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Biomedical subjects

S Williams

Publications and source records attributed to S Williams.

At least 469 records · Page 26Linked to original sources

Participation in breast cancer screening: randomised controlled trials of doctors' letters and of telephone reminders.

The study used a randomised controlled trial to find out whether supporting letters from general practitioners accompanying the invitations from a screening centre affected participation in a population-based breast cancer screening program for women aged 50 to 64. A further randomised controlled trial compared the effect of postal reminders with telephone reminders for women who did not respond to an initial invitation to participate in the program. There were 482 women in the first trial and 641 in the second. Excluding women who were ineligible or could not be contacted, participation in screening was 71 per cent in the group which received letters from their general practitioners compared with 62 per cent in the group which did not receive letters (P = 0.059). In the group that received letters, 56 per cent were screened without a reminder compared with 43 per cent of the group that did not receive letters (P = 0.01). Fewer women who received letters from their general practitioners declined the invitation to be screened (P = 0.048). In the second trial, there was no difference in participation between the group receiving telephone reminders and the group receiving postal reminders. As in breast cancer screening programs in other countries, general practitioner endorsement of invitations increased participation in breast cancer screening. Postal reminders were as effective as telephone reminders in encouraging women who did not respond to an initial invitation to participate in screening.

Breast Neoplasms↗

Activation of p56lck by p72syk through physical association and N-terminal tyrosine phosphorylation.

The p56lck and p59fyn protein tyrosine kinases are important signal transmission elements in the activation of mature T lymphocytes by ligands to the T-cell antigen receptor (TCR)/CD3 complex. The lack of either kinase results in deficient early signaling events, and pharmacological agents that block tyrosine phosphorylation prevent T-cell activation altogether. After triggering of the TCR/CD3 complex, both kinases are moderately activated and begin to phosphorylate cellular substrates, but the molecular mechanisms responsible for these changes have remained unclear. We recently found that the p72syk protein tyrosine kinase is physically associated with the TCR/CD3 complex and is rapidly tyrosine phosphorylated and activated by receptor triggering also in T cells lacking p56lck. Here we examine the regulation of p72syk and its interaction with p56lck in transfected COS-1 cells. p72syk was catalytically active and heavily phosphorylated on its putative autophosphorylation site, Tyr-518/519. Mutation of these residues to phenylalanines abolished its activity in vitro and toward cellular substrates in vivo and reduced its tyrosine phosphorylation in intact cells by approximately 90%. Coexpression of lck did not alter the catalytic activity of p72syk, but the expressed p56lck was much more active in the presence of p72syk than when expressed alone. This activation was also seen as increased phosphorylation of cellular proteins. Concomitantly, p56lck was phosphorylated at Tyr-192 in its SH2 domain, and a Phe-192 mutant p56lck was no longer phosphorylated by p72syk. Phosphate was also detected in p56lck at Tyr-192 in lymphoid cells. These findings suggest that p56lck is positively regulated by the p72syk kinase.

Amino Acid Sequence↗

Reduced collateral perfusion is a direct consequence of elevated right atrial pressure.

In the present study we determined quantitatively the effects of increased right atrial pressure (RAP) on coronary and collateral flows. In an isolated, blood-perfused, maximally vasodilated dog heart preparation in which the left ventricle was vented, we used the retrograde flow method to assess collateral flow. When RAP was elevated from 5 +/- 1 (control) to 13 +/- 1 and 23 +/- 1 mmHg, retrograde flow from the left circumflex coronary artery (which was open to atmospheric pressure) increased 29 +/- 8 and 97 +/- 21% relative to control while left anterior descending flow decreased 5 +/- 1 and 14 +/- 2%, respectively (P < 0.01; n = 7). The increase in retrograde flow could be due to 1) an increase in collateral flow due to increased pressure at the origin of the collaterals or 2) the elevated RAP (venous outflow pressure), which forces the antegrade collateral flow component in the retrograde direction. To distinguish between these possibilities we embolized the circumflex with 30-microns spheres to eliminate the antegrade flow component. After embolization there was no significant change in retrograde flow with elevated RAP, indicating that the second supposition was correct. We conclude that increased RAP 1) results in a reduction of flow to the collateral-dependent myocardium and 2) reduces perfusion of the unoccluded coronary vessel. Furthermore, we found that under conditions of varying venous outflow pressure, retrograde flow may not serve as a reliable index of collateral flow.

Animals↗

Membrane properties and synaptic responses of interneurons located near the stratum lacunosum-moleculare/radiatum border of area CA1 in whole-cell recordings from rat hippocampal slices.

1. The membrane properties and synaptic inputs of interneurons, located at the stratum (s.) lacunosum-moleculare and radiatum border (L-M) of the CA1 region, were examined with the use of current-clamp whole-cell recordings in rat hippocampal slices. 2. Biocytin-labeled L-M interneurons had nonpyramidal somata and aspinous, often beaded, dendrites that arborized in s. lacunosum-moleculare and radiatum, sometimes as far as s. moleculare of the dentate gyrus. Their axon coursed and branched in s. lacunosum-moleculare and radiatum. Axon collaterals were also observed traversing the hippocampal fissure and arborizing in s. moleculare of the dentate gyrus and s. radiatum of the CA3 region. 3. Several membrane properties of interneurons were typically nonpyramidal: they had large input resistances, short-duration action potentials followed by prominent fast afterhyperpolarizations, and responded to hyperpolarizing current pulses with little membrane rectification. L-M interneurons showed significant anodal break responses, and their mean membrane time constant was 33 ms. After-depolarizations elicited by subthreshold depolarizing current pulses were larger in amplitude and decayed more slowly at depolarized than hyperpolarized membrane potentials. 4. The majority of L-M interneurons (35 of 49 cells) were silent at resting membrane potentials, whereas other displayed either spontaneous single action potentials (n = 12) or rhythmic bursts (n = 2). The rhythmic bursts were insensitive to the N-methyl-D-aspartate (NMDA) and non-NMDA excitatory amino acid receptor antagonists, 2-amino-5-phosphonopentanoic acid (AP-5; 50 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20 microM), respectively. Both spontaneous single action potentials and burst firing were blocked by membrane hyperpolarization, suggesting that they were intrinsically rather than synaptically generated. 5. L-M interneurons responded with regular sustained firing to depolarizing current pulses at resting membrane potential. However, at more hyperpolarized membrane potentials (near -75 mV), depolarizing current pulses elicited action-potential firing with a delayed onset. This suggests that voltage-sensitive, transient outward currents may be activated in L-M interneurons from hyperpolarized membrane potentials. 6. Electrical stimulation of s. radiatum or lacunosum-moleculare elicited predominantly long-duration excitatory postsynaptic potentials (EPSPs; n = 20 cells), or both EPSPs and inhibitory postsynaptic potentials (IPSPs; n = 17 cells). In most L-M interneurons (35/37), with increasing intensities, up to two action potentials were elicited. Occasionally, larger bursts (3-5 action potentials) were observed (n = 2). 7. The multiphasic components of the synaptic responses became more evident when stimulations were repeated at different membrane potentials.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Measuring pain in pediatric oncology ICU patients.

Thirty patients (ages 5 to 13) hospitalized in a pediatric oncology intensive care unit (ICU) rated the presence and severity of their pain on the Faces Pain Scale (FPS) and the Poker Chip Tool (PCT). Parents independently rated the child's pain on these scales and each patient's nurse completed the Objective Pain Scale (OPS). Patients' ratings on the FPS correlated significantly with parents' ratings on this scale (tau = .48, P = .002) but not on the PCT (tau = .23, P = .16). Nurses' ratings on the OPS were moderately correlated with patients' FPS ratings (tau = .37, P = .02) but were only weakly associated with PCT ratings (tau = .27, P = .09). The majority of patients, parents, and nurses expressed a preference for the FPS over the PCT. The FPS appears to be a clinically useful and accurate approach for measuring the pain of pediatric oncology patients in an ICU but is limited to those who can participate in a self-report measurement.

Adolescent↗

Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group.

PURPOSE: This study was performed to determine the effectiveness of postoperative adjuvant chemotherapy in patients with surgically resected ovarian germ cell tumors. PATIENTS AND METHODS: After tumor removal and thorough surgical staging, patients were enrolled on this study and treated with three courses of cisplatin, etoposide, and bleomycin (BEP). Reassessment laparotomy was required of consenting, appropriate patients initially, but became an optional procedure in 1989. RESULTS: Of 93 patients assessable on this trial, 89 are continuously free of germ cell cancer. At second-look laparotomy, two other patients were found to have small foci of immature teratoma; both remain clinically free of recurrence. One received subsequent alternate chemotherapy and one did not. Thus, 91 of 93 patients are currently free of germ cell cancer. Follow-up duration ranges from 4.0 to 90.3 months, with 67 patients monitored for longer than 2 years. Acute toxicity was moderate. One patient developed acute myelomonocytic leukemia 22 months after diagnosis. Another patient was noted to have a malignant lymphoma 69 months after protocol treatment. CONCLUSION: Three courses of BEP will nearly always prevent recurrence in well-staged patients with completely resected ovarian germ cell tumors and should be given to all such patients. The development of acute leukemia as a complication of treatment is disturbing and mandates careful long-term follow-up, but is unusual and does not alter the risk-to-benefit ratio of treatment.

Adolescent↗

TCR/CD3-triggering causes increased activity of the p50csk tyrosine kinase and engagement of its SH2 domain.

The majority of known protein tyrosine kinases are integral membrane proteins or bound to cellular membranes via a covalently attached myristic acid. An exception is the newly described p50csk tyrosine kinase, which is believed to control the activity of the src-family of protein tyrosine kinases. This small kinase does not contain a myristylation signal or other known membrane attachment motifs, and indeed appears to be cytosolic. Recently, we found that p50csk specifically phosphorylates the negative regulatory Tyr-505 of the T cell-specific src-family kinase p56lck, and thereby suppresses its catalytic activity. Here we show that p50csk is activated in Jurkat T cells within one minute after stimulation of the cells with anti-CD3 MAbs. In parallel with this activation, p50csk formed a stable complex with one major 72 kDa tyrosine phosphorylated protein and minor polypeptides at 90 and 110 kDa. The isolated SH2 domain of p50csk specifically bound the 72 kDa protein in lysates from activated, but not resting, T or B cells. By several criteria, the 72 kDa protein was not a tyrosine kinase itself and it did not react with antibodies to a panel of known proteins of this molecular size. Our results suggest that p50csk is rapidly engaged via its SH2 domain and participates in the earliest events of T cell activation.

CSK Tyrosine-Protein Kinase↗

Patterns of breast and bottle feeding and their association with dental caries in 1- to 4-year-old South African children. 2. A case control study of children with nursing caries.

In a case control study, 109 children with nursing caries (> or = 2 decayed, missing, or filled labial or palatal surfaces of primary incisor teeth) were matched for age, race, gender, and social class to 109 children without nursing caries from the same study areas. Mean dmfs and dmft scores were statistically higher in the nursing caries group but no statistically significant differences were found for feeding patterns between the groups in relation to the prevalence of nursing caries. In the present study nursing caries was found to be unrelated to the length of type of feeding (breast or bottle).

Bottle Feeding↗

Involvement of the primary health care team in coronary heart disease prevention.

BACKGROUND: Recent years have seen a vast increase in the amount of health promotion activity undertaken in general practice. AIM: This study set out to identify the level of general practitioner and nurse involvement in activities aimed at coronary heart disease prevention and to examine variations in involvement. METHOD: A questionnaire survey was undertaken of a sample of general practitioners across England and the nurses who worked in their practices. RESULTS: Of 1696 randomly selected general practitioners 64% completed a questionnaire, of 928 practice nurses 71% responded and of 682 health visitors and 679 district nurses 52% and 40% responded, respectively. Of the general practitioners 94% reported that they were involved in assessing lifestyle risk factors in the routine consultation and regular assessments most commonly involved blood pressure testing and inquiry about smoking status. Eighty six per cent of practices were reported by the practice nurse as having well person clinics; these clinics were usually run by the practice nurse. Clinics for the management of specific lifestyle risk factors were also usually run by practice nurses, although many doctors were involved in hypertension clinics and cholesterol clinics. Health visitors and district nurses had a low level of involvement in this practice based clinic activity. Involvement of general practitioners and practice nurses in coronary heart disease prevention was associated with training in health promotion and positive attitudes towards prevention and health promotion. The level of involvement of practice nurses in health promotion was associated with the support received from primary health care facilitators, family health services authorities and district health authorities. CONCLUSION: Members of the primary health care team appeared to have their own distinct area of preventive activity. However, this division did not appear to be a result of organized teamwork and deployment of skills and expertise according to a clearly defined management protocol. Instead it seemed to be a product of general practitioner contract and management arrangements which tended to encourage an approach to general practice health promotion which revolved around the practice nurse and which hindered the development of a broader team based approach to planning and delivery of health promotion in relation to the needs of the practice population.

Coronary Disease↗

Basal forebrain control of cortical cerebral blood flow is independent of local cortical neurons.

To determine whether intrinsic cortical neurons participate in mediating increases in cortical cerebral blood flow (CBF) in response to electrical stimulation of the basal forebrain (BF), cortical CBF was assessed by laser-Doppler flowmetry in rats before and after unilaterally removing local cortical neurons with the excitotoxin ibotenic acid (IBO). On the first day of testing, CBF responses to right and left BF stimulation were nearly identical in right and left frontal cortices, corresponding to the frequency of stimulation, up to a maximum at 25 Hz (+180%). Subsequently, animals received a unilateral microinjection of IBO and a contralateral microinjection of phosphate-buffered saline (PBS) into the responsive cortical sites. After five days, responses in lesioned cortices were remarkably intact both in comparison to the contralateral PBS-injected site and to the same site tested prior to lesioning on day 1. IBO lesions of the response sites were histologically confirmed to extend through the entire depth of the frontal cortex and to encompass a large surface area (7.7 +/- 0.5 mm2). These results indicate that local cortical neurons are not critical to the mediation of increases in cortical CBF as elicited by BF stimulation. This study further supports the role of the BF as a distinct intracerebral neurogenic regulator of cortical CBF.

Animals↗

Fluoridation.

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Child↗

Cholesterol 7 alpha hydroxylase promoter separated from cyclophilin pseudogene by Alu sequence.

The promoter for human cholesterol 7-alpha hydroxylase has been cloned and sequenced. In the regions previously described, our sequence agrees well with one report but not with another. At position -469, we find a widespread MaeII polymorphism. At -2636, there is an Alu sequence flanked by runs of adenines. Upstream of the Alu sequence, there is a cyclophilin pseudogene oriented in the opposite direction.

Amino Acid Isomerases↗

Molecular mimicry in Lyme disease: monoclonal antibody H9724 to B. burgdorferi flagellin specifically detects chaperonin-HSP60.

A monoclonal antibody (H9724), specific for the 41-kDa flagellar protein of the Lyme disease pathogen Borrelia burgdorferi, cross-reacts with human axons and detects one major protein in human neuroblastoma cell extracts. The homologous cross-reacting protein has now been isolated from calf adrenal and identified as chaperonin-HSP60 by N-terminal sequencing.

Amino Acid Sequence↗

Pacemaker.

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Coronary Disease↗

Age as a prognostic factor in ovarian carcinoma. The Gynecologic Oncology Group experience.

BACKGROUND: The Gynecologic Oncology Group (GOG) has completed six major randomized trials in advanced ovarian carcinoma over the 15-year period between 1976 and 1990. This large database of 2123 patients provides a well-studied patient population with which to examine the importance of age as a prognostic factor. METHODS: The 2123 patients studied in the six GOG trials were analyzed as a group to determine important prognostic factors. Further analyses were then conducted to examine outcome by decade of life from younger than 40 years old to 70 years old and older and to evaluate the interaction of age with other significant prognostic variables. RESULTS: Three major prognostic factors were identified as exerting an influence on patient outcome in the overall patient population: age, volume of residual disease, and performance status. With regard to the effect of age, patients older than 69 years of age exhibited significantly poorer survival than those younger, even after correction for stage, residual disease, and performance status. This was not altered by variations in drugs, doses, and schedules; but there was no evidence that older patients tolerated intensive schedules less well than younger patients. CONCLUSIONS: Two practical conclusions result from this analysis. First, there is no evidence that modification of the drugs and schedules that make up the regimens used can overcome the adverse effect of older age. Second, age does not adversely affect the dose intensity that can be achieved; hence, age in itself is not reason to withhold or attenuate intensive chemotherapy, particularly in light of the fact that older patients have a poorer prognosis.

Adult↗