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P Williamson

Publications and source records attributed to P Williamson.

At least 55 records · Page 3Linked to original sources
PubMed1999

Regulation of phosphatidylserine exposure and phagocytosis of apoptotic T lymphocytes.

In lymphocytes, an asymmetric distribution of phospholipids across the plasma membrane is maintained by an ATP-dependent translocase which specifically transports aminophospholipids from the outer to the inner leaflet of the bilayer. During apoptosis, this enzyme is down-regulated and a lipid flipsite, termed the scramblase, is activated. Together, these events lead to the appearance of phosphatidylserine (PS) on the cell surface. In DO11.10 T lymphocyte hybridoma cells undergoing apoptosis, the kinetics of PS externalization are paralleled by the development of PS-sensitive phagocytosis by macrophages. This parallel is also observed when PS externalization is effected directly by application of a Ca2+ ionophore, suggesting that PS externalization is not only necessary, but sufficient, to generate a recognition signal. The broad spectrum aspartate-directed cysteine protease (caspase) inhibitor zVAD-fmk blocks externalization of PS and terminal cell lysis after induction of apoptosis by anti-CD3 antibody, but is ineffective when apoptosis is induced in the same cells by treatment with glucocorticoid. These results suggest that apoptosis induced by glucocorticoid does not require the same zVAD-sensitive caspase steps which are required for Fas/FasL-dependent death induced by anti-CD3 antibody, and that the action of these proteases is also not required for PS externalization. Extracellular Ca2+ is required to complete the later stages of apoptosis in DO11.10 cells, and its removal restores normal transport of PS, suggesting that down-regulation of the aminophospholipid translocase and up-regulation of the scramblase are not effected by irreversible protease cleavage.

Amino Acid Chloromethyl Ketones↗
PubMed1999

CD14 is a component of multiple recognition systems used by macrophages to phagocytose apoptotic lymphocytes.

Expression of the aminophospholipid phosphatidylserine (PS) on the surface of apoptotic lymphocytes and lipid-symmetric erythrocytes triggers their phagocytosis by macrophages. Phagocytosis by both activated and unactivated macrophages, which utilize different recognition systems, can be blocked by certain monoclonal antibodies directed against the LPS receptor, CD14. Here we investigate the requirement for CD14 in the phagocytosis of both apoptotic thymocytes and lipid-symmetric erythrocytes by both activated and unactivated macrophages. We show that phagocytosis of lipid-symmetric erythrocytes by both activated and unactivated macrophages is completely abolished when CD14 is removed from macrophages by cleaving its glycosylphosphatidylinositol tether with phospholipase C. This treatment also substantially reduces phagocytosis of apoptotic lymphocytes by both types of macrophages. Unactivated LR-9 mouse macrophages which are deficient in CD14 expression are completely unable to phagocytose either apoptotic thymocytes or lipid-symmetric erythrocytes. These results argue that CD14 is an absolute requirement for the phagocytosis of lipid-symmetric erythrocytes by both activated and unactivated macrophages, despite their different recognition systems, that CD14 contributes at least substantially to the phagocytosis of apoptotic lymphocytes by both activated and unactivated macrophages, and that activated macrophages may also possess an alternate, CD14-independent mechanism for phagocytosis of apoptotic lymphocytes.

Animals↗
PubMed1999

The treatment of negative symptoms: a clinical and methodological study.

The primary objective of this study was to evaluate the efficacy, safety and tolerability of remoxipride (controlled release) versus haloperidol in patients with negative symptoms. The study comprised a multicentre, randomised, double-blind, parallel-group clinical trial. Two hundred and five patients were randomised to either remoxipride or haloperidol. Patients eligible for this study were aged 18-65 years, met the DSM-III-R diagnosis for chronic schizophrenia and the Positive and Negative Symptoms Scale (PANSS) criteria for predominant negative symptoms. There was a statistically significant reduction in the PANSS scores of at least 20% from baseline to last rating for 39 remoxipride (49.4%) and 45 haloperidol (47.6%) treated patients. There were no statistical differences found between the two treatment groups with respect to improvement of negative symptoms and adverse events. The PANSS data suggest that both remoxipride and haloperidol improve the cluster of negative symptoms concerned with social functioning. In addition, the design of the study provides a methodology that is appropriate to the study of primary negative symptoms in schizophrenia.

Adult↗
PubMed1999

Use of apron flap incision for neck dissection.

Neck dissection is one of the most commonly performed surgical procedures in the management of head and neck cancer. Different skin incisions with various modifications have been described in the literature. Three commonly used but conceptually different incisions were compared with respect to the incidence of wound dehiscence in a retrospective review. There were 166 patients with 184 neck dissections carried out using a triradiate (n = 85), modified MacFee (n = 25), or an apron flap incision (n = 74). The incidence of wound dehiscence in the three groups was 11 percent, 8 percent, and 0 percent for the triradiate, modified MacFee, and apron flap incisions, respectively. There was a statistically significant difference in the incidence of wound dehiscence between the apron flap incision and the triradiate incision groups (p = 0.004). The difference in wound dehiscence was not statistically significant between the apron flap incision and the modified MacFee incision groups (p = 0.06). Overall, there was a significant increase in the incidence of wound dehiscence in previously irradiated necks (p = 0.02), but this was significant only for the triradiate incision (p = 0.005) when analyzed individually. Comparison of triradiate, apron, and MacFee incisions did not show a statistically significant difference between the incisions with regard to other postoperative complications in terms of seroma, hematoma, wound infection, and fistula formation. The apron flap incision is the recommended approach in the presence of previous neck irradiation as it gives easier access than the MacFee incision. The robustness of the flap is because of the absence of a trifurcate point as well as a good vascular supply arising from arterial territory of the external carotid artery.

Female↗
PubMed1999

National Confidential Enquiry into counselling for genetic disorders by non-geneticists: general recommendations and specific standards for improving care.

OBJECTIVES: To assess genetic counselling by non-geneticists and to improve clinical practice. DESIGN: National retrospective review of casenotes. SETTING: Antenatal, paediatric, medical, and surgical units. SAMPLE: 1293 genetic events were identified, involving potentially avoidable cases of Down's syndrome, neural tube defect, cystic fibrosis, beta thalassaemia major and late onset medullary carcinoma of the thyroid (multiple endocrine neoplasia). Notes were available for review in 888 (69%) of these cases. OUTCOMES: Documented counselling, offers of relevant genetic screening and prenatal diagnosis. RESULTS: Clinical audit was frustrated by poor quality hospital records lacking evidence of counselling. Non-geneticist clinicians concentrate on the management of disease, and may overlook the need for counselling and recording data which patients will later need for decisions about reproduction or disease prevention. Counselling, screening and prenatal diagnosis were sometimes impossible because of late booking in pregnancy, or because of delayed diagnosis of an earlier affected child with cystic fibrosis. There are marked regional inequalities of access to genetic services, particularly for minority ethnic groups with increased risks of thalassaemia. Although patients were selected for this enquiry because they had known high risks of genetic disorders, on average less than half were referred to medical geneticists. General recommendations relevant for improvement of care for patients and families with medical genetic needs and those specific for each disorder are given. CONCLUSIONS: Assessment of the quality of genetic care becomes increasingly important as genetic counselling spreads beyond the narrow confines of specialist genetic services. Even though the events studied in this enquiry largely occurred between 1991 and 1995, there is little reason to believe that clinicians in general have become markedly better trained in medical genetics. The General Medical Council and Medical Royal Colleges should urgently consider the need for a national policy for improving undergraduate and postgraduate medical, nursing and midwifery education in genetics. Commissioners of clinical services should require that genetic management be at least as well-documented as surgical operations, drug records and informed consent, perhaps by using a nationally agreed pro-forma for prenatal diagnosis. Regular audit of counselling provided by non-geneticists is necessary to confirm that clinical improvements are occurring and standards are being met. The Confidential Enquiry provides data for a systematic approach to clinical governance of genetics in all specialities. This sets the scene for multi-speciality NHS genetic services capable of giving patients greater consistency both in access and in quality.

Clinical Competence↗
PubMed1999

Development of neutralising human recombinant antibodies to pertussis toxin.

A phage antibody display library of single chain Fv (scFv) was derived from the peripheral blood of two patients recently recovered from pertussis infection. Ten scFv, differentiated by DNA fingerprinting, were isolated by panning the library against pertussis toxin. One scFv (type 1) accounted for 33% of clones after panning. Six of the panned scFv bound to pertussis toxin. The ability of the scFv to neutralise pertussis toxin was assessed using the Chinese hamster ovary cell assay. The predominant scFv (type 1) and two others (types IV and VIII) were able to neutralise the pertussis toxin.

Animals↗
PubMed1999

Hypoglycemia associated with high doses of sertraline and sulphonylurea compound in a noninsulin-dependent diabetes mellitus patient.

Unlike other selective serotonin reuptake inhibitors (SSRIs), sertraline has linear pharmacokinetics so that increases in dose lead to proportional increases in drug concentration. The half-life of sertraline is about 26 h so that it reaches a steady state in one week, according to the product monograph. Hypoglycemia associated with sertraline and coadministration of oral hypoglycemics belonging to the sulphonylurea derivatives has rarely been reported. A patient with schizoaffective disorder with non-insulin-dependent diabetes mellitus (NIDDM) treated with sertraline, risperidone and glyburide who developed hypoglycemia is presented. The article highlights that inhibition of P450 enzymes can be affected by several different factors. Interactions are possible whenever a patient concomitantly receives two drugs that bind to the same P450 system Greater inhibition was likely induced at doses higher than those recommended. This process was reversed within 10 days of discontinuing the sertraline. Good glycemic control followed discontinuation of psychotropic drugs and the oral hypoglycemic agent. Knowledge of the individual P450 enzymes is important in the metabolism of individual drugs, together with an understanding of the patient's drug metabolizing ability. These factors may lead to more appropriate prescribing and further research into specific P450 enzymes responsible for metabolism of particular drugs, which remains unclear.

Adult↗
PubMed1998

Comparing standard care with a physician and pharmacist team approach for uncontrolled hypertension.

OBJECTIVE: To assess the effect of a physician and pharmacist teamwork approach to uncontrolled hypertension in a medical resident teaching clinic, for patients who failed to meet the recommended goals of the fifth Joint National Commission on Detection, Evaluation and Treatment of High Blood Pressure. HYPOTHESIS: Physician and pharmacist teamwork can improve the rate of meeting national blood pressure goals in patients with previously uncontrolled hypertension. DESIGN: A single-blinded randomized controlled trial lasting 6 months. SETTING: A primary care outpatient teaching clinic. PATIENTS: A sample of 95 adult hypertensive patients who failed to meet national blood pressure goals based on three consecutive visits over a 6-month period. INTERVENTION: Patients were randomly assigned to a control arm of standard medical care or to an intervention arm in which a physician and pharmacist worked together as a team. MAIN RESULTS: At study completion, the percentage of patients achieving national goals due to intervention was more than double the percentage in the control arm (55% vs 20%, p < .001). Systolic blood pressure declined 23 mm Hg in the intervention arm versus 11 mm Hg in the control arm (p < .01). Diastolic blood pressure declined 14 and 3 mm Hg in the intervention and control arms, respectively (p < .001). The intervention worked equally as well in men and women and demonstrated noticeable promise in a minority of mixed-ancestry Hawaiians in whom hypertension is of special concern. CONCLUSIONS: Patients who fail to achieve national blood pressure goals under standard outpatient medical care may benefit from a program that includes a physician and pharmacist teamwork approach.

Adult↗
PubMed1998

The estimation of population microdata by using data from small area statistics and samples of anonymised records.

"Traditionally, estimates of the number of people in small areas (the smallest geographical units for which data are available) have been disaggregated only by age and sex. More recently, much research effort has been directed towards developing some form of enhanced small-area population estimation, in which the population in a small area is disaggregated not only by age and sex, but also by a wide range of additional economic and social characteristics. Solutions to this problem currently include account-based demographic models, often used by local authorities."

Age Factors↗
PubMed1998

Multiple members of a third subfamily of P-type ATPases identified by genomic sequences and ESTs.

The Saccharomyces cerevisiae genome contains five P-type ATPases divergent from both of the well-known subfamilies of these membrane ion transporters. This newly recognized third subfamily can be further divided into four classes of genes with nearly equal relatedness to each other. Genes of this new subfamily are also present and expressed in multicellular organisms such as Caenorhabditis elegans and mammals; some, but not all, can be assigned to the classes identified in yeast. Different classes of genes and different genes within a class are expressed differentially in tissues of the mouse. The recently cloned gene for the mammalian aminophospholipid translocase belongs to this new subfamily, suggesting that other subfamily members may transport other lipids or lipid-like molecules from one leaflet of the membrane bilayer to the other.

Adenosine Triphosphatases↗
PubMed1997

Long-term duct-occluded segmental pancreatic autografts: absence of microvascular diabetic complications.

BACKGROUND: Current insulin therapies for control of glucose metabolism in patients with type I diabetes mellitus prevent major metabolic consequences of insulin deficiency, but none prevents or arrests long-term complications. In experimental models of canine diabetes, retinopathy, neuropathy, and nephropathy have been shown to develop within 5 years. The aim of this study was to determine in a canine model whether glucose control provided by segmental duct-occluded pancreas autografts could prevent the long-term complications of diabetes. METHODS: Thirty-five outbred mongrel dogs underwent segmental pancreas autotransplantation with residual pancreatectomy. Follow-up over 5 years included endocrine, retinal fundus photography, fluorescein angiography, and nerve conduction studies. At endpoint, analysis of organ specific changes was undertaken. RESULTS: Long-term survival was achieved in 14 dogs for 4 to 5 years and in 3 dogs for 3 to 5 years. Glycosylated hemoglobin levels remained within normal limits, although response to glucose challenge was suboptimal. Fundus photography and fluorescein angiography demonstrated the absence of retinal vascular aneurisms, capillary leakage, and obliteration. Retinal digest showed no vascular changes and normal endothelial/pericyte ratios. Nerve conduction was normal, and histology of nerves revealed normal density of myelinated fibers and absence of intrafascicular vessels and glycogen deposits, with no change in spectrum of fiber diameters and ovoids. Renal histology revealed no evidence of nephropathy with normal glomerular basement membranes. CONCLUSIONS: We have demonstrated that duct-occluded segmental pancreatic autografts are capable of providing satisfactory metabolic control for up to 5 years, thereby preventing development of the long-term microvascular complications of diabetes.

Animals↗
PubMed1997

The state of maturation of monocytes into macrophages determines the effects of IL-4 and IL-13 on HIV replication.

The molecular mechanisms of the effects of IL-4 and IL-13 on HIV infection in human monocytes as they matured into monocyte-derived macrophages over 7 days were investigated using HIV-1(BaL), and low passage clinical strains. IL-4 and IL-13 up-regulated the expression of both genomic and spliced HIV mRNA in monocytes cultured on Teflon, as determined by Northern analysis and p24 Ag assay. Using a nuclear run-on assay, IL-4 stimulation was shown to enhance transcription by two- to threefold. IL-4 stimulated nuclear factor-kappaB nuclear translocation and binding before enhancement of HIV RNA expression. Conversely, IL-4 and IL-13 markedly and significantly inhibited HIV replication at the transcriptional level in monocyte-derived macrophages, and this occurred whether these cytokines were added before or after HIV infection. The reversal from stimulation to inhibition occurred after 3 to 5 days of adherence to plastic. IL-4 had no significant effect on HIV reverse transcription. The effect of both cytokines on the monocyte maturation/differentiation (CD11b, CD13, and CD26) and other macrophage markers (CD14 and CD68) was examined. IL-4 enhanced CD11b, but inhibited CD26 expression and delayed CD13 loss. IL-13 had similar effects on CD11b and CD13, but no effect on CD26. Hence, these cytokines do not simply enhance monocyte differentiation, but have complex and slightly divergent effects that impact on HIV replication probably through cell signaling pathways and nuclear factor-kappaB translocation.

Cell Differentiation↗
PubMed1997

Assessment of painful episode frequency in sickle-cell disease.

Frequency of painful episodes in sickle-cell disease is considered to be related to clinical severity and possibly to other aspects of the disease. Measurements of frequency often include only hospital-related or more severe, longer-lasting episodes. Since painful episodes, however, may regularly occur in nonhospital settings or be shorter-lasting with possible different pathologic effects, we measured all painful episodes in 10 adults with sickle-cell disease for 1.0-3.8 years, using a daily questionnaire. The results were related to other indices of disease severity and to possible precipitating factors, such as cold weather and menses. Sixty-one percent (on average) of the total number of episodes (243) were nonhospital-related, and 33% (on average) were shorter-lasting. Episode frequencies, whether determined as total, hospital-related, nonhospital-related, or shorter-lasting, were not related to each other or to other indicators of disease severity. The highest incidence of episode frequency occurred in the winter. The association of episodes with menses was moderately close in individual patients. The findings suggest that nonhospital-related painful episodes and shorter-lasting episodes may contribute significantly to episode frequency. Measurement of frequency of all painful episodes would require consideration when evaluating episode frequency and its relationship to disease severity, to possible precipitating factors of episodes, and to treatment of the disease, and for study of the natural course of the disease.

Adult↗
PubMed1997

The physician and pharmacist team. An effective approach to cholesterol reduction.

OBJECTIVE: To assess the effect of a program that encourages teamwork between physicians and pharmacists on attempts to lower total cholesterol levels and to meet recommended goals proposed by the National Cholesterol Education Program (NCEP). DESIGN: A single-blind, randomized, controlled trial lasting 6 months. SETTING: An ambulatory primary care center. PATIENTS: A sample of 94 patients with total cholesterol levels of 240 mg/dL (6.2 mmol/L) or higher. INTERVENTION: Equal numbers of patients were randomly assigned to a control arm in which standard medical care was received and an intervention arm which implemented close interaction between physicians and pharmacists. MEASUREMENTS AND MAIN RESULTS: Absolute change in total cholesterol levels from baseline values and the percentage of patients who achieved an NCEP goal after 6 months of intervention were determined. The rate of success in achieving NCEP goals in the intervention arm was double the rate in the control arm (43% vs 21%, P < .05). Total cholesterol levels in the intervention arm declined 44 +/- 47 mg/dL (1.1 +/- 1.2 mmol/L) versus 13 +/- 51 mg/dL (0.3 +/- 1.3 mmol/L) in the control arm (p < .01). The effect of intervention on reducing total cholesterol levels was similar for men and women and did not appeared to be altered by age. The effect of intervention was greatest in patients with coronary heart disease (p < .01) followed by those without disease but with two or more coronary heart disease risk factors (p < .05). An effect of intervention was absent in patients without coronary heart disease and with fewer than two risk factors. CONCLUSIONS: Attempts to lower total cholesterol levels and achieve NCEP goals are likely to be more successful when combined with programs that include teamwork between physicians and pharmacists. Some programs, however, may be more successful for high-risk patients, for whom it is often easier to provide more aggressive therapies. Although altering adverse lipid profiles in lower-risk patients may be difficult, achieving optimal cholesterol levels could have an important impact on preventing movement to higher risk strata.

Aged↗
PubMed1997

Multiple systems for recognition of apoptotic lymphocytes by macrophages.

In vivo, apoptotic lymphocytes are recognized and phagocytosed by macrophages well before the final stages of DNA degradation and cell lysis. The recognition process is apparently triggered by the exposure of phosphatidylserine (PS) on the cell surface, an event which precedes cell lysis by several hours. However, multiple receptors appear to respond to this event. We demonstrate here that both activated and unactivated macrophages recognize PS, but with different receptor systems. Phagocytosis of apoptotic lymphocytes by activated (but not by unactivated) macrophages is inhibited by pure PS vesicles as well as by N-acetylglucosamine, implicating involvement of a lectin-like receptor in this case. Conversely, uptake of apoptotic lymphocytes by unactivated (but not by activated) macrophages is inhibited by PS on the surface of erythrocytes as well as by the tetrapeptide RGDS and cationic amino acids and sugars, implicating involvement of the vitronectin receptor in this case. Recognition by both classes of macrophages is blocked by the monocyte-specific monoclonal antibody 61D3. The signal recognized by activated macrophages appears to develop on the lymphocyte prior to assembly of the signal recognized by unactivated macrophages. Collectively, these results suggest that PS exposure on the surface of apoptotic lymphocytes generates a complex and evolving signal recognized by different receptor complexes on activated and unactivated macrophages.

Animals↗
PubMed1997

Antecedent circumstances surrounding neural tube defect births in 1990-1991. The Steering Committee of the National Confidential Enquiry into Counselling for Genetic Disorders.

OBJECTIVE: To investigate births with neural tube defects at a time when most districts were screening for the condition. The objective was to document the circumstances surrounding each affected birth and assess the care provided against given standards. DESIGN: Retrospective review of antenatal casenotes by the obstetric team. POPULATION: Three hundred and eight births in England and Wales in 1990 to 1991 were reported to the Office of Population Census Survey (OPCS) to involve neural tube defects. Sufficient information was available to identify both the woman and the obstetrician in 213 pregnancies. Details were obtained from a questionnaire completed by the obstetric team for 168 (79%). In 20/168 cases either the reported outcome was not a live birth/stillbirth or the pregnancy did not involve a neural tube defect: eight resulted in a 'normal' infant, eight were terminated and in four the abnormality was not a neural tube defect. Thus 148 eligible cases were available for analysis. RESULTS: Of the 148 births, the anomaly was not detected prenatally or detected later than 25 weeks of gestation in 98 cases (66%), diagnosed in a multiple pregnancy in 24 (16%) and diagnosed prenatally but the woman chose to continue the pregnancy in 26 (18%). Of the 98 births not detected prenatally or detected late during pregnancy, the surrounding circumstances were that screening was declined in six cases (4%), screening was not offered due to late booking in 30 (20%), serum alpha-fetoprotein screening gave a false negative result in eight (5%), ultrasound screening gave a false negative result in 29 (20%), both screening methods gave false negative results in 17 (11%) and other reasons in eight (5%). The estimated sensitivity of ultrasound screening for anencephaly was 100%. For spina bifida the estimated sensitivity for singleton pregnancies is higher for serum alpha-fetoprotein screening, 84% to 92%, than ultrasound screening, 70% to 84%, for a range of assumptions regarding the degree of under-reporting to OPCS of live births and terminations. CONCLUSIONS: Late booking precluded the offer of screening tests in a substantial proportion (22%) of cases. The presence of multiple fetuses including one or more with a neural tube defect was a serious additional complication in prenatal screening, diagnosis and counselling. Screening for neural tube defects was widespread in 1990 to 1991, although variations in the services provided were documented. Ultrasound scanning was a major component but was associated with a lower sensitivity than maternal serum alpha-fetoprotein screening for neural tube defects other than anencephaly.

Anencephaly↗