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Biomedical subjects

R Brown

Publications and source records attributed to R Brown.

At least 325 records · Page 18Linked to original sources
PubMed1996

A death-domain-containing receptor that mediates apoptosis.

The cell-killing effects of the cytokines TNF-alpha and FasL are mediated by the distinct cell-surface receptors TNFR1, TNFR2 and Fas (also known as CD95/APO-1), which are all members of a receptor superfamily that is important for regulating cell survival. The cytoplasmic regions of TNFR1 and Fas contain a conserved 'death' domain which is an essential component of the signal pathway that triggers apoptosis and activation of the transcription factor NF-kappaB (refs 5,6). Here we report the isolation of a 54K receptor that is a new member of the TNFR superfamily, using the death domain of TNFR1 in a yeast two-hybrid system. This protein, WSL-1, is most similar to TNFR1 itself, particularly in the death-domain region. The gene wsl-1 is capable of inducing apoptosis when transfected into 3T3 and 293 cells, and can also activate NF-kappaB in 293 cells. Like TNFR1, WSL-1 will homodimerize in yeast. WSL-1 also interacts specifically with the TNFR1-associated molecule TRADD. The tissue distribution is very restricted and significantly different from that of Fas and TNFR1.

Amino Acid Sequence↗
PubMed1996

Molecular cloning and tissue-specific expression of mouse kidney 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.

A 1932 bp cDNA clone encoding a novel isozyme of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFK-2/ FBPase-2) was isolated from a mouse kidney cDNA library. The sequence encodes 519 amino acids and, based on homology to rat heart genomic sequence, appears to be the product of alternative splicing from PFK-2/FBPase-2 gene B with an extended version of exon 15. Northern blot analysis indicated that this clone corresponds to an 8 kb mRNA expressed in multiple tissues, with the strongest signal in kidney, and detects several additional transcripts which may be alternatively spliced from gene B.

Alternative Splicing↗
PubMed1996

Memory impairment in schizophrenia: its' relationship to executive function.

The presence of memory impairment in schizophrenia has frequently been documented but much less attention has been given to the qualitative aspects of this impairment and its association to executive function. Using a cognitive-process approach, we examined memory and executive function in 25 patients who met DSM-III-R criteria for schizophrenia. Patients were matched with 25 healthy volunteers. The schizophrenic group was found to have a significant impairment in immediate memory, with relatively spared long-delay memory. Performance on verbal learning and recognition memory was similar to that of controls. Memory deficits were present irrespective of the encoding strategies used and were unrelated to chronicity. In addition, the schizophrenics performed worse than controls on tests of executive function, but the degree of impairment was greater on tests of response initiation and suppression. This pattern of performance resembled that found in patients with subcortical or frontal lesions which was supported by some significant correlations between aspects of memory and executive function. Our results suggest that in schizophrenia, specific executive functions may make a selective contribution to the pattern of memory performance in schizophrenia which is subserved by frontal and to a lesser extent hippocampal/diencephalic systems.

Adult↗
PubMed1996

Cisplatin and adriamycin resistance are associated with MutLalpha and mismatch repair deficiency in an ovarian tumor cell line.

In contrast to parental A2780 ovarian tumor cells, extracts of one doxorubicin-resistant and two independent cis-diamminedichloroplatinum(II)-resistant derivatives are defective in strand-specific mismatch repair. The repair defect of the three hypermutable, drug-resistant cell lines is only evident when the strand break that directs the reaction is located 3' to the mismatch, and in each case repair is restored to extracts by addition of purified MutLalpha heterodimer. As judged by immunological assay, drug resistance is associated with the virtual absence of the MutLalpha MLH1 subunit and greatly reduced levels of the PMS2 subunit. These findings implicate a functional mismatch repair system in the cytotoxic effects of these antitumor drugs and may have ramifications for their clinical application.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells.

We have examined microsatellite instability and loss of p53 function in human tumor cell line models of acquired anticancer drug resistance. We observe acquisition of an RER(+) phenotype in cell lines selected for resistance to cisplatin or doxorubicin. The majority of independent cisplatin-resistant sublines are RER(+), whereas the parental line shows no evidence of microsatellite instability. Microsatellite mutations in random, nonselected subclones of a cislatin-resistant line are observed in the absence of further drug exposure, suggesting that the RER(+) phenotype is a stable phenotype rather than being transiently induced by DNA damage. Furthermore, a cisplatin-resistant derivative shows reduction in a G:T mismatch recognition activity compared to the parental line. Independent lines selected by multiple exposure to cisplatin show resistance factors of up to a 5-fold by clonogenic assay and have reduced cisplatin-induced apoptosis. The resistant lines that are RER(+) show evidence of loss of p53-dependent functions, as measured by a loss of radiation-induced G(1) arrest and reduced CIP1 mRNA. Induced loss of p53 function by transfection of mutant TP53 does not cause a detectable RER(+) phenotype. We speculate that tolerance of DNA damage and expansion of cells with an RER(+) phenotype may select for reduced ability to engage apoptosis and loss of p53 function.

Antibiotics, Antineoplastic↗
PubMed1996

Quantitative analysis of collagen gel contractile forces generated by dermal fibroblasts and the relationship to cell morphology.

The force generated in granulation tissue during wound contraction is thought to be cell mediated; however, it is unclear whether contractile forces are generated by fibroblast locomotion or contraction of myofibroblasts. To help clarify this question the force of this contraction can now be determined accurately in a human dermal fibroblast collagen lattice system using a novel instrument known as a Culture Force Monitor. Three distinct phases of contraction of such collagen gels could be identified over the first 24 hours. Most of the force generated by human dermal fibroblasts was produced during the first stage in parallel with cell attachment and associated changes in cell shape, and the appearance of cell processes. During this initial 24 hours no evidence could be found for the presence of myofibroblasts, but stereoscopic and electron microscopic analysis at a range of time points indicated that migratory fibroblasts were present in the system. Comparison of the contraction profiles of cells extracted from other tissues (tendon and articular cartilage), and extracted by different means from the same tissue specimen, indicated that different populations of fibroblasts can be distinguished on the basis of their pattern of contractions. It would seem that most of the force generated in this model is a result of fibroblast attachment and movement within the collagen lattice. Furthermore, different groups of fibroblasts, even within the same tissue, may vary in their contraction (hence locomotory) activity.

Animals↗
PubMed1996

Core Assessment Program for Intracerebral Transplantation in Huntington's Disease (CAPIT-HD).

Studies in Parkinson's disease using the Core Assessment Program for Intracerebral Transplantation (CAPIT) protocol have demonstrated that grafts of embryonic mesencephalic cells into striatum can survive, grow, and exert useful clinical effects. Attention in now being directed toward neural grafting in other conditions, such as Huntington's disease. As a precondition for grafting of embryonic striatal cells into diseased striatum in this complex motor and psychiatric disorder, not only is further basic research needed, but also a thorough and wide-ranging assessment protocol is essential. This article presents such a CAPIT-HD assessment protocol.

Animals↗
PubMed1996

Cell-cycle arrest and p53 accumulation induced by geldanamycin in human ovarian tumour cells.

We have analysed the cell-cycle arrests and cytotoxicity of the A2780 human ovarian cell line in response to geldanamycin, a benzoquinoid ansamycin that can inhibit tyrosine kinases. Geldanamycin causes a dose-dependent G2 arrest and reversible inhibition of entry into the S phase in A2780 cells. After a 3-h exposure to 0.1 microM geldanamycin, the cells show an increase in accumulation of p53 protein that is maximal at 24 h after drug exposure. Increased p53 levels can be induced in cells by DNA-damaging agents; however, using alkaline elution and sister chromatid exchange assays we detect no DNA damage induced by geldanamycin. Using dominant negative mutant TP53 transfectants of A2780 we have analysed the possible dependence of geldanamycin-induced cell-cycle arrests on the presence of functional p53. We observe no difference in cell-cycle arrests in mutant p53 transfectants known to have the p53-DNA damage-response pathway inactivated as compared with vector-alone controls. Similarly, we observe no difference in clonogenic resistance to the cytotoxicity of geldanamycin in these cells. These results suggest that geldanamycin can induce increased p53 protein by a mechanism not involving DNA damage. Furthermore, the cell-cycle arrests and cytotoxic effects of geldanamycin in these cells are not mediated by p53-dependent pathways.

Antibiotics, Antineoplastic↗
PubMed1996

Regression of left ventricular hypertrophy in patients with essential hypertension. Results of 6 month treatment with indapamide.

Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity in hypertensive patients. The effects of diuretics on LVH have raised controversies, but recent studies suggest that diuretics are able to reduce LVH in hypertensive patients, mainly through a reduction in ventricular diameter. The present multicenter open study was designed to test the effects of indapamide, a widely used nonthiazide diuretic, on LVH in patients with essential hypertension. Patients had to have mild-to-moderate essential hypertension (supine diastolic blood pressure [sDBP] 95 to 115 mm Hg) with echocardiographic evidence of LVH (left ventricular mass index [LVMI] > 130 g/m2 for men and > 110 g/m2 for women). After a 2 week placebo run-in period, eligible patients underwent a 6 month treatment with 2.5 mg indapamide daily. All echograms were performed by the same investigator before and after 6 months of indapamide. Clinical and biological acceptability and quality of life (visual analog scale) were also studied. One hundred and thirty patients were included in the study and 112 completed the trial. Indapamide induced a significant reduction i systolic and diastolic blood pressures. Indapamide induced a marked reduction in posterior wall thickness (from 12.1 +/- 2.0 to 11.2 +/- 1.6 mm) and in interventricular wall thickness (from 12.7 +/- 1.7 to 11.8 +/- 1.9 mm; each P < .001) and a slight decrease in left ventricular diameter (P = .049). This resulted in a 13% reduction in LVMI (from 161.9 +/- 37.9 to 140.7 +/- 33.8 g/m2, P < .001). Left ventricular fractional shortening remained unchanged. There was no significant relation between changes in LVMI and changes in systolic, diastolic, or mean blood pressure. No significant adverse clinical or biological effects were reported during the study. The increased score of the visual analog scale indicated that overall well-being was improved (P < .001). Our study indicates that indapamide, in addition to blood pressure control, is able to reduce LVH. This effect was achieved mainly through a reduction in wall thicknesses rather than in internal cavity diameter.

Adult↗
PubMed1996

Clinical use of posterior electrocardiographic leads: a prospective electrocardiographic analysis during coronary occlusion.

Posterior electrocardiographic leads have been described for quite a while; however, their use in diagnosing acute posterior wall myocardial infarction and identifying infarct-related arteries has not been well used. We prospectively studied electrocardiographic changes during balloon occlusion of single-vessel right coronary artery (RCA) and circumflex coronary arteries (LCX). Thirty four inflations were performed in RCAs and 38 in LCXS. Analysis of the patients with ECG changes revealed that the most common ECG change during RCA occlusion was inferior ST-segment elevation in leads II, III, and aVF (95 percent), and the most common change during LCX occlusion was posterior ST elevation in leads V7, V8, and V9 (68 percent). ST elevation was always seen in inferior leads in the RCA group and in posterior leads in the LCX group. Thus posterior leads helped identify RCA versus LCX as the infarct-related artery. ST elevation was also noted by posterior leads in seven (36.8 percent) additional patients. Thus there was a definite added benefit of posterior leads during LCX occlusion. In the appropriate clinical setting, posterior leads may help in differentiating LCX occlusion from RCA occlusion.

Angioplasty, Balloon, Coronary↗
PubMed1996

Prenatal diagnosis of triploidy during the second trimester of pregnancy.

OBJECTIVE: To analyze the results of prenatal findings and the outcome of triploidy and to organize an efficient approach to prenatal diagnosis during the second trimester. METHODS: We reviewed 70 cases of triploidy presenting between 13 and 29 weeks' gestation over a 10-year period. RESULTS: Each fetus had at least one measurement below the normal range, and 50 cases (71.4%) presented with asymmetrical growth restriction and normal placental appearance. All cases of triploidy associated with partial mole were diagnosed before 25 weeks. Structural fetal defects were observed antenatally in 65 (92.9%) cases. The most common defects were abnormalities of the hands (52.3%), bilateral cerebral ventriculomegaly (36.9%), heart anomalies (33.8%), and micrognathia (26.2%). The most frequent combination of abnormalities was malformation of the hands and ventriculomegaly. Decreased red blood cell counts and high mean cell volume were found in the 50 cases tested. Vaginal bleeding in the first or second trimester was the most common maternal symptom reported. CONCLUSIONS: The major features that should alert the sonographer to the possible diagnosis of triploidy are partial molar changes or severe asymmetrical fetal growth restriction in the presence of an apparently normal placenta.

Adult↗
PubMed1996

New members of the Bcl-2 family and their protein partners.

Any model of apoptosis must explain the mechanism of action of the Bcl-2 family of proteins. This has proved to be unusually difficult. This review concentrates on some of the newly isolated members of this growing family and attempts to provide an insight into the complexity of interactions through which the Bcl-2 proteins modulate apoptosis.

Animals↗
PubMed1996

Helicobacter pylori in dental plaque and gastric mucosa.

OBJECTIVE: The aim of this study was to investigate the presence of Helicobacter pylori in both dental plaque and gastric mucus. STUDY DESIGN: Dental scaling hand instruments were used to collect supragingival and subgingival dental plaque from 81 dentate participants. Denture plaque was obtained from the fitting surfaces of dentures from 41 edentulous patients. Gastric mucus from gastric mucosa of antrum and body of stomach were collected from all 122 participants (92% white) with soft gastroscopic brush. These samples were dispersed in modified urea broth and normal saline solution before being inoculated onto selective Skirrow's agar and incubated in a microaerophilic atmosphere for culturing H. pylori. RESULTS: Dental plaque from all dentate participants was negative for H. pylori culture. Only one 80-year-old edentulous patient had positive H. pylori culture in both gastric mucus and denture plaque. CONCLUSIONS: Although dental plaque has a mixed flora that may act as a reservoir for gastric reinfection, dental plaque could not be implicated as the major reservoir of H. pylori for gastric reinfection.

Aged↗
PubMed1996

Realistic animation of human figures using artificial neural networks.

We describe a new approach to the animation of human figures which can produce realistic animation and based on artificial neural networks (ANN). A fully connected ANN is trained with inputs and outputs of key frames obtained from image analysis and key postures and parameters of standing, walking and running. A behaviour index is introduced as an input to the ANN. Each index is unique to each behaviour. Other inputs include speed, cycle history and subsystem index. The subsystem index refers to the different subsystem of the human figure e.g. the right leg is a subsystem referred to by an index. The outputs are the joints displacements. The ANN is trained using the back propagation method. The ANN was able to generate realistic animations of walking and running and could merge three different behaviours, standing, walking and running. The proposed method should enable design evaluations, human factors analysis, task simulation and motion understanding easier for non-animation experts.

Biomechanical Phenomena↗
PubMed1996

The labelling index of primitive plasma cells determines the clinical behaviour of patients with myelomatosis.

For patients with multiple myeloma the most important laboratory correlate of prognosis and disease activity is the bromodeoxyuridine (BrdUrd) plasma cell labelling index (LI). However, the traditional immunofluorescent microscope LI technique, like other manual enumeration assays, can suffer from poor precision and accuracy. In this study the LI of different subpopulations of plasma cells (CD38++) as determined by flow cytometry was correlated with disease state. The mean LI of the total CD38++ population was significantly higher (2.7 +/- 0.4%) than the LI determined by the traditional slide technique (0.6 +/- 0.1%) for 65 samples tested. Primitive plasma cells (CD38++, CD45++) had a higher labelling index than mature plasma cells (CD38++, CD45-) (7.0 +/- 1.3% v 1.8% +/- 0.3%) and in one patient the LI of the primitive plasma cells was 46%. In addition, the LI of the mature plasma cells was lower than the total plasma cell population. As expected, there was a significant difference between the LI of patients in plateau phase and progressive disease but this difference was greatest when the LI of the primitive plasma cells was studied (9.2 +/- 2.9% v 2.2 +/- 0.7%; z = 19.9, P < 0.001). This study has raised some concerns about the sensitivity and accuracy of the traditional labelling index and has shown that the increased LI associated with progressive disease is almost entirely attributable to an increase in the LI of the primitive plasma cell subpopulation and that the LI of primitive plasma cells provides a more clinically significant correlation with disease status than the traditional assay.

ADP-ribosyl Cyclase↗
PubMed1996

The underestimated role of temporal comparison: a test of the life-span model.

The assumption of the life-span model (Suls & Mullen 1982)--that age affects the way people make comparisons--was tested. Three groups of participants in England--young adults (18-39 years old; n = 83), middle-aged adults (40-64 years old; n = 52), and older adults (65-87 years old; n = 50) completed a questionnaire that assessed preference for temporal comparison or social comparison. Although the present results support the general assumption of the life-span model, they suggest that preferences for comparison processes develop in accordance with another pattern. Consistent with the life-span model, the present results indicate that temporary comparison is more important for young and middle-aged adults than researchers have assumed.

Adolescent↗
PubMed1996

Does age or pseudocholinesterase activity predict mivacurium infusion rate in children?

Previous studies have suggested that the mivacurium infusion rate to maintain target twitch depression is greater in children than in adults, and that there is only a limited relationship between pseudocholinesterase activity and mivacurium infusion rate in children. We therefore examined whether mivacurium infusion rates are larger in children than in adults, and whether pseudocholinesterase activity influences mivacurium infusion rate in children. In 20 children aged 1-9 yr, mechanical twitch response to ulnar nerve train-of-four stimulation was measured; concurrent data were obtained in 14 adults aged 18-58 yr. All patients were anesthetized with N2O and isoflurane, 0.75 minimum alveolar anesthetic concentration (MAC) (age-adjusted). Mivacurium was infused at constant rates for > 15 min targeting 50% and 90% twitch depression. The Hill equation was fit to the resulting values for twitch depression versus mivacurium infusion rate to predict infusion rates producing 50% and 90% twitch depression (IR50 and IR90, respectively). The relationship of IR50 and IR90 to pseudocholinesterase activity was determined by linear regression; values for children and adults were compared by analysis of covariance. For children, IR50 (r2 = 0.22, P = 0.038) but not IR90 (r2 = 0.11 P = 0.21) was related to pseudocholinesterase activity. Infusion rates were approximately twice as large in children as in adults. We confirm that mivacurium infusion rates are larger in children than in adults and demonstrate a relationship between pseudocholinesterase activity and infusion rates.

Adult↗