Search PubMed⌕ Search

Biomedical subjects

N Robinson

Publications and source records attributed to N Robinson.

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

Two novel mutations in exons 19a and 20 and a BsaBI [correction of BsaI] polymorphism in a newly characterized intron of the neurofibromatosis type 1 gene.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder. It is caused by mutations in the NF1 gene, which comprises 60 exons and is located on chromosome 17q11.2. A total of 170 unrelated NF1 patients were screened for mutations in four exons by temperature-gradient gel electrophoresis. Preparatory work revealed the presence of a previously uncharacterized intron (19a) in what was previously designated exon 19; this allowed us to develop assays for genomic mutation screening in the newly defined exons 19a and 19b. Two novel NF1 mutations were detected: a single-base insertion in exon 19a creating a frameshift, and a second mutation affecting the splice donor site of intron 20 and leading to skipping of exon 20. A novel BsaBI polymorphism was identified in intron 19a.

Adult↗
PubMed1998

People with HIV/AIDS: who cares?

Studies have shown that some nurses, doctors and other carers have negative attitudes towards people with human immune deficiency virus/acquired immune deficiency syndrome (HIV/AIDS). Some cope by avoiding working with such patients, while others just do the best they can. But does it matter? This paper describes a review of the literature on the impact of attitudes to care and the barriers affecting the quality of care for people with HIV/AIDS by professional health care workers and other carers. Most of the reports identified were based on attitude scales, mostly unique and often unvalidated. Attitudes of health care workers based in the community, and 'house keeping' staff such as porters, receptionists, etc., have been neglected areas of research. There is also little information about the culture of organizations and the attitudes of individuals with HIV/AIDS to care. Only three references were found in which both patients' and carers' attitudes to each other were considered and none of these looked at negative feelings and their impact. There is scope therefore to investigate the attitudes of patients and carers towards each other and how this can effect the quality of care. It is anticipated that the benefits of such investigations could lead to the development of educational strategies designed to improve the quality of patient care.

Attitude of Health Personnel↗
PubMed1997

Estrogens stabilize mitochondrial function and protect neural cells against the pro-apoptotic action of mutant presenilin-1.

Mutations in presenilin-1 (PS-1) account for approximately half the cases of autosomal dominant early-onset Alzheimer's disease (AD). Recent data indicate that PS-1 mutations may render neurons vulnerable to apoptosis induced by various insults. We now report that 17beta-estradiol, which appears to reduce the risk of sporadic AD, protects cultured PC12 cells expressing mutant PS-1 against apoptosis induced by trophic factor withdrawal (TFW) and exposure to amyloid beta-peptide 25-35 (Abeta). Estriol also provided significant protection against apoptosis induced by TFW and Abeta, whereas corticosterone was ineffective. 17beta-Estradiol prevented decreases in mitochondrial transmembrane potential and energy charge/redox state following exposure of cells to TFW and Abeta in control cell lines and lines expressing mutant PS-1, suggesting an action in the apoptotic pathway upstream of mitochondrial alterations. Abeta caused an increase in mitochondrial reactive oxygen species which was enhanced by mutant PS-1, and suppressed by 17beta-estradiol. The ability of 17beta-estradiol to preserve mitochondrial function, suppress oxidative stress, and counteract the pro-apoptotic actions of mutant PS-1 suggests a generalized neuroprotective action of estrogens in both sporadic and inherited forms of AD.

Amino Acid Substitution↗
PubMed1997

Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid beta-peptide: involvement of calcium and oxyradicals.

Most autosomal dominant inherited forms of early onset Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS-1) gene on chromosome 14. PS-1 is an integral membrane protein with six to nine membrane-spanning domains and is expressed in neurons throughout the brain wherein it is localized mainly in endoplasmic reticulum (ER). The mechanism or mechanisms whereby PS-1 mutations promote neuron degeneration in AD are unknown. Recent findings suggest links among deposition of amyloid beta-peptide (Abeta), oxidative stress, disruption of ion homeostasis, and an apoptotic form of neuron death in AD. We now report that expression of the human PS-1 L286V mutation in PC12 cells increases their susceptibility to apoptosis induced by trophic factor withdrawal and Abeta. Increases in oxidative stress and intracellular calcium levels induced by the apoptotic stimuli were exacerbated greatly in cells expressing the PS-1 mutation, as compared with control cell lines and lines overexpressing wild-type PS-1. The antiapoptotic gene product Bcl-2 prevented apoptosis after NGF withdrawal from differentiated PC12 cells expressing mutant PS-1. Elevations of [Ca2+]i in response to thapsigargin, an inhibitor of the ER Ca2+-ATPase, were increased in cells expressing mutant PS-1, and this adverse effect was abolished in cells expressing Bcl-2. Antioxidants and blockers of calcium influx and release from ER protected cells against the adverse consequences of the PS-1 mutation. By perturbing cellular calcium regulation and promoting oxidative stress, PS-1 mutations may sensitize neurons to apoptotic death in AD.

Alzheimer Disease↗
PubMed1997

Cochliobolic acid, a novel metabolite produced by Cochliobolus lunatus, inhibits binding of TGF-alpha to the EGF receptor in a SPA assay.

Cochliobolic acid (1), a novel biologically active natural product, is produced by submerged fermentation of Cochliobolus lunatus. Compound 1 was determined to be a novel polyketide possessing a substituted tetrahydrofuran ring, a conjugated polyene chain and a 1,2-diketone moiety, by interpretation of NMR, MS, and UV/vis spectroscopic data. Compound 1 inhibits the binding of TGF-alpha to the EGF receptor of the human epidermal cell line A431 in a SPA assay with an IC50 of 1.6 microM.

Chemical Phenomena↗
PubMed1997

Interleukin-2 after autologous stem cell transplantation for hematologic malignancy: a phase I/II study.

The success of autologous stem cell transplantation (ASCT) for hematologic malignancy is limited largely by a high relapse rate. It is postulated that IL-2 administered after ASCT may eliminate minimal residual disease and thereby reduce relapses. A phase I/II study was performed to identify a regimen of IL-2 (Chiron) that could be given early after ASCT in phase III trials. In the phase I study, beginning a median of 46 days after ASCT for hematologic malignancy, cohorts of three to four patients received escalating doses of 'induction' IL-2 of 9, 10, or 12 x 10(6) IU/m2/day for 4 or 5 days by continuous i.v. infusion (CIV), followed by a 4-day rest period, and then 1.6 x 10(6) IU/m2/day of maintenance IL-2 by CIV for 10 days. The maximum tolerated dose (MTD) of induction IL-2 was 9 x 10(6) IU/m2/day x 4. In the phase II study, 52 patients received the MTD. Eighty percent of patients completed induction IL-2. Most patients exhibited some degree of capillary leak. One patient died of CMV pneumonia and one died of ARDS. Maintenance IL-2 was well tolerated. In the phase I/II study, 16 of 31 patients with non-Hodgkin lymphoma (NHL), 3/8 with Hodgkin disease (HD), 4/17 with AML, and 4/5 with ALL remain in CR. Two of six multiple myeloma (MM) patients remain in PR. Although the regimen of IL-2 identified had significant side-effects in some patients, it was well tolerated in the majority of patients. Phase III prospectively randomized clinical trials are in progress to determine if this IL-2 regimen will decrease the relapse rate after ASCT for AML and NHL.

Adjuvants, Immunologic↗
PubMed1997

Interleukin-12 induced cytolytic activity in lymphocytes from recipients of autologous and allogeneic stem cell transplants.

Interleukin-12 (IL-12) has been reported to enhance the cytolytic activity of NK and activated T cells and to induce low levels of lymphokine-activated killer (LAK) activity in normal human lymphocytes. Therapy with IL-12 has induced tumor eradication in murine models. These observations suggest that IL-12 might have a role as treatment for minimal residual disease following transplantation. To determine whether PBL from recipients of autologous (autoSCT) and allogeneic (alloSCT) bone marrow or peripheral blood stem cell transplants respond to IL-12 with generation of LAK activity, PBL were incubated with IL-12 for 5 days, then tested in a 51Cr release assay for lysis of Daudi. PBL from 17 normal 'control' individuals were similarly tested and lysis was observed in only 3/17 (mean 16.9% of the three). By contrast, PBL from 10/12 patients obtained a median of 30 days after autoSCT, exhibited significant IL-12-induced LAK activity (mean lysis, 35.3%, P < 0.005 vs controls). PBL from 18 of 20 patients tested a median of 44 days after alloSCT also exhibited significant LAK activity (mean lysis, 30.0%, P < 0.005 vs controls). In autoSCT recipients, IL-12 and IL-2 at high concentrations (1000 U/ml each) were additive for induction of LAK activity, whereas low, suboptimal concentration of IL-12 (250 U/ml) and IL-2 (1 U/ml) were synergistic in 3/5 experiments. The percentage of PBL expressing IL-12 receptor beta 1 chain (IL-12r beta 1) was higher in stem cell recipients than in normal individuals, P < 0.05. Moreover, a higher percentage of IL-12r beta 1-positive PBL was associated with greater IL-12-induced LAK activity in transplant recipients. These studies demonstrate that PBL obtained early after stem cell transplantation have a higher percentage of cells expressing IL-12r beta 1 and respond to IL-12 with significantly greater LAK cytotoxicity than PBL from normal controls. These results suggest that IL-12 is a potentially attractive candidate for study as consolidative immunotherapy after stem cell transplantation.

Cells, Cultured↗
PubMed1997

Microsatellite evolution--a reciprocal study of repeat lengths at homologous loci in cattle and sheep.

The application of microsatellites in evolutionary studies requires an understanding of the patterns governing their evolution in different species. The finding that homologous microsatellite loci are longer, i.e., containing more repeat units, in human and in other primates has been taken as evidence for directional microsatellite evolution and for a difference in the rate of evolution between species. However, it has been argued that this finding is an inevitable consequence of biased selection of longer-than-average microsatellites in human, because cloning procedures are adopted to generate polymorphic and, hence, long markers. As a test of this hypothesis, we conducted a reciprocal comparison of the lengths of microsatellite loci in cattle and sheep using markers derived from the bovine genome as well as the ovine genome. In both cases, amplification products were longer in the focal species, and loci were also more polymorphic in the species from which they were originally cloned. The crossing pattern that we found suggests that interspecific length differences detected at homologous microsatellite loci are the result of biased selection of loci associated with cloning procedures. Hence, comparisons of microsatellite evolution between species are flawed unless they are based on reciprocal analyses or on genuinely random selection of loci with respect to repeat length.

Animals↗
PubMed1997

Ventricular tachycardia in healing canine myocardial infarction: evidence for multiple reentrant mechanisms.

Prior studies have demonstrated that unimorphic VT, sometimes due to epicardial reentry, can be induced in healing canine MI; however, the characterization of the types of reentry involved has differed among prior studies. The purpose of this study was to further characterize the spectrum of epicardial reentrant circuits during induced VT in experimental canine MI. Experimental MI was created by total occlusion of the LAD in dogs. Five days later, programmed stimulation was used to induce VT, which was mapped on the epicardium using a combination of vector and isochronal techniques. Pathological analysis was used to determine regions of transmural MI. Epicardial reentrant circuits were identified in eight dogs. The mean cycle length of induced VT was 212 +/- 32 ms. In 3 of 8 experiments, a region of transmural MI was present, which formed at least a portion of a central zone of block around which reentrant impulses circulated. In five experiments, reentry was functional in nature, although the characteristics of the region of functional conduction block were variable. Long lines of functional block, short lines of block with slow conduction transverse to fiber orientation, and leading circle reentry were each observed in different experiments. Although a zone of slow conduction was identified in seven of the experiments, slow conduction transverse to fiber orientation appeared crucial in maintaining reentry in only three experiments. Multiple reentrant mechanisms of VT may be present in this single canine infarction model. Although a zone of slow conduction is usually present, the characteristics of the region of block are highly variable. However, epicardial reentry accounted for only a minority of induced arrhythmia episodes.

Animals↗
PubMed1997

Reproducibility of ventricular fibrillation characteristics in patients undergoing implantable cardioverter defibrillator implantation.

INTRODUCTION: The purpose of this study was to evaluate the immediate reproducibility of local electrogram characteristics recorded during repeated episodes of induced ventricular fibrillation (VF) in patients undergoing implantable cardioverter defibrillator (ICD) implantation. METHODS AND RESULTS: Power spectral analysis (using a fast Fourier transform algorithm) of electrograms recorded during 3 seconds of VF were analyzed in 24 patients undergoing ICD implantation using a Medtronic Transvene lead. Patients had 2 to 7 episodes of VF that were induced during defibrillation threshold testing. VF was induced by burst pacing (n = 20) or T wave shock (n = 4). Simultaneous electrograms during VF were recorded from a Medtronic Transvene lead with the following configurations: (1) a narrow spaced (12 mm) dedicated bipole used clinically for sensing; (2) a unipolar electrogram from the right ventricular coil; and (3) a widely spaced (18.3 mm) integrated bipole using the distal tip and the coil. Intraclass correlation coefficients (ICCs) were determined to examine the reproducibility of these VF characteristics among VF episodes in each patient. Recordings from both bipolar configurations had ICCs from 0.40 to 0.55, whereas unipolar recordings ICCs were below 0.40. Reproducibility was similar for dedicated and integrated recordings. CONCLUSIONS: Frequency characteristics of repeated episodes of VF induced in the same subjects show fair-to-good but not excellent reproducibility. Bipolar recordings were far more reproducible than unipolar recordings, but both bipolar configurations had similar reproducibility. These findings have implications for both the pathophysiology of induced VF and the design of VF detection algorithms.

Adult↗
PubMed1997

Interleukin-2 therapy after bone marrow or stem cell transplantation for hematologic malignancies.

PURPOSE: Autologous or allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT) for advanced hematologic malignancies is associated with a high relapse rate. It has been postulated that recombinant interleukin-2 (rIL-2) administered as consolidative immunotherapy early after BMT or SCT, at a time of minimal residual disease, might reduce the relapse rate. We review here preliminary results from a series of studies designed to investigate the safety, immunomodulatory effects, and clinical benefits of rIL-2 therapy following autologous and allogeneic BMT and SCT. PATIENTS AND METHODS: Patients with hematologic malignancies underwent autologous or allogeneic BMT or SCT and received rIL-2 by continuous intravenous infusion a median of 33 to 56 days later. In all trials, the rIL-2 regimen consisted of a moderate induction dose for 4 to 5 days in the hospital, 4 to 6 days of rest, and a low maintenance dose for 10 days in the outpatient setting. A phase I trial of Roche rIL-2 after autoBMT, a feasibility trial of autologous lymphokine-activated killer cells with rIL-2, and another phase I/II trial of Chiron rIL-2 after autoBMT were performed. A similar phase I trial of IL-2 after alloBMT was also performed in children with acute leukemia beyond first complete remission. RESULTS: An rIL-2 regimen has been identified that can be tolerated early after transplantation. Administration of this rIL-2 regimen induces marked increases in CD3+CD8+ T lymphocytes and CD3-CD56+ natural killer cells and enhances their antitumor cytolytic activity. Encouraging but somewhat inconsistent clinical outcomes were noted in phase I/II trials in patients with lymphoma and acute myeloid leukemia. CONCLUSIONS: The results of phase I/II trials are sufficiently encouraging to justify prospectively randomized phase III trials to determine whether rIL-2 after autologous SCT will reduce the rate of posttransplantation relapse and improve survival in patients with advanced hematologic malignancies.

Adolescent↗
PubMed1996

Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide.

Mutations in the presenilin-1 (PS-1) gene on chromosome 14 are linked to autosomal dominant early-onset Alzheimer's disease. The amino acid sequence of PS-1 predicts an integral membrane protein and immunocytochemical studies indicate that PS-1 is localized to endoplasmic reticulum (ER). We report that expression of PS-1 mutation L286V in cultured PC12 cells exaggerates Ca2+ responses to agonists (carbachol and bradykinin) that induce Ca2+ release from ER. Cells expressing L286V exhibit enhanced elevations of [Ca2+]i following exposure to amyloid beta-peptide (A beta) and increased vulnerability to A beta toxicity. An antagonist of voltage-dependent calcium channels (nifedipine), and a blocker of Ca2+ release from ER (dantrolene), counteract the adverse consequences of the PS-1 mutation. By perturbing Ca2+ homeostasis, PS-1 mutations may sensitize neurons to A beta-induced apoptosis.

Alzheimer Disease↗
PubMed1996

Structural elucidation of XR586, a peptaibol-like antibiotic from Acremonium persicinum.

A novel peptide, XR586, has been isolated from fermentations of Acremonium persicinum (Xenova culture collection number X21488). The structure of XR586 has been elucidated by means of NMR spectroscopy, electrospray and fast-atom bombardment MS, derivatization and enzymic digestion. It has been shown to be helical by CD measurements. XR586 shows many structural and conformational features in common with peptaibols, particularly the zervamicins. Peptaibol antibiotics are peptides, typically of 15-20 residues, containing a large proportion of alpha-aminoisobutyric acid (Aib) residues. These peptides adopt a helical conformation in solution and display anti-bacterial and toxic properties due to their ability to form pores in membranes. However, while XR586 contains several Aib residues, it lacks a terminal phenylalaninol and terminates in the sequence Phe-Gly. The lack of reduction of the penultimate residue at the C-terminus may indicate that this step is normally at the end of the biosynthetic pathway of peptaibols and occurs with cleavage of Gly. The 1H chemical shift assignments of XR586 are reported in Supplementary Publication SUP 50179 (3 pages), which has been deposited at the British Library Document Supply Centre, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1996) 313, 9 ("Deposition of data').

Acremonium↗
PubMed1996

Phase I trial of interleukin-2 after unmodified HLA-matched sibling bone marrow transplantation for children with acute leukemia.

Allogeneic bone marrow transplantation (BMT) for advanced acute leukemia is associated with a high risk of relapse. It is postulated that interleukin-2 (IL-2) administered after BMT might induce or amplify a graft-versus-leukemia effect and thereby reduce the relapse rate. To identify an IL-2 regimen for testing this hypothesis, a phase I trial of IL-2 (Roche) was performed in children in complete remission (CR) without active graft-versus-host disease (GVHD) off immunosuppressive agents after unmodified allogeneic matched-sibling BMT for acute leukemia beyond first remission. Beginning a median of 68 days after BMT, 17 patients received escalating doses of induction IL-2 (0.9, 3.0, or 6.0 x 10(6) IU/m2/d representing levels I, II, and III) for 5 days by continuous intravenous infusion (CIV). After 6 days of rest, they received maintenance IL-2 (0.9 x 10(6) IU/m2/d) for 10 days by CIV infusion. Levels I and II were well-tolerated, but, of 6 patients at level III, 1 developed pulmonary infiltrates, 1 developed hypotension (both resolved), and 1 died of bacterial sepsis and acute respiratory distress syndrome. Grade II acute GVHD developed in 1 patient at level I and 1 at level III. The maximum tolerated dose of induction IL-2 was level II. IL-2 induced lymphocytosis, with an increase in CD56+ and CD8+ cells. Ten patients remain in CR at 5+ to 67+ months. Thus, a regimen of IL-2 has been identified that did not induce a high incidence of acute GVHD when administered to children after unmodified allogeneic BMT. Its clinical activity will be assessed in a phase II trial.

Acute Disease↗
PubMed1996

Reproduction and development in Drosophila are dependent upon catecholamines.

Drosophila melanogaster, maintained on culture media containing alpha-methyl-p-tyrosine (alpha-MT) at millimolar levels for 7 days, fail to produce viable progeny. Lesser concentrations delay development. This effect of alpha-MT, an inhibitor of tyrosine hydroxylase (TH), is partially reversible by co-administration of L-dihydroxyphenylalanine, the product of TH. Potent inhibitors of other steps in the pathway for catecholamine biosynthesis are inactive except for a partial effect with dopamine B-hydroxylase inhibition. the effect of alpha-MT is due to a combination of ovulation suppression coupled with decreases in embryonic and larval viability. Effects similar to those of alpha-MT are found with millimolar levels of reserpine, prazosin and to a lesser extent, rauwolscine. No significant effects are found with propranolol, chlorpromazine, sulpiride and SK&F 83566. Mutant alleles of the gene coding for TH are known to be lethal at the embryonic stage when homozygous in both Drosophila and mice. Taken together, these results indicate that in addition to their established roles in the nervous system catecholamines function in animal development via an action mediated through alpha-adrenoceptors.

Animals↗