Transmission of Histoplasma capsulatum by organ transplantation.
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Adult↗
Biomedical subjects
M Sagar
Publications and source records attributed to M Sagar.
Omeprazole and CYP2C19 polymorphism: effects of long-term treatment on gastrin, pepsinogen I, and chromogranin A in patients with acid related disorders.
BACKGROUND: The polymorphic enzyme CYP2C19 is of importance for the metabolism and effects of omeprazole during short-term treatment. AIM: To investigate the relationship between CYP2C19 genotype and the effects of long-term omeprazole treatment. MATERIAL AND METHODS: A total of 180 patients with acid related disorders were genotyped for wild type and mutated CYP2C19 alleles by allele-specific PCR amplification. Gastrin and chromogranin A were assessed by radioimmunoassays, and pepsinogen I and H. pylori serology were assessed by ELISA methods. RESULTS: In 108 of the patients, who received a single dose of 20 mg omeprazole, there was no difference in gastrin and chromogranin A concentrations between the three CYP2C19 genotypes. In 72 patients on long-term treatment (> 1 year) with 20 mg omeprazole daily, serum gastrin as well as plasma chromogranin A concentrations (mean +/- s.e.) were both about threefold higher in the wild type/mutated (52.1 +/- 7.6 pM and 7.3 +/- 1.3 nM (n=19), respectively) compared to wild type/wild type (14. 7 +/- 0.9 pM and 2.5 +/- 0.1 nM (n=52), respectively; both comparisons P=0.0001). In a single mutated/mutated patient on long-term treatment, both gastrin and chromogranin A were high (88 pM and 13.7 nM, respectively). Serum pepsinogen I concentration was significantly lower in wild type/mutated (n=19) patients on long-term treatment, compared with the corresponding wild type/wild type (n=49) group (147 +/- 19 microg/L vs. 193 +/- 12 microg/L, P=0. 04). CONCLUSION: Patients with one (and probably also with two) mutated CYP2C19 allele(s) on long-term treatment with omeprazole had significantly affected serum gastrin and pepsinogen I and plasma chromogranin A concentrations compared with patients with two normal alleles. This indicates that changes in gastric mucosal morphology during omeprazole treatment might be dependent upon the degree of the individual's capacity to metabolize omeprazole.
Anti-Ulcer Agents↗
Effects of omeprazole on intragastric pH and plasma gastrin are dependent on the CYP2C19 polymorphism.
BACKGROUND & AIMS: Omeprazole is metabolized by cytochrome P450 (CYP2C19). The activity of this enzyme is polymorphic, with incidences of poor metabolizers (PMs), heterozygous extensive metabolizers (EMs), and homozygous EMs in white populations of 3%, 30%, and 67%, respectively. The importance of the CYP2C19 polymorphism for the effects of omeprazole on intragastric pH and plasma gastrin concentrations has been investigated. METHODS: Twenty-five white patients were genotyped for CYP2C19 by allele-specific polymerase chain reaction amplification, and their Helicobacter pylori status was assessed by serology and with immunoblot analysis. Intragastric pH was monitored over 24 hours, and meal-stimulated plasma gastrin concentration was measured over 4 hours (AUC 4h) before (day 0) and during (day 8) treatment with 20 mg omeprazole once daily. RESULTS: Eleven patients were homozygous for the wild-type allele (wt/wt), 12 were heterozygous EMs (wt/mut), and 2 were PMs (mut/mut). Median (95% confidence interval) 24-hour intragastric pH in the heterozygous EM group was 5.5 (range, 5.1-5. 9) compared with 3.1 (range, 2.7-3.6) in homozygous EMs (P < 0.0001) at day 8. The percentage of time with intragastric pH > 4 at day 8 was significantly higher in the wt/mut than wt/wt group (72.4% vs. 37.1%; P < 0.0001). H. pylori status had less influence than CYP2C19 on intragastric acidity. Omeprazole treatment increased meal-stimulated plasma gastrin concentrations from day 0 to day 8 in the homozygous EMs and heterozygous EMs by 16% (NS) and 157% (P = 0. 002), respectively. In heterozygous EMs, the gastrin increase was more pronounced in the H. pylori-positive group (226%) than H. pylori-negative group (80%; P = 0.02). CONCLUSIONS: The effects of omeprazole on intragastric pH and plasma gastrin are dependent on the CYP2C19 polymorphism in patients with acid-related disorders.
Aged↗
p53 and tumor necrosis factor alpha regulate the expression of a mitochondrial chloride channel protein.
A novel chloride intracellular channel (CLIC) gene, clone mc3s5/mtCLIC, has been identified from differential display analysis of differentiating mouse keratinocytes from p53+/+ and p53-/- mice. The 4.2-kilobase pair cDNA contains an open reading frame of 762 base pairs encoding a 253-amino acid protein with two putative transmembrane domains. mc3s5/mtCLIC protein shares extensive homology with a family of intracellular organelle chloride channels but is the first shown to be differentially regulated. mc3s5/mtCLIC mRNA is expressed to the greatest extent in vivo in heart, lung, liver, kidney, and skin, with reduced levels in some organs from p53-/- mice. mc3s5/mtCLIC mRNA and protein are higher in p53+/+ compared with p53-/- basal keratinocytes in culture, and both increase in differentiating keratinocytes independent of genotype. Overexpression of p53 in keratinocytes induces mc3s5/mtCLIC mRNA and protein. Exogenous human recombinant tumor necrosis factor alpha also up-regulates mc3s5/mtCLIC mRNA and protein in keratinocytes. Subcellular fractionation of keratinocytes indicates that both the green fluorescent protein-mc3s5 fusion protein and the endogenous mc3s5/mtCLIC are localized to the cytoplasm and mitochondria. Similarly, mc3s5/mtCLIC was localized to mitochondria and cytoplasmic fractions of rat liver homogenates. Furthermore, mc3s5/mtCLIC colocalized with cytochrome oxidase in keratinocyte mitochondria by immunofluorescence and was also detected in the cytoplasmic compartment. Sucrose gradient-purified mitochondria from rat liver confirmed this mitochondrial localization. This represents the first report of localization of a CLIC type chloride channel in mitochondria and the first indication that expression of an organellular chloride channel can be regulated by p53 and tumor necrosis factor alpha.
Amino Acid Sequence↗
A man with diabetes and a swollen leg.
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Adult↗
Effect of CYP2C19 polymorphism on serum levels of vitamin B12 in patients on long-term omeprazole treatment.
BACKGROUND: The S-mephenytoin hydroxylase is a polymorphic cytochrome P450 (CYP) enzyme, identified as CYP2C19, which catalyses the metabolism of omeprazole and some other drugs. AIM: To determine whether long-term treatment with omeprazole affects serum vitamin B12 levels, and if so to what extent it depends on CYP2C19 activity. METHODS: Serum vitamin B12 levels (pmol/L) were assessed in 179 patients. Genotyping for wild-type (wt) and mutated (mut) CYP2C19 alleles was performed by allele-specific PCR amplification. RESULTS: One-hundred and eleven of the patients received one dose of 20 mg omeprazole. No difference in B12 levels were found between heterozygous (wt/mut) (n = 23) and homozygous (wt/wt) (n = 85) patients (mean +/- s.d., 350 +/- 82 vs. 315 +/- 87 pmol/L, respectively). Three patients were mut/mut, with serum vitamin B12 levels of 303 +/- 50 pmol/L. In the 68 patients on long-term (>1 year) therapy with 20 mg omeprazole daily, serum vitamin B12 levels were lower in the heterozygous (wt/mut) (n = 19) compared to homozygous wt/wt (n = 49) (246 +/- 71 vs. 305 +/- 98 pmol/L, P = 0. 01, respectively). In one patient (mut/mut) who was studied both after a single dose and after long-term (15 months) treatment with omeprazole, serum vitamin B12 decreased from 360 to 178 pmol/L. In the wt/mut, but not in the wt/wt group, serum vitamin B12 levels were significantly lower in patients on long-term therapy compared with those receiving one dose (246 +/- 71 vs. 350 +/- 82 pmol/L, P < 0.0001, respectively). CONCLUSIONS: CYP2C19 polymorphism significantly affected serum vitamin B12 levels in patients on long-term therapy with omeprazole. In the future, genotyping of CYP2C19 may be useful for patients in need of long-term treatment with omeprazole or other proton pump inhibitors.
Anti-Ulcer Agents↗
Thoracic lymphadenopathy in HIV patients: spectrum of disease and differential diagnosis.
To evaluate the etiology and differential features of intrathoracic lymphadenopathy (LAD) in HIV patients, chest computed tomography (CT) records from an 18-month period were reviewed to identify all HIV-positive patients with intrathoracic LAD (nodal size > or = 1 cm). Medical records were reviewed for the documentation of specific diseases causing LAD and the CD4 count at the time of imaging. Of 45 HIV-positive patients with LAD, 40 had specific diagnoses including 22 (55%) infections and 17 (43%) tumors; one patient had both (3%). Mycobacterial disease accounted for 78% of infections; five cases were secondary to bacterial pneumonia and sepsis. Of tumors, lymphoma (7 cases, 39%) was most common, followed by lung cancer, germ cell tumors, and Kaposi's sarcoma. Mean CD4 cell count in patients with tumors was much higher than in patients with infections (314 vs. 62, p < .01). Patients with tumors were somewhat more likely than patients with infections to demonstrate axillary adenopathy (29 vs. 5%, p = .068). Cavitary disease was only observed in patients with infections (27%, p < .03). CT and clinical findings may help direct the differential diagnosis of LAD in AIDS, and promote expedient definitive diagnosis and therapy.
Adult↗
Cooperation of p53 loss of function and v-Ha-ras in transformation of mouse keratinocyte cell lines.
We previously demonstrated that after transduction with the v-Ha-ras oncogene and grafting onto nude mouse hosts, primary epidermal keratinocytes with a null mutation in the p53 gene form tumors with increased growth rates and predisposition to malignant conversion relative to p53 wild-type keratinocytes (Weinberg WC, et al., Cancer Res 54:5584-5592, 1994). To further explore the cooperation between p53 loss of function and activation of the ras oncogene, cell lines were established from the normal epidermises of newborn and adult p53-null mice, and parallel subclones were reconstituted with the p53val135 temperature-sensitive mutant. Reconstituted lines C, G, N, and V demonstrated functional p53 transcriptional activator activity at the wild-type-permissive temperature of 32 degrees C, compared with the hygromycin-selected control line X and parental p53-null lines NHK4 and AK1b. Hygromycin-selected subclones, but not the parental lines, made normal skin in vivo; all cell lines made carcinomas after introduction of v-Ha-ras, independent of p53 status. These cell lines were compared in vitro at 32 degrees C to maximize the amount of p53val135 in the wild-type conformation. Expression of v-Ha-ras did not consistently alter p53-mediated transcriptional activity, suggesting tat ras acts downstream or independently of p53. No correlation was observed between p53-mediated transcriptional activity and in vitro growth rates, colony formation after exposure to ultraviolet light, or suppression by normal neighboring keratinocytes. However, keratinocyte cell lines devoid of p53 and expressing v-Ha-ras formed colonies in soft agar; this was blocked at 32 degrees C in all cell lines reconstituted with p53val135. These keratinocyte lines provide a model for exploring the role of p53 and the interaction of p53 and ras in keratinocyte transformation.
Animals↗
Comparison of the effect of lansoprazole and omeprazole on intragastric acidity and gastroesophageal reflux in patients with gastroesophageal reflux disease.
BACKGROUND: Lansoprazole (LAN) and omeprazole (OME) heal esophagitis effectively and to similar extents, but LAN has a faster effect on the relief of symptoms of gastroesophageal reflux. However, no strict comparison of the two proton pump inhibitors' effect on acid reflux and gastric acidity has been published. The aim of this study was to compare the effects of LAN and OME on gastroesophageal reflux with simultaneous measurements of gastric acidity in patients with established gastroesophageal reflux disease (GERD) and esophagitis. METHODS: Fourteen patients with endoscopically verified erosive esophagitis and with a pretreatment esophageal 24-h pH measurement showing acid reflux to the esophagus participated in the study. This was a double-blind, randomized study with crossover design. Before (day 0) and on the last day (day 5) of each treatment period with encapsulated 30 mg LAN or 20 mg OME daily, 24-h intraesophageal and intragastric acidity were measured with antimony electrodes connected to an ambulatory pH recording system. RESULTS: Ten of 14 patients completed the study. There were no differences in intragastric or intraesophageal acidity or the number of reflux episodes on day 0 between the two treatments. Both LAN and OME treatments increased the median and nocturnal intragastric pH and decreased the 24-h area under the time curve for intragastric acidity significantly and to about the same extent (79% and 69% acid inhibition by LAN and OME, respectively) (NS). However, the percentage of time with pH below 4 in the esophagus was significantly less during LAN treatment (1.92% +/- 2.29; mean +/- standard deviation) than during OME treatment (4.76% +/- 2.88%) on day 5 (P = 0.002). There were also significantly fewer reflux episodes >5 min during treatment with LAN (1.00 +/- 1.33) than with OME (2.90 +/- 2.42) at the end of the treatment period (P = 0.031). CONCLUSIONS: In this study lansoprazole and omeprazole had a comparable effect on gastric acidity in patients with established GERD with esophagitis. However, 30 mg lansoprazole daily reduced the acidity in the oesophagus and the number of refluxes more effectively than 20 mg omeprazole daily. This might indicate that proton pump inhibitors affect the esophageal clearance and/or influence the lower esophageal sphincter differently.
2-Pyridinylmethylsulfinylbenzimidazoles↗
CYP2C19 genotype and phenotype determined with omeprazole in patients with acid-related disorders with and without Helicobacter pylori infection.
BACKGROUND: Omeprazole is to a major extent metabolized by cytochrome P450 isozyme CYP2C19. The aims of this study were to compare the phenotype of CYP2C19 determined by omeprazole with the genotype and to determine the effect of Helicobacter pylori infection on the metabolism of omeprazole. METHODS: One-hundred and forty-three Caucasian patients with acid-related disorders assessed with a combination of gastrointestinal symptoms and upper endoscopic findings were given 20 mg omeprazole orally. Three hours after intake, omeprazole and 5-hydroxyomeprazole plasma concentrations were determined with high-performance liquid chromatography, and the phenotype for metabolic capacity was expressed as metabolic ratio (MR). Genotyping of defect alleles (CYP2C19*2 and *3) was performed by polymerase chain reaction amplification. One hundred eleven patients were tested after the first dose of omeprazole and 32 patients after repetitive administration (median time, 30 days). H. pylori serology was determined with enzyme-linked immunosorbent assay at the time of phenotyping. RESULTS: Genotypically, 2.8% had two mutated alleles and were poor metabolizers (PM), and 22.4% were heterozygous extensive metabolizers (EM). Among the 111 patients who received the first omeprazole dose, 4 patients had MR >5--that is, belonged to the PM phenotype. Two of these had PM genotype (both CYP2C19*2/*2), and two had an EM genotype (CYP2C19*11*1 and *1/*3), indicating that they have still unidentified mutations. In the heterozygous EM group the mean MR was higher in patients who had been on continued omeprazole treatment than in those given the first dose (5.7 versus 2.5, P = 0.02). There were no significant differences in MR and omeprazole concentrations between H. pylori-negative (43%) and -positive (57%) patients. CONCLUSION: In all but two patients with probable unidentified mutations there was agreement between the CYP2C19 phenotype determined by omeprazole and the genotype. The metabolism of omeprazole in patients with acid-related disorders is genetically determined and without relation to H. pylori infection.
Anti-Ulcer Agents↗
Prolonged and profound acid inhibition is crucial in Helicobacter pylori treatment with a proton pump inhibitor combined with amoxicillin.
BACKGROUND: The aim was to investigate whether intragastric pH, meal-stimulated gastrin release, or demographic factors predict the outcome of Helicobacter pylori treatment. METHODS: Thirty-six patients with H. pylori infection were investigated with 24-h intragastric pH registration and meal-stimulated gastrin release before and during treatment with 20 mg omeprazole twice daily and 750 mg amoxicillin twice daily for 14 days. The influence of age, sex, smoking, ethnic origin, pH, and gastrin on treatment outcome were analysed with logistic regression. RESULTS: Eradication of H. pylori was achieved in 18 of 34 (53%) patients. The univariate analysis showed that age, ethnic origin, more than 84.2% of the time with pH above 4, and continuous periods longer than 156 min with intragastric pH above 6 were significantly associated with successful treatment of H. pylori. In the multivariate analysis only the two pH variables were found to be independent factors for predicting treatment outcome. CONCLUSION: The outcome of H. pylori treatment with omeprazole and amoxicillin may depend on several factors, such as age, ethnic origin, and a pronounced acid suppression. However, the only factor of independent importance in this study was prolonged and profound acid inhibition.
Adult↗
Refining the treatment of women with unstable angina--a randomized, double-blind, comparative safety and efficacy evaluation of Integrelin versus aspirin in the management of unstable angina.
BACKGROUND: Although women typically develop coronary artery disease several years after men, once they have symptomatic disease their thromboembolic complications are worse than in men. The mechanism mediating this gender difference in outcome after thromboembolic events is unknown. We previously studied platelet functions in siblings from patients with premature coronary artery disease. We observed that platelets from women are responsive than their male counterparts. In particular, platelets from women stimulated ex vivo with various agonists bind more fibrinogen molecules than platelets from men. HYPOTHESIS: We hypothesized that in patients with acute coronary events, the control of platelet activity might require stronger antagonists in women than in men. METHODS: To test this hypothesis, we investigated retrospectively the results of a trial on Integrelin in unstable angina. RESULTS: We report that platelet aggregation and Holter-detected ischemic episodes are significantly reduced in women with unstable angina treated with the specific GPIIb-IIIa inhibitor, Integrelin, compared with the standard platelet inhibitor aspirin. In contrast, both platelet aggregation and Holter-detected ischemic events are well controlled in men with unstable angina treated with standard therapy including aspirin. CONCLUSION: Integrelin does provide protection in men, but, in contrast with women, not beyond what can be achieved with aspirin. Our data are consistent with the concept that the platelets from women require stronger and more specific inhibitors to limit their activity, and that platelets may play a more important role in women with acute coronary syndromes than in men. Most important, specific GPIIb-IIIa inhibitors may represent a therapeutic option which provides as much suppression of ischemic events in women as they do in men with coronary artery disease.
Aged↗
Interphenotype differences in disposition and effect on gastrin levels of omeprazole--suitability of omeprazole as a probe for CYP2C19.
1. Fourteen healthy Swedish Caucasian subjects were given 20 mg of omeprazole orally each morning for 8 days. The subjects included five poor metabolisers (PM) of S-mephenytoin, four heterozygous extensive metabolisers (hetEM) and five subjects with a very rapid metabolism (rapidEM). 2. After the first dose, the relative mean areas under the plasma concentration vs time curve (AUC) of omeprazole in rapidEM, hetEM and PM were 1:3.7:20 (all different, P < 0.001). A similar relation was seen in the AUC(0,10 h) of the sulphone metabolite (1:3:12). Concentrations of hydroxyomeprazole were higher in EM than in PM confirming that the hydroxy, but not the sulphone metabolite, is formed by the S-mephenytoin hydroxylase (CYP2C19). After 8 days of treatment, the differences between groups were similar. 3. After both the first and the eighth doses, the omeprazole/hydroxyomeprazole plasma concentration ratio, determined 3 h after drug intake, correlated with the mephenytoin S/R ratio (rs = 0.94; P < 0.001; n = 14) suggesting that omeprazole might be used to phenotype for CYP2C19. 4. After the first dose of omeprazole, there was no difference in the AUC(0,10 h) of plasma gastrin between the three groups. From the first to the eighth dose, the AUC(0,10) of gastrin increased significantly in both hetEM and PM, while there was no change in the rapidEM. After the eighth dose, the AUC(0,10) of gastrin correlated significantly with the AUC of omeprazole in plasma (rs = 0.79; P < 0.01; n = 13).
2-Pyridinylmethylsulfinylbenzimidazoles↗
Education and training of nurses in a child health program.
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Child↗
Computing. Program for practice.
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Computers↗