Biomedical subjects
Publications and source records attributed to P Smith.
Immune chronic active hepatitis is a disease notorious for its unpredictability. In a patient with chronic hepatitis who has already suffered relapses a search for a second cause of jaundice is not usually necessary. This report emphasises the essential role of liver biopsy.
Attenuated hypercapnic chemosensitivity and hypoventilation are characteristics periodically associated with human obesity. We tested the hypothesis that ventilatory control is altered by genetic determinants and age-dependent factors that influence the obese phenotype. To this end, the magnitude and pattern of breathing were examined before and associated with the development of obesity in C57BL/6J mice homozygous and heterozygous at the ob gene locus. Breathing frequency and tidal volume were measured using whole body plethysmography, and minute ventilation was assessed during acute hypoxic and hypercapnic challenges with intermittent room air exposures. In age- and weight-matched mice before pronounced obesity, significant (P < 0.05) reductions in hypercapnic ventilatory sensitivity occurred in mutant (ob/ob) mice relative to wild-type (+/+) homozygotes primarily because of an attenuated tidal volume. Longitudinal studies indicated that mutant ob mice developed rapid baseline breathing relative to the wild type, accompanying a twofold greater increase in body mass. Early differences between homozygotes in hypercapnic ventilatory sensitivity were maintained through 230 days. These data demonstrate that genetic determinants at or closely linked to the ob locus influence hypercapnic ventilation before the emergence of pronounced obesity, whereas changes in baseline breathing appear due to age-dependent increases in body weight.
This study was designed to measure whether a single dose of 120 mg pseudoephedrine ingested 120 min before exercise influences performance during 1 h of high-intensity exercise. The effects of exercise on urinary excretion of the drug were also studied. Ten healthy male cyclists were tested on two occasions, separated by at least 7 days, by using a randomly assigned, double-blind, placebo-controlled, crossover design. Exercise performance was tested during a 40-km trial on a laboratory cycle ergometer, and skeletal muscle function was measured during isometric contractions. On a third occasion, subjects ingested 120 mg pseudoephedrine but did not exercise [control (C)]. Pseudoephedrine did not influence either time trial performance [drug (D) vs. placebo: 58.1 +/- 1.4 (SE) vs. 58.7 +/- 1.5 min] or isometric muscle function. Urinary pseudoephedrine concentrations were significantly increased 1 h after exercise (D vs. C: 114.3 +/- 27.2 vs. 35.4 +/- 13.1 micrograms/ml; P < 0.05). Peak plasma pseudoephedrine concentrations (P < 0.05) but not time taken to reach peak plasma concentrations or the area under the plasma pseudoephedrine concentration vs. time curve was significantly increased in the total group with exercise (D vs. C). In three subjects, plasma pseudoephedrine concentrations were not influenced by exercise. Only these subjects showed increased urinary pseudoephedrine excretion during exercise. We conclude that a single therapeutic dose of pseudoephedrine did not have a measurable ergogenic effect during high-intensity exercise of 1-h duration, but plasma drug concentrations and urinary excretion were altered by exercise. These findings have practical relevance to doping control regulations in international sporting competitions.
OBJECTIVE: The long-term effects of a combination of clozapine and psychosocial treatment were evaluated in a sample of treatment-refractory state hospital patients with schizophrenia. METHODS: A repeated-measure design was used. Thirty-one patients with schizophrenia received both clozapine and an enhanced psychosocial treatment program. Data were collected at baseline and at one-year, two-year, and three-year follow-ups. Psychiatric symptoms, cognitive functioning, dyskinetic movements, and discharge rate were evaluated. RESULTS: Significant reductions in psychiatric symptoms and improvement in cognitive functioning were found. Differences in the pattern of reductions in positive and negative symptoms over the course of the study were noted. The majority of subjects improved sufficiently to be discharged. CONCLUSIONS: Clozapine, when combined with psychosocial treatment, is effective for treatment of patients with schizophrenia who are not responsive to other medications.
This paper seeks to review the available educational palliative care experiences at post-basic level and explores different possibilities for current and future programmes. Central to this review is the exploration of the values and beliefs that underpin educational practice, and the relationship of these to palliative care practice. There are gaps in espoused theory, and theory in the practice of both is of critical importance. We locate our own values and beliefs in the new paradigm of human inquiry and propose that this paradigm and its methodologies have a considerable contribution to make to the development of both palliative care education and practice.
BACKGROUND: The paper describes the development of an index of the relative need for psychiatric services for the purposes of distributing NHS funds in England. METHOD: The study is based on an empirical analysis of all psychiatric in-patient completed episodes in England in 1991/92. Any index of need should be independent of the effect of variations in health care supply on the use of psychiatric services. In order to disentangle the influences of supply from social and clinical determinants of utilisation, two stage least squares regression and multilevel modelling techniques were used. RESULTS: The outcome was an index comprising six health and socio-economic variables. This is now being used by the NHS Executive to distribute about pound 2.2 billion of annual NHS expenditure for psychiatric services between English health authorities. CONCLUSION: It is shown that the index is much more sensitive to needs and therefore more redistributive than the previous index of need used in the NHS.
In female fetuses the Booroola gene (FecB(B)) is known to affect germ cell development and consequently the pattern of ovarian follicular growth during fetal and post-natal life. However in males, the role of this gene during fetal development is unknown. The aims of the study reported here were to examine the effects of the FecB(B) gene on development of male fetuses with respect to body and organ mass for example, pituitary gland, adrenal and mesonephros), testes development, including numbers of germ cells, and also the plasma concentrations or tissue contents of the reproductive hormones (FSH, LH and testosterone) at days 40, 55, 75, 90 and 135 of gestation. The FecB(B) gene was found to influence litter size, bodymass, crown-rump length and testis mass at most stages of gestation. Some effects were also noted on the mesonephros at days 40 and 55 and on the pituitary and adrenal at days 90 or 135 of gestation. However, the FecB(B) gene was not observed to have an effect on the patterns of germ cell development, on pituitary content or plasma concentrations of immunoreactive or bioactive FSH or immunoreactive LH or testicular content of testosterone. When embryo transfer experiments were performed to eliminate the effects of litter size at days 40, 90 and 135 of gestation nearly all of the differences in bodymass, crown-rump length and organ mass disappeared. The only exception to this was at day 90 when bodymass continued to be lighter and crown-rump lengths smaller in the BB/B + fetuses compared with the +2 fetuses; the significance of this finding remains unknown. It is concluded that for Booroola male fetuses there are no direct effects of the FecB(B) gene on pituitary gonadotrophin function or testicular development after sexual differentiation. Moreover, although there may be temporal differences around day 90 of gestation, there are no long-term, direct effects of the FecB(B) gene on total body, adrenal, testis or pituitary mass. Collectively these findings for the male are similar to those for female fetuses except with regard to germ cell development.
The heterogeneity of LH and FSH in the sheep fetus was studied by determining the median charge of pituitary and circulating isoforms. Pituitary extracts from male and female fetuses at days 75, 95, 120 and 135 of gestation were subjected to agarose suspension electrophoresis. For all fetuses except the day 75 age group, the median mobility of the gonadotrophin isoforms in matching serum samples from the individual fetuses were also determined. LH and FSH in extracts, peripheral samples and column eluates were measured using sensitive and specific sandwich fluoroimmunoassays for ovine gonadotrophins. The median charge of pituitary LH became more basic (P < 0.001) with gestational age, whereas for pituitary FSH more acidic forms (P < 0.001) were present in the older groups. The female fetuses had more basic pituitary isoforms of LH than the males (P < 0.01) between days 95 and 135, and for FSH at day 75 (P < 0.05). In the matching serum samples, the median charge of the LH (P < 0.001) and FSH (P < 0.05) isoforms were more acidic than those in the pituitary gland. No significant effects of age or sex were detected in the median charge of the gonadotrophin isoforms in serum, but in a number of instances the median charge could not be determined due to low serum concentrations which affected the group sizes. These data show that in the sheep fetus LH and FSH are differentially regulated in qualitative as well as quantitative terms, and that the charge of fetal gonadotrophin isoforms changes according to the age and sex of the fetus.
56 children with a clinical diagnosis of unilateral transient synovitis of the hip underwent bilateral sonographic assessment. On the anterior scan, the distance between the femoral neck and the fibrous joint capsule was measured. This distance, which we call the synovial capsular complex distance, was compared with age-dependent normal values. An increased distance was found in all 56 symptomatic hips (mean 10 mm, SD 1.8). This distance was also increased in 14 hips on the contralateral side (mean 8 mm, SD 1.6). An effusion was demonstrated in 53 symptomatic hips and in 8 hips on the contralateral side. These findings indicate that in one quarter of children with symptoms of unilateral transient synovitis the contralateral hip may have an increased synovial capsular complex distance due to synovial swelling or joint effusion, suggesting an asymptomatic synovitis. We therefore recommend a comparison of the synovial capsular complex distance on the symptomatic side with age-related normal values, in addition to a comparison with the asymptomatic hip.
This study describes the pharmacological characterization of SB 217242, a highly potent orally bioavailable nonpeptide antagonist of both endothelin type A (ETA) and endothelin type B (ETB) receptors. In human cloned ETA and ETB receptors, SB 217242 produced concentration-dependent displacement of [125]I-endothelin-1 (ET-1) in both receptor subtypes with Ki values of 1.1 and 111 nM, respectively. SB 217242 produced concentration-dependent, parallel rightward shifts in the ET-1 concentration-response curves in rat isolated aorta and human isolated pulmonary artery (ETA receptor-mediated vascular contraction) with Kb values of 4.4 and 5.0 nM, respectively. SB 217242 was 4-, 62- and 125-fold more potent as an ETA receptor antagonist than the previously reported compounds BQ-123, PD 142893 and Ro 46-2005, respectively. SB 217242 (10 microM) did not produce significant effects against contraction produced by other vasoactive agents. SB 217242 produced concentration-dependent antagonism of responses produced by ETB receptor activation as demonstrated by antagonism of sarafotoxin S6c-mediated contraction in the rabbit isolated pulmonary artery with a Kb value of 352 nM. In vitro cell monolayers of Caco-2 cells had high permeability to SB 217242. In vivo pharmacokinetics in the rat confirmed that SB 217242 was rapidly absorbed from the gastrointestinal tract with a bioavailability of 66%. The SB 217242 plasma half-life in rats after intraduodenal administration was 3.3 hr, with a systemic clearance of 27.3 ml/min/kg. Orally administered SB 217242 (0.3-30 mg/kg) produced dose-dependent inhibition of the pressor response to exogenous ET-1 in conscious rats; with a dose of 30 mg/kg p.o., inhibition was observed for at least 5.5 hr. The present study demonstrates that SB 217242 is a highly potent antagonist of both ETA and ETB receptors. In addition, SB 217242 has high in vitro permeability and high oral bioavailability. SB 217242 represents a new orally active pharmacological tool that should assist in the elucidation of the chronic role of endothelin in pathophysiology.
Individuals with Down's syndrome (DS) tend to display a reduction in size of permanent teeth, and reduced intercuspal distances in molars. A total of 51 permanent maxillary 1st molars of 26 DS children were examined from dental casts, 65 permanent maxillary 1st molars of normal children were examined from dental casts of 33 individuals. The following measurements were performed on both right and left molars (teeth 16 and 26 respectively): (1) all intercusp distance (distobuccal, db; distolingual, dl; mesiobuccal, mb; mesiolingual, ml); (2) the db-mb-ml, mb-db-ml, db-ml-mb, dl-mb-db, mb-dl-db, and dl-db-mb angles; (3) the area of the quadrangle shaped by connecting the cusp tips. All the intercusp distances were significantly smaller in the DS group. Stepwise logistic regression, applied to all the intercusp distances, was used to build a multivariate probability model for DS and normals. The mb-dl and mb-ml distances of the upper right molar (tooth 16) were sufficient to discriminate between DS and normal teeth: [table: see text] The probability for DS is higher when mb-ml is relatively higher in the mb-ml/mb-dl ratio. Another logistic analysis based on groups of angles revealed a combination of 3 angles which gave highly statistically significant discrimination between both groups: the mb-db-dl angle was higher in DS, the mb-dl-db angle was slightly smaller in DS, and the mb-ml-db angle was slightly smaller in DS. The dl cusp was located closer to the centre of the tooth. The change in size occurs at an early stage, while the change in shape occurs in a later stage of tooth formation in DS population. Our probability model for DS teeth is simple and practical because it requires only 2 intercusp distances to be put into the formula.
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PURPOSE: To investigate the clonal origin of malignant cells in recurrent superficial bladder cancer. MATERIALS AND METHODS: We compared the protein expression of p53 and retinoblastoma (Rb) by immunohistochemistry using antibody P1801 and PMG3-245, respectively, in 13 patients at the time of primary superficial bladder cancer resection (6 Ta and 7 T1) and their 15 corresponding recurrences of disease. Mutations in p53 and Rb were inferred on the basis of immunoperoxidase staining. RESULTS: At the time of initial tumor resection, a p53 mutation was observed in 5 patients (39%) and an Rb mutation was observed in 3 (23%). The p53/Rb mutation status of recurrent bladder cancers completely matched their corresponding primary bladder cancer. CONCLUSIONS: The chance that recurrent bladder cancer originated from independent clones in this study was extremely small (p < 10(-6)). This result strongly supports the monoclonal origin of recurrent superficial bladder cancer.
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A number of cell adhesion molecules (CAMs) promote neurite outgrowth following transfection and expression in a variety of monolayer cells. We have shown that N-cadherin, L1 and some isoforms of NCAM can stimulate neurite outgrowth from PC12 cells and primary neurons following transfection and expression at physiologically relevant levels in NIH-3T3 cells. A number of observations suggest that these CAMs stimulate neurite outgrowth by activating a convergent second messenger pathway in neurons rather than by modulating adhesion per se, and that an early or initial step in the pathway involves activation of a tyrosine kinase. The observation that the fibroblast growth factor receptor (FGFR) contains an evolutionarily conserved sequence with homology to the above CAMs (the CAM homology domain-CHD) points to the possibility that CAMs might interact with, and signal via, FGFR tyrosine kinases. This hypothesis has been substantiated by a number of independent experimental tests. We present a speculative model in which the evolutionary conservation of a pair of complementary binding motifs can account for a direct binding interaction between FGFR and the above three CAMs.
A practical and efficient multi-modal protocol for processing specimens for patients referred with a question of acute promyelocytic leukaemia (APL) is described. The initial analysis comprises haematological evaluation of the bone marrow and peripheral blood smears using Romanowsky-stained slides. Concomitantly, a sample is processed for direct preparation as well as 1- and 2-day unstimulated cultures using conventional cytogenetic techniques. Communication between the cytogenetic and haematological laboratories is of critical importance so that the optimal conditions for culture (i.e. longer term versus unstimulated overnight and direct preparations) for the cytogenetic detection of chromosome rearrangements can be selected. The likelihood of detecting the characteristic translocation of APL, t(15;17), is enhanced in a longer term culture versus unstimulated overnight and direct preparations. Fluorescent in situ hybridization (FISH), utilized as an adjunct to GTG-banding, was found to be a powerful technique for detecting the t(15;17), especially where the GTG-banded preparation was of suboptimal quality. Results of five recent representative cases of APL are described to illustrate a practical approach which can be adapted by any clinical pathology laboratory.