PBPK modeling as a basis for achieving a steady BrAC of 60 +/- 5 mg% within ten minutes.
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Breath Tests↗
Biomedical subjects
S O'Connor
Publications and source records attributed to S O'Connor.
Effects of a drug overdose in a television drama on presentations to hospital for self poisoning: time series and questionnaire study.
OBJECTIVES: To determine whether a serious paracetamol overdose in the medical television drama Casualty altered the incidence and nature of general hospital presentations for deliberate self poisoning. DESIGN: Interrupted time series analysis of presentations for self poisoning at accident and emergency departments during three week periods before and after the broadcast. Questionnaire responses collected from self poisoning patients during the same periods. SETTING: 49 accident and emergency departments and psychiatric services in United Kingdom collected incidence data; 25 services collected questionnaire data. SUBJECTS: 4403 self poisoning patients; questionnaires completed for 1047. MAIN OUTCOME MEASURES: Change in presentation rates for self poisoning in the three weeks after the broadcast compared with the three weeks before, use of paracetamol and other drugs for self poisoning, and the nature of overdoses in viewers of the broadcast compared with non-viewers. RESULTS: Presentations for self poisoning increased by 17% (95% confidence interval 7% to 28%) in the week after the broadcast and by 9% (0 to 19%) in the second week. Increases in paracetamol overdoses were more marked than increases in non-paracetamol overdoses. Thirty two patients who presented in the week after the broadcast and were interviewed had seen the episode-20% said that it had influenced their decision to take an overdose, and 17% said it had influenced their choice of drug. The use of paracetamol for overdose doubled among viewers of Casualty after the episode (rise of 106%; 28% to 232%). CONCLUSIONS: Broadcast of popular television dramas depicting self poisoning may have a short term influence in terms of increases in hospital presentation for overdose and changes in the choice of drug taken. This raises serious questions about the advisability of the media portraying suicidal behaviour.
Acetaminophen↗
Effects of a drug overdose in a television drama on knowledge of specific dangers of self poisoning: population based surveys.
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Acetaminophen↗
Markers of inappropriate placement in acute psychiatric inpatient care: a five hospital study.
BACKGROUND: Previous researchers in the UK have measured the prevalence of the 'inappropriateness' of acute adult psychiatric inpatient placements by eliciting the judgements of health professionals. We extended the methodology by identifying inpatient sub-groups with stable characteristics that were associated with elevated risk of inappropriate placement, and by calculating the level of that risk. METHODS: A 1-day census was taken in five hospitals. Using a structured instrument, consultant psychiatrists recorded judgements on current placements, recommended alternative placements and stated why alternatives had not been used. Judgements were obtained for 100% of the 261 inpatients. Risk ratios and adjusted odds ratios were calculated to identify sub-groups that were at high risk. RESULTS: Eighty-eight inpatients were inappropriately placed, a point prevalence of 34% (95% CI 28-40%). Consultants recorded that services outside hospital, if available, could have supported most of these inpatients as an alternative to at least part of their hospital stay. Diagnostic rather than socio-demographic or administrative characteristics, in particular primary diagnoses of substance-related disorder, personality disorder, anxiety/stress, and schizophrenia with co-morbid substance misuse, were the strongest markers of elevated risk. CONCLUSIONS: The point prevalence of inappropriate placement within the British mental health-care system is considerable. Diagnostic categories are reasonable pragmatic markers. Further research should aim to identify a strong marker of risk within the numerically large sub-group of schizophrenia without substance misuse.
Adolescent↗
Fulfillment of Koch's postulates and the causes of atherosclerosis.
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Arteriosclerosis↗
Effect of novel CAAX peptidomimetic farnesyltransferase inhibitor on angiogenesis in vitro and in vivo.
Ras oncogenes can contribute to tumour development by stimulating vascular endothelial growth factor (VEGF)-dependent angiogenesis. The effect of Ras on angiogenesis may be affected by farnesyltransferase inhibitors (FTI) since farnesylation of Ras is required for its biological activity. In this paper we evaluated the effect of A-170634, a novel and potent CAAX FTI on angiogenesis. Human umbilical vein endothelial cell (HUVEC) tube formation and VEGF secretion were used to assess the effect of A-170634 on angiogenesis in vitro. In vivo, nude mice were injected with the K-ras mutant colon carcinoma cell line HCT116 and treated subcutaneously with A-170634 using osmotic minipump infusion for 10 days. The effect of A-170634 on corneal angiogenesis in vivo was assessed using pellets containing hydron, VEGF, A-170634 or vehicle. In vitro, A-170634 selectively inhibited farnesyltransferase activity over the closely related geranylgeranyltransferase I, inhibited Ras processing, blocked anchorage-dependent and -independent growth of HCT116 K-ras mutated cells, decreased HUVEC capillary structure formation, decreased VEGF secretion from tumour cells and HUVEC growth stimulating activity in a dose-dependent manner. In vivo, tumour growth was decreased by 30% and vascularisation in and around the tumours was reduced by 41% following drug-treatment with no apparent toxicity to the animals. VEGF-induced corneal neovascularisation was reduced by 80% following A-170634 treatment for 7 days. The data presented here demonstrated that A-170634 was a potent and selective peptidomimetic CAAX FTI with anti-angiogenic properties. These results implied that A-170634 may affect tumour growth in vivo by one or more antitumour pathways.
Alkyl and Aryl Transferases↗
FICTION-TSA analysis of the B-cell compartment in myeloma shows no significant expansion of myeloma precursor cells.
Studies utilizing flow cytometry and PCR have shown that the B-cell compartment in myeloma contains cells which are clonally related to the myelomatous plasma cells. Current data, however, remains inconclusive regarding the extent of this involvement. By combining fluorescent immunophenotyping, tyramine signal amplification and fluorescence in-situ hybridization (FICTION-TSA), we have used the presence of numerical chromosomal abnormalities within plasma cells as a clonal marker to examine the CD20+ B-cell compartment for the presence of aneuploidy. A series of 54 cases of myeloma were screened for the presence of numerical abnormalities of chromosomes 3 and 11. FICTION-TSA was performed on 13 cases with either trisomy 3 or 11 and on a control group of six cases known to be disomic for the two chromosomes. B-cell numbers were reduced in the myeloma cases compared to the normal controls (median 1.8% v 3.0%, P = 0.05). In the cases with a chromosomal marker, three signals were seen in a median of 1.88% of CD20+ B cells compared to 2.58% within the control group. Comparison of the two groups using a Wilcoxon-Mann-Whitney U test showed no statistical significant difference. Using this data set, it was possible to exclude a 3.03% expansion of clonally related B cells (95% confidence level). We conclude that the B-cell compartment in myeloma does not represent the major site of clonal expansion, and if clonally related cells are present then the numbers are few.
Aneuploidy↗
Long-term results of vagus nerve stimulation in refractory epilepsy.
Vagus nerve stimulation (VNS) is an adjunctive antiepileptic treatment for patients with refractory epilepsy. Limited information on long-term treatment with VNS is available. The purpose of this paper is to present our experience with VNS with a follow-up of up to 4 years. Twenty-five patients (13 females and 12 males) with refractory partial epilepsy were treated with VNS. The first 15 patients with a mean age of 30 years and a mean duration of epilepsy of 17.5 years have sufficient follow-up for analysis. Mean post-implantation follow-up was 29 months and mean stimulation output 2.25 mA. There was a mean seizure frequency reduction from 14 complex partial seizures (CPS) per month before implantation to 8 CPS per month after implantation (P = 0.0016; Wilcoxon signed-rank rest (WSRT)). The mean maximum CPS-free interval changed from 9 to 312 days (P = 0.0007; WSRT). Six patients were free of CPS for at least one year. In one patient, one antiepileptic drug (AED) was tapered; in 10 patients, AEDs remained unchanged; in four, one adjunctive AED was administered. Side effects occurred in six patients, three of whom required a temporary reduction of output current. Nine patients reported no side effects at all. Treatment with VNS remains effective in the long-term. In this series 4 / 15 (27%) patients with highly refractory epilepsy experienced entirely seizure-free intervals of 12 months or more.
Adolescent↗
Management of cervical cerclage after preterm premature rupture of membranes.
The optimal management of preterm premature rupture of membranes (PPROM) in a patient with a cerclage is controversial. The issues are whether the latency period between rupture of membranes and delivery is decreased if the cerclage is removed and whether there is an increased rate of maternal or neonatal infection if the cerclage is kept in place. The data are sparse in directing management of women with prophylactic cerclages placed earlier in their pregnancies who rupture membranes. Latency seems to be increased if the cerclage is kept in place, but maternal and neonatal infectious morbidity is increased also. In women at early gestational ages, keeping the cerclage in place may be warranted until labor ensues. In more advanced gestations, it seems preferable to immediately remove the cerclage upon diagnosis of PPROM.
Adult↗
A twin study of genetic influences on the acute adaptation of the EEG to alcohol.
A two-dose alcohol challenge protocol was used to study genetic influences on the acute adaptation of the EEG to alcohol in 53 monozygotic and 38 same-sex dizygotic Caucasian twin pairs averaging 30 years of age. Equal doses of alcohol were administered at 10:00 and 11:00 AM, yielding mean peak breath alcohol concentrations of 0.057% and 0.099%, respectively. Eyes-closed, resting EEG was recorded four times: at baseline; on the ascending limb of the overall experiment at a breath alcohol concentration (BrAC) near 0.06%; on the descending limb at a BrAC near the value when the subject's EEG was obtained on the ascending limb; and, finally, when the BrAC fell to 0.02%. Genetic analyses of log-transformed values of total spectral power (L10TSP) and spectral band power (L10SBP) were performed on EEG spectra averaged across all 17 scalp lead locations. After adjusting for body weight, a significant fraction of population variance in L10TSP was attributable to genetic influence: H2 values for TSP were 0.73, 0.72, and 0.73 at the three postalcohol EEG recordings, respectively. Similar findings pertained to each L10SBP at each postalcohol recording, except forthe delta band. The change in postethanol EEG power was examined for evidence that genes influence acute adaptations in brain function. Descending-minus-ascending limb L10TSP was normalized by the individual's ascending limb L10TSP to minimize nonalcohol-related effects that can influence both measurements. Earlier analyses of the same sample's initial EEG response to alcohol noted a substantial increase in the ascending limb EEG power, compared with baseline. Thus, positive values of the postethanol change denote a progression away from baseline attributable to acute sensitization to alcohol; negative values signify a return toward baseline values suggesting acute tolerance to alcohol. Genetic analysis of the normalized difference in L10TSP had a highly significant H2 value of 0.70, indicating that both acute tolerance and acute sensitization to alcohol may represent adaptations reflecting substantial heritable influence. Slightly smaller, but significant values of H2 for the normalized difference in L10SPB were observed for delta, alpha-slow and beta-slow frequency bands. In contrast, H2 for the differences between the final and ascending limb EEG power were not significant, except for the theta band. Thus, heritable drowsiness may have contributed to detection of genetic influences on acute adaptation, but represent a potential confound only in the theta band.
Adaptation, Physiological↗
A physiologically-based pharmacokinetic (PBPK) model for alcohol facilitates rapid BrAC clamping.
Alcohol clamping is a technique that maintains a constant breath alcohol concentration (BrAC) for prolonged intervals, thereby reducing experimental variance in the time course of organ exposure to alcohol, when compared with oral alcohol administration paradigms. The technique employs an intravenous (i.v.) infusion of an ethanol solution at a rate that is intermittently adjusted based on real-time BrAC measurements. In earlier studies, when the clamped state was induced with an oral ethanol loading dose, the vagaries of gastric emptying and absorption were associated with a 45 min delay (RST: reliable start time) before collection of dependent measurements could be planned with confidence. The objective of the present study was to develop an induction method that provides an earlier RST, and to compare the performance of the two methods. The "quick-clamping" method replaced the oral loading dose with a preprogrammed infusion rate profile. A three-compartment physiologically-based pharmacokinetic (PBPK) model for ethanol was constructed, then tailored to each subject using individualized estimates of model parameters. The model was used to compute the infusion-rate profile that would produce the desired time course of BrAC when infused in the corresponding subject. The two clamping methods were compared in a two-session crossover study in 20 healthy young subjects (10 males, 10 females). Compared with the oral/i.v. method, quick clamping produced a comparable precision in the control of BrACs during the clamped interval, and provided a much earlier RST (mean +/- SE for quick-clamp: 17 +/- 4 min; for oral/i.v. clamp: 45 +/- 7 min). The quick-clamping method enables, for the first time, the examination of the early-phase neuroadaptive responses to alcohol in human subjects.
Alcohol Drinking↗
A preliminary study of acute responses to clamped alcohol concentration and family history of alcoholism.
BACKGROUND: The clamping method of alcohol administration was combined with a battery of dependent measures of frontal lobe brain function, and a novel index of acute adaptation, in a preliminary study in order to explore the paradigm's sensitivity to a familial history of alcoholism (FHA). METHODS: Ten family history-positive (FHP) and 10 family history-negative (FHN) adult social drinkers of both genders underwent alcohol clamping. Twenty minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 60+/-5 mg/dl for 150 min. Initial and adaptive responses to alcohol were assessed using scalar indices of change. One index assessed initial improvements or impairments in brain function after alcohol. The other index assessed acute adaptation (tolerance or sensitization) to alcohol while the brain's exposure to alcohol was held constant. The battery of dependent measures included subjective perceptions, neuropsychological tests, saccadic eye-movement tasks, and event-related potential (ERP) tasks. Effect sizes for FHA were estimated for 10 dependent variables that showed adequate baseline test-retest reliability (r>0.6). RESULTS: FHP subjects showed less intense initial responses to alcohol in subjective perceptions, but greater changes in the latency of volitional saccades and ERP P3 components than did the FHN controls. FHP subjects generally showed greater acute tolerance to alcohol than did controls, who showed more instances of acute sensitization at this moderate breath alcohol concentration. Effect sizes for FHA exceeded 0.4 in more than half of the indices. CONCLUSIONS: The BrAC clamping paradigm assesses initial and adaptive responses of a battery of behavioral and electrophysiological measures of frontal lobe function to ethanol that appear both reliable and sensitive to FHA.
Adult↗
Cost-benefit of vagus nerve stimulation for refractory epilepsy.
PURPOSE: Vagus nerve stimulation (VNS) is an established treatment for patients with medically refractory epilepsy who are unsuitable candidates for conventional epilepsy surgery. VNS requires an initial financial investment but apart from our own previous study there are no reports on cost-benefit published to date. The purpose of this paper is to assess prospectively the cost-benefit ratio of VNS in a series of patients with long term follow-up. METHODS: Our experience with VNS comprises 25 patients of whom 20 with sufficient follow-up will be further discussed. These 20 patients have a mean post-implantation follow-up of 26 months (range: 6-50 months). Mean age was 30 years (range: 12-45 years); mean duration of epilepsy 17 years (range: 5-35 years). We prospectively assessed seizure frequency, prescribed AEDs, number of hospital admission days and side effects and calculated the epilepsy related direct medical cost and compared this with pre-implantation data. RESULTS: Mean seizure frequency decreased from 14 seizures/month (range: 2-40) to 9 seizures/month (range: 0-30) (p = 0.0003). The mean yearly epilepsy related direct medical costs per patient dropped from 6,682 USD (range: 829-21,888 USD) to 3,635 USD (range: 684-12,486 USD) (p = 0.0046). The mean number of hospital admission days was reduced from 16 days/year (range: 0-60) to 4 days/year (range: 0-30) (p = 0.0029). CONCLUSION: VNS is an efficacious and cost-beneficial treatment for refractory partial seizures.
Adolescent↗
Electrocautery as a factor in seroma formation following mastectomy.
BACKGROUND: Electrocautery has been postulated as a factor in the risk of seroma formation after mastectomy. METHODS: Eighty consecutive mastectomies in 74 patients were randomly assigned to dissection of the mastectomy flaps with either scalpel (n = 38) or electrocautery (n = 42). Total volume of fluid output through drains and aspirated from seromas was recorded. Other factors investigated included the type of drain utilized, estimated blood loss, and complications. RESULTS: Seromas developed in 16 wounds in the electrocautery group compared with 5 in the scalpel group (38% and 13%, respectively; P = 0.01). Other factors with an independent risk for seroma included use of Jackson-Pratt drains compared with Blake drains (P = 0.006), and lower estimated blood loss (P = 0.006). No differences in characteristics of patients or in other complications were noted. CONCLUSIONS: Use of electrocautery to create skin flaps in mastectomy reduced blood loss but increased the rate of seroma formation.
Aged↗
Gender differences in alcohol metabolism: relationship to liver volume and effect of adjusting for body mass.
BACKGROUND & AIMS: Alcoholic liver disease purportedly develops more readily in women than in men. Some studies have demonstrated faster rates of alcohol elimination in women. This study examined whether gender differences in alcohol metabolism are related to differences in liver volume and/or differences in lean body mass. METHODS: Ten men and 10 women had alcohol elimination rates determined by clamping of the breath alcohol concentration at 50 mg/dL by means of a constant rate of intravenous infusion of 6% ethanol. Liver volume was determined by computed tomography. RESULTS: Mean alcohol elimination rate and mean computed liver volume were not significantly different in men and women. Lean body mass was 42% greater in men than in women. Consequently, the calculated alcohol elimination rate and liver volume per kilogram of lean body mass were 33% and 38% higher in women than in men, respectively. When the alcohol elimination rate was calculated per unit liver volume, no gender-related difference was found. CONCLUSIONS: Women have greater clearance of ethanol per unit lean body mass, confirming previous oral alcohol administration studies. Women have approximately the same liver volume as men, explaining the equivalent alcohol elimination rates seen when men and women are compared on the basis of liver size.
Adult↗
Aging and lymphocyte subpopulations: whole-blood analysis of immune markers in a large population sample of healthy elderly individuals.
Immune status was determined in a representative sample of elderly people by measuring lymphocyte subsets in whole-blood samples as part of an epidemiological study of the population aged 65 and over. Venepuncture was undertaken in more than 500 individuals who took part in an extensive interview that focused on the lifestyle and psychosocial determinants of healthy aging. The results show that median levels of all lymphocyte subsets tend to decline as the age of the sample increases. In the total sample there were significant age effects (p < 0.05) on total lymphocytes, CD3, CD4, and CD19 (B cells); age differences did not reach significance for CD8 and CD57. There were also significant sex differences (p < 0.05) on CD3, CD4, and CD19, and in all cases women had higher values than men. When we selected a particularly healthy subsample who did not report any illness and took no medication, the findings were unchanged. We conclude that the peripheral expression of lymphocytes appears little affected by aging-related illnesses in the general population, but is affected by aging itself. The study provides reference values for the lymphocyte measures, which can be regarded as having greater validity than the values usually cited.
Aged↗
Clamping breath alcohol concentration reduces experimental variance: application to the study of acute tolerance to alcohol and alcohol elimination rate.
An oral loading dose was combined with intravenous infusion of 6% alcohol at rates adjusted on-line to close the gap between measurements of breath alcohol concentration (BrAC) and a target of 50 mg%. The goal was to minimize the deviation from a prescribed course of BrAC over time. In a pilot study of 10 young men, subjects underwent three experimental sessions: twice at 50 mg% and once in a 0 mg% control condition. The pilot study assessed the performance of the BrAC clamp, its potential utility in studies of acute tolerance to alcohol, and the retest reliability of directly measuring the alcohol elimination rate (AER) calculated from the steady-state infusion rate. Reduced variance was demonstrated in 4 of 5 experimental parameters, compared with results of an earlier approach using a split-dose oral administration procedure. Subjects' perceptions about alcohol effects were measured in one BrAC clamping session, using Schuckit's Subjective High Assessment Scale: 3 of 15 Schuckit's items demonstrated statistically significant indices of acute tolerance to alcohol. Within-subject AERs calculated in the steady-state had a coefficient of variation of 6.5%. Details of the BrAC clamping procedure are provided. The pilot study demonstrated the ability to prescribe experimental parameters of the brain's exposure to alcohol while preserving experimental flexibility in studies of acute tolerance to alcohol and AER.
Adult↗
Androgen and sleep-related erections.
Sleep-related penile erections provide a unique opportunity to objectively study erectile physiology in man. Testosterone is one of several factors involved in normal sexual function and testosterone reduction can be achieved by administering luteinizing-hormone releasing-hormone agonists (LHRH-A). In this study, ten healthy, young adult males were administered LHRH-A or placebo for a 12-week period. Subjects taking LHRH-A had a marginally significant decline in sleep-related erection duration at week 4 and significant reductions at weeks 8 and 12. By contrast, no statistically reliable change was found for the number of erections over the course of study. Maximum circumference increase during sleep erections showed mixed results. These results indicate that, whereas androgen reduction adversely affects sleep-related erections, it does not eliminate them over a 12-week trial in healthy young adult men. Further study in a larger sample is needed. Nonetheless, these preliminary findings support androgen having an important role in sleep-related erections.
Adult↗