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Biomedical subjects

M Roy

Publications and source records attributed to M Roy.

At least 235 records · Page 13Linked to original sources

The history of a comprehensive pharmacokinetic service.

This paper reviews the 10 years of providing a Clinical Pharmacokinetic Service (CPS) at the Ottawa General Hospital. The history of the service is followed from the early days of selective monitoring of two drugs to the present comprehensive level of monitoring of essentially all drug concentrations analyzed in the hospital. The administrative development is presented, including that of the Subcommittee on Pharmacokinetics. A justification study is described, the results of which indicated 92 percent acceptance of the CPS' recommendations. An effort to withdraw service for digoxin was unsuccessful in that a concurrent study indicated a deterioration in the appropriateness of digoxin prescribing. Several quality assurance techniques are discussed, including a recent audit on predictability. Finally, the education and research links are summarized. Based on the experience of the authors, it is concluded that a comprehensive CPS is an indispensable clinical service.

Digoxin↗

Age-related macular degeneration: from neovascular to atrophic.

A 72-year-old man with age-related neovascular macular degeneration and recurrent episodes of macular subretinal exudation showed a spontaneous change to geographic atrophy of the macula over a period of six years. The evolution of the macular changes from exudative to atrophic illustrates the difficulty of the retrospective classification of age-related macular degeneration.

Aged↗

Antigen delivery to gut associated lymphoid tissue of rabbits.

A rabbit model was developed so that antigens, microbes or potential mucosal vaccines could be delivered in multiple doses directly to the luminal surface of the gut associated lymphoid tissue (GALT) located in the cecal appendix. A polyethylene catheter was implanted surgically into the tip of the appendix. It exited the body wall and progressed subcutaneously around the thorax to the dorsocervical region where it was attached to a subcutaneous obturator. The catheters were flushed every day with sterile saline. To assess patency of the system, radiographic contrast media was injected and the animals were radiographed. Rabbits were necropsied at 10, 30 and 60 days and tissues evaluated by histological, immunohistochemical and electron microscopic means. The microbial flora was evaluated also. All tissues examined were free of significant abnormalities. The advantage of this delivery system is its ability to provide multiple doses of immunogenic agents directly to a physiologically normal appendix over an extended period.

Animals↗

Genetic heterogeneity and population structure in eastern India: red cell enzyme variability in ten Assamese populations.

This paper is a part of the genetic study of the people of Assam (eastern India), initiated by the Anthropometry and Human Genetics Unit, Indian Statistical Institute, Calcutta, India, and the Dept. of Human Biology/Physical Anthropology, University of Bremen, W. Germany. The results of 1. allele distribution of five red cell enzyme polymorphisms in ten Assamese populations, 2. heterogeneity of allele frequencies and extent of gene differentiation among these populations, and 3. standard genetic distances are presented here. A total of 1024 blood samples was screened for aP, E D, AK, ADA and LDH enzyme systems for Brahmins, Kalitas, Kaibartas, Rajbanshis, Muslims, Ahoms, Chutiyas, Kacharis, Karbis (Mikirs) and Sonowals, of which the latter three are tribes. The gene diversity (FST) is smallest (0.0035) for pa and highest (0.1604) for HbE. The total FST value (0.0399 +/- 0.0141) appears to be statistically significant. From distance analysis two major clusters with sub-clusters in each are visible, which are in conformity with the ethnohistory of these populations.

Asian People↗

Genetic homogeneity at the Friedreich ataxia locus on chromosome 9.

Classical Friedreich ataxia, a progressive, neurodegenerative disorder involving both the central and peripheral nervous systems, has been subclassified according to the observed clinical heterogeneity. The variations in the age at onset and in the spectrum and severity of symptoms have previously been interpreted as evidence of genetic heterogeneity. We have studied the linkage between the disorder and closely linked DNA markers in families of distinct ethnic origins, including the "typical" French-Canadians and the Acadian population of Louisiana. The disease in these two populations, both of continental French origin, has a very similar initial clinical picture. However, a marked difference in the rate of progression of the obligatory symptoms after 10 years of apparent disease is observed. A total of 553 individuals from 80 families with 202 affected members have been typed with the chromosome 9 marker MCT112, which we have previously shown to be closely linked to the disease locus. Evidence for linkage was observed in all families with the generation of a combined total lod score of 25.09 at a recombination fraction of theta = .00, providing strong evidence for genetic homogeneity at this locus for the classical form of this disease.

Canada↗

Detection and identification of transient intermediates in the reactions of tryptophan synthase with oxindolyl-L-alanine and 2,3-dihydro-L-tryptophan. Evidence for a tetrahedral (gem-diamine) intermediate.

The reactions of 2,3-dihydro-L-tryptophan (DHT) and oxindolyl-L-alanine (OXA) with tryptophan synthase have been investigated by rapid-scanning stopped-flow (RSSF) spectroscopy and by the concentration dependence of rates measured by single-wavelength stopped-flow (SWSF) spectroscopy. The RSSF spectral changes for DHT and OXA show the disappearance of the internal aldimine (lambda max 412 nm), the formation and decay of intermediates absorbing less than or equal to 340 nm, and the appearance of the quinonoid (lambda max 492 and 480 nm, respectively). Rate constants determined by SWSF were either well resolved (i.e., k1[DHT], k-1 greater than k2, k-2 greater than k3, k-3) or indicative of a tightly coupled system (i.e., k1[OXA], k-1 greater than or equal to k2, k-2 greater than k3, k-3). The RSSF spectral changes and SWSF kinetic studies together with computer simulations of the kinetic time courses are consistent with a mechanism that includes formation of a bleached species. Detection of these shorter wavelength species in the reactions of OXA and DHT indicates that substrate analogues with tetrahedral geometry at C-3 induce new protein-substrate interactions that result in the accumulation of species not previously detected in the tryptophan synthase system. The bleached species with lambda max less than or equal to 340 nm are proposed as the gem-diamine intermediates.

Alanine↗

Stereoelectronic control of bond formation in Escherichia coli tryptophan synthase: substrate specificity and enzymatic synthesis of the novel amino acid dihydroisotryptophan.

The reactions of the indole analogues indoline and aniline with the Escherichia coli tryptophan synthase alpha-aminoacrylate Schiff base intermediate have been characterized by UV-visible and 1H NMR absorption spectroscopy and compared with the interactions of indole and the potent inhibitor benzimidazole. Indole, via the enamine functionality of the pyrrole ring, reacts with the alpha-aminoacrylate intermediate, forming a transient quinonoid species with lambda max 476 nm as the new C-C bond is synthesized. Conversion of this quinonoid to L-tryptophan is the rate-limiting step in catalysis [Lane, A., & Kirschner, K. (1981) Eur. J. Biochem. 120, 379-398]. Both aniline and indoline undergo rapid N-C bond formation with the alpha-aminoacrylate to form quinonoid intermediates; benzimidazole binds rapidly and tightly to the alpha-aminoacrylate but does not undergo covalent bond formation. The indoline and aniline quinonoids (lambda max 464 and 466 nm, respectively) are formed via nucleophilic attack on the electrophilic C-beta of the alpha-aminoacrylate. The indoline quinonoid decays slowly, yielding a novel, new amino acid, dihydroisotryptophan. The aniline quinonoid is quasi-stable, and no new amino acid product was detected. We conclude that nucleophilic attack requires the precise alignment of bonding orbitals between nucleophile and the alpha-aminoacrylate intermediate. The constraints imposed by the geometry of the indole subsite force the aromatic rings of indoline, aniline, and benzimidazole to bind in the same plane as indole; thus nucleophilic attack occurs with the N-1 atoms of indoline and aniline.(ABSTRACT TRUNCATED AT 250 WORDS)

Aniline Compounds↗

Binding characteristics of Ah receptors from rats and mice before and after separation from hepatic cytosols. 7-Hydroxyellipticine as a competitive antagonist of cytochrome P-450 induction.

The Ah receptor, a soluble protein implicated in the mechanism of action of the toxic halogenated aryl hydrocarbons has been examined in rodent livers. Due to the difficulty of making reliable quantitative determinations on binding parameters for hydrophobic compounds in cytosols that contain several components, Ah receptors from livers of Sprague-Dawley rats and C57BL/6 mice have been separated, in a preparative manner, using sucrose density gradient centrifugation in a vertical rotor. The binding characteristics of Ah receptors, before and after separation, were assessed by competition of various chemicals as 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, 3-methylcholanthrene, benzo[a]pyrene, beta-naphthoflavone and ellipticines with [3H]3-methylcholanthrene and 2,3,7,8-tetrachloro[3H]dibenzo-p-dioxin as radioligands. The rationale of this approach is supported by the results obtained and the major conclusions are as follows. 1. The intrinsic binding characteristics of Ah receptors were dependent on the presence or absence of other cytosolic binding components (light-density component and 4-S carcinogen-binding protein). 2. In contrast with many previous unsuccessful attempts, the separation of the C57BL/6 Ah receptor allowed the unambiguous detection of a 9-S binding peak with [3H]benzo[a]pyrene as a radioligand. 3. The intrinsic binding characteristics of the separated Ah receptors of Sprague-Dawley rats and C57BL/6 mice were similar if not identical. 4. A good correlation exists between the competitive potency (IC50) of chemicals and their ability to induce aryl hydrocarbon hydroxylase activity, except for 7-hydroxyellipticine which binds to the Ah receptors of rat and mouse liver (IC50 approximately 5-10 microM) without inducing aryl hydrocarbon hydroxylase. 5. When coadministered with various inducers, 7-hydroxyellipticine antagonizes (from about 20% to 65%) the inducing ability of chemicals displaying similar (ellipticines) or weaker (chlorpromazine, phenothiazine) binding affinities for the Ah receptor.

Alkaloids↗

Binding characteristics of 4-S proteins from rat and mouse liver. High affinity of ellipticines.

The binding characteristics of 4-S components (carcinogen-binding protein) from livers of Sprague-Dawley rats, C57BL/6 and DBA/2 mice have been examined before and after separation from other binding components presents in the cytosol. Competitive potency of 3-methylcholanthrene, benzo[alpha]pyrene, beta-naphthoflavone and 20 ellipticines, a series of compounds differently substituted on the dimethyl-pyrido-carbazole nucleus and deprived of carcinogenic activity, has been determined with [3H]3-methylcholanthrene and/or [3H]benzo[a]pyrene as radioligands. The inducing ability of the same compounds for aryl hydrocarbon hydroxylase and for ethoxyresorufin-O-deethylase has been compared to their affinity for the 4-S protein and the Ah receptor respectively. The main results of this study are as follows. 1. The intrinsic binding characteristics of 4-S proteins were dependent on both the nature of the radioligand used and the presence or absence of other cytosolic binding components. 2. The heterocyclic ellipticines were revealed as strong ligands for the carcinogen-binding protein (stronger than benzo[alpha]pyrene for five derivatives substituted in the A ring of ellipticine), with IC50 values ranging from 0.047 microM (8-hydroxyellipticine) to 5.8 microM (N2-ethyl-9-hydroxyellipticinium). 3. When the affinity of ellipticines was plotted versus their inducing ability of aryl hydrocarbon hydroxylase and ethoxyresorufin-O-deethylase, it appears that a good correlation exists for the Ah receptor but not for the 4-S protein. It is concluded that these data, as well as the lack of enzymatic induction after benzo[alpha]pyrene treatment of DBA/2 mice, which display a high level of 4-S protein, do not support the implication of this binding component in the positive control of cytochrome P-450 induction.

Alkaloids↗

In vivo generation of R68.45-pPGH1 hybrid plasmids conferring a Phl+ (meta pathway) phenotype.

Plasmid pPGH1 originating from Pseudomonas putida strain H carries all the genes required for the degradation of phenol (or cresols) via the meta cleavage pathway. Besides mobilization of pPGH1 by a plasmid of the incompatibility group P-1, hybrid plasmids conferring the Phl+ phenotype could be selected, when R68.45 was the conjugative plasmid. The hybrids contain the complete R68.45 and part of pPGH1. Integration of Phl-DNA of pPGH1 into R68.45 occurred exclusively via the IS21 region of R68.45.

Cloning, Molecular↗

Lanthony desaturated panel D15 test in sickle cell patients.

The Lanthony D15 desaturated test was used to compare color vision in sickle cell patients with 20/20 visual acuity and peripheral lesions of sickle cell retinopathy with normal controls. Sickle cell patients had significantly higher Lanthony error scores and significantly more blue-yellow and mixed color vision defects than controls. Among patients with sickle cell anemia (SS), Lanthony and Farnsworth Munsell 100 Hue test scores were significantly correlated, and both tests showed good agreement in identifying the presence or absence of a color defect. These results suggest that the Lanthony D15 test may be a useful clinical tool to identify blue-yellow color defects, especially because of its brevity and simplicity of administration.

Adult↗

Adriamycin and cisplatin in the treatment of stage III and IV epithelial ovarian carcinoma.

A total of 342 eligible, previously untreated patients with Stage III or IV epithelial ovarian carcinoma were treated with Adriamycin and cisplatin, both at 50 mg/m2, for nine courses. Of the 210 patients who had clinically detectable disease after initial surgery, 85 (41%) had a complete clinical response and 45 (21%) had a partial clinical response. A total of 197 were clinically free of disease at the completion of chemotherapy and 175 of these had a second-look laparotomy; 55 had no macroscopic or microscopic evidence of residual disease after multiple random biopsies were examined histologically (complete surgical/histologic response). The major determinants of complete surgical/histologic response were diameter of largest residual tumor prior to treatment, ECOG performance status, and grade, patients with grade 3 tumors having a higher complete response rate than those with grade 1 or 2 tumors. The major determinants of survival were ECOG performance status and diameter of largest residual tumor prior to treatment. Median survival of the total group was 1.8 years.

Adult↗

Condyloma and intraepithelial neoplasia of the uterine cervix: a case-control study.

Cervical condyloma and cervical intraepithelial neoplasia are related to human papillomavirus infections, some of which may be involved in the etiology of cancer of the uterine cervix. This case-control study was designed to assess the relation of age at first sexual intercourse, number of sexual partners, and cigarette smoking to the risk of cervical condyloma and cervical intraepithelial neoplasia. Cases and controls were premenopausal women under age 50 years who had been referred for examination at the Colposcopy Clinic of Saint-Sacrement Hospital in Quebec from 1982 to 1985. These were 136 cases of histologically confirmed cervical condyloma and 247 cases of cervical intraepithelial neoplasia. The 137 controls were women without anogenital condyloma, dysplasia, or carcinoma. Information on personal characteristics and exposures of subjects was obtained by interview. Associations observed with age at first intercourse were different for condyloma and cervical intraepithelial neoplasia. Relative risk of condyloma varied little with age at first intercourse. In contrast, relative risk of cervical intraepithelial neoplasia increased as age at first intercourse decreased. For the two types of lesions, relative risk was elevated among women with more than one sexual partner and increased steadily with increasing number of cigarettes smoked per day. The association with cigarette smoking was, however, somewhat stronger for cervical intraepithelial neoplasia.

Adult↗

Hemoglobin E distribution in ten endogamous population groups of Assam, India.

Previous studies have reported a high incidence of hemoglobin E (HbE) in Northeast Indian populations. In the present study 10 endogamous populations of Assam belonging to two racial groups, Caucasoid and Mongoloid, were examined. The frequency of HbE gene (Hb beta E) in the Caucasoid caste populations is around 0.1, whereas the gene is highly prevalent in the Mongoloid populations, frequencies ranging between 0.2 and 0.6. Predominance of Hb beta E in the Tibeto-Burman speakers is contrary to observations made in Southeast Asia, where an association between Austro-Asiatic speakers and high prevalence of HbE exist. The highest occurrence of the gene in this area, which is on the far end of the proposed centre of distribution in Northern Kampuchea and Northeast Thailand, is also a deviation from the expected pattern of gene distribution. It is speculated that Hb beta E in the Tibeto-Burman populations of Assam arose by an independent mutation which contributed to the high frequencies of Hb beta E in the Northeast Indian populations.

Asian People↗

Ultrastructure and morphometric measurements of mesenteric arteries from newborn spontaneously hypertensive rats.

A morphometric and ultrastructural study of superior mesenteric arteries and large mesenteric arteries from newborn spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) was carried out. Morphometric measurements showed that in both vessel types, cross-sectional areas of the lumen and vessel wall components (e.g., media, adventitia) were similar between SHR and WKY. There was also no ultrastructural difference between SHR and WKY in the two types of arteries. We therefore conclude that vascular alterations found in older SHR take place after birth.

Animals↗