Biomedical subjects
S Williams
Publications and source records attributed to S Williams.
Reconstitution of T cell antigen receptor-induced Erk2 kinase activation in Lck-negative JCaM1 cells by Syk.
The two related protein-tyrosine kinases Syk and Zap are rapidly phosphorylated on tyrosine residues and enzymatically activated upon crosslinking of the T cell antigen receptor. We have previously reported that the activation of Syk is less dependent on the Src family kinase Lck than the activation of Zap. Here we report that overexpression of Syk in the Lck-negative JCaM1 cells enabled the T cell antigen receptor/CD3 complex to induce a normal activation of the mitogen-activated protein kinase (MAPK) pathway and expression of a nuclear factor of activated T cells reporter construct. In contrast, Zap and other protein-tyrosine kinases were unable to reconstitute these signaling pathways when expressed at the same levels. In parallel, Syk was phosphorylated on tyrosine, while Zap was not. The Syk-mediated T cell antigen receptor-induced MAPK activation was detectable within 1 min of receptor stimulation and peaked at 3-5 min. The capacity of Syk to reconstitute the MAPK response required the catalytic activity of Syk, an intact autophosphorylation site (Y518 and Y519), both Src homology 2 domains and it was blocked by the inhibitory N17-mutated dominant-negative Ras construct. A Y341-->F mutant of Syk, which is deficient in its interaction with phospholipase Cy1 and Vav, was less efficient than wild-type Syk. Our results suggest that Syk, in contrast to Zap, can transduce signals from the T cell antigen receptor independently of Lck.
Senior house officers' work related stressors, psychological distress, and confidence in performing clinical tasks in accident and emergency: a questionnaire study.
OBJECTIVE: To investigate the relation between accident and emergency senior house officers' psychological distress and confidence in performing clinical tasks and to describe work related stressors. DESIGN: Questionnaire survey with data collected at four points during senior house officers' six month attachment to accident and emergency departments. SUBJECTS: 171 newly appointed accident and emergency senior house officers from 27 hospitals in the South Thames region. MAIN OUTCOME MEASURES: Psychological distress measured with a 25 item questionnaire; confidence in performing a range of 35 clinical and practical activities (visual analogue scales); reported consultation stress factors, other work related stressors, and personal stressors. RESULTS: Overall confidence scores in carrying out a range of clinical and practical activities increased significantly between the end of the first and the end of the fourth month (Z = -6.05, P < 0.001). Senior house officers with higher psychological distress scores at the end of their first and fourth month had significantly lower confidence scores (Z = -3.20, P < 0.001; Z = -1.90, P < 0.05). Senior house officers with lower increases in confidence between the first and fourth month had significantly higher distress than those with greater increases (Z = -2.62, P < 0.001). Factors identified as causing stress during consultations included difficulties with communication, certain clinical presentations, and department organisational factors (particularly the intensity of workload). CONCLUSIONS: Psychological distress is linked to confidence in senior house officers. This supports the need to monitor and build confidence in senior house officers and to address work related stressors. Additional communication skills training needs to be considered.
Perspectives. Denver demonstration tests use of enrollment broker.
Explore the source record for details and available documents.
Facilitation of N-type calcium current is dependent on the frequency of action potential-like depolarizations in dissociated cholinergic basal forebrain neurons of the guinea pig.
Voltage-dependent inhibition of high voltage-activated (HVA) calcium currents by G-proteins can be transiently relieved (facilitated) by strong depolarizing prepulses. However, with respect to the physiological significance of facilitation, it remains to be established if it can be induced by action potentials (AP) in central neurons. With the use of whole-cell recordings of dissociated cholinergic basal forebrain neurons of the guinea pig, it is shown that the GTPgammaS-inhibited HVA currents that occur through N-ethylmaleimide (NEM)-sensitive Gi-Go subtypes of G-proteins can be facilitated. Furthermore, although different types of HVA channels are present in these neurons, facilitation occurred mostly through disinhibition of the N-type current. On the basis of data indicating that the recovery from facilitation was relatively slow, we tested if more physiological stimuli that crudely mimicked APs (2 msec long depolarizations to 40 mV from a holding of -50 mV) potentially could induce facilitation of HVA currents inhibited by GTPgammaS and cholinergic agonists. Indeed, evidence is provided that the extent of facilitation is dependent on both the number and frequency of AP-like depolarizations. These results suggest that firing rates and patterns of discharge of neurons could influence their responsiveness to transmitters acting on N-type HVA calcium channels.
Regulation of the low molecular weight phosphotyrosine phosphatase by phosphorylation at tyrosines 131 and 132.
Activation of resting T lymphocytes is initiated by rapid but transient tyrosine phosphorylation of a number of cellular proteins. Several protein tyrosine kinases and protein tyrosine phosphatases are known to be important for this response. Here we report that normal T lymphocytes express the B isoform of low molecular weight protein tyrosine phosphatase B (LMPTP-B). The cDNA was cloned from Jurkat T cells, and an antiserum was raised against it. LMPTP immunoprecipitated from resting Jurkat T cells was found to be tyrosine phosphorylated. On stimulation of the cells through their T cell antigen receptor, the phosphotyrosine content of LMPTP-B declined rapidly. In co-transfected COS cells, Lck and Fyn caused phosphorylation of LMPTP, whereas Csk, Zap, and Jak2 did not. Most of the phosphate was located at Tyr-131, and some was also located at Tyr-132. Incubation of wild-type LMPTP with Lck and adenosine 5'-O-(thiotriphosphate) caused a 2-fold increase in the activity of LMPTP. Site-directed mutagenesis showed that Tyr-131 is important for the catalytic activity of LMPTP, and that thiophosphorylation of Tyr-131, and to a lesser degree Tyr-132, is responsible for the activation.
Implementing guidance on hepatitis B for applicants to medical school is time consuming.
Explore the source record for details and available documents.
Considerations for toxicology studies of respiratory drug products.
The standard approaches for the preclinical development of chronically administered drugs also apply to most respiratory drugs. Modifications from the standard preclinical development plan, however, may be necessary if the drug is administered intranasally or by inhalation. Administration by these routes may result in airway toxicity and the intended patient population is often particularly susceptible. Current and former representatives of the Division of Pulmonary Drug Products (CDER, U.S. FDA) present this article to describe general principles of preclinical development for respiratory drug indications. The article addresses drugs intended for administration by the intranasal or inhalation routes. The article describes the types of studies recommended, considers the initial human dose, and discusses dose-escalation strategies in clinical trials. Other areas of special concern with intranasal or inhalation administration include immunotoxicity, reproductive toxicity, types of dosing apparatus, excipients and extractables, and formulation changes. The approaches described in this article are intended as general information and should be adapted to the scientific considerations and circumstances of a particular drug under development.
Current status of preimplantation diagnosis.
Explore the source record for details and available documents.
Psychometric properties of the Centre for Epidemiologic Studies Depression Scale (CES-D) in a sample of women in middle life.
The Centre for Epidemiologic Studies Depression Scale (CES-D) was completed by 675 women taking part in a longitudinal investigation of health-related issues. The data were submitted to confirmatory factor analysis using LISREL 7 and a 4-factor model was found to fit the data moderately well. A second-order depression factor was also identified. The results provide support for the construct validity of the total and subscale scores from this measure. The scale was found to have good reliability. Evidence was found that scores on the subscale measuring somatic features of depression may be inflated in women who have experienced a chronic health problem in the past 12 months.
Depot medroxyprogesterone acetate. Patterns of use and reasons for discontinuation.
Little information is available from outside clinic settings about the acceptability of depot medroxyprogesterone acetate (DMPA, Depo-Provera) as an injectable contraceptive. In this national, population-based study, New Zealand women aged 25 to 54 years were selected at random from voter rolls. The 1864 subjects were interviewed by telephone after an initial approach by letter. More than 1 in 8 women (13.7%) had used DMPA at some time. The proportion was higher among Maori women and among those of lower income and education, but DMPA had been used by a substantial proportion of all socioeconomic groups. A quarter of all users reported receiving only a single injection of DMPA, and only 53% had used this method for a total of 12 months or more. Only 5 (1.6%) of discontinuations were attributed to contraceptive failure; this corresponds to a contraceptive failure rate of 0.9 per 100 woman-years. Side effects were given as the most common reasons for stopping, with menstrual disturbances and weight gain being cited most often. Other reasons for stopping included no further need for contraception or doubts about the appropriateness of DMPA. In this developed country population, DMPA is widely used for short periods but its acceptability is limited by the occurrence of side effects.
Level of education, age of bearing children and mental health of women.
The present study examined the longitudinal relationship between women's mental health and both their level of education and age at which they had their first child. The women were divided into four groups depending on whether or not they had further education after leaving school and whether or not they had a baby before the age of 21. Longitudinal data collected over a 19-year period from this group of women suggested that psychological morbidity was relatively stable across this time span. Women who left school without proceeding to further education and those who became mothers before the age of 21 had higher psychological symptom scores than the other groups throughout this period. These two factors were associated with poorer mental health in an additive fashion. The women were also more likely to have separated from the father of their child and continued to be economically disadvantaged into mid-life.
Modulation of cholinergic nucleus basalis neurons by acetylcholine and N-methyl-D-aspartate.
Known to exert an important modulatory influence on the cerebral cortex, the cholinergic neurons of the basal forebrain are modulated in turn by neurotransmitters which may include acetylcholine released from processes of brainstem or forebrain neurons. In the present study, we examined the effect of carbachol, a non-specific cholinergic agonist, either alone or in the presence of N-methyl-D-aspartate upon electrophysiologically identified cholinergic basalis neurons in guinea-pig basal forebrain slices. Carbachol produced a direct postsynaptic hyperpolarization, accompanied by a decrease in membrane resistance. Muscarine could mimic this hyperpolarizing effect, whereas nicotine produced a direct postsynaptic membrane depolarization. The interaction of carbachol with N-methyl-D-aspartate was subsequently tested since, in a prior study, N-methyl-D-aspartate was shown to induce rhythmic bursting in cholinergic cells when they were hyperpolarized by continuous injection of outward current. Applied simultaneously with N-methyl-D-aspartate in the absence of current injection, carbachol was also found to promote rhythmic bursting in half of the cells tested. Since the bursts under these conditions were markedly longer in duration than those observed in the presence of N-methyl-D-aspartate alone, it was hypothesized that carbachol might have another action, in addition to the membrane hyperpolarization. Using dissociated cells, it was found that brief applications of carbachol could indeed diminish the slow afterhyperpolarizations that follow single spikes, short bursts or long trains of action potentials in cholinergic basalis neurons. These results indicate that, through its dual ability to hyperpolarize cholinergic neurons and to reduce their afterhyperpolarizations, acetylcholine can promote the occurrence of rhythmic bursting in the presence of N-methyl-D-aspartate. Accordingly, whether derived from brainstem or local sources, acetylcholine may facilitate rhythmic discharge in cholinergic basalis neurons which could in turn impose a rhythmic modulation upon cortical activity during particular states across the sleep-waking cycle.
First-time mothers' perceptions of prenatal care services.
This study sought to uncover information regarding prenatal care services as reported by primiparas. Inadequate prenatal care has been linked with the delivery of low birth weight (LBW) infants and infant mortality. This secondary analysis of a larger study (N = 426) examined the need for and availability, accessibility, and use of prenatal care services by primiparas (n = 141). Results indicated that primiparas delivering LBW infants reported less satisfaction with information on birth control and less information on infant feeding. In addition, mothers of LBW infants reported more often than mothers of normal birthweight infants that transportation and finances were barriers to prenatal care. Childbirth preparation class was the only predictor variable for birth weight in this study.
Combinatorial signaling by Twisted Gastrulation and Decapentaplegic.
The Twisted Gastrulation (TSG) protein is one of five secreted proteins required to pattern the dorsal part of the early Drosophila embryo. Unlike the Decapentaplegic (DPP) protein that is required to pattern the entire dorsal half of the embryo, TSG is needed only to specify the fate of the dorsal midline cells. Here we have misexpressed the tsg gene with different promoters to address its mechanism of action and relationship to DPP. When expressed in a ventral stripe of cells, TSG protein can diffuse to the dorsalmost cells and can rescue the dorsal midline cells in tsg mutant embryos. Despite elevated levels that exceed that exceed those needed for biological activity, there was no change in dorsal midline or lateral cell fates under any conditions tested. We conclude that TSG does not modulate an activity gradient of DPP. Instead, it functions in a permissive rather than instructive role to elaborate cell fates along the dorsal midline after peak levels of DPP activity have 'primed' cells to respond to TSG. The interaction between TSG and DPP defines a novel type of combinatorial synergism.
Tracheostomy and radiotherapy in the management of laryngeal carcinoma causing airway obstruction.
Between 1977 and 1985, 66 patients presenting with airway obstruction due to laryngeal squamous cell carcinoma were treated by tracheostomy and subsequent radiotherapy. Female survival (64% at 2 years and 35% at 5 years) was significantly better than male survival (19% at 2 years and 10% at 5 years). When four forms of management were compared, it appeared that 40 Gy in ten fractions over 21 days was associated with better survival. Because two of the treatment groups contained few patients, these were excluded from further analysis. When adjustments were made for sex, delay between tracheostomy and treatment, and residual disease, the difference in treatment response between those receiving 60+ Gy in 28-30 fractions over 42 days and those receiving 40 Gy in ten fractions over 21 days was not significant (hazard ratio 1.37; 95% CI 0.64-3.91).
A comparison of time trade-off and quality of life measures in patients with advanced cancer.
Quality of life (QOL) measures are now accepted as indicators of efficacy in the palliative treatment of cancer. Utility measures may also provide valuable information in this area yet they have rarely been applied. To assess the concordance of QOL and utility scales, 93 patients with advanced, symptomatic cancer completed two QOL instruments, the Spitzer Quality of Life Index (QLI) and Spitzer Uniscale, and a time-trade off (TTO) question reflecting the utility of their health states. The scales were self-administered. All patients completed the QLI and Uniscale but only 37% of participants were prepared to trade time. The remainder comprised 39% who felt too well to trade time and 24% who did not wish to consider trading time at all. Those prepared to trade time had significantly worse scores on both QLI and Uniscale instruments than those who felt too well to trade. However the correlation between time traded and QLI and Uniscale scores was poor. We conclude that the TTO question used in this study, while not strongly related to QOL, provides a measure of the patient's attitude to their health state. This may explain why patients differ in their attitude to quantity vs. quality of life.