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Biomedical subjects

D Porter

Publications and source records attributed to D Porter.

At least 55 records · Page 3Linked to original sources
PubMed1997

Fluorescence properties of pteridine nucleoside analogs as monomers and incorporated into oligonucleotides.

Eighteen fluorescent pteridine-based nucleoside analogs have been prepared that are suitable for synthesis as phosphormidites and site-specific incorporation into oligonucleotides. Their quantum yields ranged from < or = 0.03 to 0.88. The maximum excitation and emission wavelenghts of seven selected probes with quantum yields > 0.15 ranged from 334 to 358 and 400 to 444 nm, respectively. Fluorescence decay curves of the seven probes were biexponential, and the mean intensity-weighted lifetimes ranged from 0.87 to 6.54 ns. Incorporation of probes 4 and 17 (3-methylisoxanthopterin and 6-methylisoxanthopterin) into oligonucleotides significantly quenched their fluorescence signal, and the degree of quench correlated with the number and proximity of purines in the oligonucleotide. Incorporation also resulted in a shift in absorbance-, emission-, and decay-associated spectra for 6-methylisoxanthopterin. An increase in the complexity of the decay curve and a decrease in the mean lifetime occurred for both probes. Formation of double-stranded oligonucleotides did not substantially increase the degree of quenching but generally increased the complexity of decay curves and decreased the mean lifetimes. Melting temperature, Tm, depression equivalent to that of a single base pair mismatch was observed in 3-methylisoxanthopterin-containing double-stranded oligonucleotides, while the Tm of 6-methylisoxanthopterin-containing double-stranded oligonucleotides were unperturbed, e.g., equivalent to unlabeled double-stranded oligonucleotides. This new class of fluorophore yields promising probes for the study of protein/DNA interactions.

Fluorescent Dyes↗
PubMed1997

Gastrointestinal complications following cardiac surgery. An analysis of 1477 cardiac surgery patients.

OBJECTIVE: To determine preoperative and perioperative risk factors for gastrointestinal (GI) complications following cardiac surgery. DESIGN: A database including records of patients who underwent cardiac surgery was reviewed, with univariate analysis of several variables thought to be relevant to GI complications. Using a risk-adjusted model, preoperative stratification was used to fit a logistic regression model including operative features. SETTING AND PATIENTS: All patients undergoing cardiac surgery from January 1, 1991, to December 31, 1994, at a university-affiliated teaching hospital. MAIN OUTCOME MEASURES: Incidence of GI complications, postoperative mortality, length of hospital stay, and relative risk of GI complications based on multivariate analyses. RESULTS: Gastrointestinal complications occurred in 2.1% of patients and had an associated mortality of 19.4%; this was higher than the mortality in patients without GI complications (4.1%; P < .001). Length of hospital stay was significantly longer in patients with GI complications (43 vs 13.4 days; P < .001). In patients who underwent coronary artery bypass grafting only, cardiopulmonary bypass time was significantly longer in patients with GI complications (166 vs 138 minutes; P = .004). In patients who underwent valve replacement, bypass time was not associated with GI complications. Use of a left internal mammary artery graft was associated with a lower incidence of GI complications. CONCLUSIONS: Patients who have GI complications after cardiac surgery have a higher mortality and a longer hospital stay. The use of a left internal mammary artery seems to have a protective effect against GI complications. Based on these observations, patients may be stratified into low-, medium-, and high-risk groups.

Aged↗
PubMed1997

Visual detection of transport-P in peptidergic neurones.

1. Hypothalamic peptidergic neurones possess an uptake process for amines (transport-P), for which prazosin is a substrate. It is characterized by a paradoxical increase in the accumulation of [3H]-prazosin when the concentration of unlabelled prazosin is increased above 10(-7) M. This increase is due to activation of a proton-dependent, vacuolar-type ATPase-linked pump that is blocked by tricyclic antidepressants. This study utilized a fluorescence method to detect amine uptake in individual cells. 2. Prazosin is fluorescent but most of its emission spectrum is in the ultraviolet range. We therefore used an analogue of prazosin in which the furan ring had been substituted with a fluorescent group, BODIPY FL. This compound's emission maximum is in the green part of the visible spectrum. 3. BODIPY FL prazosin accumulated in immortalised peptidergic neurones and the characteristic emission spectrum of the compound was evident in these cells. Accumulation of BODIPY FL prazosin was saturable and was inhibited by the tricyclic antidepressant desipramine and by unlabelled prazosin. As previously described for prazosin, uptake of BODIPY FL prazosin was blocked by cold temperature and by the organic base chloroquine. Thus, prazosin and BODIPY FL prazosin were accumulated by the same uptake process. 4. BODIPY FL prazosin accumulated in a granular distribution, which is compatible with storage in intracellular vesicles. 5. Hypothalamic cells from foetal rats in primary culture also accumulated BODIPY FL prazosin by a desipramine-sensitive process. Uptake was predominantly in neurones and glial cells did not accumulate the amine. 6. Fluorescent detection provides visual evidence for amine uptake in peptidergic neurones and should enable detailed study of the distribution of this process in the brain.

Adrenergic alpha-Antagonists↗
PubMed1997

Effect of social deprivation on disease severity and outcome in patients with rheumatoid arthritis.

OBJECTIVE: Social deprivation is now recognised to have an important impact on morbidity and mortality. This study sought to ascertain the effect of deprivation, if any, on disease severity, functional disability, and outcome in rheumatoid patients in Glasgow. METHODS: 814 patients with rheumatoid arthritis (RA) were assessed for clinical, functional, and laboratory indices of disease activity. Deprivation categories for individual patients were determined using the Carstairs index. Five year follow up is available for 440 patients. RESULTS: The study population of RA patients live largely in the most deprived areas. Patients from deprived areas have significantly poorer function at outset and at five years as defined by the Health Assessment Questionnaire (HAQ) score. This is not attributable to differences in disease duration in patients from the most deprived regions or compliance with treatment. Furthermore, these patients do not achieve over five years the initial functional level of those living in the most advantaged localities. CONCLUSION: RA patients from deprived areas have poorer function, which is associated with greater need--medical, social, and paramedical. Strategies and resources for healthcare need to be adjusted according to this variation.

Adult↗
PubMed1996

Molecular/clinical correlations in females with fragile X.

Females who are affected by fragile X syndrome (FXS) can have significant physical, neuropsychological and emotional involvement. This study was designed to explore the relationships between these three domains and to learn how the degree of involvement in each of these phenotypic areas relates to molecular parameters including CGG repeat length and activation ratio (the proportion of normal FMR1 alleles on the active X chromosome). Three groups of females were studied: 35 women who grew up in a fragile X family but do not carry an FMR1 mutation, 92 women with a premutation, and 29 women with a full mutation. Correlations between neurocognitive, physical and emotional traits were calculated for each of the three groups. Within the full mutation group significant correlations were seen between schizotypal traits and full scale IQ. The Lie scale was significantly correlated with the physical findings index. The activation ratio correlated significantly with the measure of executive function (r = .50, P = .01). There was a trend toward correlations of activation ratio with the physical index score, outer ear prominence and IQ. CGG repeat number significantly correlated only with the physical index (r = .44, P = .01). Thus, activation ratio may be the more pertinent molecular parameter in full mutation women in determining the degree of cognitive and physical phenotypic involvement.

Adolescent↗
PubMed1996

Critical amino acids in the transcriptional activation domain of the herpesvirus protein VP16 are solvent-exposed in highly mobile protein segments. An intrinsic fluorescence study.

Eukaryotic transcriptional regulatory proteins typically comprise both a DNA binding domain and a regulatory domain. Although the structures of many DNA binding domains have been elucidated, no detailed structures are yet available for transcriptional activation domains. The activation domain of the herpesvirus protein VP16 has been an important model in mutational and biochemical studies. Here, we characterize the VP16 activation domain using time-resolved and steady-state fluorescence. Unique intrinsic fluorescent probes were obtained by replacing phenylalanine residues with tryptophan at position 442 or 473 of the activation domain of VP16 (residues 413-490, or subdomains thereof), linked to the DNA binding domain of the yeast protein GAL4. Emission spectra and quenching properties of Trp at either position were characteristic of fully exposed Trp. Time-resolved anisotropy decay measurements suggested that both Trp residues were associated with substantial segmental motion. The Trp residues at either position showed nearly identical fluorescence properties in either the full-length activation domain or relevant subdomains, suggesting that the two subdomains are similarly unstructured and have little effect on each other. As this domain may directly interact with several target proteins, it is likely that a significant structural transition accompanies these interactions.

Cesium↗
PubMed1996

Transcriptional activation domain of the herpesvirus protein VP16 becomes conformationally constrained upon interaction with basal transcription factors.

The transcriptional activation domain of the herpesvirus protein VP16 resides in the carboxyl-terminal 78 amino acids (residues 413-490). Fluorescence analyses of this domain indicated that critical amino acids are solvent-exposed in highly mobile segments. To examine interactions between VP16 and components of the basal transcriptional machinery, we incorporated (at position 442 or 473 of VP16) tryptophan analogs that can be selectively excited in complexes with other Trp-containing proteins. TATA-box binding protein (TBP) (but not transcription factor B (TFIIB)) caused concentration-dependent changes in the steady-state anisotropy of VP16, from which equilibrium binding constants were calculated. Quenching of the fluorescence from either position (442 or 473) was significantly affected by TBP, whereas TFIIB affected quenching only at position 473. 7-aza-Trp residues at either position showed a emission spectral shift in the presence of TBP (but not TFIIB), indicating a change to a more hydrophobic environment. In anisotropy decay experiments, TBP reduced the segmental motion at either position; in contrast, TFIIB induced a slight change only at position 473. Our results support models of TBP as a target protein for transcriptional activators and suggest that ordered structure in the VP16 activation domain is induced upon interaction with target proteins.

Binding Sites↗
PubMed1996

Lignocellulolysis by ascomycetes (fungi) of a saltmarsh grass (smooth cordgrass).

Lignocellulose (LC) makes up greater than 70% of the mature shoots of the prodigiously photosynthetically productive saltmarsh grass Spartina alterniflora. Naturally decaying shoots of this cordgrass were examined by transmission electron microscopy (after high-pressure freezing and freeze-substitution) as a means of directly detecting lysis of the LC-rich tissues. Portions of the cordgrass were selected that contained ascomata (sexual reproductive structures) of only one of each of four species of fungi (Kingdom Fungi; Subdivision Ascomycotina): Phaeosphaeria spartinicola and Buergenerula spartinae from leaf blades, Phaeosphaeria spartinae from leaf sheaths, and Passeriniella obiones from naked stems. All four of the ascomycetes were LC-lytic. Phaeosphaeria spartinicola caused both thinning of LC-rich secondary walls of fiber cells from cell lumina outwards (type 2 soft rot, akin to white rot) and digestion extending from hyphae within longitudinal cavities in the secondary walls (type 1 soft rot). The other three species caused either one or the other type of soft rot. Bacterial erosion of cordgrass cells was found only in the samples of naked stems. Ascomycetous decomposers of standing-dead grasses may have potential for biotechnological applications involving alterations of lignocellulose or toxic polyphenolic substances.

Ascomycota↗
PubMed1996

Peripheral vascular complications after intracoronary stent placement: prevention by use of a pneumatic vascular compression device.

Peripheral vascular complications are a significant source of morbidity after coronary artery stent implantation. The goal of this study was to assess the incidence, risk factors, and management of vascular complications after stent placement. The study population consisted of 101 consecutive patients who underwent stent placement for either elective or bailout indications. All patients received a standardized anticoagulation regimen of aspirin, dipyridamole, low molecular weight dextran, heparin, and warfarin. Peripheral vascular access sites were examined daily until hospital discharge. Vascular complications occurred in 16 of 101 (16%) patients, including femoral artery pseudoaneurysm (n = 11), hematoma requiring transfusion or surgery (n = 4), and arteriovenous fistula (n = 1). Intervention was required in 14 of 16 (88%) patients with complications. These included transfusion (n = 7), ultrasound-guided compression (n = 8), and/or vascular surgery (n = 7). Length of hospital stay was prolonged in patients with complications (14 +/- 9 vs. 8 +/- 5 d, P < 0.001). The development of peripheral vascular complications did not correlate with clinical or procedural variables such as age, cardiovascular risk factors, arterial sheath size, or elective vs. bailout indication. After the introduction of a pneumatic vascular compression device (FEMOSTOP, C.A. Bard, Billerica, MA), a significant reduction in vascular complications was observed. Complications occurred in only 1 of 41 (2.4%) patients in whom the compression device was used in contrast to 13 of 58 (22.4%) patients compressed manually (P < 0.01). Thus peripheral vascular complications are frequent after coronary artery stent placement and are associated with serious morbidity and prolongation of hospital stay. These complications are significantly reduced by the use of a pneumatic vascular compression device despite intensive systemic anticoagulation.

Hemostasis, Surgical↗
PubMed1996

Bioequivalence assessment of etoposide phosphate and etoposide using pharmacodynamic and traditional pharmacokinetic parameters.

The bioequivalence of etoposide phosphate, a prodrug of etoposide, to etoposide was assessed in a randomized, crossover study in 29 patients with histologically established solid tumors that had failed conventional treatment. Cohorts of patients received one treatment course each of etoposide and etoposide phosphate which consisted of a 100 mg/m2 per day etoposide equivalent dose infused i.v. over 1 hr on a Day 1 to 5 schedule of treatment. The second course was administered 21 days later or on recovery of blood cell counts. Plasma and urine samples were collected over 24 hr on Day 1 of each course and assayed for etoposide content by a validated HPLC/UV method. Resulting data were subjected to noncompartmental pharmacokinetic analysis. Hematology profiles were obtained by collecting blood samples prior to the first course and twice a week after each course. The pharmacodynamics and pharmacokinetics of etoposide were virtually identical after the two treatments. The point estimates (90% confidence intervals) for nadir WBC, granulocytes, hemoglobin, and platelets expressed as % decrease from the baseline, and for the pharmacokinetic parameters, Cmax, and AUC0 infinity, after intravenous etoposide phosphate relative to etoposide were 100% (96%, 105%), 97% (91%, 103%), 95% (82%, 109%), 95% (84%, 106%), 107% (101%, 113%), and 113% (107%, 119%), respectively. Therefore, etoposide phosphate is bioequivalent to etoposide based on pharmacokinetic and pharmacodynamic assessments.

Adult↗
PubMed1996

Low dose desensitisation does not reduce the toxicity of sulphasalazine in rheumatoid arthritis.

OBJECTIVE: To examine the proposal that pretreatment low dose desensitisation may reduce the incidence of toxicity of sulphasalazine in the treatment of rheumatoid arthritis (RA). METHODS: A double blind, placebo controlled trial was performed with 422 patients satisfying the American College of Rheumatology criteria for RA who required sulphasalazine treatment because of increased disease activity. Patients received either sulphasalazine desensitisation, or placebo, for three weeks before commencement of sulphasalazine treatment. The frequency and nature of adverse effects and changes in clinical and laboratory parameters of disease activity were measured after three and six months. RESULTS: Improvement in the efficacy of sulphalasazine (measured by clinical and laboratory parameters) was significant and similar in magnitude in both groups. There was no significant difference between actively and placebo desensitised patients as regards the incidence or profile of adverse effects (toxicity). CONCLUSION: Pretreatment low dose desensitisation is unhelpful in reducing the toxicity associated with sulphasalazine treatment of RA.

Anorexia↗
PubMed1996

Sulfasalazine has a better efficacy/toxicity profile than auranofin--evidence from a 5 year prospective, randomized trial.

OBJECTIVE: To compare results of medium to longterm sulfasalazine and auranofin treatment in active rheumatoid arthritis (RA). METHODS: 200 patients with active RA were enrolled in a prospective, randomized trial comparing sulfasalazine (target dosage, 40 mg/kg/day) with auranofin (6-9 mg/day). Patients were assessed annually for 5 years, using clinical and laboratory measures of disease activity. Risk of discontinuing treatment was compared using life table analysis. RESULTS: 31% of patients continued sulfasalazine for at least 5 years, compared to only 15% continuing auranofin (p < 0.05). Patients previously given intramuscular (i.m.) gold did particularly badly during auranofin treatment (only 1/26 continued therapy for 5 years), but after excluding all patients previously treated with i.m. gold from both groups more patients continued sulfasalazine for > 5 years (p < 0.05). Patients continuing therapy at 5 years had significantly milder disease at enrollment than those who did not. The patients continuing auranofin treatment at 5 years were no better than at the outset of the trial, and may represent a subgroup of patients with a good prognosis. Patients continuing sulfasalazine, however, showed sustained response over the 5 year period. CONCLUSION: Sulfasalazine therapy was more likely to be continued for 5 years, suggesting better tolerability and/or efficacy than auranofin, and produced evidence of continuing benefit. Patients previously withdrawn from i.m. gold therapy because of inefficacy or minor toxicity should not be given auranofin therapy.

Antirheumatic Agents↗