Search PubMed⌕ Search

Biomedical subjects

P Doyle

Publications and source records attributed to P Doyle.

At least 37 records · Page 2Linked to original sources
PubMed2000

Fetal death and congenital malformation in babies born to nuclear industry employees: report from the nuclear industry family study.

BACKGROUND: There is some concern about the genetic effects of exposure to low-level ionising radiation, but the evidence is sparse and conflicting. Most work has concentrated on cancer in offspring and little has been done on adverse reproductive outcome. We aimed to assess whether the offspring of men and women who are occupationally exposed to ionising radiation are at increased risk of fetal death and congenital malformation. METHODS: We analysed pregnancies reported by an occupational cohort of nuclear industry workers in the UK, employed at establishments operated by the Atomic Energy Authority, Atomic Weapons Establishment, and British Nuclear Fuels. Employment and radiation monitoring data supplied by employers was linked to each pregnancy. FINDINGS: 11,697 men and 1903 women reported one or more singleton pregnancy conceived after first employment within the nuclear industry, the men reporting a total of 23,676 singleton pregnancies and the women 3585. The risks of fetal death and congenital malformation were not related to whether the father had been monitored before conception or to the dose of radiation received. Among pregnancies reported by women, the risk of early (<13 weeks of gestation) miscarriage was higher if the mother had been monitored before conception (odds ratio [OR] 1.3, 95% CI 1.0-1.6), but there was no trend with dose. The risk of stillbirth was also higher if the mother had been monitored before conception (OR 2.2, 95% CI 1.0-4.6), but the finding was based on only 29 cases (13 exposed). The risk of any major malformation, or of specific groups of malformations, was not associated with maternal monitoring, or dose received, before conception. INTERPRETATION: We found no evidence of a link between exposure to low-level ionising radiation before conception and increased risk of adverse reproductive outcome in men working in the nuclear industry. Similarly for women there was no evidence of an association between monitoring before conception and malformation in offspring. The findings relating maternal preconceptual monitoring to increased risk of fetal death are equivocal and require further investigation.

Abnormalities, Radiation-Induced↗
PubMed2000

BRL37344, but not CGP12177, stimulates fuel oxidation by soleus muscle in vitro.

The beta(3)-adrenoceptor agonist, (RR+SS)-(+/-)-4-[2-)2-)3-chlorophenyl)-2-hydroxyethyl)amino)propyl]ph enoxyacetate (BRL37344), stimulated fuel utilisation by isolated mouse soleus muscle at concentrations 10- to 100-fold lower than those required to stimulate lipolysis in brown adipocytes. At 1x10(-10) M BRL37344, uptake and phosphorylation of 2-deoxyglucose was increased (40%), as was glucose-oxidation (50%), palmitate-oxidation (70%) and oxidation of [2-14C]pyruvate (2-fold), indicating stimulation of tricarboxylic acid cycle reactions. Oxidation of [1-14C]pyruvate was unaffected, indicating no stimulation of pyruvate dehydrogenase activity. Other beta(3)-adrenoceptor agonists, disodium(RR)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]- 1,3-benzodioxazole-2,2-dicarboxylate (CL316,243, 1x10(-7) M) and (S)-4-¿2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]ethyl¿pheno xymeth ylcyclohexylphosphiric acid lithium salt (SB226552, 1x10(-9) M), achieved similar stimulation of 2-deoxyglucose uptake and phosphorylation but (+/-)-4-(3-t-butylamino-2-hydroxypropoxy)benzimidazol-2-one (CGP12177A) had no effect. The inhibitor of protein kinase A, H-89 (isoquinolinesulfonamide), had little effect on the stimulation of pyruvate-oxidation by BRL37344, while the specific inhibitor of protein kinase C, bisindolylmaleimide IX, reduced the stimulated rate to slightly below basal values. We consider that these responses provide evidence of the presence of a novel beta-adrenoceptor in skeletal muscle, which we have termed beta(skel)-adrenoceptor.

Adrenergic beta-Agonists↗
PubMed2000

CI-1017, a functionally M1-selective muscarinic agonist: design, synthesis, and preclinical pharmacology.

The five muscarinic receptor subtypes (M1-M5) are characterized by seven helices that define a transmembrane cavity which serves as the binding pocket for agonists and antagonists. The five cavities appear to be topographically different enough to permit subtype selectivity among antagonists but not among classical agonists which tend to be smaller in size than antagonists. It was reasoned that synthesis of muscarinic agonists longer/larger than their classical counterparts might result in subtype selectivity. M1 subtype selectivity was found in a class of 1-azabicyclo[2.2.1]heptan-3-one, O-(3-aryl-2-propynyl) oximes. One of these, CI-1017, improved spatial memory of hippocampally deficient mice and nbM-lesioned rats at doses of 1.0-3.2 and 0.1-0.3 mg/kg, respectively, while producing parasympathetic side effects only at very high doses (100-178 mg/kg). Additionally, CI-1017 inhibited production of amyloidogenic A beta and increased secretion of soluble APP. Thus, CI-1017, besides treating AD symptomatically, may also retard its progression. CI-1017 has recently completed phase I clinical trials.

Animals↗
PubMed2000

Successful autologous bone marrow transplant without the use of blood product support.

We describe a successful autologous bone marrow transplant without the use of any blood products. The patient had relapsed large cell lymphoma. He was a Jehovah's Witness and would not accept transfusions of red blood cells or platelets. He enrolled in our Bloodless Medicine and Surgery Program and was maintained on a regimen of erythropoietin, iron, Amicar, and G-CSF throughout the transplant. He tolerated the transplant well and is alive with no evidence of disease 10 months after autografting.

Adult↗
PubMed2000

Propofol anesthesia for craniotomy: a double-blind comparison of remifentanil, alfentanil, and fentanyl.

For patients undergoing craniotomy, it is desirable to have stable and easily controllable hemodynamics during intense surgical stimulation. However, rapid postoperative recovery is essential to assess neurologic function. Remifentanil, an ultra-short-acting mu-opioid receptor agonist, may be the ideal agent to confer the above characteristics. In this prospective randomized study, we compared the hemodynamic stability, recovery characteristics, and the dose of propofol required for maintaining anesthesia supplemented with an infusion of remifentanil, alfentanil, or fentanyl in 34 patients scheduled for supratentorial craniotomy. With routine monitors in place, anesthesia was induced with propofol (2-3 mg/kg), atracurium (0.5 mg/kg), and either remifentanil (1 microg/kg), alfentanil (10 microg/kg), or fentanyl (2 micro/kg). The lungs were ventilated with O2/air to mild hypocapnia. Anesthesia was maintained with infusions of propofol (50-100 microg/kg/min) and either remifentanil (0.2 microg/kg/min), alfentanil (20 microg/kg/h), or fentanyl (2 microg/kg/h). There were no significant differences among the groups in the dose of propofol maintenance required, heart rate, or mean arterial pressure. However, the time to eye opening (minutes) was significantly shorter in the remifentanil compared to the alfentanil group (6+/-3; 21+/-14; P = 0.0027) but not the fentanyl group (15+/-9). We conclude that remifentanil is an appropriate opioid to use in combination with propofol during anesthesia for supratentorial craniotomy.

Alfentanil↗
PubMed2000

Montgomery Thyroplasty Implant for vocal fold immobility: phonatory outcomes.

Forty-three patients with a diagnosis of unilateral vocal fold immobility underwent thyroplasty type I with the Montgomery Thyroplasty Implant System. Preoperative and postoperative evaluations were completed by means of videostroboscopic, acoustic, and aerodynamic measures. Clinicians' perceptions of vocal quality and patients' satisfaction with the surgery and vocal quality were determined. Improvements after surgery were observed for glottal closure, vocal fold amplitude, mucosal wave activity, average intensity, maximum intensity range, maximum phonation time, glottal airflow, average sound pressure, and subglottal pressure. Average postsurgical fundamental frequency values fell within normal limits and did not display significant changes relative to presurgical values. The clinicians' perceptual evaluations indicated an improvement in voice quality for most patients. A majority of patients expressed satisfaction with the surgery and resulting voice quality. The results of the present study, in combination with the surgical advantages that have been described for the Montgomery Thyroplasty Implant System, support the view that this approach offers an attractive alternative for treating unilateral vocal fold immobility.

Adolescent↗
PubMed1999

Cancer in children of nuclear industry employees: report on children aged under 25 years from nuclear industry family study.

OBJECTIVE: To determine whether children of men and women occupationally exposed to ionising radiation are at increased risk of developing leukaemia or other cancers before their 25th birthday. DESIGN: Cohort study of children of nuclear industry employees. SETTING: Nuclear establishments operated by the Atomic Energy Authority, Atomic Weapons Establishment, and British Nuclear Fuels. SUBJECTS: 39 557 children of male employees and 8883 children of female employees. MAIN OUTCOME MEASURES: Cancer incidence in offspring reported by parents. Employment and radiation monitoring data (including annual external dose) supplied by the nuclear authorities. RESULTS: 111 cancers were reported, of which 28 were leukaemia. The estimated standardised incidence ratios for children of male and female employees who were born in 1965 or later were 98 (95% confidence interval 73 to 129) and 96 (50 to 168) for all malignancies and 109 (61 to 180) and 95 (20 to 277) for leukaemia. The leukaemia rate in children whose fathers had accumulated a preconceptual dose of >/=100 mSv was 5.8 times that in children conceived before their fathers' employment in the nuclear industry (95% confidence interval 1.3 to 24.8) but this was based on only three exposed cases. Two of these cases were included in the west Cumbrian ("Gardner") case-control study. No significant trends were found between increasing dose and leukaemia. CONCLUSIONS: Cancer in young people is rare, and our results are based on small numbers of events. Overall, the findings suggest that the incidence of cancer and leukaemia among children of nuclear industry employees is similar to that in the general population. The possibility that exposure of fathers to relatively high doses of ionising radiation before their child's conception might be related to an increased risk of leukaemia in their offspring could not be disproved, but this result was based on only three cases, two of which have been previously reported. High conceptual doses are rare, and even if the occupational association were causal, the number of leukaemias involved would be small; in this study of over 46 000 children, fewer than three leukaemias could potentially be attributed to such an exposure.

Adolescent↗
PubMed1999

The U.K. Human Fertilisation and Embryology Authority. How it has contributed to the evaluation of assisted reproduction technology.

The Human Fertilisation and Embryology Act of the United Kingdom was passed in 1990, leading to the formation of the Human Fertilisation and Embryology Authority (HFEA), the first statutory body to regulate and control assisted conception anywhere in the world. The principal function of the HFEA is to license and monitor clinics that carry out in vitro fertilization (IVF), donor insemination (DI), and embryo research. Information on over 135,000 treatment cycles, 20,000 pregnancies, and 25,000 babies following IVF has now been collected as part of the regulatory process, and these data have permitted unbiased and accurate evaluation of treatment efficacy using pregnancy and live-birth rates. The treating clinics are required by law to provide information on the outcome of all births, including neonatal mortality and congenital malformations, but there is no systematic validation of these data using medical records or any follow-up of treated women, or babies, over time. In addition, the strict confidentiality of data supplied to the HFEA means that outside researchers have been unable to access the database for research projects. Thus, at the present time, it is not possible to evaluate the long-term safety of assisted conception procedures using HFEA data. There is reasonable scientific evidence to justify full investigation of the health of both treated women and resulting children. Particular health outcomes requiring evaluation include obstetric complications, preterm births, cerebral palsy, and cancer. The HFEA has recognized the need for follow-up studies and is currently investigating ways of enabling research projects using HFEA data to be undertaken.

Congenital Abnormalities↗
PubMed1999

Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats.

Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P<0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 microg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P<0. 01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P<0. 01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P<0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons.

Animals↗
PubMed1999

The effect of reproductive history on future pregnancy outcomes.

The aim of this study was to examine the separate and joint effects of previous pregnancy history, year of pregnancy outcome, maternal age, height, smoking and fertility on risk of fetal death. Data were available from a study of female radiographers. Analyses were carried out on 3053 women with a total of 6993 pregnancies. Women reporting problems with conception or previous fetal losses had an increased risk of a pregnancy ending in a fetal death. In particular, women with primary or secondary infertility had an approximately fourfold increase in risk compared with women who reported no difficulties [odds ratio (OR): 3.92; 95% confidence interval (CI): (3.02, 5.07)]. This relationship was independent of pregnancy order and pregnancy history and was more marked in older maternal ages. The effect of pregnancy history was cumulative and possibly multiplicative in effect, with a threefold increase in the risk of losing a third pregnancy following two previous losses [OR: 3.19; 95% CI: (1.60, 6.35)]. There were no consistent patterns of risk associated with year of pregnancy outcome, maternal age, height or smoking status. These results suggest that previous pregnancy outcomes and problems with conception may be the strongest determinants of fetal loss in subsequent pregnancies.

Adult↗
PubMed1999

Nuclear industry family study:methods and description of a United Kingdom study linking occupational information held by employers to reproduction and child health.

OBJECTIVE: To describe the methods used in the nuclear industry family study for which a comprehensive database has been assembled that links employment in the nuclear industry and dosimetry records to information on employees' reproductive health and the health of their children. To discuss the response rates and characteristics of the study population. METHODS: Occupational cohort design leading to a retrospective cohort study of reproductive outcomes reported by 46 396 current and former employees of both sexes in the nuclear industry. Employees of nuclear establishments in the United Kingdom operated by the Atomic Energy Authority, the Atomic Weapons Establishment, and British Nuclear Fuels were surveyed with postal questionnaires ot collect information on pregnancies, children,and periods of infertility. Information on employment and monitoring for ionising radiation was supplied by the employing nuclear authority and was linked to pregnancies and periods of infertility with unique personal identification numbers. RESULTS: The design and completion of this study resulted in high quality data on a representative population of the Atomic Energy Authority, Atomic Weapons Establishment, and British Nuclear Fuels workforces. The response to the survey was extremely good (82% for male workers and 88% for female workers, excluding undelivered questionnaires), and a unique relational database has been created which will enable infertility, pregnancy, and child health outcomes to be examined with respect to the employment and radiation monitoring characteristics of parents. CONCLUSION: This is the first United Kingdom study to link detailed reproductive history data to occupational information held by employers. The methods developed for the study were found to be feasible and successful. The design can be adapted for other investigations of reproductive hazards to men and women in the workplace and is currently in use to survey over 100 000 armed forces personnel in an investigation of reproductive outcome among veterans of the Gulf war.

Adult↗
PubMed1999

Infectious mononucleosis in an outpatient population: diagnostic utility of 2 automated hematology analyzers and the sensitivity and specificity of Hoagland's criteria in heterophile-positive patients.

OBJECTIVES: To determine the sensitivity and specificity of 2 modern hematology analyzers in flagging heterophile-positive patients; to determine if heterophile-positive, instrument-flagged specimens contain a larger number or a different spectrum of atypical lymphocytes; to document the overall sensitivity and specificity of Hoagland's morphologic criteria in identifying heterophile-positive patients in an outpatient population with a clinical diagnosis of mononucleosis; and to examine whether individual morphologic features might aid in the diagnosis of suspected infectious mononucleosis. DESIGN: A prospective study of patients referred with a clinical diagnosis of infectious mononucleosis who subsequently tested positive for the heterophile antibody. The control group consisted of a similar population of patients who tested negative for the heterophile antibody. INTERVENTION: Hematology profiles of peripheral blood samples were determined with Coulter STKS and Sysmex NE-8000 analyzers. A corresponding Wright-Giemsa-stained blood smear was subsequently examined by a single skilled technologist, who performed a 200-cell white blood cell differential and a 200-cell lymphocyte differential. A specific morphologic search was made for the presence of smudge cells or lymphocytes with cloverleaf nuclei. RESULTS: Using a combination of all flagging criteria, the 2 analyzers identified 156 (86.2%) of 181 heterophile-positive patients as meriting further review. The sensitivity and specificity values of the Coulter analyzer in predicting positive heterophile status for the blast flag were 41% and 97.1%, respectively; for the variant lymphocyte flags, 72.4% and 79.1%, respectively; and for both flags, 40% and 98.1%, respectively. For the Sysmex analyzer, the sensitivity and specificity values in predicting positive heterophile status for the blast flag were 43.4% and 88.6%, respectively; for the variant lymphocyte flag, 15.8% and 90.8%, respectively; and for both flags, 10.5% and 96%, respectively. Considering the classic criteria developed by Hoagland, a lymphocytosis of at least 50% was present in 120 (66.3%) heterophile-positive patients, while an atypical lymphocytosis of at least 10% of the total WBC count was noted in 135 patients (74.6%). The sensitivity and specificity values of a lymphocytosis > or =50% for diagnosing heterophile-positive status were 66.3% and 84.5%, respectively, while the sensitivity and specificity of an atypical lymphocytosis > or =10% were 74.6% and 92.3%, respectively. The presence of smudge cells or cloverleaf lymphocyte nuclei was verified as having high specificity but low sensitivity for suggesting a diagnosis of infectious mononucleosis. CONCLUSION: Although a number of patients did not meet Hoagland's criteria for the diagnosis of infectious mononucleosis, the flagging systems of modern hematology analyzers successfully identified most cases as requiring further review.

Adolescent↗
PubMed1999

Comparable vasorelaxant effects of 17alpha- and 17beta-oestradiol on rat mesenteric resistance arteries: an action independent of the oestrogen receptor.

17beta-Oestradiol (17betaE(2)) has vasorelaxant properties that may contribute to its beneficial cardiovascular effects. The mechanism of vasorelaxation remains controversial, but does not appear to involve interaction of 17betaE(2) with its nuclear receptor. The present study examined the effects on resistance arteries of 17betaE(2) and its isomer, 17alpha-oestradiol (17alphaE(2)), which does not bind to the classical oestrogen receptor. In arteries precontracted with either noradrenaline or KCl, 17betaE(2) and 17alphaE(2) caused comparable relaxation in a concentration-dependent manner over the concentration range 0.1-10 micromol/l, with no significant difference in the maximal effect obtained. Pre-incubation of the arteries with 17betaE(2) or 17alphaE(2) for 15 min reduced the magnitude and duration of the force generated with both noradrenaline and KCl to a comparable degree. Vasorelaxation induced by either 17betaE(2) or 17alphaE(2) was not blocked by an inhibitor of NO synthase or by protein synthesis inhibitors, indicating that vasodilatation is not dependent upon either NO generation or protein synthesis. In the absence of extracellular calcium, both oestradiols still relaxed arteries precontracted with NA, suggesting that they inhibit intracellular calcium release. Both 17betaE(2) and 17alphaE(2) therefore have important and comparable vasorelaxant properties that do not require interaction with the nuclear oestrogen receptor. Direct interactions with the cell membrane or with ion-channel proteins may be responsible.

Analysis of Variance↗
PubMed1998

A novel multi-domain mucin-like glycoprotein of Cryptosporidium parvum mediates invasion.

Cryptosporidium parvum is a protozoan parasite which produces self-limited disease in immunocompetent hosts and devastating, persistent diarrhea in immunocompromised individuals. There is no effective treatment for cryptosporidiosis and little is known about the basic biology of the organism. Cloning and sequence analysis of the gene encoding GP900, a previously identified > 900 kDa glycoprotein, predicts a mucin-like glycoprotein composed of distal cysteine-rich domains separated by polythreonine domains and a large membrane proximal N-glycosylated core region. A trinucleotide repeat composed predominantly of the triplet ACA encodes the threonine domains. GP900 is stored in micronemes prior to appearance on the surface of invasive forms. The concentration of native GP900 which inhibits 50% (IC50) of invasion in vitro is low picomolar; the IC50 for a recombinant cysteine rich-domain is low nanomolar. These observations indicate that GP900 is a parasite ligand for a host receptor involved in attachment/invasion and suggest that immunotherapy or chemotherapy directed against GP900 may be feasible.

Amino Acid Sequence↗