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Biomedical subjects

B Perry

Publications and source records attributed to B Perry.

At least 19 recordsLinked to original sources
PubMed1999

Biopharmaceutical approaches for developing and assessing oral peptide delivery strategies and systems: in vitro permeability and in vivo oral absorption of salmon calcitonin (sCT).

PURPOSE: To evaluate a biopharmaceutical approach for selecting formulation additives and establishing the performance specifications of an oral peptide delivery system using sCT as a model peptide. METHODS: The effect of formulation additives on sCT effective permeability and transepithelial electrical resistance (TEER) was evaluated in side-by-side diffusion chambers using rat intestinal segments. Baseline regional oral absorption of sCT was evaluated in an Intestinal and Vascular Access Port (IVAP) dog model by administration directly into the duodenum, ileum, and colon by means of surgically implanted, chronic catheters. The effect of varying the input rate and volume of the administered solution on the extent of sCT absorption was also evaluated. Citric acid (CA) was utilized in all studies to cause a transient reduction in local pH. In vitro samples and plasma samples were analyzed by radioimmunoassay (RIA). Two oral delivery systems were prepared based on the results of the in vitro and IVAP studies, and evaluated in normal dogs. RESULTS: Maximal permeability enhancement of sCT was observed using taurodeoxycholate (TDC) or lauroyl carnitine (LC) in vitro. Ileal absorption of sCT was higher than in other regions of the intestine. Low volume and bolus input of solution formulations was selected as the optimal condition for the IVAP studies since larger volumes or slower input rates resulted in significantly lower sCT bioavailability (BA). Much lower BA of sCT was observed when CA was not used in the formulation. The absolute oral bioavailability (mean+/-SD) in dogs for the control (sCT + CA) and two proprietary sCT delivery systems was 0.30%+/-0.05%, 1.10+/-0.18%, and 1.31+/-0.56%, respectively. CONCLUSIONS: These studies demonstrate the utility of in vitro evaluation and controlled in vivo studies for developing oral peptide delivery strategies. Formulation additives were selected, the optimal intestinal region for delivery identified, and the optimal release kinetics of additives and actives from the delivery system were characterized. These methods were successfully used for devising delivery strategies and fabricating and evaluating oral sCT delivery systems in animals. Based on these studies, sCT delivery systems have been fabricated and tested in humans with favorable results.

Administration, Oral↗
PubMed1999

Determination of the sum of bilirubin sugar conjugates in plasma by bilirubin oxidase.

BACKGROUND: A reliable indicator of cholestasis is the presence of abnormal concentrations of bilirubin mono- and diglucuronide [conjugated bilirubin (CB)] in blood. A routine assay of CB is available only to those who possess a certain type of clinical analyzer. We describe a two-point manual method for CB that could be adapted as a rate assay to automated clinical analyzers. METHODS: The measurement of CB is based on its oxidation to biliverdin by bilirubin oxidase. The resulting decrease in absorbance at 460 nm is proportional to the CB concentration. The assay is calibrated with solutions of ditaurobilirubin in human serum. RESULTS: Under the conditions of the assay (0.1 mol/L glycine buffer, pH 10.0; reaction time, 2 min), only 5% of unconjugated bilirubin is oxidized and delta-bilirubin is not oxidized at all. Results obtained with the bilirubin oxidase method agreed well with those obtained by HPLC. The long-term CVs at CB concentrations of 6 and 63.4 mg/L were 20% and 2.6%, respectively. The reference values, established by analyzing 51 plasma specimens from healthy adults, were 0.0-1.2 mg/L, with a mean value of 0.2 mg/L. CONCLUSIONS: The proposed method for CB has good analytical specificity and obviates the requirement for HPLC or a dry chemistry analyzer. The measurement of CB in blood is superior to the measurement of direct bilirubin because an abnormal concentration of direct bilirubin does not necessarily indicate the presence of cholestasis.

Bilirubin↗
PubMed1998

Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage.

As stroke is a major cause of disability and death in the western world, there is great interest in the basic mechanisms by which ischemia/reperfusion (I/R) causes damage. To this end, extensive research has been carried out which identifies reactive oxygen species (ROS) as key participants in brain damage resultant from I/R. Brain tissue is protected from ROS damage by antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GP). Overexpression of SOD in transgenic mice has already been demonstrated to confer protection against I/R damage in murine stroke models. We are using transgenic mice overexpressing the intracellular form of glutathione peroxidase (GP1) to determine the protective capacity of overexpression of this enzyme on stroke damage. 1 h of focal cerebral ischemia followed by 24 h of reperfusion was induced using the intraliminal suture method. Volume of infarction was reduced by 48% in GP1 mice compared to nontransgenic littermates. Brain edema was reduced by 33%. Behavioral deficits agreed with histologic data. Overexpression of glutathione peroxidase confers significant protection against I/R damage in our stroke model possibly through direct scavenging of ROS or through the influencing of signalling mechanisms which lead to tissue damage.

Animals↗
PubMed1998

Beliefs of eight exemplary oncology nurses related to Watson's nursing theory.

In this paper selected findings of a qualitative study of eight exemplary oncology nurses are presented. The focus is on the views of these nurses about key elements of nursing practice, namely, the nature of health, human beings, nurse-patient relationships, nursing care, and the nursing environment. In the first part of the paper, the research methodology used in the study is outlined. Subsequently, the oncology nurses' beliefs about the five central components of nursing practice are described and related to Jean Watson's theory of nursing.

Attitude of Health Personnel↗
PubMed1997

Combination of dobutamine and myocardial contrast echocardiography to differentiate postischemic from infarcted myocardium.

OBJECTIVES: This study tested whether the combination of dobutamine echocardiography (DE) and myocardial contrast echocardiography (MCE) was superior to either technique alone in identifying postischemic myocardium and in differentiating it from necrotic myocardium. BACKGROUND: Wall motion abnormalities at rest occur in postischemic myocardium in the presence of infarction, stunning or hibernation, alone or in combination. Various investigators have suggested that either DE or MCE can be used to identify the presence of myocardial viability. METHODS: We studied a total of 53 mongrel dogs in an open chest model of coronary occlusion of various durations followed by reperfusion and dobutamine administration (10 microg/kg body weight per min). MCE with aortic root injections of Albunex (area under the curve) and DE (percent thickening fraction) were performed at the different stages. Postmortem triphenyltetrazolium chloride (TTC) staining was used to identify myocardial necrosis. RESULTS: Thirteen dogs underwent brief (15 min) occlusions and developed no necrosis (Group I). Of 40 dogs that underwent prolonged (30 to 360 min) occlusions, 14 had no infarction (Group II), whereas 26 did (Group III: 12 papillary muscle, 7 subendocardial, 7 transmural). MCE (expressed as percent change from baseline) demonstrated changes that paralleled the blood flow changes observed by radiolabeled microspheres at all interventions (r = 0.67, p < 0.0001). Regional ventricular function improved with dobutamine administration in the ischemic region in all three groups. The sensitivity (88%) for detecting myocardial viability was superior when the two techniques were combined; however, a poor specificity (61%) was observed. CONCLUSIONS: Contractile reserve and perfusion data are complementary when assessing regional wall motion abnormalities in postischemic myocardium. DE alone cannot differentiate postischemic from infarcted myocardium; simultaneous data on myocardial perfusion are required. The combination of DE and MCE is superior to either technique alone for identifying the absence of myocardial necrosis.

Animals↗
PubMed1997

Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice.

The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta 42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid beta-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels, alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A beta 42 secretion in all mutant clones. Likewise, mutant but not wildtype PS1 transgenic mice showed significant overproduction of A beta 42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta generation. The extent of A beta 42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta 42 production, thus promoting cerebral beta-amyloidosis.

Alzheimer Disease↗
PubMed1996

Fluorinated benzazepines: 1. Synthesis, radiosynthesis and biological evaluation of a series of substituted benzazepines as potential radiotracers for positron emission tomographic studies of dopamine D-1 receptors.

We have prepared N-alkyl, aryl, fluoroalkyl, fluoroaryl and iodoaryl derivatives of 7-chloro-8-hydroxy-3-methyl-1-(3'-aminophenyl)-2,3,4,5-tetrahydro-1 H-3-benzazepine (SCH 38548) as high-affinity ligands for the dopamine D1 receptor. Binding affinities of the compounds for dopamine D1, D2, and serotonin 5-HT2 receptor sites in rat brain homogenates were measured. The affinity of SCH 38548 for dopamine D1 receptors was found to be 0.53 +/- 0.46 nM, whereas lower affinities (in the micromolar range) for dopamine D2 and serotonin 5-HT2 receptors were found. Alkylation (ethyl, n-propyl and benzyl) and acylation (benzoyl) of the amino group of SCH 38548 did not decrease affinities for the D1 receptors significantly. The fluoroethyl, fluoropropyl, and fluorobenzyl derivatives showed approximately an 8-fold, 9-fold, and 3-fold decrease in affinity for the D1 sites compared to SCH 38548. The N-4-fluorobenzoyl derivative, however, showed a similar affinity for the D1 sites as for SCH 38548. All four fluorinated derivatives exhibited weak binding at D2 and serotonin 5-HT2 receptors. The N-(4-18F-fluorobenzoyl)SCH 38548 was prepared by reacting SCH 38548 with 4-18F-fluorobenzoyl fluoride in 2-5% radiochemical yield with a specific radioactivity of approximately 600-700 Ci/mmol. The N-(3-18F-fluoropropyl)SCH 38548 was prepared by reacting SCH 38548 with 18F-fluoropropyl iodide in 2-5% radiochemical yield with a specific radioactivity of approximately 600-700 Ci/mmol. N-(4-18F-fluorobenzoyl)SCH 38548 failed to localize in the dopaminergic sites in the rat and rhesus monkey brain. Biodistribution of N-(3-18F-fluoropropyl)SCH 38548 in rats showed specific uptake and retention (0.64% injected dose/g at 30 min) of the radiotracer in the striata, with striata-to-cerebellum ratios reaching 12 at 2 h postinjection (p.i.). Positron emission tomography scans in rheusus monkeys indicate selective uptake of the radiotracer in the striata. After IV injection of N-(3-18F-fluoropropyl)SCH 38548, a rapid brain uptake of the tracer from blood was observed. Initial uptake in the striata and cerebellum was approximately 0.02% of injected dose/cc. Nonspecific uptake from the tissue surrounding the striata cleared slowly. The striata-to-cerebellum ratio increased from 1.20 to 3.5 min postinjection to approximately 2.5 at 120 min p.i. The specific uptake of N-(3-18F-fluoropropyl)SCH 38548 in the striata was displaced by IV administration of SCH 24518 (2 mg/kg).

Animals↗
PubMed1996

Myocardial contrast echocardiography: reliable, safe, and efficacious myocardial perfusion assessment after intravenous injections of a new echocardiographic contrast agent.

Reliable and reproducible myocardial opacification after intravenous administration of echocardiographic contrast agents has remained elusive. This study was performed to determine whether a new agent, FS069, a suspension of perfluoropropane-filled albumin microspheres (3.6 microns average microbubble size, concentration 8 x 8(8)/ml), could achieve safe and successful myocardial opacification in open-chest dogs. Seventeen dogs (group 1, n = 7, group 2, n = 10) underwent two-dimensional echocardiography before, during, and after the administration of intravenous FS069. Safety was evaluated by measuring arterial and pulmonary artery pressures, heart rate, blood gases, systolic function, myocardial blood flow, and postmortem analysis of myocardial viability by triphenyl-tetrazolium chloride staining. Efficacy to detect changes in regional myocardial perfusion was assessed by injecting FS069 at baseline, after sequential coronary occlusions and reperfusion, and during intravenous vasodilators with and without coronary occlusions. Results were compared with radiolabeled microspheres. FS069 was found to be safe and effective. In the absence of coronary occlusions, uniform myocardial opacification was observed in all dogs. A perfusion defect was observed in all dogs during coronary occlusions. Background-subtracted peak contrast intensity in the myocardium correctly identified regional myocardial blood flow changes and showed a significant correlation with radiolabeled microspheres (r = 0.65, p = 0.0001).

Albumins↗
PubMed1996

Potential clinical implications of abnormal myocardial perfusion patterns immediately after reperfusion in a canine model: a myocardial contrast echocardiography study.

During myocardial infarction, lack of myocardial opacification after reperfusion has been associated with poor or no recovery of function. We have previously documented the presence of perfusion abnormalities after brief coronary occlusions without infarction and the absence of perfusion abnormalities after prolonged occlusions with infarction. To characterize myocardial perfusion patterns immediately after reperfusion, we studied 53 animals in two groups in a coronary occlusion-reperfusion model. Temporary occlusions (group 1, 15 minutes; group 2, 30 to 360 minutes) were performed, followed by reperfusion with and without dobutamine. Myocardial contrast echocardiography was performed with aortic root injections of sonicated 5% serum human albumin (Albunex) during each intervention. Group 1 dogs showed no evidence of myocardial infarction. In group 2, 26 of 40 dogs had infarctions. After reperfusion, no perfusion abnormalities were seen in 13 of 26 group 2 dogs with infarctions; perfusion abnormalities were identified after reperfusion in 2 of 13 group 1 and in 8 of 14 group 2 dogs without infarctions. In animals subjected to prolonged ischemia, the absence of perfusion abnormalities after reperfusion did not rule out the presence of necrosis. Similarly, in animals without infarction subjected to ischemia, the presence of a perfusion defect after reperfusion did not represent the presence of necrosis but an abnormal microvascular reserve. These results suggest that early after reperfusion, assessment of perfusion by myocardial contrast echocardiography has significant limitations in the evaluation of myocardial viability and salvage.

Animals↗
PubMed1996

Second annual Helene Hudson Memorial Lecture. I am a nurse.

The focus of this study was an exploration of the nature of exceptionally competent oncology nursing practice. Through a combination of data gathering approaches--conversation, observation and narrative exchange--the beliefs, actions and effects of the actions of eight exemplary nurse informants were studied. Analysis revealed three themes related to the action of the exemplary nurses: Dialogue in silence, mutual touch and sharing the lighter side of life. Additional analysis led to a category called effects of nursing actions. Again, three themes were highlighted as effects: Affirmation of the nurse and patient, connecting and joint transcendence.

Health Knowledge, Attitudes, Practice↗
PubMed1996

Searching for the Magic Johnson effect: AIDS, adolescents, and celebrity disclosure.

The objectives of this study were to measure changes in AIDS-related attitudes and behaviors in adolescents in the 13 months following Magic Johnson's disclosure that he was HIV positive, and to test whether gender, race, age, sexual experience, and pre-existing HIV-avoidant behaviors would emerge as significant dependent variables. Adolescent clinic attendees (N = 181) ages 12-19 in four cities completed a questionnaire assessing change in AIDS-related attitudes and behaviors since Johnson's announcement. Respondents were divided into low-risk and at-risk groups. Sixty percent of respondents reported that Magic Johnson's announcement had increased their awareness of AIDS, 65.4% reported increased self-efficacy in a sexual situation, 37.2% reported that they had changed their perceived AIDS risk, 37.8% described increased resistance to peer pressure for sexual intercourse. The low-risk group was more likely to report increased self-efficacy and resistance to peer pressure but no change in perceived risk or increased AIDS awareness. Significant relationships were found between gender and increased AIDS awareness, gender and increased resistance to peer pressure to engage in sexual intercourse, race and increased AIDS awareness, and more lifetime sex partners and increased self-efficacy.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Increased activity of porcine pancreatic phospholipase A2 by designed long-range electrostatic stabilisation of the transition state.

Stabilisation of the catalytic transition state by long-range charge interactions has been tested with mutagenesis for porcine pancreatic phospholipase A2. Electrostatics calculations were used to determine locations which would interact preferentially with one part of the dipolar charge separation that is believed to develop in the transition state. Experiment shows increased enzyme activity relative to wild-type recombinant enzyme for mutants N97D and N101D, consistent with the design.

Animals↗
PubMed1995

Regional renal blood flow measurements using radioactive microspheres in a chronic porcine model with unilateral vesicoureteral reflux.

95Niobium labeled radioactive microspheres were used to determine regional renal blood flows in a porcine model of chronic sterile vesicoureteral reflux. Unilateral vesicoureteral reflux was surgically created in 5 mini-pigs and regional renal blood flows were determined by microsphere injection 6 months later. The contralateral nonrefluxing kidney acted as a control. There was a significant reduction of flow in the inner cortical regions of the middle (78% of control, p < or = 0.0437) and lower poles (69% of control, p < or = 0.0274), and the juxta-medullary cortical region of the lower pole (67% of control, p < or = 0.0124). There was no difference in flow in the other regions or when comparing whole kidneys. There were no differences between refluxing and nonrefluxing kidneys when comparing ratios of inner to outer cortical flow level by level. These observations are in contrast to those in acutely created vesicoureteral reflux in a porcine model, which had no significant differences in flow in any region using the microsphere technique. Decreases of blood flow in certain cortical regions may help explain some of the physiological changes in vesicoureteral reflux in children and experimental models of reflux.

Animals↗
PubMed1994

Making a small enzyme smaller; removing the conserved loop structure of hen lysozyme.

Engineering a smaller lysozyme is a challenge for both random and site-directed mutagenesis. This paper illustrates the power of knowledge-based protein engineering in the design of a smaller lysozyme that folds correctly and has activity against bacterial cell walls. In this smaller lysozyme the conserved disulphide bridged loop is replaced by a short loop. The long loop was selected because it buries a predominantly hydrophilic surface. The short loop was discovered by searching for appropriate fragments in the protein databank. This approach is important in the design of small enzymes useful to the food industry.

Animals↗
PubMed1993

Physiological consequence of expression of soluble and active hen egg white lysozyme in Escherichia coli.

Hen egg white lysozyme was expressed as a protein fusion with the OmpA signal sequence and an octapeptide linker in Escherichia coli. The expression yielded soluble and enzymatically active lysozyme. Lysozyme activity was detected in the periplasmic space, in the cytosol and in the insoluble cytosolic fraction of E. coli. The results indicate that the environmental conditions in both the cytosol and the periplasmic space of E. coli were sufficient for correct protein folding and disulphide bond formation of eukaryotic recombinant lysozyme. However, the expression of active enzyme in E. coli consequently led to bacterial cell lysis due to hydrolysis of the peptidoglucan.

Animals↗