Frequency distribution of the Q188R mutation in the Irish galactosaemic population.
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Base Sequence↗
Biomedical subjects
C O'Neill
Publications and source records attributed to C O'Neill.
cis-Diamminedichloroplatinum(II)-induced cell death through apoptosis in sensitive and resistant human ovarian carcinoma cell lines.
We have studied the effects of the chemotherapeutic drug cis-diamminedichloroplatinum(II) (cis-platin) on three human ovarian carcinoma cell lines - one sensitive to the drug (CH1), one with acquired resistance (CH1cisR) and one with intrinsic resistance (SKOV-3). Previous work has shown that the 50% inhibitory concentrations (IC50 values) after a 2-h exposure to the drug are: CH1, 2.5 microM; CH1cisR, 7.5 microM; and SKOV-3, 33 microM. Despite the variation in sensitivity, the amount of Pt bound to DNA and the rate of removal of Pt was similar for the three lines. There were significant differences in the rates of formation of DNA cross-links but these were not large enough to account for the high resistance of the SKOV-3 line. We have reported that in the L1210 murine leukaemia cell line there are two mechanisms of cisplatin-induced cell death - one of which involves apoptosis. In this paper, we report on an investigation into whether sensitivity to apoptosis played a role in the resistance of these ovarian lines toward cisplatin. After a 2-h incubation with the drug, cells from the three lines showed evidence of death through apoptosis. The cells detached from the culture dish in a time- and dose-dependent fashion. These cells morphologically were quite distinctive from the attached cells and showed changes in their chromatin structure indicative of apoptosis. Their DNA had not been degraded into oligonucleosomal fragments (200 bp and multiples thereof) but had been cut into larger fragments (30 kilobase pairs, kbp) of a size associated with chromatin domains (chromatin loops). At equitoxic doses of drug, the quantity of cells undergoing apoptosis was similar for the three cell lines. The most prominent effect on cell-cycle kinetics was a slowdown in S-phase transit during which the cells underwent apoptosis. Cells that successfully completed the S phase subsequently suffered a temporary G2 block. We propose that the sensitivity of these cell lines to cisplatin was governed by their ability to handle damage caused by platination of the DNA and that the major mechanism of cisplatin-induced cell death in all three cell lines was the induction of apoptosis.
Antineoplastic Agents↗
Oxidative stress and apoptosis in neurodegeneration.
The pathogenesis of neurodegenerative diseases such as Parkinson's diseases, amyotrophic lateral sclerosis and Alzheimer's disease is unknown. These diseases are characterized by a slow, progressive loss of particular subsets of neurons. Much evidence has accumulated which supports the hypothesis that oxidative stress and damage by free radicals may play an important part in these diseases. In particular recent studies with the inherited form of amyotrophic lateral sclerosis have revealed mutations in the superoxide dismutase gene, which is one of the cell's main defence mechanisms against oxidative stress. These findings suggest a direct link between oxidative stress and the development of a neurodegenerative disease.
Apoptosis↗
Ovine endometrium synthesizes and releases platelet-activating factor, which can cause the release of prostaglandin F2 alpha by the uterus in situ.
Explanted endometrial tissue from ovariectomized ewes that had received hormone replacement to mimic the luteal phase released platelet-activating factor (PAF) into medium in vitro. On Day 14, 310.1 (261-2185), and on Day 15, 424.4 (14.1-590.7) pg PAF (median 25th-75th percentile; p > 0.05) was released per 100 mg endometrial tissue after a 20-min incubation. A regulatory and final enzyme in the PAF biosynthetic pathway, lysoPAF:acetyltransferase, was also present with a specific activity of 0.533 +/- 0.124 pmol acetate/50 micrograms protein/30 min in Day 14 endometrial tissue and 0.810 +/- 0.468 in Day 15 tissue (mean +/- SEM; p > 0.05). PAF:acetylhydrolase, the metabolic enzyme regulating PAF's half-life, was present in uterine luminal washings, with a specific activity of 3.78 +/- 1.37 nmol acetate released/min/mg protein on Day 14 and 3.41 +/- 0.34 on Day 15 (mean +/- SEM; p > 0.05). Intrauterine infusion of 50-400 micrograms PAF caused a dose-dependent release of prostaglandin (PG) F2 alpha (measured as venous 14-dihydro-15-keto-prostaglandin F2 alpha, PGFM) within 10 min on Days 13-15. The enantiomeric form of PAF was significantly less effective in inducing a rise in venous PGFM. WEB 2086 is reported to be a competitive receptor antagonist for PAF, but a 10-fold excess of WEB 2086 failed to inhibit PAF-induced release of PGFM. It was observed that this dose of WEB alone induced PGFM release, suggesting that in this model this agent may not work as a true competitive antagonist. Repeat challenges at intervals of 0, 90, and 120 min with either 200 micrograms PAF or micrograms oxytocin resulted in a marked tachyphylaxis of response by the third challenge. This desensitization after repeated PAF challenge suggests a specificity of its actions. Infusion of 200 micrograms PAF on Day 14 or 15 at five 60-min intervals resulted in a tachyphylaxis such that by the fourth and fifth challenges, essentially no response was observed. The tachyphylaxis that was induced by four repeat challenges with PAF had no apparent effect on the capacity of the uterus to respond to a fifth challenge with oxytocin. Thus, PAF and oxytocin both caused homologous desensitization of their own capacity to mobilize uterine PGF2 alpha, but PAF did not cause heterologous desensitization of the response to oxytocin. This failure of heterologous desensitization suggests differences in the mechanism of action of the two ligands. Kinetic binding studies showed that PAF did not compete for the oxytocin receptor in vitro. This result demonstrated that the ovine endometrium produces PAF and responds to it by the release of PGF2 alpha in situ. The dynamics of the response elicited by PAF were similar to those of oxytocin, yet the two mediators apparently act separately. PAF may be a modulator of PGF2 alpha release by the ovine uterus during the luteal phase.
1-Alkyl-2-acetylglycerophosphocholine Esterase↗
Neurotransmitters, signal transduction and second-messengers in Alzheimer's disease.
It has long been assumed that widespread changes in postsynaptic neurotransmitter receptor function are not a feature of the disrupted neurotransmission seen in the brains with Alzheimer's disease (AD). However, recent evidence from postmortem brain and fibroblast studies suggests that both the neurotransmitter receptor/G-protein-modulated adenylyl cyclase and the phosphatidylinositol hydrolysis signal transduction cascades are disrupted in AD. Such disruptions may severely limit the functional integrity of key receptor types and undermine pharmacological attempts to ameliorate disease symptomatology through neurotransmitter replacement strategies. The involvement of some signalling mechanisms in the regulation of beta-amyloid precursor protein metabolism suggests also that disrupted signal transduction may exacerbate AD pathology.
Alzheimer Disease↗
A comparison of three measures of perceived distress: results from a study of angina patients in general practice in Northern Ireland.
OBJECTIVE: To establish the effect of health education on the level of distress felt by patients with angina and to compare the results obtained using different measures. DESIGN: Randomised controlled trial of personal health education given every four months. SETTING: Eighteen general practices in the greater Belfast area. SUBJECTS: These comprised 688 patients aged less than 75 years and known to have had angina for at least six months: 342 were randomised to receive education and 346 no education. MAIN OUTCOME MEASURES: These were the Nottingham health profile (NHP), functional limitation profile (FLP), and a simple categorical scale (SCS). RESULTS: The intervention group showed a statistically significant improvement in health relative to the control group in terms of physical mobility and social isolation using the NHP. In terms of overall wellbeing, both the NHP and SCS results showed the intervention group had experienced statistically significant improvements in health relative to the control group. Results obtained using the NHP, FLP, and SCS were found to be correlated regardless of whether weighted or unweighted scores were used. CONCLUSION: The intervention produced a significant improvement in health status. Results from different survey instruments were correlated using both weighted and unweighted scores. An SCS was capable of detecting the improvement in health status.
Aged↗
Cost effectiveness of personal health education in primary care for people with angina in the greater Belfast area of Northern Ireland.
STUDY OBJECTIVE: To investigate the cost effectiveness of personal health education for angina patients being treated in general practice. DESIGN: A randomised controlled trial in which people were randomised to intervention and control groups. All were assessed at the start and end of the study, with details recorded of disease status, coronary heart disease risk factors, and self assessed quality of life. A note was taken of their current use of drugs and over the course of the study their use of all health services. Those in the intervention group had three visits per year from a health visitor, whose brief was discuss ways of living more easily with their disease and in which risks of further events might be reduced. PATIENTS: Altogether 688 patents in the Greater Belfast area aged less than 75 years and known to have angina for at least six months. MAIN RESULTS: Significant improvements in survival and self assessed quality of life were found between the study and control groups. The intervention was associated with a reduction in drug usage and there was no significant difference between the intervention and control groups in terms of their use of other health services. CONCLUSION: Given the improvement in survival and self assessed quality of life and no significant differences in costs to the health service between the two groups, the intervention was deemed to be cost effective.
Angina Pectoris↗
PAF promotes the development of the preimplantation embryo.
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Animals↗
Strategies for reducing coronary risk factors in primary care: which is most cost effective?
OBJECTIVE: To examine the relative cost effectiveness of a range of screening and intervention strategies for preventing coronary heart disease in primary care. SUBJECTS: 7840 patients aged 35-64 years who were participants in a trial of modifying coronary heart disease risk factors in primary care. DESIGN: Effectiveness of interventions assumed and the potential years of life gained estimated from a risk equation calculated from Framingham study data. MAIN OUTCOME MEASURE: The cost per year of life gained. RESULTS: The most cost effective strategy was minimal screening of blood pressure and personal history of vascular disease, which cost 310 pounds-930 pounds per year of life gained for men and 1100 pounds-3460 pounds for women excluding treatment of raised blood pressure. The extra cost per life year gained by adding smoking history to the screening was 400 pounds-6300 pounds in men. All strategies were more cost effective in men than in women and more cost effective in older age groups. Lipid lowering drugs accounted for at least 70% of the estimated costs of all strategies. Cost effectiveness was greatest when drug treatment was limited to those with cholesterol concentrations above 9.5 mmol/l. CONCLUSIONS: Universal screening and intervention strategies are an inefficient approach to reducing the coronary heart disease burden. A basic strategy for screening and intervention, targeted at older men with raised blood pressure and limiting the use of cholesterol lowering drugs to those with very high cholesterol concentrations would be most cost effective.
Adult↗
A phase I and pharmacology study of an oral platinum complex, JM216: dose-dependent pharmacokinetics with single-dose administration.
JM216 [bis-acetato-ammine-dichloro-cyclo-hexylamine-platinum (IV)] is an oral platinum complex with in vivo activity against murine and human tumor models and a lack of nephro- and neurotoxicity in rodents. During a phase I study of a single-dose schedule, JM216 was given in dry-filled hard gelatin capsules by mouth without hydration or diuresis. In all, 37 patients were given a total of 88 courses at doses ranging from 60 to 700 mg/m2. The study was stopped before the MTD was reached because of nonlinear pharmacokinetics. Myelosuppression was manifest by leucopenia or thrombocytopenia and showed marked variability at 420-700 mg/m2. Vomiting was mild and controllable by antiemetics in approximately 50% of courses. The onset of vomiting was delayed to 4 h after during ingestion. There was no nephro-, oto- or neuro-toxicity. A partial response was recorded in a patient with recurrent ovarian cancer, and significant falls in plasma tumour markers (CA125) were seen in two further cases. Plasma pharmacokinetics were linear and showed moderate interpatient variability at dose levels of < or = 120 mg/m2. At dose levels of > or = 200 mg/m2, Cmax and AUC increased less than proportionally to dose. This was associated with greater interpatient pharmacokinetic variability and reduced urinary platinum recovery. A significant sigmoidal relationship existed between ultrafilterable plasma AUC and the percentage of reduction in platelet count (r2 = 0.78). Nonlinear absorption was a limitation to this single-dose schedule of oral NM216; however, little non-haematological toxicity was seen at doses associated with myelosuppression and antitumour activity. Clinical studies of divided dose schedules using doses within the range of pharmacokinetic linearity (< or = 120 mg/m2) are now being investigated.
Administration, Oral↗
Membrane alterations in Alzheimer's disease and aging.
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Aging↗
Fertilization rates using intracytoplasmic sperm injection are greater than subzonal insemination but are dependent on prior treatment of sperm.
OBJECTIVE: To determine a suitable method of sperm preparation for use in micromanipulation. To compare the fertilization rates of sibling oocytes inseminated by intracytoplasmic sperm injection (ICSI) and subzonal insemination (SUZI). DESIGN: Two methods of gamete micromanipulation to overcome male factor infertility were compared. Within this study, three trials were conducted to determine the most suitable method of sperm preparation. This method then was used to complete the study. SETTING: Procedures were performed in a teaching hospital research environment. PATIENTS: Ninety-six patients were recruited for this study, undergoing 99 stimulation cycles. INTERVENTIONS: Sibling oocytes were inseminated by subzonal sperm or intracytoplasmic injection. MAIN OUTCOME MEASURES: Fertilization, zygote development, and pregnancy rates. RESULTS: In the absence of manipulative pretreatment of sperm (trial 1), there was no difference in normal fertilization rates between ICSI and SUZI (19% and 25%, respectively). In the second trial there again was no sperm pretreatment for SUZI but, for ICSI, a polyvinylpyrrolidone (PVP) solution was used to reduce sperm velocity and the sperm tails were incised before injection. The fertilization rates were significantly different between ICSI (44%) and SUZI (17%). In the third trial, PVP was added to the sperm used for both types of insemination and the sperm tails also were incised for the ICSI insemination. Fertilization was again significantly different (16% for SUZI and 44% for ICSI). The trial 2 method of sperm preparation then was used to complete the study (trial 4) and confirmed the results of trial 2 (21% for SUZI and 42% for ICSI). The results suggest that ICSI can give improved fertilization compared with SUZI provided the sperm are treated before injection. No significant differences were found in the development rates of zygotes suitable for transfer or cryopreservation between the two micromanipulation methods.
Cytoplasm↗
Manipulation of sperm before intracytoplasmic sperm injection improves fertilization rates.
OBJECTIVE: To determine the effect of sperm manipulation before intracytoplasmic sperm injection (ICSI) on fertilization rates. DESIGN: Three methods of sperm manipulation before direct ICSI were compared in two sibling oocyte trials. SETTING: In vitro fertilization unit within a teaching hospital. PATIENTS: Patients undergoing infertility treatment using ICSI. INTERVENTIONS: Oocytes were inseminated by ICSI. MAIN OUTCOME MEASURE: Fertilization rate. RESULTS: In the first trial, a standard manipulation technique gave a 67% fertilization rate compared with 64% with a minimal manipulation technique. In the second trial the standard technique gave a significantly greater fertilization rate compared with no prior manipulation (67% versus 45%). CONCLUSIONS: Manipulation of sperm before direct ICSI is not mandatory for fertilization but significantly improves the fertilization rate.
Cytoplasm↗
Comparative immunoblot analysis of the guanine nucleotide binding protein Gq alpha in control and Alzheimer's disease brains.
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Aged↗
Platelet-activating factor-antagonists reduce implantation in mice at low doses only.
The effects of a number of platelet-activating factor (PAF)-antagonists on embryo implantation were investigated. Mice were treated from Day 1 to Day 4 of pregnancy with three defined PAF-antagonists: SRI 63 441, BN 52021, and WEB 2086. Necroscopies were performed on Day 8 and the number of implantation sites, the implantation rate (number of implanted embryos compared with the number of corpora lutea) and the proportion of animals pregnant were determined. Each agent caused a reduction in the number of implantation sites at relatively low doses. The dose that had a maximum contragestational effect was 40 micrograms, 10 micrograms and 10 micrograms (per 30 g bodyweight per day) for SRI 63 441, WEB 2086 and BN 52021 respectively. This contragestational effect was completely lost at twice (SRI 63 441), five times (WEB 2086) and ten times (BN 52021) the most effective dose. Treatment with WEB 2086 on the day of implantation (Day 4) by intraperitoneal injection or instillation into the uterus only did not significantly reduce the implantation rate and neither did treatment after implantation (Days 5-8). The results show that the pharmacology of PAF-antagonists in early pregnancy is not simple. An understanding of the actions of these agents in early pregnancy will require a detailed knowledge of their pharmacokinetics, pharmacodynamics and targets of action in early pregnancy.
Animals↗
Clinical intracytoplasmic sperm injection (ICSI) results from Royal North Shore Hospital.
The technique of intracytoplasmic sperm injection (ICSI) was first introduced to the Royal North Shore Hospital in April 1993 as part of a controlled study of 100 patient cycles in which sibling oocytes were inseminated by either subzonal insemination (SUZI) or ICSI. This trial showed direct sperm injection to be superior in terms of fertilization. In that study, 58 embryo transfers of 101 ICSI-derived embryos resulted in 10 pregnancies. No miscarriages have occurred and a total of 10 fetal hearts (9.8% per embryo transferred) were detected on ultrasound. There have been 10 deliveries of 10 babies. Since the beginning of 1994, intracytoplasmic injection has been used exclusively for patients requiring micromanipulation to achieve fertilization. There have been 200 patient cycles with 1650 oocytes collected (8.8 oocytes per cycle). Of these oocytes, 1548 were mature (94%) and were subjected to ICSI, and normal fertilization occurred in 874 (56%) of the injected oocytes. The number of oocytes which cleaved and were suitable for fresh transfer or cryopreservation was 818 (94%). There have been 153 fresh embryo transfers of 326 embryos. Twenty-six pregnancies (17% per embryo transfer) have resulted, 22 of which proceeded to ultrasound examination in which 23 fetal hearts were detected (7% per embryo transferred). Three miscarriages have occurred, leaving 19 ongoing pregnancies. There have been 127 cryopreservation procedures involving 492 embryos. To date, there have been 47 embryo thaw cycles, and 93 of the 115 (81%) thawed embryos survived and were transferred. These 47 embryo transfers resulted in 10 pregnancies (21% per embryo transfer), one of which one has miscarried.(ABSTRACT TRUNCATED AT 250 WORDS)
Australia↗
Increase in the rate of diploidy with maternal age in unfertilized in-vitro fertilization oocytes.
Human oocytes which failed to fertilize in vitro were fixed for cytogenetic analysis. Metaphase II chromosomes were identified in 286 oocytes, of which 233 were suitable for cytogenetic analysis. In all, 181 oocytes had a normal haploid karyotype (77.7%), while the remaining 52 were abnormal (28 aneuploid, 14 diploid and 10 tetraploid). The rate of aneuploidy did not increase with maternal age. However, the proportion of diploid oocytes increased significantly with advancing maternal age (P < 0.01), being particularly obvious in women aged > 35 years.
Adult↗
Activity of platelet-activating factor acetylhydrolase in the mouse uterus during the estrous cycle, throughout the preimplantation phase of pregnancy, and throughout the luteal phase of pseudopregnancy.
Platelet-activating factor (PAF) is a potent autacoid produced by the embryo and the endometrium during early pregnancy. Its actions in vivo are dependent upon its half-life, which in turn is largely governed by its metabolism. PAF:acetylhydrolase is a major metabolic enzyme for PAF and is widespread in body tissues and fluids. This study was an examination of the activity of this enzyme in the uterus (uterine luminal fluids and endometrial scrapings) of mice in the periovulatory period, throughout the preimplantation phase of pregnancy, and throughout the luteal phase of pseudopregnancy. PAF:acetylhydrolase activity was found in uterine washings and endometrial tissue; it was dependent upon incubation time and protein concentration and was destroyed by boiling. The activity was not affected by cations (Mg2+ and Ca2+) and was not inhibited by bromophenacyl bromide, a phospholipase A2 inhibitor. The specific and total activity changed dramatically throughout the reproductive cycle. Total tissue activity did not change significantly during the follicular phase. On the day after ovulation, tissue activity was lower in naturally mated mice and was maintained at this level until Day 4; there was no difference in this value between pregnant and pseudopregnant animals. On days 5 and 6 of pseudopregnancy the total tissue activity increased, reaching a peak on Day 6 of 4609 pmol acetate released.min-1, approximately 780% higher than the value obtained on Day 4. Activity then decreased so that by Day 8 it was not different from preovulatory levels. For uterine luminal fluids, total activity significantly decreased during the follicular phase. This continued throughout the preimplatation phase with minimum activity being reached on Days 3 and 4 (7.68 pmol acetate.min-1 on Day 4 pseudopregnancy).(ABSTRACT TRUNCATED AT 250 WORDS)
1-Alkyl-2-acetylglycerophosphocholine Esterase↗