CASPE accreditation--the day of reckoning. Aberdeen Royal Hospitals NHS Trust.
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Accreditation↗
Biomedical subjects
C Henderson
Publications and source records attributed to C Henderson.
[The statute of deinstitutionalization in Great Britain].
The aim of this article is to explain the current status of deinstitutionalisation and of community care development by studying the extent to which community care can or should take over the functions of the asylum. These functions include those that are manifest, or explicit, and those that are latent, or unintended but implicit (Bachrach 1976). The continuing relevance of both sets of functions is argued to be exerting a powerful influence on the processes of asylum closure and community care development. The results include delayed asylum closures and transinstitutionnalisation, the shift of some patients from asylums to other institutions, which stifle the development of community care by concentrating spending in hospitals.
Community Mental Health Services↗
Differential effects of neuroleptic agents on hepatic cytochrome P-450 isozymes in the male rat.
We report the effects of various dopamine receptor-blocking drugs on gene and protein expression, as well as the activity of several hepatic cytochrome P-450 (CYP) enzymes in the male Sprague-Dawley rat. At equipotent doses (with respect to receptor blockade and behavioural tests), the dopamine D2-receptor selective sulpiride and remoxipride gave a conspicuous down-regulation of CYP2C11 and its associated androstenedione 16 alpha-hydroxylation activity as well as of the CYP2C11-specific mRNA. The average immunoidentified CYP2C11 levels correlated with the CYP2C11-specific mRNA levels in all treatment groups (r = 0.994), indicating a transcriptional mechanism. The CYP3A protein was also selectively down-regulated. In contrast, androstenedione 5 alpha-reduction was significantly increased. Clozapine, a non-selective neuroleptic, gave the same effects on the steroid metabolism as sulpiride and remoxipride. In contrast, diverging effects were observed for clozapine, compared to sulpiride and remoxipride, on the immunoidentified CYP1A2, CYP2B1, and CYP3A. These proteins were elevated by clozapine, and down-regulated by sulpiride and remoxipride. Our results are of interest for the interpretation of preclinical dose ranging toxicity tests of neuroleptic agents in rats. They may also be relevant in relation to certain interactions and adverse reactions observed in the clinical use of these drugs. The down-regulation of certain CYP enzymes is most likely mediated by an interaction with the growth hormone secretion.
Androstenedione↗
Incidence of and treatment for ductal carcinoma in situ of the breast.
OBJECTIVE: To describe trends in incidence and treatment for ductal carcinoma in situ (DCIS) of the breast in the United States between 1973 and 1992 and to estimate total numbers of in situ cases diagnosed and numbers treated by mastectomy since 1983, when screening mammography for breast cancer began to become widespread. DESIGN: Analysis of population-based breast cancer incidence data collected by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program since 1973 and treatment data collected by the SEER program since 1983. STUDY POPULATION: All women in the geographic areas af the United States included in the SEER program. MAIN OUTCOME MEASURES: Annual age-adjusted and age-specific incidence rates for DCIS; time trends in distribution of cases by type of treatment; percentage of cases treated by mastectomy by geographic area; and estimated numbers for the entire United States of DCIS cases, mastectomies for DCIS, and cases attributable to mammography. RESULTS: There was a marked increase in DCIS incidence beginning in the early 1980s. Average annual increases in rates between 1973 and 1983 and between 1983 and 1992 changed from 0.3% to 12.0% among women aged 30 to 39 years, from 0.4% to 17.4% among women aged 40 to 49, and from 5.2% to 18.1% among women aged 50 years or older. The total estimated number of DCIS cases in the United States in 1992 (23,368) was 200% higher than expected based on 1983 rates and trends between 1973 and 1983. Between 1983 and 1992, there was a marked decline in the proportion of DCIS cases treated by mastectomy (from 71% to 43.8%) and an increase in those treated by lumpectomy (from 25.6% to 53.3%). In 1992, 23.3% of cases were treated by lumpectomy and radiation, 30.2% by lumpectomy alone, and 2.6% with no surgery. Treatment patterns varied substantially by geographic area, with 57.7% of cases in New Mexico treated by mastectomy in 1992 compared with 28.8% in Connecticut. Despite the decline in the proportion of cases treated by mastectomy, the increased DCIS incidence rates resulted in an increase in the absolute number of cases treated by mastectomy until 1990 (n=10,657); in 1992, there were an estimated 10,242 DCIS cases treated by mastectomy. CONCLUSIONS: Incidence rates of DCIS of the breast have increased dramatically since 1983. This increase correlates with the widespread adoption of modern mammographic screening. While early detection of invasive breast cancer is beneficial, the value of DCIS detection is currently unknown. There is cause for concern about the large number of DCIS cases that are being diagnosed as a consequence of screening mammography, most of which are treated by some form of surgery. In addition, the proportion of cases treated by mastectomy may be inappropriately high, particularly in some areas of the United States.
Adult↗
Intracellular [Ca2+] staircase in the isovolumic pressure--frequency relationship of Langendorff-perfused rat heart.
Fluorescence and 31P magnetic resonance spectroscopy have been used to monitor simultaneously, the [Ca2+]i staircase and high energy phosphate metabolism in isolated Langendorff-perfused rat heart paced at 2, 4 and 6 Hz. In order to investigate further the relationship between high energy phosphate metabolism and the calcium staircase we perturbed the intracellular phosphocreatine (PCr)/creatine concentration with dietary beta-guanidinopropionic acid (beta-GPA). We have observed that: (a) At 2 Hz stimulation, the ventricular -Ca2+-i-dependent fluorescence decay is biexponential and continues to decay throughout the interstimulus interval; (b) at 4 Hz and 6 Hz, the [Ca2+]i decay is monoexponential; (c) end-diastolic [Ca2+]i is elevated at higher stimulation frequencies; (d) net [Ca2+]i flux per cycle is reduced at higher stimulation frequencies and is therefore correlated inversely with stimulation frequency and end-diastolic [Ca2+]i; (e) "heart rate * [Ca2+]i flux product" which is a measure of the work done in cycling calcium, is directly proportional to stimulation frequency; (f) the hysteresis between peak ventricular isovolumic pressure and peak fluorescence is decreased at higher stimulation frequencies; (g) no correlation was detected between the PCr/ATP ratio and stimulation frequency; (h) despite a 60% decrease in the myocardial PCr/ATP ratio after beta-GPA feeding, rat heart is able to maintain the end-diastolic [Ca2+]i-dependent fluorescence, and therefore the [Ca2+]i staircase relationship, similar to that of normal rat heart. In conclusion, using a physiological stimulation range and substrate supply we have observed a negative staircase of both [Ca2+]i and isovolumic pressure in whole heart which is not hypoxic. We propose that the inability of the sarcoplasmic reticulum to sequester sufficient cytosolic calcium at high stimulation frequencies leads to an elevation in end-diastolic [Ca2+]i, decreased net calcium flux per cycle resulting in a negative [Ca2+]i staircase and thus a negative isovolumic pressure-frequency relationship. We did not detect any correlation between steady-state high energy phosphate metabolism and stimulation frequency.
Adenosine Triphosphate↗
Species differences in the covalent binding of [14C]tamoxifen to liver microsomes and the forms of cytochrome P450 involved.
Species differences in the NADPH-dependent covalent binding of [14C]tamoxifen to liver microsomes have been studied using preparations from humans, female F344 rats and DBA/2 mice. Protein binding has been used as an index of metabolic activation and as a surrogate for DNA binding in order to establish which forms of cytochrome P450 are responsible for genotoxicity. A panel of 12 human liver microsomes has been characterized and immunoquantified for nine cytochrome P450 isoenzymes. Binding of tamoxifen (45 microM) (25 +/- 2.5 pmol/15 min/mg protein, mean +/- SE) correlated (P < 0.05) with CYP3A4 and CYP2B6 content. Covalent binding of [14C]tamoxifen to microsomal preparations from human breast tumour tissue could also be detected but at levels 7-fold lower than in liver. The covalent binding of tamoxifen to mice, rat or human liver microsomal preparations increased with increasing substrate concentration. Covalent binding of [14C]tamoxifen (45 microM) in rats was 3.8-fold and mice 17-fold higher than in human liver microsomal preparations. In mice, the apparent Km (9.6 +/- 1.9 microM) was very much lower than for rats (119 +/- 41 microM). Pretreatment of female rats with phenobarbitone or dexamethasone resulted in a 4- to 5-fold increase in [14C]tamoxifen binding, relative to controls, consistent with the involvement of CYP2B1 and CYP3A1 in the metabolic activation. It cannot be distinguished at present if the same reactive metabolites are involved in protein and DNA binding. The greater potential of mouse liver microsomes to activate tamoxifen, relative to rats, does not reflect DNA damage or hepatocarcinogenicity seen following dosing with tamoxifen in vivo. It is concluded that covalent binding of tamoxifen to protein in vitro cannot be directly related to the carcinogenic potential of this compound. However, in the three species investigated, results suggest that the rat is a better model than the mouse for human liver microsomal activation of tamoxifen both with respect to kinetic parameters and the pattern of metabolic products.
Animals↗
Adaptive Silicon Monochromators for High-Power Insertion Devices. Tests at CHESS, ESRF and HASYLAB.
X-ray wigglers which produce tens of kilowatts of photon power within the white beam will soon become available at third-generation sources of synchrotron radiation. Insertion devices that produce several kilowatts already exist and we have used those at CHESS, ESRF and HASYLAB to test adaptive 111 silicon water-jet-cooled monochromators at up to 2 kW total incident beam power. This development from earlier work at the Brookhaven National Synchrotron Light Source (NSLS) uses the pressure in the water coolant to provide active compensation of the strain field in the thermal footprint, nulling its effect to within residual variations in Bragg angle of only a few arc s. The design is robust, vacuum compatible and uses no moving mechanical parts.
Journal Article↗
Ondansetron improves cognitive performance in the Morris water maze spatial navigation task.
In the present studies we investigated the actions of ondansetron, a prototypic 5-hydroxytryptamine3 (5-HT3) receptor antagonist, on performance in a complex spatial navigation/memory task in rats. Specifically, we compared the activity of ondansetron to that of the cholinesterase inhibitor physostigmine in attenuating two distinct cognitive deficits in the Morris water maze. In the first model, rats treated with the muscarinic receptor antagonist atropine (30 mg/kg) had significantly longer latencies to find the submerged platform across two days of testing. Physostigmine (0.03, 0.1 and 0.3 mg/kg) and ondansetron (0.03-1 mg/kg) significantly reduced the latencies to find the submerged platform in atropine-treated animals, suggesting an increase in cognitive performance. There was little evidence of a dose-response relationship for either compound, and a loss of efficacy for ondansetron was seen at 3 mg/kg. In the second model, pre-screened, aged (23 months), cognition-impaired and nonimpaired rats were tested. Ondansetron (0.1 mg/kg), but not physostigmine (0.1 mg/kg), decreased the latencies to find the submerged platform in the aged-impaired rats, while neither compound improved performance of aged-nonimpaired rats. These data suggest that ondansetron may have cognition enhancing properties in animal models of aging and cholinergic hypofunction.
Animals↗
Carpentier-Edwards supraannular porcine bioprosthesis: clinical performance to twelve years.
The Carpentier-Edwards supraannular porcine bioprosthesis, a second-generation biologic prosthesis, has had clinical performance assessment to 12 years. This bioprosthesis was used in 2,489 operations in 2,444 patients between 1982 and 1992, inclusive (mean age 64.1 years, age range 6 to 89 years). There were 1,335 aortic valve replacements (AVR), 938 mitral valve replacements (MVR), and 200 multiple valve replacements (MR). Concomitant procedures were performed in 1,017 cases (40.9%). The age group distribution was: 35 years or younger, 83 patients; 36 to 50 years, 245; 51 to 64 years, 728; 65 to 69 years, 458; and 70 years and older, 975. The total follow-up was 12,785 patient-years (mean, 5.1 years) and was 96% complete. The early mortality rate was 7.4% (185 patients), and the late mortality was 4.9%/patient year (623). Concomitant procedures influenced both early and late mortality (p < 0.05). The overall patient survival at 12 years was 44% +/- 3% (p < 0.05, AVR > MVR, MR). The freedom from thromboembolism was not different by valve position. The freedom from major thromboembolism at 12 years was 82% +/- 4% (p = not significant by valve position). The overall freedom from antithromboembolic hemorrhage was 96% +/- 1% at 12 years (p < 0.05, AVR > MVR > MR). The overall freedom from valve-related reoperation at 12 years was 58% +/- 5% (p < 0.05, AVR > MVR, MR), and from valve-related mortality 89% +/- 2% (p < 0.05, AVR > MVR > MR). The freedom from residual morbidity (permanent impairment) at 12 years was 87% +/- 4% (p = not significant by valve position).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Pregnancy and bioprostheses: influence on structural valve deterioration.
The long-term performance of bioprostheses was evaluated in women 35 years of age or less to determine the influence of pregnancy on structural valve deterioration. Between 1972 and 1992, 237 female patients received 255 biological prostheses. Of the total operations, 53 were performed in patients who experienced pregnancy (P) and 202 in patients who were never pregnant (nonpregnant [NP]). The mean age of the P group was 23.0 +/- 5.8 years (standard deviation) (12 to 34 years) and of the NP group it was 27.1 +/- 6.3 years (8 to 35 years) (p < 0.05). The mean follow-up for the NP group was 6.8 years and for the P group it was 7.9 years. The late mortality was 2.26%/patient-year overall, 2.71%/patient-year for the NP group and 0.89%/patient-year for the P group (p = not significant [NS]). The P group of 52 patients had 94 pregnancies: 70 deliveries (74.5%) and 24 abortions (25.5%) (therapeutic, 14 [15%]). There were a total of 143 valve-related complications (P, 35; NP, 108); the majority for structural valve deterioration (SVD) 43% (109 patients), P 51% (27 patients) and NP 41% (82 patients) (p = NS). The valve-related reoperation rate paralleled the SVD rate at 42% (107 patients), P 51% (27 patients) and NP 40% (80 patients) (p = NS). The overall reoperative mortality rate was 6.0%. The interval from initial implant to reoperation was 99.6 +/- 3.6 months (p = NS groups P and NP).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Limited efficacy of experimental anti-epileptic drugs in refractory temporal lobe epilepsy: implications for patient management and study recruitment.
Patients with refractory temporal lobe epilepsy (TLE) are commonly recruited for investigational anti-epileptic drug (XAED) studies. However, the long-term outcome of TLE after exposure to XAEDs is poorly documented. In this pilot study, we report the USC Epilepsy Center's experience of 19 patients with TLE enrolled in three XAED trials. The data reinforce that TLE is a drug-resistant epilepsy, and referral of good surgical candidates for surgery rather than XAED trials is more likely to result in remission.
Anticonvulsants↗
Isolation and characteristics of a wheatbran-degrading Butyrivibrio from human faeces.
Screening over 100 isolates from human faeces for cellulolytic activity led to the isolation of a weakly cellulolytic anaerobic, curved, motile bacterium which produced H2, lactate and butyrate from wheatbran. The mol% of G + C in the DNA was 39-42. These properties, together with the Gram-positive cell wall ultrastructure and SDS-PAGE profile, are consistent with the genus Butyrivibrio. The isolate is believed to be the most active wheatbran-degrading bacterium so far described.
Adult↗
The search for nursing leadership: departing from the traditional.
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Humans↗
Hypofibrinolysis: a common, major cause of osteonecrosis.
In 30 patients with osteonecrosis of the hip (12 idiopathic, 18 secondary), we assessed the role of hypofibrinolysis mediated by high levels of plasminogen activator inhibitor (PAI). We evaluated hypofibrinolysis as a common, potentially reversible, pathophysiologic cause of idiopathic osteonecrosis. In all 18 patients with secondary osteonecrosis, PAI was normal, as was the ability to activate fibrinolysis. Nine of the 12 patients with idiopathic osteonecrosis had exceptionally high PAI levels and could not normally elevate tissue plasminogen activator (tPA-Fx), the major stimulator of fibrinolysis, after 10 min of venous occlusion at 100 mm Hg. The group of 12 patients with idiopathic osteonecrosis, compared to the 18 with secondary osteonecrosis, had low mean stimulated tPA-Fx (1.92 vs. 7.6 IU/ml, P < or = .001) and very high stimulated PAI-Fx (70 vs. 7.6 U/ml, P < or = .01). Three of the 12 patients with idiopathic osteonecrosis had both normal PAI and normal stimulated tPA-Fx. These three patients and 14 of the 18 with secondary osteonecrosis had high lipoprotein (a) [Lp(a)] (> 20 mg/dl). Mean Lp(a) was much higher (60 mg/dl) in the patients with secondary osteonecrosis than Lp(a) (16 mg/dl, P < or = .001) in the 12 patients with idiopathic osteonecrosis. These findings suggest that hypofibrinolysis mediated by high PAI is a common cause of idiopathic osteonecrosis, whereas high Lp(a) may play an etiologic role in secondary osteonecrosis. Prospective studies of patients with high PAI and/or high Lp(a) should be carried out to assess further their apparently causal roles in osteonecrosis.
Adult↗
Intracellular Ca2+ transients in isolated perfused rat heart: measurement using the fluorescent indicator Fura-2/AM.
We have investigated the nature of Fura-2/AM loading into isolated perfused rat heart and the temporal and kinetic relationship between left ventricular [Ca2+]i dependent fluorescence and isovolumic pressure. The contribution of hydrolysed mitochondrial matrix Fura-2 fluorescence to that measured from the surface of the heart was estimated to be 43.9 +/- 5.5% by the addition of 100 microM Mn2+ to the perfusate. Maximum endothelial Fura-2 fluorescence ratio, estimated by the addition of 3 microM bradykinin to the perfusate, was found to constitute 33.6 +/- 2.7% of the maximum myocardial Fura-2 fluorescence ratio. Approximately 11.2% of the 340 nm surface fluorescence was insensitive to 20 mM Mn2+ in the presence of ionomycin (3 microM) and therefore indicates the degree of partial hydrolysis of Fura-2/AM. Thus, depending on the contribution of endothelial Fura-2 fluorescence at a physiological endothelial calcium concentration, cytosolic fluorescence may comprise between 11-45% of the total cellular fluorescence at 340 nm. Net tissue interference of the Fura-2 fluorescence ratio by NADH emission and myoglobin absorption remained unaltered, providing the oxygenation state of the tissue was unaltered throughout the experiment. The [Ca2+]i dependent fluorescence decay from peak systole was best fitted to a biexponential decay with fast and slow rate constants of 18.08 +/- 1.97 s-1 and 0.23 +/- 0.02 s-1, respectively. In addition, a phase shift was observed between temporal and kinetic measurements of the left ventricular isovolumic pressure and calcium dependent fluorescence traces during a contraction-relaxation cycle. We conclude that despite imperfect Fura-2/AM loading, the temporal and kinetic characteristics of intracellular [Ca2+] transients in normal isolated perfused rat heart are similar to those reported in more controlled preparations such as isolated myocytes and cardiac trabeculae.
Animals↗
Alterations in the myocardial creatine kinase system during chronic anaemic hypoxia.
OBJECTIVE: The aim was to use a model of chronic anaemia in the rat, in which there is an increase in cardiac mitochondrial creatine kinase activity (mito-CK) per mitochondrion, to test the hypothesis that creatine stimulated respiration in saponin skinned fibres is correlated with mito-CK activity. In order to discuss the altered regulation of mitochondrial respiratory rate in the context of other metabolic alterations, steady state metabolite concentrations and maximum extracted activities of regulatory enzymes in glycolysis were also investigated. METHODS: Weanling male Wistar Albino rats were randomly distributed into two experimental groups. One group received a powdered diet deficient in iron (5-7 mg iron.kg-1) while the second group was placed on a standard laboratory chow diet (109 mg iron.kg-1) for 4-8 weeks. RESULTS: Total cardiac creatine kinase activity was unchanged in anaemic rats; however, a 25% increase in nascent or functional mito-CK activity per mitochondrion was detected [0.969(SEM 0.005), control group and 1.203(0.040), anaemic group, p < 0.001]. The sensitivity of creatine (40 mM creatine, VCr) and ADP (0.1 mM ADP, V0.1) stimulated respiration, as a percentage of maximum respiratory rate (2.0 mM ADP, V2.0), was increased by 48% and 52% respectively in the anaemic skinned cardiac fibres. An increase in basal respiration with glutamate and malate as substrates was detected in the anaemic group compared to the control group, at 6.77(0.74) v 4.58(0.35) ng O.min-1 x mg-1 dry weight (p < 0.025). Cytosolic ATP was decreased in isolated perfused hearts from anaemic animals, at 35.18(3.11) mumol.g-1 dry weight in control hearts versus 23.66(1.42) in anaemic hearts (p < 0.01). A significant increase in myocardial glycolytic capacity was detected in anaemic cardiac tissue, as evidenced by a 20% increase in phosphofructokinase activity (p < 0.01). Phosphorylase activity was unaltered in anaemic hearts, indicating that the increased glucose requirement originated from exogenous sources. Lactate dehydrogenase (LDH) was increased by 30% in anaemic hearts (p < 0.001). The LDH isozyme profile was shifted in favour of lactate and NAD+ production, thus supporting anaerobic glycolysis. CONCLUSIONS: In support of the phosphocreatine circuit model, the increased mito-CK per mitochondrion in the anaemic skinned fibre preparation was associated with an increase in creatine stimulated respiration. In addition, the sensitivity of mitochondrial respiratory rate to ADP and the maximum glycolytic capacity were increased in anaemic fibres. Although the net effect of these changes in metabolic capacity and regulation on in vivo high energy phosphate flux is unknown, it is likely that they are adaptive alterations that compensate for the lower steady state cytosolic nucleotide concentration.
Adenosine Diphosphate↗
Glibenclamide, but not class III drugs, prevents ischaemic shortening of the refractory period in guinea-pig hearts.
The effective refractory period was measured in paced (4 Hz) perfused guinea-pig hearts in vitro. The effective refractory period was linearly correlated with temperature of the perfusing solution: as temperature was reduced the effective refractory period was increased. Reduction of the coronary flow rate to 10% of control resulted in a marked reduction in the effective refractory period. UK-66,914, dofetilide, ibutilide and phentolamine caused a prolongation in the effective refractory period, but during ischaemia the effective refractory period was reduced by the same degree as in vehicle-treated hearts. Glibenclamide had no effect on the effective refractory period prior to ischemia but it abolished the ischaemia-induced shortening. These results suggest that the opening of KATP channels may be responsible for the ischaemia-induced shortening of the effective refractory period in perfused guinea-pig hearts and that the class III effects of UK-66,914, dofetilide and ibutilide are attenuated during ischaemia.
Analysis of Variance↗
Identification of P450 enzymes involved in metabolism of verapamil in humans.
The calcium channel blocker verapamil[2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6- azaoctanitrile] is widely used in the treatment of hypertension, angina pectoris and cardiac arrhythmias. The drug undergoes extensive and variable hepatic metabolism in man with the major metabolic steps comprising formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile] and norverapamil [2,8-bis-(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]. The enzymes involved in metabolism of verapamil have not been characterized so far. Identification of these enzymes would enable estimation of both interindividual variability in verapamil metabolism introduced by the respective pathway and potential for metabolic interactions. We therefore characterized the enzymes involved in formation of D-617 and norverapamil. The maximum rate of formation of D-617 and norverapamil was determined in the microsomal fraction of 21 human livers which had been previously characterized for the individual expression of various P450 enzymes (CYP1A2, CYP2C, CYP2D6, CYP2E1 and CYP3A3/4) by means of Western blotting. Specific antibodies directed against CYP3A were used to inhibit formation of D-617 and norverapamil. Finally, formation of both metabolites was investigated in microsomes obtained from yeast cells which were genetically engineered for stable expression of human P450. Formation of D-617 was correlated with the expression of CYP3A (r = 0.85; P < 0.001) and CYP1A2 (r = 0.57; P < 0.01) in the microsomal fraction of 21 human livers after incubation with racemic verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)
Biotransformation↗