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Biomedical subjects

M Robbins

Publications and source records attributed to M Robbins.

At least 19 recordsLinked to original sources
PubMed2006

Fatty acid synthase: a novel target for antiglioma therapy.

High levels of fatty acid synthase (FAS) expression have been observed in several cancers, including breast, prostate, colon and lung carcinoma, compared with their respective normal tissue. We present data that show high levels of FAS protein in human and rat glioma cell lines and human glioma tissue samples, as compared to normal rat astrocytes and normal human brain. Incubating glioma cells with the FAS inhibitor cerulenin decreased endogenous fatty acid synthesis by approximately 50%. Cell cycle analysis demonstrated a time- and dose-dependent increase in S-phase cell arrest following cerulenin treatment for 24 h. Further, treatment with cerulenin resulted in time- and dose-dependent decreases in glioma cell viability, as well as reduced clonogenic survival. Increased apoptotic cell death and PARP cleavage were observed in U251 and SNB-19 cells treated with cerulenin, which was independent of the death receptor pathway. Overexpressing Bcl-2 inhibited cerulenin-mediated cell death. In contrast, primary rat astrocytes appeared unaffected. Finally, RNAi-mediated knockdown of FAS leading to reduced FAS enzymatic activity was associated with decreased glioma cell viability. These findings suggest that FAS might be a novel target for antiglioma therapy.

Animals↗
PubMed2005

Regulation of TNF-related apoptosis-inducing ligand-mediated death-signal pathway in human beta cells by Fas-associated death domain and nuclear factor kappaB.

Transfectants of human CM and NES2Y beta cell lines and primary islets transfected by FADD-DN (dominant-negative form of Fas-associated death domain), a mutant of FADD and/or a superrepressor of nuclear factor kappaB (NF-kappaB) (AdIkappaB(SA)2), were examined for their susceptibility to the TRAIL (TNF-related apoptosis-inducing ligand)-induced death signal pathway, compared with controls, wild-type cells, and vector transfectants in caspase fluorescence, Western blot, electrophoretic mobility shift, apoptosis, and cytotoxicity assays. FADD-DN inhibited caspase-8 activation induced by TRAIL in the transfectants of CM and NES2Y cells. TRAIL-induced apoptosis and cytotoxicity to the FADD-DN transfectants were decreased in comparison to those responses in controls (CM, p < 0.01 and p < 0.01; NES2Y, p < 0.05, and p < 0.02, respectively). When CM, NES2Y, and primary islet cells were transfected by AdIkappaB(SA)2, TRAIL-induced IkappaB degradation and nuclear translocation of NF-kappaB p50/p65 were blocked. TRAIL-induced apoptosis and cytotoxicity to AdIkappaB(SA)2 transfectants of these cells were also reduced (CM, p < 0.02 and p < 0.02; NES2Y, p < 0.01 and p < 0.01, respectively, and islet p < 0.01 for cytotoxicity). Finally, cytotoxicity induced by TRAIL in CM and NES2Y cells transfected with both FADD-DN and AdIkappaB(SA)2 was reduced, compared with that observed in these cells transfected with either FADD-DN alone or AdIkappaB(SA)2 alone, suggesting that FADD and NF-kappaB have synergistic proapoptotic regulatory effects on the susceptibility of beta cell lines and islet cells to TRAIL-induced destruction.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Molecular analysis of the cucumber leaf spot virus genome.

Full-length clones of the genome of the Aureusvirus, Cucumber leaf spot virus (CLSV), have been constructed and infectious T7 polymerase derived synthetic transcripts have been produced. Mutational analysis of the genome indicates a role for p84 in viral RNA replication, the CP in systemic movement, p27 in viral cell-to-cell movement and p17 in symptom induction. A CLSV mutant lacking ORFs for the CP, p27 and p17 (CLSV YX) was capable of replication and systemic movement in transgenic Nicotiana benthamiana plants expressing the Red clover necrotic mosaic virus (RCNMV) movement protein (MP) suggesting that p25 and p84 are sufficient for viral RNA replication and that the RCNMV MP can permit CLSV cell-to-cell as well as systemic movement. Moreover, CLSV YX induced severe necrosis in both inoculated and uninoculated leaves of transgenic plants suggesting that CLSV p25 and/or p84 are important determinants of the necrotic phenotype. Another mutant similar to CLSV YX but expressing only limited amino-terminal portions of CP, p27 and p17 failed to produce necrosis or to move systemically in RCNMV MP transgenic N. benthamiana plants. These results suggest that these short translated regions or cis-acting sequences present in the CLSV CP, p27 and/or p17 ORFs suppress the necrosis induced by p25/p84 and also suppress systemic movement mediated by the RCNMV MP.

Amino Acid Sequence↗
PubMed2003

A UK multicentre study of the antimicrobial susceptibility of bacterial pathogens causing urinary tract infection.

OBJECTIVES: To determine the prevalence of resistance amongst urinary tract pathogens against antimicrobials used to treat urinary tract infections (UTIs) in the UK to provide data to help direct empirical therapy. METHOD: During 1999-2000, a total of 1291 bacterial isolates causing UTI were collected from 8 centres in the UK. Isolates were cultured from patients with (1). community-acquired UTI in those less than 65 years old (397), (2). hospital-acquired UTI other than those admitted with pyelonephritis (394), (3). pyelonephritis (108) and (4). community-acquired UTI in those greater than 65 years old (392). After re-identification, MICs for a range of antimicrobials were determined and interpreted using NCCLS procedures and interpretive guidelines. RESULTS: Escherichia coli was the predominant pathogen in all categories but the total percentage for each category varied (56.3-77.3%). The next three pathogens of importance were Enterococcus faecalis, Klebsiella pneumoniae and Proteus mirabilis which varied in prevalence slightly from category to category. The activity of amoxycillin against E. coli (51.3% susceptible) was greatly reduced as a result of beta-lactamase production and only partially restored by the addition of clavulanic acid (78.8% susceptible). Cefuroxime was very active against E. coli using parenteral form breakpoints (97.1% susceptible) but less so using oral form breakpoints (68.6% susceptible). Cefuroxime was inactive against Enterococcus spp. and Pseudomonas spp. Nitrofurantoin was very active against isolates of E. coli (96.3% susceptible) and E. faecalis but not against K. pneumoniae, P. mirabilis or Pseudomonas aeruginosa. Overall susceptibility to trimethoprim ranged from 58.1% to 84.5% for the most prevalent pathogens. Ciprofloxacin was highly active against the UTI pathogens examined in this study with susceptibilities of between 88.6% and 97.7% for the most prevalent pathogens (E. coli, n=864, 97.7% susceptible) and was the only oral agent tested with activity against Pseudomonas spp. CONCLUSION: These data provide much needed information on the prevalence of antimicrobial resistance amongst pathogens currently causing UTI in the UK.

Adolescent↗
PubMed2002

The imPaCT study: a randomised controlled trial to evaluate a hospital palliative care team.

A randomised controlled trial was undertaken to assess the effectiveness of a hospital Palliative Care Team (PCT) on physical symptoms and health-related quality of life (HRQoL); patient, family carer and primary care professional reported satisfaction with care; and health service resource use. The full package of advice and support provided by a multidisciplinary specialist PCT ('full-PCT') was compared with limited telephone advice ('telephone-PCT', the control group) in the setting of a teaching hospital trust in the SW of England. The trial recruited 261 out of 684 new inpatient referrals; 175 were allocated to 'full-PCT', 86 to 'telephone-PCT' (2 : 1 randomisation); with 191 (73%) being assessed at 1 week. There were highly significant improvements in symptoms, HRQoL, mood and 'emotional bother' in 'full-PCT' at 1 week, maintained over the 4-week follow-up. A smaller effect was seen in 'telephone-PCT'; there were no significant differences between the groups. Satisfaction with care in both groups was high and there was no significant difference between them. These data reflect a high standard of care of patients dying of cancer and other chronic diseases in an acute hospital environment, but do not demonstrate a difference between the two models of service delivery of specialist palliative care.

Activities of Daily Living↗
PubMed2001

Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice.

The recent cloning of two GABA(B) receptor subunits, GABA(B1) and GABA(B2), has raised the possibility that differences in GABA(B) receptor subunit composition may give rise to pharmacologically or functionally distinct receptors. If present, such molecular diversity could permit the selective targeting of GABA(B) receptor subtypes specifically involved in pathologies such as drug addiction, spasticity, pain, and epilepsy. To address these issues we have developed a GABA(B1) subunit knockout mouse using gene targeting techniques. In the brains of GABA(B1) null mice, all pre- and postsynaptic GABA(B) receptor function was absent demonstrating that the GABA(B1) subunit is essential for all GABA(B) receptor-mediated mechanisms. Despite this, GABA(B1) null mice appeared normal at birth, although by postnatal week four their growth was retarded and they developed a generalized epilepsy that resulted in premature death. In addition, GABA(B1) heterozygote animals showed enhanced prepulse inhibition responses compared to littermate controls, suggesting that GABA(B1) deficient mice exhibit increased sensorimotor gating mechanisms. These data suggest that GABA(B) receptor antagonists may be of benefit in the treatment of psychiatric and neurological disorders in which attentional processing is impaired.

Action Potentials↗
PubMed2001

Tissue distribution and measurement of cartilage oligomeric matrix protein in patients with magnetic resonance imaging-detected bone bruises after acute anterior cruciate ligament tears.

Histologic and immunostaining analyses were performed on articular cartilage/subchondral bone biopsy specimens overlying MRI-detected bone bruises in 12 patients with anterior cruciate ligament (ACL) tears. Staining with toluidine blue for proteoglycan revealed loss of staining from the superficial portion of the articular cartilage. Immunostaining for cartilage oligomeric matrix protein (COMP) showed an increased staining in the superficial matrix of the articular cartilage. Using polyclonal antisera against COMP, the authors performed a competitive enzyme-linked immunosorbent assay (ELISA) on the synovial fluid from the injured and uninjured knees. There was an approximately 10-fold higher synovial fluid COMP levels in injured knees. The COMP levels were greater in those patients who had synovial fluid samples harvested closer to the date of initial injury. Western blot analysis of the synovial fluid showed an increased presence of COMP degradation fragments from injured knees. These results are indicative of a significant injury to the articular cartilage, and may represent preclinical posttraumatic osteoarthritic lesions.

Adolescent↗
PubMed2001

Clinical application of procedural platelet monitoring during percutaneous coronary intervention among patients at increased bleeding risk.

The goal of platelet function testing in the catheterization laboratory is to provide information about the platelet contributions to the risk of thrombotic or hemorrhagic events and optimization of anti-platelet therapy for percutaneous interventions. We present several illustrative cases in which platelet monitoring with the Rapid Platelet Function Assay (RPFA, Accumetrics) was used to guide dosing of a glycoprotein (GP) IIb/IIIa inhibitor for coronary and peripheral intervention among patients at increased bleeding risk.

Abciximab↗
PubMed2000

Adjunctive medical therapy for acute coronary syndromes.

Adjunctive therapy is critical in treating acute coronary syndromes. Aspirin, nitrates, beta-blockers, ACE inhibitors, HMG-CoA reductase inhibitors (statins), and intra-aortic balloon pumps all have important roles and should be considered on a case-by-case basis.

Coronary Disease↗
PubMed1999

Ventilatory and heart rate responses to exercise : better predictors of heart failure mortality than peak oxygen consumption.

BACKGROUND: An abnormally low chronotropic response and an abnormally high ventilatory response (V(E)/V(CO2)) to exercise are common in patients with severe heart failure, but their relative prognostic impacts have not been well explored. METHODS AND RESULTS: Consecutive patients with heart failure referred for metabolic stress testing who were not taking beta-blockers or intravenous inotropes (n=470) were followed for 1.5 years. The chronotropic index was calculated while peak V(O2) and V(E)/V(CO2) were directly measured. Chronotropic index and peak V(O2) were considered abnormal if in the lowest 25th percentiles of the patient cohort, whereas V(E)/V(CO2) was considered abnormal if in the highest 25th percentile. For comparative purposes, a group of 17 healthy controls underwent metabolic testing as well. Compared with controls, heart failure patients had markedly abnormal ventilatory and chronotropic responses to exercise. In the heart failure cohort, there were 71 deaths. In univariate analyses, predictors of death included high V(E)/V(CO2) low chronotropic index, low V(O2), low resting systolic blood pressure, and older age. Nonparametric Kaplan-Meier plots demonstrated that by dividing the population according to peak V(E)/V(CO2) and peak V(O2), it is possible to identify low, intermediate, and very high risk groups. In multivariate analyses, the only independent predictors of death were high V(E)/V(CO2) (adjusted relative risk [RR] 3.20, 95% CI 1.95 to 5.26, P<0.0001) and low chronotropic index (adjusted RR 1.94, 95% CI 1.18 to 3.19, P=0.0009). CONCLUSIONS: The ventilatory and chronotropic responses to exercise are powerful and independent predictors of heart failure mortality.

Adolescent↗
PubMed1999

Effectiveness of an educational strategy to improve family physicians' detection and management of depression: a randomized controlled trial.

BACKGROUND: Depression, a common disorder often treated by family physicians, may be both underdiagnosed and undertreated. The objective of this study was to determine whether the diagnosis and treatment of depression by family physicians could be improved through an educational strategy. METHODS: In this study, conducted between July and December 1997, 42 family physicians in Newfoundland were randomly assigned to an intervention group (3-hour case-based educational session on clinical practice guidelines [CPGs] for depression and access to a psychiatrist for consultation) or to a control group (receipt of CPGs without educational session or access to the psychiatrist). Physicians were asked to keep a log of patients with newly diagnosed depression and to record information on severity of depression, medications and referrals to mental health professionals. Patients were asked to complete the Centre for Epidemiologic Studies Depression (CES-D) scale before treatment and after 6 months of follow-up. The primary outcome measure was the "gain" score (difference between first and last CES-D scores). RESULTS: During the study period physicians in the intervention group diagnosed 91 new cases of depression (mean 4.1 per physician) and those in the control group diagnosed 56 (mean 2.8 per physician); the difference was not significant. Most patients (91.2% in the intervention group and 89.3% in the control group received a prescription for an antidepressant on their first visit. Similar proportions (46.2% in the intervention group and 37.5% in the control group) took their medication for the full 6 months; however, significantly more patients in the intervention group were taking an antidepressant at the 6-month follow-up (56% v. 39.3%, p = 0.02). The mean number of visits per patient was similar in the 2 groups (7.7 in the intervention group and 7.6 in the control group). Physicians in the intervention group consulted the psychiatrist 9 times. The overall rate of referrals to psychiatrists and other mental health professionals was 10.9%; however, referrals were significantly higher in the intervention group (15.4% v. 3.5%, p = 0.05). After 6 months of follow-up, a significant difference in gain scores was detected between the intervention and control groups for both the patient's self-rated CES-D scores (mean gain score 19.3 v. 15.5 respectively, p = 0.04) and the physicians' ratings of depression severity before treatment and at 6 months (mean gain 1.1 v. 0.7 respectively, p = 0.02). INTERPRETATION: The educational strategy had a modest beneficial effect on the outcomes of patients with depression, but there are still concerns regarding the low rates of drug treatment and referral to mental health professionals by family physicians.

Adult↗