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Biomedical subjects

R Dean

Publications and source records attributed to R Dean.

At least 19 recordsLinked to original sources
PubMed1999

Inheritance of a mitochondrial DNA defect and impaired glucose tolerance in BHE/Cdb rats.

As they age, BHE/Cdb rats develop impaired glucose tolerance. We hypothesized that this intolerance is associated with a previously reported base substitution in the mitochondrial genome. A new screening test was devised to identify animals with the mutation. These animals were bred to animals without the mutation. The progeny were then tested for the presence of the mutation and their glucose tolerance at 100 and 300 days of age. Phenotype and genotype were found to be closely linked and we conclude that the mutation in the mitochondrial ATPase 6 gene explains the age related impaired glucose tolerance in BHE/Cdb rats.

Animals↗
PubMed1999

One hundred consecutive advanced breast biopsy instrumentation procedures: complications, costs, and outcome.

BACKGROUND: Needle localization and excision have been the preferred techniques for treating nonpalpable mammographic abnormalities. Recently, a less invasive approach, using the Advanced Breast Biopsy Instrumentation (ABBI) system, was introduced. This study was undertaken to determine the feasibility, utility, and cost of this new alternative approach. METHODS: Between April 1996 and May 1997, 100 consecutive women underwent excisional breast biopsies using the ABBI system. Demographic information, mammographic findings, pathological findings, hospital/professional fees, complications, and subsequent interventions were documented. RESULTS: Excisional biopsies using the ABBI system were successful for 99 women (average age, 62 years; range, 34-87 years). Of the 99 lesions removed with the ABBI system, 27 were microcalcifications, 60 were suspicious solid nodules, and 12 were nodules with microcalcifications. The ABBI system was used in an outpatient surgical setting, with only one patient requiring sedation (because of anxiety). Cancer was seen in the biopsy specimens for 18 patients, seven of whom (35%) exhibited no residual tumor at the time of definitive treatment. Postoperative hematomas occurred in two patients; one hematoma required surgical drainage. One missed cancer was detected in follow-up mammograms 6 months after biopsy. The total average procedural cost was $3406.44 +/- 486.63. CONCLUSIONS: Excisional breast biopsy using the ABBI system is an effective diagnostic method. It has a low complication rate, and its cost is comparable to that of classical needle localization.

Adult↗
PubMed1999

Rat renomedullary interstitial cells possess bradykinin B2 receptors in vivo and in vitro.

1. Renomedullary interstitial cells (RMIC), abundant throughout the medulla of the kidney, have been demonstrated to have binding sites for many vasoactive peptides, including atrial natriuretic peptide, endothelin, angiotensin II and bradykinin (BK). These observations would support the hypothesis that interactions between RMIC and vasoactive peptides are important in the regulation of renal function. 2. We aimed to localize the BK B2 receptor binding site to RMIC in vivo and to also demonstrate that these receptors are biologically active in vitro. 3. The present study demonstrates BK B2 binding sites on RMIC of the inner stripe of the outer medulla and the inner medulla of the rat kidney in vivo. 4. We further demonstrate that the BK B2 radioligand [125I]-HPP-Hoe140 specifically bound to rat RMIC in vitro. In addition, reverse transcription-polymerase chain reaction detected the mRNA for the BK B2 receptor subtype in cell extracts. 5. For RMIC in vitro, cAMP levels were increased at 1 min and cGMP levels were increased at 2 min after treatment with 10(-10) and 10(-7) mol/L BK, respectively. Inositol 1,4,5-trisphosphate was increased at 10 s treatment with both 10(-6) and 10(-7) mol/L BK. 6. For RMIC in vitro, BK induced an increase in cell proliferation ([3H]-thymidine incorporation) and an increase in extracellular matrix synthesis (ECM; trans-[35S] incorporation), both effects mediated by BK B2 receptors. 7. We conclude that BK B2 receptors are present on RMIC both in vivo and in vitro. These receptors are coupled to intracellular second messenger systems and, in vitro, their stimulation results in cellular proliferation and synthesis of ECM.

Animals↗
PubMed1999

Localization of the insulin-like growth factor system in a rat model of heart failure induced by myocardial infarction.

Although cardiac effects of growth hormone (GH) and insulin-like growth factor (IGF)-I have been reported in experimental models of heart failure and in human dilated cardiomyopathy, the IGF system has not been comprehensively assessed in the failing heart. We therefore localized the IGF system in the left ventricle during congestive heart failure after myocardial infarction (MI) in the rat. The left anterior descending coronary artery was ligated in adult female Sprague-Dawley rats and hearts were examined after 6 months when congestive heart failure had developed. In situ hybridization histochemistry was used to localize mRNA for the components of the IGF system in the left ventricle of sham and congestive heart failure animals. We were able to detect changes in the spatial distribution of mRNA for IGF-I and IGF binding proteins 3, 4, 5, and 6 in the left ventricle during congestive heart failure after MI. IGF-I and the binding proteins were predominantly increased in the infarct/peri-infarct area of the left ventricle. Other components of the IGF system were indistinguishable from the low to undetectable levels in sham-operated rats. These results demonstrate that the IGF system is altered in the failing heart and suggest that the IGF system plays an important role in the response of the heart to MI and consequent failure.

Animals↗
PubMed1998

The hydroxyl radical in lens nuclear cataractogenesis.

Cataract is the major cause of blindness; the most common form is age-related, or senile, cataract. The reasons for the development of cataract are unknown. Here we demonstrate that nuclear cataract is associated with the extensive hydroxylation of protein-bound amino acid residues, which increases with the development of cataract by up to 15-fold in the case of DOPA. The relative abundance of the oxidized amino acids in lens protein (assessed per parent amino acid) is DOPA > o- and m-tyrosine > 3-hydroxyvaline, 5-hydroxyleucine > dityrosine. Nigrescent cataracts, in which the normally transparent lens becomes black and opaque, contain the highest level of hydroxylated amino acids yet observed in a biological tissue: for example, per 1000 parent amino acid residues, DOPA, 15; 3-hydroxyvaline, 0.3; compared with dityrosine, 0.05. The products include representatives of the hydroperoxide and DOPA pathways of protein oxidation, which can give rise to secondary reactive species, radical and otherwise. The observed relative abundance corresponds closely with that of products of hydroxyl radical or metal-dependent oxidation of isolated proteins, and not with the patterns resulting from hypochlorite or tyrosyl-radical oxidation. Although very little light in the 300-400-nm range passes the cornea and the filter compounds of the eye, we nevertheless also demonstrate that photoxidation of lens proteins with light of 310 nm, the part of the spectrum in which protein aromatic residues have residual absorbance, does not give rise to the hydroxylated aliphatic amino acids. Thus the post-translational modification of crystallins by hydroxyl radicals/Fenton systems seems to dominate their in vivo oxidation, and it could explain the known features of such nuclear cataractogenesis.

Amino Acids↗
PubMed1998

Somatostatin receptor subtype specificity and in vivo binding of a novel tumor tracer, 99mTc-P829.

Recent data suggest that somatostatin receptors (SSTRs) are expressed on various tumor cells. High-level expression of SSTR on the tumor cell surface provides the basis for the successful clinical use of radiolabeled ligands for the in vivo localization of tumor sites. We have characterized the in vitro binding properties of the novel SSTR ligand 99mTc-P829 using primary human tumors (carcinoids, breast cancers, intestinal adenocarcinomas, pheochromocytomas, small cell and non-small cell lung cancer, and melanomas; n = 28), various tumor cell lines, and COS7 cells transfected with the human SSTR (hSSTR) subtypes 1, 2, 3, 4, and 5. 99mTc-P829 bound to primary tumor cells and tumor cell lines with high affinity and high capacity. The dissociation constants (Kd) ranged between 1 and 20 nM. 99mTc-P829 also bound with high affinity to the transfected hSSTR2 (Kd, 2.5 nM), hSSTR5 (Kd, 2 nM), and hSSTR3 (Kd, 1.5 nM). Binding of 99mTc-P829 to hSSTR3 was found to be displaceable by unlabeled P829/([ReO]-P829), SST-14, and vasoactive intestinal peptide (VIP; IC50, 2 nM) and, less effectively, by Tyr3-octreotide (IC50, 20 nM). In contrast, the binding of 99mTc-P829 to hSSTR2 and hSSTR5 could be displaced by P829/([ReO]-P829) and Tyr3-octreotide but not by VIP. 99mTc-P829 scintigraphy revealed in vivo binding to primary or metastatic tumor sites in seven of eight patients with breast cancer and six of six patients with melanoma. In summary, our data show that 99mTc-P829 binds with high affinity to many different types of primary and cloned tumor cells. Furthermore, our data identify hSSTR2, the VIP acceptor hSSTR3, and hSSTR5 as the respective target receptors. Because these receptors are frequently expressed at high levels on primary tumor cells, 99mTc-P829 appears to be a promising novel peptide tracer for tumor imaging.

Animals↗
PubMed1998

Localization and interactions of vasoactive peptide receptors in renomedullary interstitial cells of the kidney.

Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the localization of their receptors and mechanisms of actions are currently unknown. Using electron microscopic autoradiography, we have mapped the receptors for angiotensin II (Ang II [AT1 and AT2]), endothelin (ET(A) and ET(B)), and bradykinin (B2) in the rat renal medulla. Although these peptide receptors show distinct vascular and tubular distributions, they overlap strikingly in renomedullary interstitial cells (RMICs) of the inner stripe and the papilla. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern analysis, mRNAs for AT1A, ET(A), and B2 receptors were detected in cultured adult RMICs. Ang II increases intracellular inositol 1,4,5-triphosphate (IP3) and [Ca2+]i and stimulates [3H]thymidine incorporation and extracellular matrix (ECM) synthesis via AT1A receptors. Endothelin and bradykinin also stimulate cell proliferation and ECM synthesis in RMICs through ET(A) and B2 receptors, respectively, but the actions of endothelin are modulated by concurrent nitric oxide production. By contrast, AT2 receptor mRNA was detected only in embryonic RMICs, in which Ang II inhibits cell proliferation through this receptor. These results suggest that multiple vasoactive peptides may interact with RMICs to exert endocrine and/or paracrine influences on renal medullary microcirculation and tubular function.

Animals↗
PubMed1997

Population analysis of the pharmacokinetics and pharmacodynamics of seratrodast in patients with mild to moderate asthma.

BACKGROUND: Seratrodast, a potent thromboxane receptor antagonist, is approved in Japan for the treatment of asthma and currently is being developed in the United States. METHODS: This was a phase II, randomized, double-blind, parallel-group, placebo-controlled 15-center study of seratrodast in patients with mild to moderate asthma. A total of 183 patients were randomly assigned to receive daily doses of either placebo, or 80 mg seratrodast, or 120 mg seratrodast for 8 weeks. Pharmacokinetic and pharmacodynamic modeling was carried out by means of the population approach. A two-compartment model with zero-order input and first-order elimination best fitted the plasma concentration-time data. RESULTS AND CONCLUSIONS: The pharmacokinetics of seratrodast were linear after single and multiple dosing for 8 weeks. The population estimates for oral clearance and apparent volume of distribution were 8.5 ml/hr/kg and 43.3 ml/kg, respectively. All pharmacokinetic parameters (the oral central compartment clearance, the volumes of distribution of the central and peripheral compartments, and the intercompartmental clearance) were estimated with a precision of 10% or less and were found to be associated with body weight. The residual variability was 30%. The values of oral clearance estimated in this study in male patients were similar to those previously estimated in healthy male subjects. Seratrodast at a dose of 120 mg daily produced an increase in forced expiratory volume in 1 second (FEV1) from baseline that was linearly correlated with its plasma concentrations. The average slope of the concentration-effect relationship was 0.222% and 0.470% per microgram/ml after single and multiple dosing, respectively. Interpatient variability in response was mainly affected by the initial severity of the disease. A lower percentage of predicted FEV1 (i.e., more severe obstruction) was associated with higher slopes, and greater increases in FEV1.

Adult↗
PubMed1997

Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.

Bradykinin exerts important influences on renal hemodynamics and tubular function by acting on renal bradykinin B2 receptors. However, the precise sites and mechanisms of its actions on the kidney are not known. To help elucidate the mechanisms of renal actions of bradykinin in vivo, we have employed high resolution electron microscopic autoradiography to localize bradykinin B2 binding sites in the rat kidney following intravenous administration of a radiolabeled ligand, 125I-HPP-Hoe140 (3-4-Hydroxyphenyl-propionyl-DArg0-[Hyp3-Thi5-D-Tic 7-Oic8]-bradykinin), a derivative of the highly selective bradykinin B2 receptor antagonist, Hoe140. In non-treated rats, bradykinin B2 binding sites were localized to the cell bodies and the luminal brush border of the proximal convoluted tubules in the cortex. In the medulla (except for the outer stripe of the outer medulla), binding occurred in the distal tubules, thin limbs of the loop of Henle, collecting ducts, peritubular capillary endothelium and renomedullary interstitial cells. To exclude the possibility that the radioligand may bind to angiotensin converting enzyme, rats were pretreated with the angiotensin converting enzyme inhibitor, perindopril. In these rats, binding to the cell bodies and the luminal brush border of the proximal convoluted tubules in the cortex was completely abolished, while binding remained unaltered in the medulla. Further studies using high performance liquid chromatography revealed that while the radioligand was degraded following systemic administration in nontreated rats, the degradation was significantly reduced in the rats pretreated chronically with perindopril. These results indicate that binding detected in the proximal tubules in the normal rats is due primarily to the tubular uptake of the degraded radioligand, and that bradykinin B2 binding sites occur predominantly in the renal tubules, vascular endothelium, and renomedullary interstitial cells of the renal medulla.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Our journey.

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Canada↗
PubMed1996

Expression of c-Fos in subcutaneous adipose tissue of the fetal pig.

Subcutaneous adipose tissue from fetal pigs was examined for c-Fos expression in developing adipocytes. Enhanced c-Fos expression was found in the nuclei of adipocytes and cells closely associated with fat cell clusters from 75 and 105 day old fetuses. 50 day old fetuses which had no adipocytes showed no enhanced c-Fos expression in undifferentiated cells. c-Fos expression in adipocytes was not transient, but persisted through the gestational period from 75 to 105 days. The timing of c-Fos induction appears to be closely related to adipocyte differentiation and was found only in developing adipocytes and cells closely associated with fat cell cluster and was not found in independent stromal-vascular cells.

Adipocytes↗
PubMed1996

Permeability of the blood brain barrier by the bradykinin agonist, RMP-7: evidence for a sensitive, auto-regulated, receptor-mediated system.

The novel bradykinin (BK) analog, RMP-7, was characterized in a series of in vitro tests to establish its selectivity as a B2 agonist. It was then used to study bradykinin's role in permeabilizing the blood brain barrier (BBB) and blood brain-tumor barrier (BTB), using an RG2 rat glioma model. These studies demonstrated that: (1) B2 receptor stimulation permeabilizes both the BBB and BTB in a dose-related fashion with greater effects observed in brain tumor-associated tissue, (2) the increased permeability is sensitive, rapid and transient, and (3) tachyphylaxis occurs with continuous agonist administration, suggesting autoregulation of the system's effects. These data therefore support the existence of a sophisticated, responsive and tightly regulated BK system whose activity modulates the permeability of the BBB.

Animals↗
PubMed1996

A comparative study of unsedated transnasal esophagogastroduodenoscopy and conventional EGD.

BACKGROUND: A significant portion of the cost and complications associated with conventional esophagogastroduodenoscopy (EGD) is attributed to conscious intravenous sedation, which usually results in loss of work on the day of the endoscopy. Earlier studies have described the feasibility and safety of unsedated transnasal EGD in normal volunteers. METHODS: We compared the diagnostic yield and patient acceptability of this new technique performed first, with conventional EGD performed second in 24 outpatients. RESULTS: The sensitivity of transnasal EGD was 89% and its specificity was 97%. Transnasal EGD was more acceptable and less stressful to the patients than conventional EGD (p < 0.05). Oxygen saturation and blood pressure did not change during transnasal EGD. CONCLUSION: Transnasal EGD is feasible, safe, and well tolerated by patients. Specificity of transnasal EGD is similar to, but its sensitivity is lower than, conventional EGD. By eliminating the need for sedation-related work loss and postprocedural monitoring, transnasal EGD potentially is more cost-effective than conventional EGD.

Adult↗
PubMed1996

Residential care in hospital and in the community--quality of care and quality of life.

BACKGROUND: The reduction of beds in long-stay hospitals has led to concerns over the quality of care offered to the remaining residents as well as that provided in the community. This study seeks to compare the quality of care and quality of life (reported satisfaction) from residents in both types of setting. METHOD: A cross-sectional comparison was made of community residential homes and hospital wards drawn randomly from lists provided by local authorities in the outer London area. Samples were drawn from all the main provider types (local authority, housing association, private and joint NHS/voluntary sector). Measures were taken of the quality of the physical environment, staff and resident characteristics, external management arrangements and internal management regimes, resident satisfaction and staff stress. Direct observations were also made of the amount and quality of staff-resident interactions. RESULTS: In general, the most disabled residents were found to be still living in hospital in the Worst conditions and receiving the poorest quality of care. Although there were some problems with missing data, hospital residents also seemed most dissatisfied with their living situation. There were few differences between community providers regarding either the quality of care provided or the levels of reported satisfaction. Quality of care in the community homes seemed to be much more determined by the personality and orientation of project leaders. CONCLUSIONS: Purchasers and providers still need to give attention to the problems of selectively discharging the most able residents to the community, leaving the most disabled being looked after in progressively deteriorating conditions. All residential providers need to review their internal management practices and try to ensure that residents are offered, as far as possible, the opportunity to make basic choices about where and how they will live. Staff training and quality assurance practices need to be reviewed in order to improve the direct quality of care offered to the most disabled individuals.

Activities of Daily Living↗
PubMed1996

Evaluation of intrapleural analgesia in the management of blunt traumatic chest wall pain: a clinical trial.

Intrapleural analgesia (IPA) has been successfully used for the relief of chest wall pain. Previous studies investigating its use have yielded conflicting results and have often suffered from design defects. The theoretical lower incidence of respiratory and circulatory depression with IPA suggests significant advantages over epidural analgesia. Patients who had documented blunt chest wall trauma were entered into a prospective, randomized, double-blinded, crossover, placebo-controlled study within 16 hours of their injury. Patients who were intubated or had significant trauma outside of the chest wall were not entered. Intrapleural catheters were placed using a standardized technique. Each patient received either a placebo solution of normal saline or a combination of bupivacaine/lidocaine in a blinded, crossover fashion for two 24-hour periods. Data were obtained on the use of supplementary narcotics, transcutaneous pCO(2') pulse oximetry, pulmonary function tests, and both patient and nursing evaluations of pain based on a numeric analogue scale. A series of 16 patients from a Level I trauma center were identified over a 2-year period. The ratio of male to female was approximately 2:1, with an age range of 35-80 years. There were no complications related to catheter placement or anesthetic toxicity. Mean values for patient and nursing pain ratings revealed opposite trends. We found no significant difference in the mean values for supplemental narcotic use, pCO(2') p0(2') forced vital capacity, or forced expiratory volume between the placebo and the test solution. Although previous studies have suggested that IPA may be beneficial in the management of chest wall pain, this was not confirmed in our study for blunt chest injuries. The addition of IPA to the more traditional use of opioid analgesics was not more effective for management of blunt chest wall pain. Despite our small patient population (n = 16), the crossover design should have allowed clinically significant differences to become evident (alpha value = 0.95). A review of the literature and a historical basis for the evolution in the management of this type of pain is included.

Adult↗
PubMed1996

Presence of angiotensin II AT2 receptor binding sites in the adventitia of human kidney vasculature.

1. Angiotensin II (AngII) receptor subtypes in adult human kidney were pharmacologically characterized by in vitro autoradiography using the AngII receptor subtype-selective antagonists, losartan and PD 123319, and the sensitivity to the reducing agent, dithiothreitol. 2. High densities of AngII AT1 receptor binding occur in the glomeruli and the inner stripe of the outer medulla, while a moderate AT1 receptor binding is localized in the proximal convoluted tubules. 3. AT2 receptor binding is observed predominantly in the intrarenal large blood vessels, including the arcuate, inter- and intra-lobular arteries, and in the renal capsule. 4. In the major renal artery, AT1 receptor binding is abundant in the media and adventitia, while AT2 receptor binding is observed mainly in the adventitia. 5. At the light microscopic level using emulsion autoradiography, AT1 receptors are localized in the glomeruli and juxtaglomerular apparatus, as expected. However, in larger renal blood vessels, including the arcuate arteries, inter- and intra-lobular arteries, intense AT2 receptor labelling occurs primarily in the adventitia, while the endothelium and vascular smooth muscle layers contain only low levels of AngII receptor binding. 6. These results indicate that the adult human kidney displays two pharmacologically distinct AngII receptor subtypes, with AT1 predominating in the glomeruli, juxtaglomerular apparatus, proximal tubules and the inner stripe of the outer medulla, while AT2 predominates in the adventitia of the arcuate and interlobular arteries and the renal capsule. The functional significance of AT2 receptor binding sites in the adventitia of adult human kidney vessels remains to be elucidated.

Adult↗
PubMed1995

The pharmacokinetics and cardiovascular pharmacodynamics of HP 749 (besipirdine HCl) and metabolite P86-7480 in the conscious monkey.

HP 749 was absorbed slowly in the conscious monkey after single oral doses (10, 20, and 40 mg/kg), with gradual metabolism to the N-despropyl metabolite, P86-7480. The tmax was 2 to 4 hours after dosing, with nonlinear increases in Cmax and the AUC0-4th for HP 749. The calculated elimination half life (t1/2) after oral administration was 7.4 +/- 2.1 hours; however, absorption appeared to influence the terminal phase because the t1/2 after intravenous administration of 10 mg/kg was 1.5 hours. Plasma concentration of HP 749 2 minutes after intravenous bolus was 26.08 micrograms/mL. The HP 749 was rapidly distributed (t1/2 alpha = 0.064 +/- 0.033 hours) after intravenous administration, and displayed a VZ of 2.6 +/- 0.85 L/kg. The CL of HP 749 was 20.8 +/- 6.9 mL/min/kg, whereas renal clearance (CLR) of unchanged drug was only 0.13 +/- 0.04 mL/min/kg. Thus, only about 1% of the administered dose was excreted unchanged by the kidney. The P86-7480 also was rapidly distributed and eliminated after an intravenous bolus, but was less extensively distributed than HP 749. HP 749 administered either as an intravenous bolus or orally caused a significant pressor effect soon after dosing. A significant tachycardia resulted from intravenous administration, but not after oral administration of the drug. An intravenous bolus of P86-7480 (0.1 mg/kg) resulted in an immediate increase in MAP and decreased heart rate. The duration of these cardiovascular events was significantly shorter after intravenous administration of P86-7480 than with intravenous or oral administration of the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗