning in the rat.

Motor skill learning in rats has been linked to cerebellar function as well as to cortical and striatal influences. The present study evaluated the contribution of the hippocampus to motor learning. Adult male rats received electrolytic lesions designed to selectively destroy the hippocampus; a sham-lesioned group of animals served as a control. The animals with hippocampal lesions acquired a patterned motor learning task as well as sham controls. In contrast, rats with hippocampal lesions were impaired in spatial, but not cued, learning in the Morris water maze. In addition, lesioned rats showed profound impairment in the novel object recognition memory task, when a 1-h delay was used between training and testing. Taken together, these results suggest that the hippocampus is not necessary during acquisition of the motor learning task.

Animals↗
PubMed2001

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

Administration, Oral↗
PubMed2001

BMS-196085: a potent and selective full agonist of the human beta(3) adrenergic receptor.

A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.

Administration, Oral↗
PubMed2001

Memory impairment in abstinent MDMA ("Ecstasy") users: a longitudinal investigation.

To examine the neurotoxic potential of continued MDMA ("Ecstasy") use in humans and its functional consequences over the course of 1 year, 15 MDMA users participated in a longitudinal study in which they completed a brief neuropsychological test battery composed mainly of retrospective and prospective memory tasks. Subjects were abstinent for 2 weeks on initial and 1-year testing. Continued use of MDMA was associated with progressive decline in terms of immediate and delayed recall.

Adolescent↗
PubMed2001

Olfactory fingerprints for major histocompatibility complex-determined body odors.

Recognition of individual body odors is analogous to human face recognition in that it provides information about identity. Individual body odors determined by differences at the major histocompatibility complex (MHC or H-2) have been shown to influence mate choice, pregnancy block, and maternal behavior in mice. Unfortunately, the mechanism and extent of the main olfactory bulb (MOB) and accessory olfactory bulb (AOB) involvement in the discrimination of animals according to H-2-type has remained ambiguous. Here we study the neuronal activation patterns evoked in the MOB in different individuals on exposure to these complex, biologically meaningful sensory stimuli. We demonstrate that body odors from H-2 disparate mice evoke overlapping but distinct maps of neuronal activation in the MOB. The spatial patterns of odor-evoked activity are sufficient to be used like fingerprints to predict H-2 identity using a novel computer algorithm. These results provide functional evidence for discrimination of H-2-determined body odors in the MOB, but do not preclude a role for the AOB. These data further our understanding of the neural strategies used to decode socially relevant odors.

Algorithms↗
PubMed2001

Ageing with spinal cord injury: cross-sectional and longitudinal effects.

STUDY DESIGN: Longitudinal and cross-sectional. OBJECTIVE: To determine whether, for studies of ageing with a spinal cord injury, the cross-sectional differences in outcomes across both age and years post injury (YPI) differ from the longitudinal change. SETTING: Two SCI centres in England: the National Spinal Injuries Centre in Aylesbury, and the Regional Spinal Injuries Centre in Southport. METHODS: A total of 315 people who sustained spinal cord injuries prior to 1971 underwent comprehensive health and psychosocial status interviews at one or more of the study assessments (1990, 1993, 1996, and 1999). A range of continuous and dichotomous outcomes was analyzed to detect both cross-sectional differences by age and average individual changes over multiple measurements. RESULTS: Frequently, outcomes changed longitudinally without showing any cross-sectional differences. Cross-sectional age was more commonly associated with the worsening of a condition while cross-sectional YPI was commonly associated with improvement. After controlling for cross-sectional effects, psychological measures generally showed minor deterioration, measures of community integration both improved and deteriorated, upper extremity pain increased, lower enxtremity pain decreased, and participants tended to quit smoking. CONCLUSION: Using longitudinal findings that control for cross-sectional differences produces a more complete description of ageing with a spinal cord injury.

Activities of Daily Living↗
PubMed2001

Inhibition of thrombin by iopromide in vitro.

Iopromide is a nonionic, iodinated, monomeric, radiographic contrast agent used in various indications, including coronary angiography and visceral and peripheral arteriography. Nonionic contrast media have been postulated to increase thrombogenicity when compared with ionic contrast media. The goal of this study was to characterize the interaction of iopromide with thrombin, specifically to determine the rate, extent, specificity, and reversibility of the thrombin inhibition by iopromide, the integrity of the thrombin-iopromide complex, and the inhibitory potency of iopromide using a validated assay methodology. Iopromide was mixed with purified thrombin or pooled serum from healthy male and female donors. The final concentrations of iopromide in the presence of estimated physiologic concentrations of thrombin (1 nmol/L) were 0-184 mmol/L. After incubation for defined time intervals, the activity of thrombin was determined by adding substrate and measuring the absorbance of the generated chromophores at 405 nm. The possible inhibition of the protease trypsin by iopromide was investigated to evaluate the specificity of thrombin inhibition by iopromide. Iopromide was compared with Thromstop, a known thrombin inhibitor, to assess the relative potency of iopromide. The inhibition of thrombin by iopromide was immediate, rapidly reversible, and proportionate to the iopromide concentrations. The minimum inhibitory concentration of iopromide was 50 mmol/L. At the highest iopromide concentration tested, 184 mmol/L, the mean inhibition of thrombin activity was 44.5%. The mean concentration of iopromide associated with a 50% inhibition was 206 mmol/L. The inhibitory potency of iopromide was 4 x 10(6) times smaller than that of Thromstop. The inhibition of thrombin by iopromide is specific, because trypsin was not inhibited by iopromide. The results indicate that in vitro iopromide at clinically relevant concentrations partially inhibits thrombin activity. However, the in vitro model used does not consider other factors that may be relevant for the overall coagulation response in vivo.

Adult↗
PubMed2001

Beryllium particulate exposure and disease relations in a beryllium machining plant.

We examined the relationship between exposure to beryllium and the presence of beryllium sensitization (BeS) and chronic beryllium disease (CBD) in a cohort of workers in a beryllium precision machining facility. Twenty workers with BeS or CBD (cases) were compared with 206 worker-controls in a case-control study. Exposure for each job title was measured using cascade impactors placed in the workers' breathing zone to measure total beryllium exposure and exposure to particles < 6 microns and < 1 micron in aerodynamic diameter. Cumulative exposure was calculated as sigma (job title exposure estimate x years in job title). Individual lifetime-weighted (LTW) exposure was calculated as sigma [(job title exposure x years in job title) divided by total years employment)]. Workers in the case group were more likely to have worked as machinists (odds ratio, 4.4; 95% confidence interval, 1.1 to 17.5) than those in the control group. The median cumulative exposure was consistently greater in the cases compared with the controls for all exposure estimates and particle size fractions, although this was not statistically significant. The median cumulative exposure was 2.9 micrograms/m3-years in the cases versus 1.2 micrograms/m3-years in the controls for total exposure, and 1.7 micrograms/m3-years in the cases versus 0.5 microgram/m3-years in the controls for exposure to particles < 6 microns in diameter. With cumulative exposure categorized into low-, intermediate-, and high-exposure groups, the odds ratios were 2.4 (95% confidence interval, 0.7 to 8.2) for the intermediate-exposure group and 1.2 (95% confidence interval, 0.4 to 4.2) for the high-exposure group compared with the low-exposure group. The median LTW exposure was 0.25 microgram/m3 in both groups. The median LTW exposure to particles < 6 microns was 0.20 microgram/m3 in the cases compared with 0.14 microgram/m3 in the controls. The differences in cumulative and LTW exposure were not statistically significant. None of the 22 workers with LTW exposure < 0.02 microgram/m3 had BeS or CBD. Twelve workers (60%) in the case group had LTW exposures > 0.20. In conclusion, increased cumulative and LTW exposure to total and respirable beryllium was observed in workers with CBD or BeS compared with the controls. These results support efforts to control beryllium exposure in the workplace.

Adult↗
PubMed2001

Women at altitude: forearm hemodynamics during acclimatization to 4,300 m with alpha(1)-adrenergic blockade.

We hypothesized that blockade of alpha(1)-adrenergic receptors would prevent the rise in peripheral vascular resistance that normally occurs during acclimatization. Sixteen eumenorrheic women were studied at sea level (SL) and at 4,300 m (days 3 and 10). Volunteers were randomly assigned to take the selective alpha(1)-blocker prazosin or placebo. Venous compliance, forearm vascular resistance, and blood flow were measured using plethysmography. Venous compliance fell by day 3 in all subjects (1.39 +/- 0.30 vs. 1.62 +/- 0.43 ml. Delta 30 mmHg(-1) x 100 ml tissue(-1) x min(-1) at SL, means +/- SD). Altitude interacted with prazosin treatment (P < 0.0001) such that compliance returned to SL values by day 10 in the prazosin-treated group (1.68 +/- 0.19) but not in the placebo-treated group (1.20 +/- 0.10, P < 0.05). By day 3 at 4,300 m, all women had significant falls in resistance (35.2 +/- 13.2 vs. 54.5 +/- 16.1 mmHg x ml(-1) x min(-1) at SL) and rises in blood flow (2.5 +/- 1.0 vs. 1.6 +/- 0.5 ml. 100 ml tissue(-1) x min(-1) at SL). By day 10, resistance and flow returned toward SL, but this return was less in the prazosin-treated group (resistance: 39.8 +/- 4.6 mmHg x ml(-1) x min(-1) with prazosin vs. 58.5 +/- 9.8 mmHg x ml(-1) x min(-1) with placebo; flow: 1.9 +/- 0.7 ml. 100 ml tissue(-1) x min(-1) with prazosin vs. 2.3 +/- 0.3 ml x 100 ml tissue(-1) x min(-1) with placebo, P < 0.05). Lower resistance related to higher circulating epinephrine in both groups (r = -0.50, P < 0.0001). Higher circulating norepinephrine related to lower venous compliance in the placebo-treated group (r = -0.42, P < 0.05). We conclude that alpha(1)-adrenergic stimulation modulates peripheral vascular changes during acclimatization.

Acclimatization↗
PubMed2001

Reduced hippocampal volume in association with p50 nonsuppression following traumatic brain injury.

Traumatic brain injury (TBI) may produce persistently impaired auditory gating. This cholinergic-dependent, hippocampally mediated preattentive cognitive function that facilitates filtering of auditory stimuli may be indexed by the P50 evoked waveform to paired auditory stimuli. Abnormal P50 suppression post TBI is believed to result from injury to the hippocampus and/or its afferent cholinergic projections. This hypothesis was tested by comparing hippocampal and total brain volumes on MRI between ten P50-nonsuppressing TBI patients and ten normal control subjects matched for age, gender, and education. TBI subjects had highly significant bilateral hippocampal volume reductions, even when covaried for reductions in total brain volume. Degree of volume loss was not correlated with initial TBI severity. Findings support the hypothesis that hippocampal injury underlies P50 nonsuppression post TBI and suggest that such structural abnormalities may be observed even in "mildly" injured persons.

Adult↗
PubMed2001

Evidence for a direct role of cyclo-oxygenase 2 in implant wear debris-induced osteolysis.

Aseptic loosening is a major complication of prosthetic joint surgery and is manifested as chronic inflammation, pain, and osteolysis at the bone implant interface. The osteolysis is believed to be driven by a host inflammatory response to wear debris generated from the implant. In our current study, we use a selective inhibitor (celecoxib) of cyclo-oxygenase 2 (COX-2) and mice that lack either COX-1 (COX-1-/-) or COX-2 (COX-2-/-) to show that COX-2, but not COX-1, plays an important role in wear debris-induced osteolysis. Titanium (Ti) wear debris was implanted surgically onto the calvaria of the mice. An intense inflammatory reaction and extensive bone resorption, which closely resembles that observed in patients with aseptic loosening, developed within 10 days of implantation in wild-type and COX-1-/- mice. COX-2 and prostaglandin E2 (PGE2) production increased in the calvaria and inflammatory tissue overlying it after Ti implantation. Celecoxib (25 mg/kg per day) significantly reduced the inflammation, the local PGE2 production, and osteolysis. In comparison with wild-type and COX-1-/- mice, COX-2-/- mice implanted with Ti had a significantly reduced calvarial bone resorption response, independent of the inflammatory response, and significantly fewer osteoclasts were formed from cultures of their bone marrow cells. These results provide direct evidence that COX-2 is an important mediator of wear debris-induced osteolysis and suggests that COX-2 inhibitors are potential therapeutic agents for the prevention of wear debris-induced osteolysis.

Animals↗
PubMed2001

Preliminary observations of transtracheal augmented ventilation for chronic severe respiratory disease.

OBJECTIVE: Evaluate the potential safety and efficacy of transtracheal augmented ventilation (TTAV), which is the transtracheal delivery of high flows of a humidified air-oxygen blend. METHODS: The first of 2 observational studies evaluated patients before and after a 3-month intervention with the nocturnal (Noc) administration of TTAV at 10 L/min. Resting physiologic studies evaluated standard low-flow transtracheal oxygen (LFTTO), TTAV, and breathing without transtracheal flow via mouthpiece (MP). Patients also underwent nocturnal polysomnography, bronchoscopy, ventilatory drive evaluation, and treadmill exercise. The second study assessed the safety of Noc TTAV for up to 60 months. Each study evaluated 15 different transtracheal patients with severe lung disease. RESULTS: Pleural pressure-time index and respiratory duty cycle were significantly lower (p < 0.05) when comparing MP to TTAV. TTAV contributed more (p < 0.05) than LFTTO to the total volume delivered to the lung (V(L)). Arterial blood gases and (V(L)) were unaltered by TTAV. Sleep quality and nocturnal oxygenation with TTAV were similar to LFTTO, and Noc TTAV had no effect on ventilatory drive. Bronchoscopy showed no evidence of substantial injury. Treadmill exercise tests showed a longer exercise time (p < 0.005) and greater total work (p < 0.05) following Noc TTAV. During exercise, the changes in slope for heart rate and pH were less steep (p < 0.05) following Noc TTAV. The 3-month study and a long-term evaluation showed that Noc TTAV was well-tolerated and safe, with a reported high compliance. CONCLUSIONS: Patients with chronic hypoxemia and severe respiratory insufficiency may benefit from Noc TTAV.

Aged↗
PubMed2000

The human tissue inhibitor of metalloproteinases (TIMP)-1 gene contains repressive elements within the promoter and intron 1.

Expression of the TIMP-1 (tissue inhibitor of metalloproteinases-1) gene is tightly controlled during embryonic development and in the adult animal. Previous studies have focused on elements within the gene promoter which activate transcription of the gene. Here, we identify two regions of the gene which repress transcription: An element upstream of the basal gene promoter at -1718/-1458, represses expression of a reporter gene by approximately 50%; addition of the first intron to any promoter-reporter construct also strongly represses gene expression. The TIMP-1 gene has a short first exon which is transcribed but not translated, with the translation start site located in exon 2. Deletion analysis through intron 1 reveals a number of potential regions which might mediate its effect. Protein binding studies and mutational analyses reveal that a repressive element at +684/+748 binds Sp1, Sp3, and an unidentified Ets-related factor to suppress transcription.

Base Sequence↗
PubMed2000

Requirement of sphingolipid alpha-hydroxylation for fungicidal action of syringomycin E.

Syringomycin E is an antifungal cyclic lipodepsinonapeptide produced by Pseudomonas syringae pv. syringae. To understand the mechanism of action of syringomycin E, a novel resistant Saccharomyces cerevisiae strain, BW7, was isolated and characterized. Lipid analyses revealed that BW7 contained only the hydrophobic subspecies of sphingolipids that are normally minor components in wild type strains. This aberrant sphingolipid composition was the result of lack of alpha-hydroxylation of the amide-linked very long chain fatty acids, suggesting a defective sphingolipid alpha-hydroxylase encoded by the FAH1 gene. A yeast strain that lacks the FAH1 gene was resistant to syringomycin E, and failed to complement BW7. These results demonstrate that BW7 carries a mutation in the FAH1 gene, and that the lack of alpha-hydroxylated very long chain fatty acids in yeast sphingolipids confers resistance to syringomycin E.

Antifungal Agents↗
PubMed2000

The P50 auditory event-evoked potential in adult attention-deficit disorder: comparison with schizophrenia.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and schizophrenia are both conceptualized as disorders of attention. Failure to inhibit the P50 auditory event-evoked response, extensively studied in schizophrenia, could also occur in ADHD patients, if these two illnesses have common underlying neurobiological substrates. METHODS: This study examined the inhibition of the P50 auditory event-evoked potential in 16 unmedicated adults with ADHD, 16 schizophrenic outpatients, and 16 normal control subjects. Auditory stimuli were presented in a paired stimulus, conditioning-testing paradigm. RESULTS: The amplitude of initial or conditioning P50 response did not differ between the three groups; however, significant effects of psychiatric diagnosis on the amplitude of the test response and the ratio of the test to the conditioning response amplitudes were observed. Schizophrenic patients' P50 ratios and test amplitudes were higher than both the ADHD and normal groups. CONCLUSIONS: Adults with ADHD do not have the inhibitory deficit seen in patients with schizophrenia, suggesting that the mechanism of attentional disturbance in the two illnesses may be fundamentally different.

Adult↗
PubMed2000

IL-4, IL-10, IL-13, and TGF-beta from an altered peptide ligand-specific Th2 cell clone down-regulate adoptive transfer of experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is induced in the SJL/J mouse by adoptive transfer of activated proteolipid protein peptide (PLP) 139-151-specific Th1 cells. T cells responding to altered peptide ligands (APL) of PLP, previously shown to induce Th2 differentiation and regulate disease in PLP-immunized mice, do not transfer EAE. However, the exact mechanism of disease regulation by APL-specific T cells has not been elucidated. In this report, we show that 1F1, a Th2 clone specific for an APL of PLP139-151 can prevent adoptive transfer of EAE when cocultured with PLP-encephalitogenic spleen cells (PLP-spleen). Cytokines from activated 1F1 cells were detected by hybridization of mRNA to oligonucleotide arrays (DNA chip) and by ELISA. The Th2 cytokines found to be present at the highest protein and mRNA levels were evaluated for their role in suppression of adoptive transfer of EAE from PLP-activated spleen cell cultures. Abs to individual cytokines in 1F1 PLP-spleen cocultures suggested that IL-4, IL-13, and TGF-beta played a significant role in suppressing EAE. Abs to the combination of IL-4, IL-10, IL-13, and TGF-beta completely neutralized the protective effect of 1F1. Addition of Th2 cytokines to PLP-spleen cultures showed that IL-13 and TGF-beta were each individually effective and low levels of IL-4 synergized with IL-13 to inhibit disease transfer. IL-5, IL-9, and IL-10 had little or no effect whereas GM-CSF slightly enhanced EAE. Our results demonstrate that Th2 cytokines derived from APL-specific Th2 cells can effectively down-regulate the encephalitogenic potential of PLP-spleen cells if present during their reactivation in culture.

Adoptive Transfer↗