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Biomedical subjects

P Williamson

Publications and source records attributed to P Williamson.

At least 73 records · Page 4Linked to original sources

Confidential inquiry into families with two siblings with cystic fibrosis.

OBJECTIVE: To audit the care that had been provided to couples before the birth of a child with cystic fibrosis where a sibling had been previously diagnosed. DESIGN: Retrospective review of case notes. SAMPLE: Families where at least one affected child had been born between 1 January 1991 and 30 June 1995 and the diagnosis in the first child was made before the second affected pregnancy reached 20 weeks. The combination of information on these families with data from the prenatal diagnosis register allowed the reconstruction of a cohort of pregnancies in women with a previous affected child. MAIN RESULTS: Forty six eligible families with a second affected child were identified. Details from the paediatrician who had diagnosed the first affected child were obtained in 43 cases: all 43 couples were offered genetic counselling, but where provided by a paediatrician this was difficult to assess as no couple was sent a summary letter. Details were obtained from the obstetrician in the subsequent affected pregnancy in 42 cases: prenatal diagnosis was not offered in 10 (24%), offered and declined in 24 (57%), offered and accepted but termination declined in eight (19%). In the overall cohort of at risk pregnancies, the estimated rate of prenatal diagnosis offer was 97%, prenatal diagnosis uptake 86%, false negative prenatal diagnosis rate 0%, and uptake of termination 95%. CONCLUSIONS: (1) Parental choice was an important determinant of second affected births. (2) Despite widespread availability, prenatal diagnosis was not offered in an estimated 3% of at risk pregnancies. (3) There were shortcomings in counselling documentation, in particular failure to send a summary letter to counselled couples.

Abortion, Legal↗

Randomised controlled double blind study of role of recombinant erythropoietin in the prevention of chronic lung disease.

AIM: To evaluate the role of recombinant human erythropoietin (R-HuEpo) in reducing iron infusion, which may exacerbate free radical damage, leading to chronic lung disease. METHODS: A multicentre, randomised, placebo controlled, double blind study was carried out in four neonatal intensive care units in Yorkshire. Infants were randomly allocated and received either R-HuEpo (480 U/kg/wk) or placebo by twice weekly subcutaneous injection. The primary outcome measure was the number of days on respiratory support and a secondary outcome the number of blood transfusions required. RESULTS: Forty two very low birthweight (VLBW) infants were randomly allocated. There was little difference in the need for respiratory support one month after randomisation, but subsequently there was a trend towards a reduction in the proportion requiring respiratory support in the R-HuEpo group (difference at three months -0.50, 95% confidence interval -1.00, 0.17). During stay in hospital, the median number of blood transfusions was lower for infants in the R-HuEpo group (difference in medians -2, 95% CI -4, 0). The study was stopped early because of failure to recruit babies at the expected rate. CONCLUSIONS: R-HuEpo seems to reduce the number of days in oxygen for ill VLBW infants. These data could be used to construct a larger multicentre study to evaluate this effect further.

Blood Transfusion↗

The uptake and acceptability to patients of cystic fibrosis carrier testing offered in pregnancy by the GP.

OBJECTIVE: To determine the uptake and acceptability of cystic fibrosis (CF) carrier testing when offered to women at the first antenatal booking appointment by their general practitioner. SETTING: Eight-general practices in the north west region with a combined patient list size of 42000. DESIGN: Offer of carrier screening at first antenatal booking appointment to pregnant women below 14 weeks' gestation; women accepting were alternately allocated to either couple testing (with full disclosure) or stepwise testing: SUBJECTS: Six hundred and twenty three women were offered CF carrier testing. MAIN OUTCOME MEASURES: (1) Acceptance of the offer of CF carrier testing. (2) Acceptability of the test to women following screening, evaluated through (i) postal questionnaire, (ii) semistructured interview. RESULTS: Five hundred and twenty-nine (84.9%) women accepted the test; the level of uptake varied across the eight practices (range 11-99%). In 26/249 (10%) couple tests no paternal sample was provided. When asked what had influenced their decision to be tested, 59/377 (16%) women did not refer to CF in their answers and six (2%) said that they did not feel they could refuse the test. After receiving their results, 368/379 (97%) women felt that they had made the right decision to be tested, but two carriers and three non-carriers had felt unhappy about testing. Couple testing with full disclosure was associated with lower anxiety levels two weeks after receiving the result for the pregnancy than stepwise testing and 82/278 (29%) non-carriers believed that they had no residual risk in relation to CF. CONCLUSIONS: The response from women accepting CF carrier testing was largely positive but a minority of women expressed concern about the test and the way it was offered and a substantial proportion of women were falsely reassured by their "negative" result. Higher levels of acceptance tended to occur in the practices which offered the test there and then rather than giving couples more time to decide about testing. Some women appeared to have accepted the test because of a belief in the importance of testing in pregnancy rather than because of the disease in question.

Adolescent↗

Evidence for a prolonged postimplantation period in the Australian sea lion (Neophoca cinerea).

Concentrations of circulating progesterone and oestradiol were measured in 96 free-ranging, female Australian sea lions Neophoca cinerea from Kangaroo Island, South Australia. There was a marked increase in the concentrations of both hormones (progesterone from approximately 12 ng ml-1 to approximately 24 ng ml-1; oestradiol from approximately 1.5 pg ml-1 to approximately 14 pg ml-1) about 3.5 months after the probable date of mating, reaching peak values in the 5 months after parturition. Progesterone concentrations remained at peak concentrations for about 2 months, decreasing at approximately 8 months to concentrations approximating those of the first 3 months after parturition. Oestradiol concentrations decreased, after reaching a peak, to 3-4 pg ml-1 at about 8 months after parturition. The timing of the increase in the concentrations of circulating progesterone and oestradiol provides evidence that the blastocyst reactivates and implants between 3.5 and 5 months of pregnancy in Australian sea lions, indicating an embryonic diapause of similar duration to that of other pinnipeds. This would suggest a prolonged postimplantation period of up to 14 months (to fit with the gestation period of 18 months reported for this species) the longest postimplantation period recorded for pregnancy in any pinniped.

Animals↗

Reconstitution of phospholipid scramblase activity from human blood platelets.

Cellular activation, accompanied by elevation of cytoplasmic Ca2+ levels, can induce a progressive loss of plasma membrane phospholipid asymmetry, resulting from increased transbilayer movement (flip-flop) of phospholipids. While this process has been demonstrated in a variety of different cells, it is most active in blood platelets. In order to test whether this lipid scrambling process is mediated by a membrane protein, platelet membranes were solubilized in cholate and fractionated by anion exchange chromatography, and fractions were reconstituted into phospholipid vesicles by detergent dialysis in the presence of small amounts of fluorescent (NBD) phospholipids. Using dithionite reduction to monitor the transbilayer location of NBD phospholipids, it was shown that addition of Ca2+ and ionomycin to vesicles reconstituted with a particular fraction results in transbilayer movement of the fluorescent phospholipid analogs from the vesicle's inner to outer leaflet. Lipid vesicles reconstituted in the absence of membrane protein, or reconstituted with another platelet membrane protein fraction, were devoid of this activity. Heating the active fraction or incubating it with pronase or the SH reagent pyridyldithioethylamine markedly diminished the ability of the vesicles to translocate fluorescent phospholipid analogs across the bilayer in response to Ca2+ and ionophore. These results argue that a membrane protein (or proteins) from blood platelets is required to catalyze Ca2+-induced transbilayer movement of phospholipids, suggesting its (or their) involvement in the loss of lipid asymmetry that can occur during cellular activation.

4-Chloro-7-nitrobenzofurazan↗

A subfamily of P-type ATPases with aminophospholipid transporting activity.

The appearance of phosphatidylserine on the surface of animal cells triggers phagocytosis and blood coagulation. Normally, phosphatidylserine is confined to the inner leaflet of the plasma membrane by an aminophospholipid translocase, which has now been cloned and sequenced. The bovine enzyme is a member of a previously unrecognized subfamily of P-type adenosine triphosphatases (ATPases) that may have diverged from the primordial enzyme before the separation of the known families of ion-translocating ATPases. Studies in Saccharomyces cerevisiae suggest that aminophospholipid translocation is a general function of members of this family.

Adenosine Triphosphatases↗

Mechanisms for recognition and phagocytosis of apoptotic lymphocytes by macrophages.

Erythrocytes have an asymmetric distribution of phospholipids across the bilayer of their plasma membranes, maintained by an ATP-dependent aminophospholipid translocase, and dissipated by activation of a non-specific lipid flipsite. Loss of asymmetry provokes recognition by the reticuloendothelial system. In vitro, enhanced phagocytosis of erythrocytes with a symmetric bilayer can be inhibited by artificial lipid vesicles made of phosphatidylserine (PS), indicating that macrophages recognize the PS that appears on the erythrocyte surface upon loss of asymmetry. It is becoming increasingly clear that these same fundamental membrane structure/function relationships established in the erythrocyte paradigm also apply to lymphocytes. All evidence suggests that lymphocytes maintain an asymmetric transbilayer distribution of phospholipids in their plasma membranes, maintained by an aminophospholipid translocase. Asymmetry is lost as part of the program of cell death, by down-regulation of the translocase and activation of the non-specific lipid flipsite, exposing PS on the cell surface. That PS exposure has functional consequences is demonstrated by the ability of artificial lipid vesicles containing PS to inhibit enhanced phagocytosis of apoptotic lymphocytes by macrophages. However, other signals besides PS are also involved in recognition of apoptotic lymphocytes. Studies with other inhibitors indicate that macrophages also utilize integrin-mediated and lectin-like recognition systems, although each is restricted to either unactivated or activated macrophages. These results indicate that although many fundamental features of recognition by the reticuloendothelial system may be analogous in erythrocytes and lymphocytes, the signals for recognition of apoptotic lymphocytes ae more complex and involve multiple recognition systems.

Animals↗

Measuring diabetes-related attitudes: the use of a USA-developed instrument with Australian nurses.

The revised Diabetes Attitudes Scale (DAS) was completed by nearly 1000 nurses and nursing students in South Australia. Confirmatory factor analysis was used to compare the factor structure with that previously obtained in the USA with patients with diabetes. The instrument was found to be robust. It was concluded that only one item of the 50-item scale is unsuitable for inclusion in studies which aim to compare patient and health professional attitudes.

Attitude of Health Personnel↗

Epitope mapping the Fim2 and Fim3 proteins of Bordetella pertussis with sera from patients infected with or vaccinated against whooping cough.

Antibody-binding epitopes on the Fim2 and Fim3 proteins of Bordetella pertussis, which have been associated with the induction of protective antibody, were located using sera from 12 patients with whooping cough and 4 vaccinated children. Fifteen epitopes were identified on both Fim2 and Fim3. In each case 9 were recognised by serum antibody from 11 or more infected patients. Epitopes associated with the highest IgG activity were not the same as those associated with the highest IgA activity. None of the vaccinated patients had detectable IgA. Most epitopes showed little or no evidence of serotype-specific responses, suggesting this is largely directed towards conformational epitopes. The reactivity of all but two epitopes was confirmed in an ELISA with patients' sera in which epitopes were re-synthesised as free soluble peptides. The short linear epitopes described may therefore be useful in the development of serodiagnostic assays but are unlikely vaccine candidates.

Amino Acid Sequence↗

Aberrant interhemispheric alpha coherence on electroencephalography in schizophrenic patients during activation tasks.

Thirty schizophrenic patients (20 medicated, 10 off medication) were compared with 30 normal controls subjects matched for age, sex, handedness and intelligence. During the performance of a frontal activation task, normal subjects showed increased interhemispheric coherence between anterior brain regions. Schizophrenic patients did not show the same amount of bilateral anterior activation. During the performance of right hemisphere cognitive activation tasks, normal subjects and medicated schizophrenic patients showed significantly reduced bilateral interhemispheric coherence patterns, while the drug-free schizophrenic patients showed a trend towards this same pattern. It is suggested that these findings provide additional evidence for an aberrant functional organization of the brain in schizophrenia.

Adult↗

Middle ear barotrauma in patients undergoing hyperbaric oxygen therapy.

Hyperbaric oxygen therapy is associated with a risk of barotrauma to the middle ear. This prospective study of 82 patients undergoing long-term therapy for chronic conditions was designed to measure the incidence and severity of middle ear barotrauma. Twenty-four patients (29.3%) required the insertion of ventilation tubes for otalgia, significantly more of whom were suffering from radionecrosis of the head and neck region (P < 0.01). Thirty-two of the remaining 58 patients (55%) underwent specialist ENT assessment by otoscopy and tympanometry. Five ears (8%) showed the otoscopic changes of barotrauma (TEED grade 3 or 4), and one ear (2%) showed tympanometric evidence of a middle ear effusion (Type B tympanogram). We conclude that despite careful tuition in pressure equalization and the appropriate use of ventilation tubes, up to 8% of ears sustain significant barotrauma. Tympanometry is unreliable in detecting these changes, otoscopy provides the most reliable screening technique.

Aged↗

The Yorkshire slide exchange external quality assessment (EQA) scheme.

A slide circulation scheme measuring cervical screening performance of individual cytologists in 15 laboratories in Yorkshire Regional Health Authority is described. The advantages and disadvantages are compared with the current National Proficiency Testing (NPT) scheme. The results indicate that a slide circulation scheme can be successfully used in cervical cytology external quality assessment (EQA). Levels of participation are better than those currently achieved by regional variations of the NPT scheme, and the use of laboratory consensus in the selection of scoring slides appears to be no less valid than the use of a pre-selected slide pool assembled by an expert panel. The volume of data accumulated in one round is considerably greater than that achieved by proficiency testing and the educational value is regarded as high. However, the scheme is very time consuming for participants and consequently expensive for laboratories. The lack of external supervision increases the risk of unfair practices within individual laboratories. Because of these problems, Yorkshire has now switched to an NPT scheme.

Cytodiagnosis↗

Prenatal genetic services for Down's syndrome: access and provision in 1990-1991. Steering Committee of the National Confidential Enquiry into Counselling for Genetic Disorders.

OBJECTIVE: To examine access to and provision of prenatal genetic services relating to Down's syndrome. DESIGN: Retrospective review of obstetric casenotes. SAMPLE: Pregnancies involving Down's syndrome in England and Wales in 1990-1991 in women aged 38 or over. Information was obtained in 430 cases from a questionnaire completed by the obstetric team who were asked to provide details based only on documentation in the antenatal casenotes. The outcome of pregnancy was a termination in 268 (62%) cases, a liveborn child with Down's syndrome in 144 (34%), a stillbirth in 9 (2%), a miscarriage in 8(2%) and in one case was not known. RESULTS: Overall, prenatal diagnosis was not offered in 7% pregnancies (95% CI: 4.4-9.2%) with late booking given as the main reason. Of women offered prenatal diagnosis, 76% accepted (95% CI: 72.3-80.6%). Counselling was documented before prenatal diagnosis in 89% of cases (95% CI: 86.0-92.3%) and after the procedure, to discuss the results, in 73% (95% CI: 67.5-77.7%). In 10% of pregnancies terminated for Down's syndrome, fetal products were not sent to the laboratory. There was no report of a normal fetus having been terminated as a consequences of incorrect prenatal diagnosis. However, in 10% (95% CI: 5.9 to 14.0%) of cases examined in the laboratory the diagnosis of Down's syndrome could not be confirmed. Details of prenatal diagnosis were not provided in five cases where a child with Down's syndrome was born. Of the remaining 139 livebirths, prenatal diagnosis was not offered in 27 (19%) cases, offered and declined in 92 (66%) and accepted in 20 (14%). In two cases a normal fetal karyotype was reported following prenatal diagnosis. CONCLUSIONS: The study has demonstrated that in 1990-1991: 1. There were certain shortcomings in the documentation of antenatal care; 2. Late booking was the main factor precluding the offer of prenatal diagnosis to women aged 38 or over, and 3. The rate of confirmation of Down's syndrome in terminated fetuses was incomplete.

Abortion, Induced↗

Sensitive and universal method for microbial DNA extraction from blood products.

A new method of extracting bacterial and yeast DNA from blood products dependent on guanidinium thiocyanate acid extraction and proteinase K treatment is described. In spiked samples the sensitivity per 0.1 ml of serum and blood, respectively, was 26 and 150 colony forming units (cfu) for Escherichia coli, 80 and 120 cfu for Staphylococcus aureus and 20 and 26 cfu for Candida albicans. This compared well with existing methodologies, worked on limited clinical samples and was not pathogen specific.

Blood↗

Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes.

The appearance of phosphatidylserine (PS) on the cell surface during apoptosis in thymocytes and cytotoxic T lymphocyte cell lines provokes PS-dependent recognition by activated macrophages. Flow cytometric analysis of transbilayer lipid movements in T lymphocytes undergoing apoptosis reveals that downregulation of the adenosine triphosphate-dependent amino-phospholipid translocase and activation of a nonspecific lipid scramblase are responsible for PS reaching the surface from its intracellular location. Both mechanisms are expressed at the same time, and precede DNA degradation, zeiosis, and cell lysis in the apoptotic pathway.

Animals↗

The complex of phosphatidylinositol 4,5-bisphosphate and calcium ions is not responsible for Ca2+-induced loss of phospholipid asymmetry in the human erythrocyte: a study in Scott syndrome, a disorder of calcium-induced phospholipid scrambling.

Elevation of cytoplasmic Ca2+ levels in human erythrocytes induces a progressive loss of membrane phospholipid asymmetry, a process that is impaired in erythrocytes from a patient with Scott syndrome. We show here that porcine erythrocytes are similarly incapable of Ca2+-induced redistribution of membrane phospholipids. Because a complex of phosphatidylinositol 4,5-bisphosphate (PIP2) and Ca2+ has been proposed as the mediator of enhanced transbilayer movement of lipids (J Biol Chem 269:6347,1994), these cell systems offer a unique opportunity for testing this mechanism. Analysis of both total PIP2 content and the metabolic-resistant pool of PIP2 that remains after incubation with Ca2+ ionophore showed no appreciable differences between normal and Scott erythrocytes. Moreover, porcine erythrocytes were found to have slightly higher levels of both total and metabolic-resistant PIP2 in comparison with normal human erythrocytes. Although loading of normal erythrocytes with exogenously added PIP2 gave rise to a Ca2+-induced increase in prothrombinase activity and apparent transbilayer movement of nitrobenzoxadiazolyl (NBD)-phospholipids, these PIP2-loaded cells were also found to undergo progressive Ca2+-dependent cell lysis, which seriously hampers interpretation of these data. Moreover, loading Scott cells with PIP2 did not abolish their impaired lipid scrambling, even in the presence of a Ca2+-ionophore. Finally, artificial lipid vesicles containing no PIP2 or 1 mole percent of PIP2 were indistinguishable with respect to transbilayer movement of NBD-phosphatidylcholine in the presence of Ca2+. Our findings suggest that Ca2+-induced redistribution of membrane phospholipids cannot simply be attributed to the steady-state concentration of PIP2, and imply that such lipid movement is regulated by other cellular processes.

4-Chloro-7-nitrobenzofurazan↗