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Biomedical subjects

D Collins

Publications and source records attributed to D Collins.

At least 55 records · Page 3Linked to original sources
PubMed1995

The utilisation and economic evaluation of antibiotics prescribed in primary care.

This was an observational study of efficacy and resource utilisation over three years in a cohort of 917 patients who received at least one prescription for an oral antibiotic between January and March 1989 in a large rural primary care health centre in Tayside, Scotland. Three thousand, six hundred and sixty three prescriptions were issued (2286 to females) for; 1502 upper respiratory tract infections, 419 lower respiratory tract infections, 441 urinary tract infections, 177 skin and soft tissue infections, 97 gynaecological infections, 103 cases of acne and 71 other infections. Excluding acne, 14% of infections required more than one antibiotic to achieve a successful outcome. The highest success rates for antibiotics were amoxycillin (92%) and penicillin V (92%) in upper respiratory tract infections, erythromycin (90%) in lower respiratory tract infections and co-trimoxazole (83%) in urinary tract infections. The most cost-effective antibiotics were penicillin V for upper respiratory tract infection, erythromycin for lower respiratory tract infection and co-trimoxazole for urinary tract infection. Varying the value placed on general practitioners' time did not change the rank order of antibiotic cost-effectiveness. The efficacy and cost-effectiveness of the treatment of acute infections in primary care varies considerably with the antibiotic used as first choice. More expensive antibiotics might be justified in cost-effectiveness terms if they had high cure rates in clinical practice.

Adolescent↗
PubMed1994

Interactions of liposome bilayers composed of 1,2-diacyl-3-succinylglycerol with protons and divalent cations.

Bilayer liposomes were prepared by using pure DOSG (1,2-dioleoyl-3-succinylglycerol) or DPSG (1,2-dipalmitoyl-3-succinylglycerol) at pH 7.4 or above. These liposomes undergo destabilization upon incubation with acid. When calcein was used as an entrapped aqueous marker, half maximal content leakage was observed between pH 5.8-6.3. Differential scanning calorimetry showed that at pH 7.4, the chain-melting temperature (Tm) of DPSG was 60.4 degrees C, and increased with decreasing pH (Tm = 57.0 degrees C and 62.7 degrees C at pH 8.9 and 6.7, respectively). Below pH 6.7, extensive phase separation occurred as the major chain melting peak split into three peaks. These three peaks coalesced into one peak below pH 5. Freeze fracture electron micrographs of DOSG liposomes at pH 4 showed the formation of non-bilayer as well as hexagonal phase structures. The effects of divalent cations, such as Ca2+ and Mg2+, on the destabilization of DASG bilayers have also been studied. Differential scanning calorimetry studies of bilayers composed of DPSG showed that both Ca2+ and Mg2+ could increase the Tm of DPSG with increasing concentrations. However, under identical conditions Mg2+ was more effective than Ca2+ in increasing the Tm of DPSG. X-ray diffraction indicated that both Ca2+ and Mg2+ could induce DPSG bilayers to undergo a complete lamellar to hexagonal phase transition. There was a size-dependency on the plasma stability of DOSG liposomes. DOSG liposomes that were smaller in size were more stable in plasma than the larger ones. After incubation with plasma, DOSG liposomes became less acid-sensitive. DOSG immunoliposomes entrapping diphtheria toxin A chain were used as a model for cytoplasmic delivery of the novel pH-sensitive liposomes. The delivery activity was comparable to that of the conventional pH-sensitive liposomes containing unsaturated phosphatidylethanolamine. Our data indicate that the mechanism of liposome destabilization involves extensive bilayer phase separation as well as the formation of non-bilayer structures.

Calorimetry, Differential Scanning↗
PubMed1994

Interaction of recombinant granulocyte colony stimulating factor with lipid membranes: enhanced stability of a water-soluble protein after membrane insertion.

The interaction of recombinant granulocyte colony stimulating factor (rhG-CSF) with lipid vesicles was studied. In the presence of dioleoylphosphatidylglycerol (DOPG) vesicles, the intrinsic fluorescence of rhG-CSF exhibits dramatic changes. In particular, tryptophan fluorescence is greatly enhanced and the emission maximum shifted to lower wavelengths. The presence of DOPG vesicles causes the protein tryptophans to become inaccessible to iodide, a water-soluble quencher of tryptophan fluorescence, yet accessible to quenching via energy transfer to pyrenyl decanoic acid, a lipid-soluble fluorescent probe. The data suggest that rhG-CSF inserts into lipid vesicles composed of DOPG. The driving force for the insertion may be a conformational change induced by the low pH at the lipid-water interface of DOPG vesicles. The DOPG-inserted form of rhG-CSF retains biological activity and shows remarkable stability, even under high-temperature conditions which lead to denaturation of rhG-CSF alone. Membrane insertion of G-CSF may be involved in the in vivo activity of this important cytokine.

Decanoic Acids↗
PubMed1994

Efficient encapsulation of proteins within liposomes for slow release in vivo.

A highly efficient method for the liposome encapsulation of granulocyte colony stimulating factor (rhG-CSF) was developed. The method was found to be gentle and led to no protein aggregation, denaturation or loss of protein activity. The liposomes obtained were judged to be oligolamellar based on a comparison of the actual with the theoretical trapped volumes. Slow release of encapsulated material from the liposomes was demonstrated both in vitro (90% serum, 37 degrees C) and in vivo after subcutaneous injection.

Animals↗
PubMed1994

inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis.

Isoniazid (isonicotinic acid hydrazide, INH) is one of the most widely used antituberculosis drugs, yet its precise target of action on Mycobacterium tuberculosis is unknown. A missense mutation within the mycobacterial inhA gene was shown to confer resistance to both INH and ethionamide (ETH) in M. smegmatis and in M. bovis. The wild-type inhA gene also conferred INH and ETH resistance when transferred on a multicopy plasmid vector to M. smegmatis and M. bovis BCG. The InhA protein shows significant sequence conservation with the Escherichia coli enzyme EnvM, and cell-free assays indicate that it may be involved in mycolic acid biosynthesis. These results suggest that InhA is likely a primary target of action for INH and ETH.

Amino Acid Sequence↗
PubMed1994

Granulocyte-colony stimulating factor, granulocyte-macrophage colony stimulating factor, PIXY-321, stem cell factor, interleukin-3, and interleukin-7: receptor binding and effects on clonogenic proliferation in acute lymphoblastic leukemia.

Cytokines are frequently used after chemotherapy of leukemias and solid tumors to augment recovery of normal hematopoiesis. While the regulation of normal and leukemic myelopoiesis is well investigated, little is known about effects of cytokines on growth and differentiation of lymphoblastic leukemia. In this study, we investigated the expression of receptors for G-CSF, GM-CSF, SCF, IL-3, and IL-7 on acute lymphoblastic leukemia (ALL) blasts and the effects of these growth factors (GF) on ALL blast colony formation. The binding of fluorescence-tagged cytokines to receptors on ALL blasts was studied by flow-cytometry in 27 cases of ALL (24 precursor B-ALL, 3 T-ALL). Receptor-binding for myeloid-associated GF was observed in the majority of precursor B-ALL (G-CSF = 100%, GM-CSF = 65%, IL-3 = 83%, SCF = 74%), but not in T-ALL. Binding of labelled IL-7 was detected in both precursor B- (92%) and T-ALL (100%). The presence of receptors for SCF in ALL was confirmed by polymerase chain reaction for c-kit mRNA in 19/21 cases tested. Expression of receptors for G-CSF, GM-CSF, IL-3, and SCF was not associated with expression of myeloid antigens, or with specific cytogenetic abnormalities. The effects of these GF on clonogenic cells were tested in the ALL blast colony assay and varied between samples, but all cytokines were able to increase clonogenic growth. The GM-CSF/IL-3 fusion molecule PIXY-321 was most effective in promoting colony growth. In some cases inhibition of colony formation was found. We conclude that ALL blast cells have receptors not only for IL-7, but also for G-CSF, GM-CSF, SCF, and IL-3. ALL precursors can respond to these GF with changes in their clonogenic growth indicating the presence of functional receptors. Results may have implications for therapeutic approaches combining cytokines and chemotherapy.

Adolescent↗
PubMed1994

A Canadian survey of current methotrexate prescribing practices in rheumatoid arthritis.

OBJECTIVE: To conduct a cross sectional survey of methotrexate (MTX) prescribing practices of Canadian rheumatologists in their treatment of rheumatoid arthritis (RA). METHODS: A 15-item questionnaire was mailed to 197 rheumatologists with a 79% response rate after 3 mailings. RESULTS: The usual starting dose was 7.5 mg/week (range = 2.5-15.0) and the usual maximum dose prescribed was 15 mg/week (range = 10-50); 81% routinely coadministered MTX and non-steroidal antiinflammatory drugs; 28% routinely used folic acid prophylaxis; 97% of respondents performed regular assessments of liver function. Only 17% requested a liver biopsy after a certain time and 23% after a certain cumulative dose. Sixty-two percent performed pre-MTX liver biopsy on patients with liver function abnormalities. Only 14% of respondents routinely performed pulmonary function tests. Ninety-one percent of respondents noted that 1-50% (mode = 10%) of patients refused to accept MTX therapy after it had been recommended, usually because of fear of side effects. CONCLUSION: Despite potential toxicity, the majority of respondents used MTX in the treatment of adult RA.

Arthritis, Rheumatoid↗
PubMed1994

Germ-line mutations in the von Hippel-Lindau tumor-suppressor gene are similar to somatic von Hippel-Lindau aberrations in sporadic renal cell carcinoma.

von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome predisposing to multifocal bilateral renal cell carcinomas (RCCs), pheochromocytomas, and pancreatic tumors, as well as angiomas and hemangioblastomas of the CNS. A candidate gene for VHL was recently identified, which led to the isolation of a partial cDNA clone with extended open reading frame, without significant homology to known genes or obvious functional motifs, except for an acidic pentamer repeat domain. To further characterize the functional domains of the VHL gene and assess its involvement in hereditary and nonhereditary tumors, we performed mutation analyses and studied its expression in normal and tumor tissue. We identified germline mutations in 39% of VHL disease families. Moreover, 33% of sporadic RCCs and all (6/6) sporadic RCC cell lines analyzed showed mutations within the VHL gene. Both germ-line and somatic mutations included deletions, insertions, splice-site mutations, and missense and nonsense mutations, all of which clustered at the 3' end of the corresponding partial VHL cDNA open reading frame, including an alternatively spliced exon 123 nt in length, suggesting functionally important domains encoded by the VHL gene in this region. Over 180 sporadic tumors of other types have shown no detectable base changes within the presumed coding sequence of the VHL gene to date. We conclude that the gene causing VHL has an important and specific role in the etiology of sporadic RCCs, acts as a recessive tumor-suppressor gene, and appears to encode important functional domains within the 3' end of the known open reading frame.

Adult↗
PubMed1993

Selectivity information on desogestrel.

Improvement in oral contraceptive formulations was originally achieved through dose reduction of the estrogen and progestogen components. Recently, further improvement was achieved by increasing the selectivity of contraceptive progestins. The ratio between the affinity for the progesterone receptor and the affinity for the androgen receptor is an indicator of progesterone (or androgen) selectivity of a progestin. This ratio (selectivity index) reflects the relative amount of androgenic or progestational effect at a given dose. Relative selectivity can be characterized with in vitro receptor-binding studies and animal pharmacologic experiments. In comparison with levonorgestrel, desogestrel displays markedly lower androgenicity and slightly increased relative progestational activity. In receptor-binding experiments and animal pharmacologic studies, 3-keto-desogestrel, the active metabolite of desogestrel, shows the highest selectivity index. The favorable effect of desogestrel-containing oral contraceptives on lipoprotein metabolism and preexisting androgen-dependent skin disorders and the absence of adverse effects on blood pressure and body weight are attributed to the increased progestin selectivity of desogestrel.

Animals↗
PubMed1993

Regional binding of 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP) to muscarinic receptors in rat brain and comparative analysis of minimum energy conformations.

The binding of the muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), which has been suggested as an M3-selective antagonist in peripheral tissues, was examined through quantitative autoradiographic techniques in brain. The ability of 4-DAMP to displace [3H](R)-quinuclindinyl benzilate (QNB) binding to rat brain sections was compared with the known distribution of M1 and M2 muscarinic receptor subtypes as measured previously with pirenzepine and AF-DX 116 (Messer et al., 1989a). 4-DAMP displayed a high affinity for [3H](R)-QNB binding sites in rat brain sections. Analysis of 4-DAMP binding to various brain regions revealed heterogeneous binding profiles, suggesting an interaction with multiple receptor sites. Quantification of the autoradiograms indicated that 4-DAMP bound with the highest affinity to muscarinic receptors in the midline thalamus (IC50 values < 30 nM), and had a slightly lower affinity for hippocampal receptors (IC50 values between 30 and 46 nM). 4-DAMP also displayed a lower affinity for cortical receptors with IC50 values between 30 and 50 nM. The binding profile of the putative M3 muscarinic antagonist did not exhibit a marked selectivity for any single region of brain. The data suggest that whereas 4-DAMP may be selective for M3 receptors in peripheral tissues, it has limited selectivity in the CNS. Minimum energy conformations for 4-DAMP were calculated using molecular mechanics calculations. 4-DAMP displayed two global minimum energy conformations, differing in the relative position of the piperidine ring with respect to the aromatic rings. The minimum energy conformations of 4-DAMP were compared with conformations generated for pirenzepine (Messer et al., 1989a). The lowest energy conformation of 4-DAMP was superimposable on the lowest energy conformation of pirenzepine (RMS = 0.297 A). It is suggested that the conformations available to 4-DAMP permit binding to several muscarinic receptors in the CNS.

Animals↗
PubMed1993

Ethical dilemmas in continuing a zidovudine trial after early termination of similar trials.

Ethical dilemmas caused by external events and an interim subset analysis raised concerns about continuing a long-term VA clinical trial comparing early with later zidovudine therapy for symptomatic human immunodeficiency virus (HIV) infection. The first external event was the early termination of other, apparently similar, trials conducted by the AIDS Clinical Trials Group (ACTG) and the announced clear benefits for the zidovudine-treated patients. Interim analysis of the VA trial at this time did not show similar benefits. Subset analyses were performed to explore factors that might explain the different results. These suggested a difference in response to zidovudine in white and minority groups. The Data Monitoring Board and a special advisory panel reviewed these data and concluded that, since the VA results were neutral overall and the subset analyses based on small numbers, the trial should continue. By conference call, the study cochairmen and biostatistician discussed this decision with study personnel without revealing interim results, and study personnel passed the information on to patients at the participating centers. The second event was in March 1990, when the Food and Drug Administration (FDA) approved earlier use of zidovudine, which applied to patients still in the VA trial. Patients were asked to reaffirm their participation by signing a new informed consent that explained the findings reported by the ACTG, the FDA-approved revised recommendations, and the rationale for continuation of the VA trial. The consent form emphasized that continued masked therapy was optional and that unmasked treatment and follow-up would be provided to patients requesting it. Seventy-four percent of the participants chose to continue masked therapy. We conclude that when new external data are announced, informed participation in a long-term clinical trial may require a revised consent form and that it is ethical and practical to present this without disclosure of interim study results.

Acquired Immunodeficiency Syndrome↗
PubMed1993

The self-efficacy-performance link in maximum strength performance.

To examine whether manipulating self-efficacy affects strength performance on a bench press, and to see if these situation-specific changes would affect levels of physical self-efficacy, 24 undergraduates untrained in weightlifting were randomly assigned to three groups: 'light', who lifted less weight than they believed; 'heavy', who lifted more weight than they believed; and control, for whom there was no manipulation. Self-efficacy measures were taken before and after the manipulation. Physical self-efficacy was measured using the Physical Self-Efficacy Scale (PSE). 'Light' subjects lifted significantly greater increases in weight than the other subjects. 'Heavy' subjects significantly decreased self-efficacy following the manipulation. Initial self-efficacy was found to be a significant predictor of baseline maximum, while manipulated self-efficacy was significant for performance change. The PSE scores did not change pre- to post-study. The results suggest that self-efficacy is a situation-specific construct which can be manipulated, and which relates to both past performance experience and future performance.

Adult↗
PubMed1993

Systemic versus nonsystemic reperfusion of the transplanted liver.

Reperfusion of the orthotopically transplanted liver can result in severe hemodynamic instability. This instability can result in the postreperfusion syndrome (PRS), which includes decreases in mean arterial pressure (MAP), systemic vascular resistance (SVR), and heart rate, and increases in central venous pressure and pulmonary capillary wedge pressure. This syndrome appears to be mediated by the left ventricular mechanoreceptor reflex (LVMRR), which can be activated by changes in preload, afterload, or left ventricular contractility, and by the infusion of alkaloids or potassium into the right atrium. In an attempt to prevent activation of the LVMRR and PRS, we have inserted a cannula into the retrohepatic vena cava and have allowed the initial 500-600 cc of portal blood reperfusing hepatic allografts to be discarded. We compared this nonsystemic reperfusion (NSRP) of livers with systemic reperfusion (SRP), in which the initial portal blood reperfusing livers is allowed to enter the systemic circulation. In the NSRP group (n = 14) there was no decrease in MAP, heart rate, or SVR, and the serum potassium did not increase after reperfusion. In the SRP group (n = 14), six patients (42%) developed PRS and there were statistically significant decreases in MAP and SVR, and increases in pulmonary capillary wedge pressure and serum potassium, as compared with the NSRP group. In conclusion, NSRP results in less hemodynamic instability during reperfusion, and should be considered the preferred method for reperfusion of the transplanted liver.

Adult↗