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Biomedical subjects

A Wilson

Publications and source records attributed to A Wilson.

At least 55 records · Page 3Linked to original sources
PubMed2001

Biased V beta usage in immature thymocytes is independent of DJ beta proximity and pT alpha pairing.

During thymus development, the TCR beta locus rearranges before the TCR alpha locus. Pairing of productively rearranged TCR beta-chains with an invariant pT alpha chain leads to the formation of a pre-TCR and subsequent expansion of immature pre-T cells. Essentially nothing is known about the TCR V beta repertoire in pre-T cells before or after the expression of a pre-TCR. Using intracellular staining, we show here that the TCR V beta repertoire is significantly biased at the earliest developmental stage in which VDJ beta rearrangement has occurred. Moreover (and in contrast to the V(H) repertoire in immature B cells), V beta repertoire biases in immature T cells do not reflect proximity of V beta gene segments to the DJ beta cluster, nor do they depend upon preferential V beta pairing with the pT alpha chain. We conclude that V gene repertoires in developing T and B cells are controlled by partially distinct mechanisms.

Animals↗
PubMed2001

A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee.

OBJECTIVE: To perform a randomized, double-blind, crossover clinical trial of diclofenac + misoprostol versus acetaminophen in ambulatory patients with osteoarthritis of the hip or knee. METHODS: Patients in 12 ambulatory care settings were eligible if they were age >40 years and if they had Kellgren/Lawrence radiographic grade 2-4 osteoarthritis of the knee or hip and a score of > or =30 mm on a 100-mm visual analog pain scale. Patients were randomized to one of two groups, 75 mg diclofenac + 200 microg misoprostol twice daily or 1,000 mg acetaminophen 4 times daily (each for 6 weeks), and were then crossed over to the other treatment for 6 weeks. A placebo was included in each treatment regimen to enable double blinding. The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index and the visual analog pain scale of the Multidimensional Health Assessment Questionnaire. Safety was assessed using a standard form to review adverse events. RESULTS: We enrolled 227 patients, of whom 218 provided data for the first treatment period and 181 provided data for both treatment periods. Significantly higher levels of improvement in the primary outcomes were seen for diclofenac + misoprostol than for acetaminophen (P < 0.001). Adverse events were more common when patients took diclofenac + misoprostol (P = 0.046). Diclofenac + misoprostol was rated as "better" or "much better" by 57% of the 174 patients who provided such ratings for both treatment periods, while acetaminophen was rated as "better" or "much better" by 20% of these patients, and 22% reported no difference (P < 0.001). Differences favoring diclofenac + misoprostol over acetaminophen were greater in patients with more severe osteoarthritis according to baseline pain scores, radiographs, or number of involved joints. CONCLUSION: Patients with osteoarthritis of the hip or knee had significantly greater improvements in pain scores over 6 weeks with diclofenac + misoprostol than with acetaminophen, although patients with mild osteoarthritis had similar improvements with both drugs. Acetaminophen was associated with fewer adverse events.

Acetaminophen↗
PubMed2001

Influence of photoperiod on N-acetyltransferase activity and melatonin in the fiddler crab Uca pugilator.

Melatonin and N-acetyltransferase (NAT) activity were measured in the eyestalks of fiddler crabs acclimated to various photoperiods: constant light, a L:D 12:12 h photoperiod, or constant dark. Following acclimation, eyestalks were collected every 3 h over a 24-h period; they were assayed for melatonin with a radioimmunoassay and for NAT activity with a radioenzymatic assay. In constant light, melatonin levels increased at 1300 h, from 142 to 431 pg x mg(-1) eyestalk; NAT activity increased concurrently, from 97 to 203 pmol x h(-1) x mg(-1) eyestalk, and both remained elevated until 0400 h. In the L:D 12:12 h photoperiod, melatonin levels increased at 1300 h from 28 to 230 pg x mg(-1) eyestalk, and though NAT activity increased significantly, from 80 to 122 pmol x h(-1) x mg(-1) eyestalk, an even greater increase occurred at 0400 h, when melatonin levels were low. In constant dark, melatonin levels increased at 1600 h, from 22 to 196 pg x mg(-1) eyestalk, with a concurrent increase in NAT activity from 93 to 140 pmol x mg(-1) x h(-1) eyestalk. However, the second peak in melatonin (111 pg x mg(-1)), occurring at 0400 h, was out of phase with the second peak of NAT activity (113 pmol x mg(-1) x h(-1) eyestalk) which occurred at 0700 h. NAT may be a rate-limiting step in melatonin synthesis in fiddler crabs under some conditions (constant light and the 1300 h peak in constant dark); however, NAT activity correlates poorly with melatonin levels in a L:D 12:12 h photoperiod and in constant dark relative to the 0400 h melatonin peak.

Animals↗
PubMed2001

The gene mutated in cocoa mice, carrying a defect of organelle biogenesis, is a homologue of the human Hermansky-Pudlak syndrome-3 gene.

Hermansky-Pudlak syndrome (HPS) is a group of human disorders of organelle biogenesis characterized by defective synthesis of melanosomes, lysosomes, and platelet dense granules. In the mouse, at least 15 loci are associated with mutant phenotypes similar to human HPS. We have identified the gene mutated in cocoa (coa) mice, which is associated with an HPS-like mutant phenotype and thus represents a strong candidate for human HPS. Analysis of coa-mutant mice and cultured coa-mutant mouse melanocytes indicates that the normal coa gene product is involved in early stages of melanosome biogenesis and maturation.

Alleles↗
PubMed2001

Threshold doses for nicotine discrimination in smokers and non-smokers.

RATIONALE: Tobacco use during initial experimentation often involves modest nicotine exposure, escalating to larger doses and more frequent exposure with the onset of tobacco dependence. Threshold doses for nicotine discrimination therefore may differ between naive and experienced tobacco users. OBJECTIVES: We determined the lowest (threshold) dose of nasal spray nicotine that smokers and non-smokers could reliably discriminate from placebo spray. METHODS: Male and female smokers (n=18) and non-smokers (n=17) were initially trained to discriminate 20 microg/kg from placebo before proceeding to threshold determination sessions, which involved discrimination of progressively lower doses below 20 microg/kg ("descending order" subgroup) or higher doses above 1 microg/kg ("ascending order" subgroup). Threshold was determined by the lowest dose reliably discriminated from placebo (correct on > or =80% of testing trials) and by failure to discriminate the next lowest dose. RESULTS: Threshold doses for nicotine discrimination were low and not different between smokers and non-smokers (median thresholds of 3 versus 2 microg/kg and approximate blood levels of 2.6 versus 1.6 ng/ml, respectively). Thresholds were similar between descending and ascending order subgroups. Several subjective responses differentiated threshold dose from the dose just below threshold, particularly in non-smokers. CONCLUSIONS: Threshold doses for nasal spray nicotine discrimination in humans are low, well below the typical nicotine delivery of most cigarette brands, and may not change after long-term smoking exposure.

Administration, Intranasal↗
PubMed2001

Quitting cigarette smoking produces minimal loss of chronic tolerance to nicotine.

RATIONALE: Long-term exposure to nicotine is associated with chronic tolerance to its acute effects, adaptation that may lead to tobacco dependence. The time course for loss of this tolerance after cessation of exposure is not known in humans but could relate to risk of smoking relapse. OBJECTIVES: We examined changes in responses to nicotine as a function of days, weeks, or years of smoking cessation in formerly dependent smokers to determine at what point sensitivity to nicotine is reinstated (i.e., loss of tolerance). METHODS: Acute subjective, cardiovascular, performance, and reinforcing (self-administration) effects of nicotine nasal spray (0-20 microg/kg) were assessed prospectively in men and women smokers before and then day-by-day (study 1) or 3 weeks (study 2) after stopping smoking. A smoking resumption period (study 1) and a group of non-quitting smokers (study 2) were included to control for the passage of time. These effects were also compared cross-sectionally between those who had quit for 1-4 years and those who had for 6-19 years in a separate sample of long-time ex-smokers to determine whether lengthier abstinence causes greater loss of tolerance (study 3). RESULTS: No clear loss of tolerance was observed on any measure in studies 1 or 2, suggesting that chronic tolerance is fully maintained for at least weeks after quitting smoking. Sensitivity to nicotine's effects was also not different as a function of years quit in study 3. CONCLUSIONS: Chronic tolerance to nicotine is not lost within several weeks of quitting smoking and may not change even after years of abstinence from tobacco use.

Administration, Intranasal↗
PubMed2001

SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety.

SB-243213 (5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline hydrochloride) is a new, selective 5-hydroxytryptamine (5-HT)2C receptor inverse agonist. SB-243213 has high affinity for the human 5-HT2C receptor (pK(i) 9.37) and greater than a 100-fold selectivity over a wide range of neurotransmitter receptors, enzymes and ion channels. In in vitro functional studies, SB-243213 acted as an inverse agonist at the human 5-HT2C receptor with a pK(b) of 9.8. In in vivo studies, SB-243213 was a potent inhibitor of central 5-HT2C receptor-mediated function in rats, blocking meta-chlorophenylpiperazine-induced hypolocomotion with an ID50 of 1.1 mg/kg p.o. and a long duration of action (>8 h). In rats, SB-243213 exhibited anxiolytic-like activity in both the social interaction and Geller-Seifter conflict tests. Importantly, unlike diazepam, chronic administration of SB-243213 did not result in the development of either tolerance to the anxiolytic-like effects or withdrawal anxiogenesis. Furthermore, in rodents, SB-243213 did not affect seizure threshold, did not increase body weight or induce catalepsy, but attenuated the haloperidol-induced catalepsy. SB-243213 did not affect amphetamine-, MK-801- or phencyclidine-induced hyperactivity. In conclusion, SB-243213 may possess an improved anxiolytic profile compared to benzodiazepines. SB-243213 also modulates dopaminergic transmission, lacks pro-psychotic properties and may have utility in the treatment of schizophrenia and motor disorders.

Animals↗
PubMed2001

T cell fate specification and alphabeta/gammadelta lineage commitment.

The development of T cells from pluripotent stem cells involves a coordinated series of lineage-commitment steps. Common lymphoid precursors in the fetal liver or adult bone marrow must first choose between a T, B or NK cell fate. Committed T cell precursors in the thymus then differentiate into cells committed to the alphabeta or gammadelta lineages. Recent advances have been made in our understanding of the mechanisms underlying T cell fate specification and alphabeta/gammadelta lineage divergence.

Animals↗
PubMed2001

Notch1 and T-cell development: insights from conditional knockout mice.

Notch proteins influence cell-fate decisions in many developmental systems. Gain-of-function studies have suggested a crucial role for Notch1 signaling at several stages during lymphocyte development, including the B/T, alphabeta/gammadelta and CD4/CD8 lineage choices. Here, we critically re-evaluate these conclusions in the light of recent studies that describe inducible and tissue-specific targeting of the Notch1 gene.

Animals↗
PubMed2001

Characterisation of strains of enteroaggregative Escherichia coli isolated during the infectious intestinal disease study in England.

Strains of Escherichia coli, hybridising with a DNA probe for enteroaggregative E. coli (EAggEC), were isolated from patients with infectious intestinal disease (IID) or gastro-enteritis, and healthy controls during the study of IID in England. Of 3506 cases presenting with an IID, 160 (4.6%) had faecal EAggEC as compared with 46 (1.7%) of 2772 healthy controls, 53% of EAggEC isolated from each of the 'case' and the 'control' groups adhered in a 'stacked-brick' formation. Strains from cases and controls belonged to over 39 and 14 different serogroups respectively, and approximately half of the strains isolated did not react with antisera in the current somatic antigen serotyping scheme. Forty-nine cases with EAggEC (31%) had a known history of foreign travel. Over 50% of strains isolated from cases and controls were resistant to one or more of eight antimicrobials, and antimicrobial resistance was not statistically significantly more common among cases with a known history of foreign travel (p = 0.57). These data form part of the largest investigation carried out on these organisms in the UK to date and provide the most comprehensive analysis of strains of EAggEC isolated from the general population of England.

Case-Control Studies↗
PubMed2001

Reinforcing effects of nicotine as a function of smoking status.

The authors compared acute nicotine self-administration among 4 groups varying in current or past dependence: dependent smokers, nondependent smokers, ex-smokers who had quit at least 1 year ago, and nonsmokers. Nicotine (0 vs. 12 microg/kg/8 sprays) available by nasal spray was self-administered with a choice procedure. Self-administration also was related to participant characteristics (sex, alcohol and caffeine intake, sensation-seeking score) and to subjective responses to initial nicotine spray exposure. Nicotine self-administration was similar between dependent and nondependent smokers but was greater in those groups than in ex-smokers and nonsmokers, who did not differ from each other. Self-administration was unrelated to most other participant characteristics. In nonsmokers, self-administration was related directly to pleasurable effects but inversely to aversive effects. Few effects were related to self-administration in the other groups.

Administration, Intranasal↗
PubMed2001

Subjective responses to nicotine in smokers may be associated with responses to caffeine and to alcohol.

Sensitivity in responses to one drug may relate to sensitivity to other drugs, suggesting broad individual differences in characteristic responsivity across drugs. Data from two separate studies of smokers were reanalyzed to examine associations between acute subjective and cardiovascular effects of nicotine vs. caffeine and between nicotine vs. alcohol. Typical intakes of cigarettes, alcohol, and caffeine were included as covariates when they were correlated with the responses of interest. Significant associations between nicotine and caffeine were seen for most of the subjective measures and for blood pressure responses. Fewer significant associations were observed between nicotine and alcohol. Responses associated between nicotine and both of the other drugs tended to reflect psychomotor stimulation. These results suggest that smokers who are more responsive to some of nicotine's subjective and blood pressure effects are also more sensitive to the same effects of caffeine and, to a lesser extent, of alcohol.

Administration, Intranasal↗
PubMed2001

Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8T cell development.

Notch proteins influence cell-fate decisions in many developing systems. Several gain-of-function studies have suggested a critical role for Notch 1 signaling in CD4-CD8 lineage commitment, maturation and survival in the thymus. However, we show here that tissue-specific inactivation of the gene encoding Notch 1 in immature (CD25+CD44-)T cell precursors does not affect subsequent thymocyte development. Neither steady-state numbers nor the rate of production of CD4+ and CD8+ mature thymocytes is perturbed in the absence of Notch 1. In addition, Notch 1-deficient thymocytes are normally sensitive to spontaneous or glucocorticoid-induced apoptosis. In contrast to earlier reports, these data formally exclude an essential role for Notch 1 in CD4-CD8 lineage commitment, maturation or survival.

Animals↗
PubMed2001

Use of deltamethrin 'pour-on' insecticide for the control of cattle trypanosomosis in the presence of high tsetse invasion.

A deltamethrin 'pour-on' insecticide was applied monthly to over 2000 cattle exposed to a high challenge of drug-resistant trypanosomes and high tsetse re-invasion pressure in the Ghibe valley, south-west Ethiopia. Blood samples were taken monthly from an average of 760 cattle for determination of PCV and presence of trypanosomes. The area of the valley is approximately 350 km2 and the cattle grazed in roughly four locations covering about a quarter to half of the area. Two years before the trial commenced, Glossina morsitans submorsitans Newstead (Diptera: Glossinidae) began to invade the valley. Despite the use of the pour-on the mean apparent density of G. m. submorsitans continued to rise, and, during the 4 years of tsetse control, was more than three-fold higher than that recorded during the previous 18 months. Over the same period there was little change in the apparent density of Glossina pallidipes Austen (Diptera: Glossinidae). By contrast, the mean monthly prevalence of trypanosome infections in cattle over 36 months of age decreased from 38.3 to 29.0%, the incidence of new infections decreased from 26.6 to 16.0% (a reduction of 40%), and packed cell volume in cattle increased from 21.7 to 24.1%. Evidence of a change in apparent parasite transmission rate was demonstrated by regression of infection incidence in cattle on the logarithm of apparent density of G. m. submorsitans. Before the trial started the regression coefficient was 45.8 +/- 6.3 and this reduced to 9.2 +/- 2.5% incidence per log(e) (flies/trap/day) during the period of tsetse control. It was concluded that this indicated reductions in tsetse numbers in the immediate vicinities of cattle in a way that was not reflected in overall tsetse catches. Nevertheless, the comparatively high levels of trypanosome prevalence that persisted in the cattle demonstrates that, where invasion prevalence is high, treatment of small pockets of cattle will not eradicate tsetse. To achieve more significant reduction in trypanosome prevalence in cattle, integrated methods of control utilizing target barriers in the major routes of invasion will be needed.

Administration, Topical↗
PubMed2001

What is chronic fatigue syndrome? Heterogeneity within an international multicentre study.

OBJECTIVE: We sought to compare the characteristics of patients presenting with chronic fatigue (CF) and related syndromes in eight international centres and to subclassify these subjects based on symptom profiles. The validity of the subclasses was then tested against clinical data. METHOD: Subjects with a clinical diagnosis of CF completed a 119-item self-report questionnaire to provide clinical symptom data and other information such as illness course and functional impairment. Subclasses were generated using a principal components-like analysis followed by latent profile analysis (LPA). RESULTS: 744 subjects returned complete data sets (mean age 40.8 years, mean length of illness 7.9 years, female to male ratio 3:1). Overall, the subjects had a high rate of reporting typical CF symptoms (fatigue, neuropsychological dysfunction, sleep disturbance). Using LPA, two subclasses were generated. Class one (68% sample) was characterized by: younger age, lower female to male ratio; shorter episode duration; less premorbid, current and familial psychiatric morbidity; and, less functional disability. Class two subjects (32%) had features more consistent with a somatoform illness. There was substantial variation in subclass prevalences between the study centres (Class two range 6-48%). CONCLUSIONS: Criteria-based approaches to the diagnosis of CF and related syndromes do not select a homogeneous patient group. While substratification of patients is essential for further aetiological and treatment research, the basis for allocating such subcategories remains controversial.

Adult↗
PubMed2001

Expression of cyclin-dependent kinase 5 and its activator p35 in models of induced apoptotic death in neurons of the substantia nigra in vivo.

Cyclin-dependent kinase 5 is predominantly expressed in postmitotic neurons and plays a role in neurite elongation during development. It has also been postulated to play a role in apoptosis in a variety of cells, including neurons, but little is known about the generality and functional significance of cdk5 expression in neuronal apoptosis in living brain. We have therefore examined its expression and that of its known activators, p35, p39 and p67, in models of induced apoptosis in neurons of the substantia nigra. We find that cdk5 is expressed in apoptotic profiles following intrastriatal injection of 6-hydroxydopamine and axotomy. It is expressed exclusively in profiles which are in late morphologic stages of apoptosis. In these late stages, derivation of the profiles from neurons, and localization of expression to the nucleus, can be demonstrated by co-labeling with a neuron-specific nuclear marker, NeuN. In another model of induced apoptotic death in nigra, produced by developmental striatal lesion, kinase activity increases in parallel with cell death. While mRNAs for all three cdk5 activators are expressed in nigra during development, only p35 protein is expressed in apoptotic profiles. We conclude that cdk5/p35 expression is a general feature of apoptotic neuron death in substantia nigra neurons in vivo.

Animals↗
PubMed2001

The usefulness of masks in preventing transient carriage of epidemic methicillin-resistant Staphylococcus aureus by healthcare workers.

We assessed the usefulness of wearing masks in preventing epidemic methicillin-resistant Staphylococcus aureus (EMRSA) carriage in nursing and physiotherapy staff on two dedicated EMRSA units. In the first phase of the study, members of staff were screened for EMRSA carriage immediately before and after periods of duty using nose, throat and hand swabs. During the second phase of the study, masks were worn by staff carrying out procedures associated with significant EMRSA exposure and examined for EMRSA as described for the first phase. Both phases were conducted over a period of two months. Forty-eight percent of nursing staff were colonized with EMRSA at some time during the first phase of the study. Wearing masks significantly reduced nasal, throat and hand carriage of EMRSA (P= 0.05). We conclude that the wearing of masks by healthcare workers performing certain activities for EMRSA positive patients may prevent transient colonization and hence may be a useful intervention in the control of EMRSA in the hospital environment.

Carrier State↗