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Biomedical subjects

A Brown

Publications and source records attributed to A Brown.

At least 127 records · Page 7Linked to original sources
PubMed2000

Gastrointestinal autonomic nerve sarcoma presenting as a giant intra-abdominal cyst.

Gastrointestinal autonomic nerve sarcomas are rare tumours. A 36-year-old man presented with abdominal pain, distension and constipation. Abdominal ultrasound and CT scanning demonstrated a giant cystic intra-abdominal mass. Laparotomy confirmed a large cystic mass arising from the ileum with multiple metastases. Immunohistochemical staining was positive for vimentin, neuronal-specific enolase and PGP9.5. This is the first reported case to present as a giant intra-abdominal cyst. Specialist histopathological and immunohistochemical analysis is essential to establish the diagnosis of this rare tumour.

Abdomen↗
PubMed2000

Can readmission after stroke be prevented? Results of a randomized clinical study: a postdischarge follow-up service for stroke survivors.

BACKGROUND AND PURPOSE: About 50% of stroke survivors are discharged to their homes with lasting disability. Knowledge, however, of the importance of follow-up services that targets these patients is sparse. The purpose of the present study was to evaluate 2 models of follow-up intervention after discharge. The study hypothesis was that intervention could reduce readmission rates and institutionalization and prevent functional decline. We report the results regarding readmission. METHODS: This randomized study included 155 stroke patients with persistent impairment and disability who, after the completion of inpatient rehabilitation, were discharged to their homes. The patients were randomized to 1 of 2 follow-up interventions provided in addition to standard care or to standard aftercare. Fifty-four received follow-up home visits by a physician (INT1-HVP), 53 were provided instructions by a physiotherapist in their home (INT2-PI), and 48 received standard aftercare only (controls). Baseline characteristics for the 3 groups were comparable. Six months after discharge, data were obtained on readmission and institutionalization. RESULTS: The readmission rates within 6 months after discharge were significantly lower in the intervention groups than in the control group (INT1-HVP 26%, INT2-PI 34%, controls 44%; P=0.028). Multivariate analysis of readmission risk showed a significant favorable effect of intervention (INT1-HVP or INT2-PI) in interaction with length of hospital stay (P=0.0332), indicating that the effect of intervention was strongest for patients with a prolonged inpatient rehabilitation. CONCLUSIONS: Readmission is common among disabled stroke survivors. Follow-up intervention after discharge seems to be a way of preventing readmission, especially for patients with long inpatient rehabilitation.

Aged↗
PubMed2000

Relation of familial schizophrenia to negative symptoms but not to the deficit syndrome.

OBJECTIVE: Although a family history of schizophrenia has been associated with negative symptoms, family history is inconsistently related to the presence of the deficit syndrome. METHOD: The authors assessed family history and the deficit syndrome in 99 patients with DSM-III-R-diagnosed schizophrenia who were assessed during clinical treatment. Of these 99 patients, 45 were assessed both while antipsychotic free and during antipsychotic treatment to index their treatment response. RESULTS: Patients with (N=39) and without (N=60) a family history of schizophrenia had similar proportions of the deficit syndrome. Yet family history and deficit syndrome categorizations identified a group with greater negative symptoms on the Positive and Negative Syndrome Scale. Those with a family history had greater emotional withdrawal, poor rapport, and lack of spontaneity. Groups with and without the deficit syndrome similarly differed in these symptoms but also in affective blunting, motor retardation, and passive or apathetic social withdrawal. The study involving antipsychotic-free and antipsychotic treatment phases showed main medication effects explaining positive, psychopathology, depression, and activation symptoms but not negative symptoms. Only patients without a family history had improved negative symptoms with antipsychotic treatment. CONCLUSIONS: Patients with a family history of schizophrenia had greater and more treatment-resistant negative symptoms than those without a family history. They were not more likely to have the deficit syndrome. The group with a family history had more pathology only in negative symptoms related to psychosocial function. The stable negative symptoms specifically related to the genetic vulnerability to inherit schizophrenia might be those associated with psychosocial functioning.

Adaptation, Psychological↗
PubMed2000

The pharmacokinetics and tolerability of the oral neuraminidase inhibitor oseltamivir (Ro 64-0796/GS4104) in healthy adult and elderly volunteers.

The tolerability and pharmacokinetics of Ro 64-0802, a potent, selective inhibitor of influenza neuraminidase, and its oral prodrug oseltamivir were investigated in three double-blind, placebo-controlled studies. Two studies involved healthy adult volunteers (18-55 years) (n = 48) who received single (20-1000 mg) or bid doses (50-500 mg) (n = 32) of oseltamivir or placebo for 7 days. Healthy elderly volunteers (> or = 65 years) (n = 24) received oseltamivir 100 to 200 mg bid or placebo for 7 days in a third study. Measurable plasma concentrations of the active metabolite appeared rapidly in plasma and were significantly higher and longer lasting than those of oseltamivir. Pharmacokinetics of both compounds were linear. Multiple-dose exposure was predictable from single-dose data, and steady-state plasma concentrations were achieved within 3 days of bid drug administration. Oseltamivir was well tolerated at single doses of up to 1000 mg and twice-daily doses of up to 500 mg. Adverse events were mild in intensity. Exposure to both prodrug and active metabolite was increased in elderly patients by approximately 25%. However, due to the wide safety margin of both compounds, no dose adjustment is necessary for elderly patients.

Acetamides↗
PubMed2000

Asymptomatic occlusion of the left main coronary artery by an aortic pseudoaneurysm.

Extrinsic compression of the left main coronary artery is a rare cause of coronary ischemia. We describe a 35-year-old Asian woman with complete asymptomatic occlusion of the left main coronary artery by a large aortic pseudoaneurysm. She underwent repair of the pseudoaneurysm and coronary artery bypass grafting at the Mayo Clinic in Rochester, Minn. The differential diagnosis is discussed. Based on this patient's age and associated vascular lesions, we conclude that Takayasu arteritis was the most likely cause of her condition.

Adult↗
PubMed2000

Telemedicine improved diabetic management.

Effective control of diabetes is known to delay or prevent the end-organ complications of this disease. Can telemedicine improve a patient's ability to self-manage diabetes? Twenty-eight patients entered a study comparing home telemedicine consultation with standard outpatient care. A nurse case manager contacted the telemedicine group once a week under the direction of a primary care physician, who contacted the telemedicine group once a month. Laboratory studies and total body weight were measured at the beginning and at the end of the 3-month study. The hemoglobin A1c (HbA1c) and total body weight improved significantly in the intervention (telemedicine) group, as shown by a 16% reduction in mean HbA1c level (from 9.5 to 8.2%) and a 4% mean weight reduction (from 214.3 to 206.7 pounds). Based on our experience, we present a functionally based telemedicine classification system to improve the application of electronic medicine in future studies.

Adult↗
PubMed1999

Chemically synthesized ubiquitin extension proteins detect distinct catalytic capacities of deubiquitinating enzymes.

We have used solid-phase chemistry to synthesize proteins equivalent to a human ubiquitin precursor (ubiquitin-52-amino-acid ribosomal protein fusion; UBICEP52) and representative of isopeptide-linked ubiquitin-protein conjugates [ubiquitin-(epsilonN)-lysine]; these proteins were precisely cleaved by a purified recombinant Drosophila deubiquitinating enzyme (DUB), UCH-D. Along with the previously synthesized ubiquitin-(alphaN)-valine, these synthetic proteins were used as substrates to assess the catalytic capacities of a number of diverse DUBs expressed in Escherichia coli: human HAUSP; mouse Unp; and yeast Ubps 1p, 2p, 3p, 6p, 11p, and 15p and Yuh1p. Distinct specificities of these enzymes were detected; notably, in addition to UCH-D, isopeptidase activity [ubiquitin-(epsilonN)-lysine cleavage] was only associated with Yuh1p, Unp, Ubp1p, and Ubp2p. Additionally, human placental 26S proteasomes were only able to cleave UBICEP52 and ubiquitin-(epsilonN)-lysine, suggesting that 26S proteasome-associated DUBs are class II-like. This work demonstrates that the synthetic approach offers an alternative to recombinant methods for the production of small proteins in vitro.

Animals↗
PubMed1999

Aggregation of RANTES is responsible for its inflammatory properties. Characterization of nonaggregating, noninflammatory RANTES mutants.

The biology of RANTES (regulated on activation normal T cell expressed) aggregation has been investigated using RANTES and disaggregated variants, enabling comparison of aggregated, tetrameric, and dimeric RANTES forms. Disaggregated variants retain their G(i)-type G protein-coupled receptor-mediated biological activities. A correlation between RANTES aggregation and cellular activation has been demonstrated. Aggregated RANTES, but not disaggregated RANTES, activates human T cells, monocytes, and neutrophils. Dimeric RANTES has lost its cellular activating activity, rendering it noninflammatory. Macrophage inflammatory protein 1alpha, macrophage inflammatory protein-1beta, and erythrocytes are potent natural antagonists of aggregated RANTES-induced cellular activation. There is a clear difference in the signaling properties of aggregated and disaggregated RANTES forms, separating the dual signaling pathways of RANTES and the enhancing and suppressive effects of RANTES on human immunodeficiency virus infection. Disaggregated RANTES will be a valuable tool to explore the biology of RANTES action in human immunodeficiency virus infection and in inflammatory disease.

Amino Acid Substitution↗
PubMed1999

Manipulation of cholesterol and cholesteryl ester synthesis has multiple effects on the metabolism of apolipoprotein B and the secretion of very-low-density lipoprotein by primary hepatocyte cultures.

Inhibition of esterified and non-esterified cholesterol synthesis by lovastatin in primary rat hepatocytes suppressed the net synthesis and very-low-density lipoprotein (VLDL) secretion of apolipoprotein B (apoB)-48 and apoB-100. Lovastatin did not alter the rates of apoB-48 and apoB-100 post-translational degradation. 25-Hydroxycholesterol, which inhibited non-esterified cholesterol synthesis but increased the synthesis of cholesteryl ester, showed differential effects on the metabolism of apoB-48 and apoB-100. Whereas the secretion of apoB-48 VLDL was suppressed there was no effect on the secretion of apoB-100 VLDL. The post-translational degradation of apoB-48, but not of apoB-100, was enhanced by 25-hydroxycholesterol. The net synthesis rates of apoB-48 and apoB-100 were unaffected by 25-hydroxycholesterol. The inhibitory effect of lovastatin alone on the net synthesis of apoB-48 and apoB-100 was reversed by the simultaneous presence of 25-hydroxycholesterol, suggesting a role for newly synthesised cholesteryl ester. Prevention of the reversal effect by the acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor YM 17E supported this interpretation. In the presence of lovastatin, restoration of the net synthesis of apoB by 25-hydroxycholesterol was not accompanied by an increased VLDL output of apoB-48 and apoB-100. However, under these conditions there was an increased post-translational degradation of apoB-48 and apoB-100. These results suggest that interference with intracellular cholesterol and cholesteryl ester metabolism interrupts VLDL assembly at sites of both apoB net synthesis and post-translational degradation.

Animals↗
PubMed1999

Clinical pathways.

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Critical Pathways↗
PubMed1999

Identification of amino acid residues critical for aggregation of human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES. Characterization of active disaggregated chemokine variants.

Human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation normal T cell expressed) self-associate to form high-molecular mass aggregates. To explore the biological significance of chemokine aggregation, nonaggregating variants were sought. The phenotypes of 105 hMIP-1alpha variants generated by systematic mutagenesis and expression in yeast were determined. hMIP-1alpha residues Asp26 and Glu66 were critical to the self-association process. Substitution at either residue resulted in the formation of essentially homogenous tetramers at 0.5 mg/ml. Substitution of identical or analogous residues in homologous positions in both hMIP-1beta and RANTES demonstrated that they were also critical to aggregation. Our analysis suggests that a single charged residue at either position 26 or 66 is insufficient to support extensive aggregation and that two charged residues must be present. Solution of the three-dimensional NMR structure of hMIP-1alpha has enabled comparison of these residues in hMIP-1beta and RANTES. Aggregated and disaggregated forms of hMIP-1alpha, hMIP-1beta, and RANTES generally have equivalent G-protein-coupled receptor-mediated biological potencies. We have therefore generated novel reagents to evaluate the role of hMIP-1alpha, hMIP-1beta, and RANTES aggregation in vitro and in vivo. The disaggregated chemokines retained their human immunodeficiency virus (HIV) inhibitory activities. Surprisingly, high concentrations of RANTES, but not disaggregated RANTES variants, enhanced infection of cells by both M- and T-tropic HIV isolates/strains. This observation has important implications for potential therapeutic uses of chemokines implying that disaggregated forms may be necessary for safe clinical investigation.

Amino Acid Sequence↗
PubMed1999

Remarkable stabilization of zwitterionic intermediates may account for a billion-fold rate acceleration by thiamin diphosphate-dependent decarboxylases.

When the E91D variant of apo-yeast pyruvate decarboxylase (EC 4.1.1. 1) is exposed to C2alpha-hydroxybenzylthiamin diphosphate, this putative intermediate is partitioned on the enzyme between release of the benzaldehyde product (as evidenced by regeneration of active enzyme) and dissociation of the proton at C2alpha to form the enamine-C2alpha-carbanion intermediate. While the pKa (the negative log of the acid dissociation constant) for this dissociation is approximately 15.4 in water, formation of the enamine at pH 6.0 on the enzyme indicates a >9 unit pKa suppression by the enzyme environment. The dramatic stabilization of this zwitterionic enamine intermediate at the active center is sufficient to account for as much as a 10(9)-fold rate acceleration on the enzyme. This "solvent" effect could be useful for achieving the bulk of the rate acceleration provided by the protein over and above that afforded by the coenzyme on all thiamin diphosphate-dependent 2-oxo acid decarboxylases.

Binding Sites↗
PubMed1999

Noncytopathic clearance of lymphocytic choriomeningitis virus from the hepatocyte.

We have previously shown that interferon and tumor necrosis factor noncytopathically abolish hepatitis B virus (HBV) replication from the hepatocyte and kidney tubular epithelial cells in vivo. Here we show that a persistent lymphocytic choriomeningitis virus (LCMV) infection is cleared from the hepatocyte noncytopathically when the same cytokines are induced in the liver by antigen-nonspecific stimuli. These results indicate that, like HBV, LCMV is also susceptible to intracellular inactivation by cytokine-induced antiviral mechanisms that are operative in the hepatocyte. In contrast, LCMV is not cleared from intrahepatic nonparenchymal cells or splenocytes, indicating that, unlike the hepatocyte, these cells do not produce the factors required to inactivate LCMV. Antiviral mechanisms like these may have evolved to maintain the functional integrity of vital organs in the face of massive infection.

Adenoviridae↗
PubMed1999

Cloning and localization of Rab3 isoforms in bovine, rat, and human parathyroid glands.

Rab3 proteins are small GTP-binding proteins known to play a role in regulated exocytosis processes. This study examines the expression of Rab3 mRNA and protein in bovine, rat and human parathyroid glands. mRNAs of several Rab3 isoforms were detected in bovine (Rab3A, Rab3B and Rab3C) and rat (Rab3A, Rab3B and Rab3D) parathyroid glands by RT-PCR and sequencing. Rab3A protein was detected in the cytosolic extract from bovine parathyroid gland by Western blotting using a monoclonal antibody for Rab3A. Rab3A protein was localized to parathyroid hormone-containing chief cells by immunohistochemical staining. Subcellular localization of Rab3A protein by immunogold electron microscopy revealed that the majority of Rab3A protein was not associated with dense-core vesicles, but localized in the cytosol of the chief cells. Altogether, our results demonstrate that Rab3 isoforms are expressed in parathyroid chief cells, suggesting that they may play a role in regulated exocytosis in these cells.

Animals↗
PubMed1999

Hospital in the home: a randomised controlled trial.

OBJECTIVES: To compare treatment of acute illness at home and in hospital, assessing safety, effect on geriatric complications, and patient/carer satisfaction. DESIGN: Randomised controlled trial. SETTING: A tertiary referral hospital affiliated with the University of New South Wales. PARTICIPANTS: 100 patients (69% older than 65 years) with a variety of acute conditions, who were assessed in the emergency department as requiring admission to hospital. INTERVENTIONS: Patients were allocated at random to be treated by a hospital-in-the-home (HIH) service in their usual residence or to be admitted to hospital. MAIN OUTCOME MEASURES: Geriatric complications (confusion, falls, urinary incontinence or retention, faecal incontinence or constipation, phlebitis and pressure areas), patient/carer satisfaction, adverse events, and death. RESULTS: There was a lower incidence of confusion (0 v. 20.4% [95% CI, 9.1%-31.7%]; P = 0.0005), urinary complications (incontinence or retention) (2.0% [95% CI, -1.8%, 5.8%] v. 16.3% [95% CI, 6.0%, 26.6%]; P = 0.01), and bowel complications (incontinence or constipation) (0 v. 22.5% [95% CI, 10.7%, 34.1%]; P = 0.0003) among HIH-treated patients. No significant difference in number of adverse events and deaths (to 28 days after discharge) in the two groups was found (although numbers were small). Patient and carer satisfaction was significantly higher in the HIH group. CONCLUSIONS: Home treatment appears to provide a safe alternative to hospitalisation for selected patients, and may be preferable for some older patients. We found high levels of both patient and carer satisfaction with home treatment.

Aged↗
PubMed1999

Slow axonal transport of neurofilament protein in cultured neurons.

We have investigated the axonal transport of neurofilament protein in cultured neurons by constricting single axons with fine glass fibers. We observed a rapid accumulation of anterogradely and retrogradely transported membranous organelles on both sides of the constrictions and a more gradual accumulation of neurofilament protein proximal to the constrictions. Neurofilament protein accumulation was dependent on the presence of metabolic substrates and was blocked by iodoacetate, which is an inhibitor of glycolysis. These data indicate that neurofilament protein moves anterogradely in these axons by a mechanism that is directly or indirectly dependent on nucleoside triphosphates. The average transport rate was estimated to be at least 130 micrometer/h (3.1 mm/d), and approximately 90% of the accumulated neurofilament protein remained in the axon after detergent extraction, suggesting that it was present in a polymerized form. Electron microscopy demonstrated that there were an abnormally large number of neurofilament polymers proximal to the constrictions. These data suggest that the neurofilament proteins were transported either as assembled polymers or in a nonpolymeric form that assembled locally at the site of accumulation. This study represents the first demonstration of the axonal transport of neurofilament protein in cultured neurons.

Animals↗
PubMed1999

A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway.

The yeast serine/threonine kinase STE20 activates a signaling cascade that includes STE11 (mitogen-activated protein kinase kinase kinase), STE7 (mitogen-activated protein kinase kinase), and FUS3/KSS1 (mitogen-activated protein kinase) in response to signals from both Cdc42 and the heterotrimeric G proteins associated with transmembrane pheromone receptors. Using degenerate polymerase chain reaction, we have isolated a human cDNA encoding a protein kinase homologous to STE20. This protein kinase, designated HPK/GCK-like kinase (HGK), has nucleotide sequences that encode an open reading frame of 1165 amino acids with 11 kinase subdomains. HGK was a serine/threonine protein kinase that specifically activated the c-Jun N-terminal kinase (JNK) signaling pathway when transfected into 293T cells, but it did not stimulate either the extracellular signal-regulated kinase or p38 kinase pathway. HGK also increased AP-1-mediated transcriptional activity in vivo. HGK-induced JNK activation was inhibited by the dominant-negative MKK4 and MKK7 mutants. The dominant-negative mutant of TAK1, but not MEKK1 or MAPK upstream kinase (MUK), strongly inhibited HGK-induced JNK activation. TNF-alpha activated HGK in 293T cells, as well as the dominant-negative HGK mutants, inhibited TNF-alpha-induced JNK activation. These results indicate that HGK, a novel activator of the JNK pathway, may function through TAK1, and that the HGK --> TAK1 --> MKK4, MKK7 --> JNK kinase cascade may mediate the TNF-alpha signaling pathway.

Amino Acid Sequence↗