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Biomedical subjects

A Bell

Publications and source records attributed to A Bell.

At least 73 records · Page 4Linked to original sources
PubMed1998

The effect of F-actin on the binding and hydrolysis of guanine nucleotide by Dictyostelium elongation factor 1A.

Indirect evidence implicates actin as a cofactor in eukaryotic protein synthesis. The present study directly examines the effects of F-actin on the biochemical properties of eukaryotic elongation factor 1A (eEF1A, formerly EF1alpha), a major actin-binding protein. The basal mechanism of eEF1A alone is determined under physiological conditions with the critical finding that glycerol and guanine nucleotide are required to prevent protein aggregation and loss of enzymatic activity. The dissociation constants (Kd) for GDP and GTP are 2.5 microM and 0.6 microM, respectively, and the kcat of GTP hydrolysis is 1.0 x 10(-3) s-1. When eEF1A binds to F-actin, there is a 7-fold decrease in the affinity for guanine nucleotide and an increase of 35% in the rate of GTP hydrolysis. Based upon our results and the relevant cellular concentrations, the predominant form of cellular eEF1A is calculated to be GTP.eEF1A.F-actin. We conclude that F-actin does not significantly modulate the basal enzymatic properties of eEF1A; however, actin may still influence protein synthesis by sequestering GTP.eEF1A away from interactions with its known translational ligands, e.g. aminoacyl-tRNA and ribosomes.

Actins↗
PubMed1998

A family with attenuated familial adenomatous polyposis due to a mutation in the alternatively spliced region of APC exon 9.

A family is presented with attenuated familial adenomatous polyposis of variable phenotype. The clinical features range from sparse right-sided polyposis and cancer in the proximal colon at the age of 34 to pan-colonic polyposis and cancer at the age of 68. Rectal sparing is common to all affected members. Heteroduplex analysis detected bands of altered mobility in exon 9 of the APC gene in all affected family members. Subsequently, a frameshift mutation was found in the alternatively spliced region of exon 9 at codon 398 which resulted in a stop signal 4 codons downstream. Alternatively spliced transcripts that delete the mutation were readily amplified from normal colonic mucosa and therefore create a mechanism for the attenuated phenotype seen in this family.

Adenomatous Polyposis Coli↗
PubMed1998

Plasmodium chabaudi chabaudi and P. falciparum: inhibition of aminopeptidase and parasite growth by bestatin and nitrobestatin.

The major leucine aminopeptidase of the rodent malarial parasite Plasmodium chabaudi chabaudi was partially purified using a combination of high-pressure liquid chromatography on a size-exclusion column and affinity chromatography using the aminopeptidase-specific inhibitor bestatin as the ligand. The purified enzyme showed simple Michaelis-Menten kinetics when the fluorogenic peptide analogue leucyl-7-amino-4-methyl-courmarin served as the substrate, and it was strongly inhibited by both bestatin (Ki = 50.7 +/- 21.0 nM) and nitrobestatin (Ki = 2.51 +/- 0.2 nM) in a competitive manner. These inhibitors were also potent blockers of the growth of P. c. chabaudi and the human parasite P. falciparum in culture, and nitrobestatin was again the more potent. Therefore, the leucine aminopeptidase represents an important target to which novel anti-malarial agents could be directed.

Animals↗
PubMed1998

Microtubule inhibitors as potential antimalarial agents.

The Steering Committee on Drugs for Malaria (CHEMAL) of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) has identified tubulin as a potential drug target, but one that is not yet ;validated'. Several inhibitors of tubulins, the principal proteins of microtubules, are potent inhibitors of the development and multiplication of malarial parasites in culture and in vivo. However, most of these compounds are also inhibitors of mammalian cell proliferation. Here, Angus Bell reviews the structure and properties of microtubules, their roles in Plasmodium cells, and the effects of various microtubule inhibitors on the parasite. He argues that microtubule inhibitors are not equally toxic to all proliferating cells but, by virtue of differential tubulin binding, show selective toxicity that might allow their use as antimalarial drugs.

Journal Article↗
PubMed1998

Erratum.

Explore the source record for details and available documents.

Journal Article↗
PubMed1998

Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions.

AIMS: The primary objective of this study was to determine whether pharmacokinetic interactions occurred between interferon alpha-2b (IFN) and ribavirin in patients with chronic hepatitis C infections. Additionally this study assessed the single and multiple-dose pharmacokinetics of ribavirin and IFN, and compared the safety, tolerability and antiviral pharmacodynamics of IFN plus ribavirin compared with either drug alone. METHODS: In this open label parallel group study, patients with chronic hepatitis C were randomized to receive IFN 3 million IU thrice weekly s.c. alone, ribavirin 600 mg twice daily p.o. alone or both drugs in combination over 6 weeks. Single and multiple dose pharmacokinetics and indices of antiviral pharmacodynamics were assessed during weeks 1 and 6, along with safety assessments during the study. RESULTS: The range of mean ribavirin terminal phase half-lives after single doses was 44-49 h. Comparison of week 1 and week 6 AUC(0,12h) values showed accumulation in plasma of approximately 6-fold. The range of mean washout half-lives after week 6 was 274-298 h, reflecting release of ribavirin from deep compartment stores. The range of single and multiple dose IFN terminal phase half-lives was 5-7 h. IFN demonstrated an increase in bioavailability (approximately 2-fold) upon multiple dose administration. Ribavirin and IFN pharmacokinetic parameters for combined ribavirin and IFN were similar to those during monotherapy with either compound, although the power of this study to detect differences was low. Serum HCV-RNA titers and ALT concentrations were reduced by IFN alone, ribavirin alone reduced ALT concentrations only, and combined IFN plus ribavirin produced numerically greater falls in both measurements than either treatment alone. Serum concentrations of neopterin and activity of 2',5'-oligoadenylate synthetase (2'5'-OAS) were increased by IFN alone and in combination with ribavirin, whereas serum 2'5'-OAS activity was decreased and neopterin concentrations unaltered by ribavirin monotherapy. IFN and ribavirin monotherapy produced characteristic changes in safety laboratory tests (IFN--reductions in white cells, neutrophils and platelets; ribavirin--reduced haemoglobin) and characteristic adverse event profiles (IFN--headache, flu-like symptoms, fatigue, anorexia, nausea, myalgia, and insomnia; ribavirin--headache, fatigue, myalgia, and pruritus). There was no additive effect of combination therapy on safety laboratory tests or reported adverse events. All changes were fully reversible upon treatment cessation. CONCLUSIONS: There was no evidence of pharmacokinetic interactions between IFN and ribavirin in this study. There were numerical trends indicating that the combination of IFN and ribavirin reduced titers of HCV-RNA to a greater extent than did either treatment alone, and the safety profile of combination therapy was similar to those of both monotherapy treatments.

Adolescent↗
PubMed1998

Antifungal efficacy, safety, and single-dose pharmacokinetics of LY303366, a novel echinocandin B, in experimental pulmonary aspergillosis in persistently neutropenic rabbits.

LY303366 is a novel semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1,3)-beta-D-glucan synthase. The antifungal efficacy and safety of LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of body weight per day or with LY303366 at 1, 5, 10, and 20 mg/kg/day. In rabbits treated with LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured by the number of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. Rabbits receiving prophylactic LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and LY303366 had comparable therapeutic efficacies by all parameters with the exception of reduction in tissue burden of A. fumigatus, where AmB was superior to LY303366. LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels above the MIC for 18 h, and dosages of >/=5 mg/kg maintained plasma drug levels above the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in LY303366-treated rabbits. In summary, LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic rabbits.

Amphotericin B↗
PubMed1998

Effects of nebulized nitroprusside on pulmonary and systemic hemodynamics during pulmonary hypertension in piglets.

We tested the effects of nebulized nitroprusside (Neb-NP) on pulmonary and systemic hemodynamics during pulmonary hypertension induced by hypoxia or group B streptococci infusion in piglets. Twenty-three anesthetized and mechanically ventilated piglets received Neb-NP under four experimental conditions: 1) normoxia; 2) 15 and 60 min of pulmonary hypertension induced by hypoxia; 3) after pretreatment with dipyridamole; 4) pulmonary hypertension induced by infusion of group B streptococci. In addition, Neb-NP was contrasted to nebulization of tolazoline. During hypoxia-induced pulmonary hypertension, Neb-NP significantly reduced pulmonary artery pressure [PAP; -8.4+/-0.9 (SEM) mm Hg] and pulmonary vascular resistance (-25+/-2.1%) (both p < 0.001), whereas neither systemic arterial pressure nor cardiac output changed significantly. Selective pulmonary vasodilation began within 2 min of the onset of Neb-NP, and did not wane over 1 h. In contrast, within 5 min after Neb-NP was discontinued while hypoxia persisted, PAP rose significantly. Pretreatment with dipyridamole did not enhance the pulmonary vasodilation induced by Neb-NP, but did reduce systemic arterial pressure. Nebulized tolazoline did not reduce PAP significantly, but did lower systemic arterial pressure. Selective pulmonary vasodilation induced by Neb-NP was significantly smaller during group B streptococci-induced versus hypoxia-induced pulmonary hypertension. In sum, Neb-NP produced prompt, significant, selective reduction of PAP in piglets with pulmonary hypertension. Cautious extrapolation of these findings to selected clinical conditions in human infants may be warranted.

Administration, Inhalation↗
PubMed1998

The Mental Health Nursing Clinical Confidence Scale: a tool for measuring undergraduate learning on mental health clinical placements.

A significant proportion of the undergraduate preparation of student nurses in the tertiary sector involves the opportunity for experience in a variety of clinical placements. The majority of nursing students in Australian universities spend time in mental health settings. This compulsory clinical experience provides the opportunity for the application of nursing theory and the development of clinical confidence. Whereas there have been attempts to quantify the attainment of confidence to perform skills in general nursing settings, there has been little attention to this issue in mental health settings. The Mental Health Nursing Clinical Confidence Scale was developed as part of a larger study aimed at investigating the impact of mental health clinical placements on undergraduate nurses' attitudes and clinical confidence. Students were surveyed using the scale before and after a mental health nursing placement. The scale revealed robust psychometric properties. Significant changes in the self-reported confidence levels of students were found at the completion of the clinical placement. A number of key factors impacted on student confidence levels both before the clinical and after the placement. The 20 item scale will be a useful instrument in future evaluations of the effectiveness of student learning in mental health settings.

Adolescent↗
PubMed1997

New gene for autosomal recessive non-syndromic hearing loss maps to either chromosome 3q or 19p.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of prelingual inherited hearing impairment. A small consanguineous family with this disorder was ascertained through the Institute of Basic Medical Sciences in Madras, India. Conditions such as rubella, prematurity, drug use during pregnancy, perinatal trauma, and meningitis were eliminated by history. Audiometry was performed to confirm severe-to-profound hearing impairment in affected persons. After excluding linkage to known DFNB genes, two genomic DNA pools, one from the affected persons and the other from their non-affected siblings and the parents, were used to screen 165 polymorphic markers evenly spaced across the autosomal human genome. Two regions showing homozygosity-by-descent in the affected siblings were identified on chromosomes 3q21.3-q25.2 and 19p13.3-p13.1, identifying one (or possibly both) as the site of a novel ARNSHL gene.

Algorithms↗
PubMed1997

Outbreak of toxoplasmosis associated with municipal drinking water. The BC Toxoplasma Investigation Team.

BACKGROUND: Outbreaks of toxoplasmosis are recognised infrequently. In March, 1995, a sudden increase of serologically diagnosed cases of acute toxoplasmosis was noted in the Greater Victoria area of British Columbia, Canada. Concurrently, but independently, seven cases of acute toxoplasma retinitis were diagnosed against a background of no cases in the previous 5 years. METHODS: Cases were defined by serological testing, clinical presentation, and residence in Greater Victoria. A screening programme for women who were or had been pregnant was started. Geographical mapping of cases, and case-control studies of symptomatic cases and of women enrolled in the screening programme were done. FINDINGS: 100 individuals aged 6 to 83 years met the definition for an acute, outbreak-related case. 94 resided in Greater Victoria and six had visited it; 19 had retinitis, 51 had lymphadenopathy, four others had symptoms consistent with toxoplasmosis, seven had other symptoms, 18 were symptom-free, and one would not provide information. 36 (0.9%) of 3812 screened pregnant and postnatal women were cases. Excess cases were not detected outside Greater Victoria and no conventional source of toxoplasmosis was implicated. Mapping studies of cases and of the screened women, and both case-control studies showed significant associations between acute infection and residence in the distribution system of one reservoir supplying water to Greater Victoria (ORs or RRs: 3.53, 3.05, 8.27, and 5.42, respectively). The epidemic curve appeared bimodal, with peaks in December, 1994, and March, 1995, that were preceded by increased rainfall and turbidity in the implicated reservoir. INTERPRETATION: A municipal water system that uses unfiltered, chloraminated surface water was the likely source of this large community-wide outbreak of toxoplasmosis.

Adolescent↗
PubMed1997

Transcriptional regulation of the hepatocyte growth factor (HGF) gene by the Sp family of transcription factors.

In this study, we have localized an enhancer element in the 5'-flanking region of the HGF gene promoter and have identified its functional transcriptional factors. Through transient transfection of NIH3T3 fibroblast cells and gel mobility shift assays, the functional binding site was localized to a short region (-318 to -303 bp from the transcription start site) which has a CTCCC sequence. This motif is also conserved in the human HGF promoter and acts as a binding site for the Sp family of transcription factors. In the presence of NIH3T3 nuclear protein extracts, this enhancer region formed specific DNA-protein complexes which were totally abrogated by excess amounts of consensus Sp1 oligonucleotide. In gel mobility supershift assays, anti-Sp1 and anti-Sp3 antibodies specifically recognized these complexes as was evident by their slower migration. Site-specific mutation of this binding motif resulted in total loss of Sp1 and Sp3 binding and a concomitant loss of enhancer function within the context of the HGF promoter. Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. DNaseI hypersensitive analysis of freshly isolated nuclei from NIH3T3 cells revealed that five hypersensitive sites (HSS) are present within the 2 kb region immediately upstream of the HGF promoter. One of these sites was mapped to position -0.3 kb from the transcription start site. These data show that both Sp1 and Sp3 transcription factors upregulate HGF promoter activity by binding to the Sp1 binding site at position -318 to -303 bp in the HGF gene promoter.

3T3 Cells↗
PubMed1997

Transcriptional regulation of the hepatocyte growth factor gene by the nuclear receptors chicken ovalbumin upstream promoter transcription factor and estrogen receptor.

Hepatocyte growth factor (HGF) is a multifunctional cytokine that controls the growth and differentiation of various tissues. Previously, we described the existence of a negative cis-acting regulatory element(s) within the -1- to -0.7-kilobase pair (kb) portion of the 5'-flanking region of the mouse HGF promoter. In the present study, we show that the repressor element is located at position -872 to -860 base pairs and comprises an imperfect estrogen-responsive element 5'-AGGTCAGAAAGACCA-3'. We demonstrate that chicken ovalbumin upstream promoter transcription factor (COUP-TF), a nuclear orphan receptor belonging to the steroid/thyroid hormone receptor superfamily, through binding to this site effectively silences the transcriptional activity of the HGF promoter. We show that estrogen receptor, on the other hand, relieves the repressive action of COUP-TF, resulting in the induction of the HGF promoter. Using mice transgenic for either 2.7 or 0.7 kb of the HGF promoter region linked to the chloramphenicol acetyltransferase reporter gene, we found that injection of estradiol stimulates HGF promoter activity in tissues such as the mammary gland and ovary of mice harboring 2.7 but not 0.7 kb of the mouse HGF promoter region. Potential involvement of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors in the regulation of HGF gene expression is also discussed.

Animals↗
PubMed1997

Allogeneic peripheral blood stem cell transplantation for haematological malignancies--an analysis of kinetics of engraftment and GVHD risk.

We have carried out an analysis of 44 patients undergoing allogeneic PBSC transplants from fully HLA-matched related donors with particular emphasis on engraftment kinetics and the incidence and severity of GVHD. The recipients had a median age of 37 years (range 5-56 years), 16 patients had standard-risk disease and 28 had poor-risk disease. GVHD prophylaxis was with cyclosporin A and methotrexate (n = 41), cyclosporin A alone (n = 2) or cyclosporin A and methyl-prednisolone (n = 1). Stem cells were mobilised using G-CSF, collecting a median of 5.75 x 10(6) CD34+ cells/kg recipient weight (range 0.94-35 x 10(6) CD34+ cells/kg). Engraftment times to a neutrophil count > 0.5 x 10(9)/1 and platelets > 20 x 10(9)/1 were achieved at a median of day +14 (range 10-25) and day +14 (range 9-130) respectively. Patients receiving > or = 4 x 10(6) CD34+ cells/kg had significantly accelerated neutrophil and platelet engraftment and this number of CD34+ cells would appear to be a prerequisite for maximum engraftment using PBSC. Acute GVHD occurred in 25 of 43 evaluable patients although in only 12 was this clinically significant (grades II-IV). Chronic GVHD has occurred in 17 out of 36 evaluable patients, there was no significant difference between the standard- and poor-risk groups in incidence of either acute or chronic GVHD. In conclusion, these results confirm the feasibility of using PBSC for allogeneic transplantation without evidence for increased risk of either acute or chronic GVHD and provide further evidence supporting the potential of PBSC to replace bone marrow as the major source of haemopoietic cells for allogeneic transplantation.

Adolescent↗
PubMed1997

Sequence-specific interactions of minor groove binders with the 154 base pair HindIII-RsaI restriction fragment of cDNA of the human Tau 40 protein involved in pathology of Alzheimer's disease.

The DNA minor groove binders netropsin, distamycin and four structurally related bisquaternary ammonium heterocycles (BQA), SN 6999, SN 6570, SN 6132 and SN 6131, were investigated for sequence-specific interactions with the 154 base pair fragment of cDNA of the human Tau 40 protein (h Tau 40 protein), involved in pathology of Alzheimer's disease. The base sequences 5' AATCTT 3', 5' AATATT 3' and 5' TTTCAATCTTTTTATTT 3' were identified as ligand specific binding sites and demonstrate the obvious dA.dT binding preference. Footprinting titration experiments were performed to estimate sequence-specific binding constants (KA). The KA-values were in the order of 10(6)M-1 and dependent on DNA base sequence as well as ligands used. The highest values estimated were for netropsin (KA = 5.0 x 10(6)M-1) and the quinoline derivative SN 6999 (KA = 6.2 x 10(6)M-1) binding to the sequence 5' ATAAT 3'. Microscopic binding constants are determined by the base sequence rather than by the length of dA.dT stretches. In the extended dA.dT run, 5' TTTCAATCTTTTTATTT 3', netropsin and distamycin binding tolerates the presence of two dG.dC base pairs, as indicated by nearly unaffected footprints. In contrast, the failure of BQAs to form footprints demonstrates their significantly decreased binding selectivity.

Alzheimer Disease↗