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P Jacob

Publications and source records attributed to P Jacob.

At least 73 records · Page 4Linked to original sources
PubMed2000

Expression and function of Na+HCO3- cotransporters in the gastrointestinal tract.

The stomach, duodenum, colon, and pancreas secrete HCO3- ions into the lumen. Although the importance of HCO3- secretion for the maintenance of mucosal integrity, a normal digestion, and the reabsorption of Cl- has been well established, the molecular nature of the apical and basolateral HCO3- transporting proteins has remained largely unknown. Functional studies have suggested that a Na+HCO3- cotransport system, similar but not identical to the well-characterized Na+HCO3- cotransporter in the basolateral membrane of the kidney proximal tubule, is present in duodenal and colonic enterocytes, pancreatic ducts cells, and gastric cells and involved in HCO3- uptake from the interstitium. This report describes our work towards understanding the molecular nature, cellular origin, and functional relevance of the Na+HCO3- cotransporter(s) in the stomach and intestine and reviews work by others on the function and localization of Na+HCO3- cotransport processes in the gastrointestinal tract.

Animals↗
PubMed1999

Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines.

Methcathinone and methylone, the beta-ketone analogues of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), respectively, were tested for neurotransmitter uptake inhibition in vitro. The beta-ketones were threefold less potent than the nonketo drugs at inhibiting platelet serotonin accumulation, with IC(50)'s of 34.6+/-4.8 microM and 5.8+/-0.7 microM, respectively. Methcathinone and methylone were similar in potency to methamphetamine and MDMA at catecholamine transporters individually expressed in transfected glial cells. For dopamine uptake, IC(50)'s were 0.36+/-0.06 microM and 0.82+/-0.17 microM, respectively; for noradrenaline uptake, IC(50) values were 0.51+/-0.10 microM and 1. 2+/-0.1 microM, respectively. In chromaffin granules, IC(50)'s for serotonin accumulation were 112+/-8.0 microM for methcathinone and 166+/-12 microM for methylone, 10-fold higher than the respective values for methamphetamine and MDMA. Our results indicate that methcathinone and methylone potently inhibit plasma membrane catecholamine transporters but only weakly inhibit the vesicle transporter.

3,4-Methylenedioxyamphetamine↗
PubMed1999

Quantitation of levorphanol in human plasma at subnanogram per milliliter levels using capillary gas chromatography with electron-capture detection.

A gas chromatographic method for the determination of levorphanol in human plasma is described. The method utilizes extractive alkylation with tetrabutylammonium cation as the phase-transfer catalyst and pentafluorobenzyl bromide as the alkylating agent, and employs a structural analog, d-3-hydroxy-N-ethylmorphinan, as the internal standard. The pentafluorobenzyl ethers formed are separated by capillary gas chromatography and detected by electron capture. The method has good precision and accuracy for concentrations ranging from 0.25 ng/ml to 100 ng/ml and has been used to measure plasma concentrations as part of a study to evaluate the management of chronic neuropathic pain with levorphanol.

Analgesics, Opioid↗
PubMed1999

[Diagnosis and evaluation of the extent of cancer of the esophagus].

Oesophageal cancer includes two distinct tumours: squamous cell cancer is related to alcohol and tobacco consumption; adenocarcinoma develops on a metaplastic columnar mucosa lining the oesophagus (Barrett's oesophagus). In Western countries the ratio of the 2 tumors is 6 to 4. Dysphagia is a late symptom in the evolution and corresponds in most cases to advanced cancer with poor prognosis. Treatment decision required evaluation of the performance status, search for associated tumors (mouth, pharynx and respiratory tract), and evaluation of the locoregional extension of the primary tumour. In the absence of dysphagia, detection of oesophageal cancer at an early stage is compatible with a curative option.

Adenocarcinoma↗
PubMed1999

Simulation of DNA fragment distributions after irradiation with photons.

The Monte Carlo track structure code PARTRAC has been further improved by implementing electron scattering cross-sections for liquid water and by explicitly modelling the interaction of water radicals with DNA. The model of the genome inside a human cell nucleus in its interphase is based on the atomic coordinates of the DNA double helix with an additional volume for the water shell. The DNA helix is wound around histone complexes, and these nucleosomes are folded into chromatin fibres and further to fibre loops, which are interconnected to build chromosomes with a territorial organisation. Simulations have been performed for the irradiation of human fibroblast cells with carbon K and aluminium K ultrasoft x-rays, 220 kVp x-rays and 60Co gamma-rays. The ratio single-strand breaks to double-strand breaks (ssb/dsb) for both types of ultrasoft x-rays is lower than for gamma-rays by a factor of 2. The contributions of direct and indirect effects to strand break induction are almost independent of photon energy. Strand break patterns from indirect effects reflect differences in the susceptibility of the DNA helix to OH* attack inside the chromatin fibre. Distributions of small DNA fragments (<3 kbp) are determined by the chromatin fibre structure irrespective of whether direct or indirect effects are causing the breaks. In the calculated fragment size distributions for larger DNA fragments (>30 kbp), a substantial deviation from random breakage is found only for carbon K irradiation, and is attributed to its inhomogeneous dose distribution inside the cell nucleus. For the other radiation qualities, the results for larger fragments can be approximated by random breakage distributions calculated for a yield of dsb which is about 10% lower than the average for the whole genome. The excess of DNA fragments detected experimentally in the 8-300 kbp region after x-ray irradiation is not seen in our simulation results.

Chromatin↗
PubMed1999

Childhood exposure due to the Chernobyl accident and thyroid cancer risk in contaminated areas of Belarus and Russia.

The thyroid dose due to 131I releases during the Chernobyl accident was reconstructed for children and adolescents in two cities and 2122 settlements in Belarus, and in one city and 607 settlements in the Bryansk district of the Russian Federation. In this area, which covers the two high contamination spots in the two countries following the accident, data on thyroid cancer incidence during the period 1991-1995 were analysed in the light of possible increased thyroid surveillance. Two methods of risk analysis were applied: Poisson regression with results for the single settlements and Monte Carlo (MC) calculations for results in larger areas or sub-populations. Best estimates of both methods agreed well. Poisson regression estimates of 95% confidence intervals (CIs) were considerably smaller than the MC results, which allow for extra-Poisson uncertainties due to reconstructed doses and the background thyroid cancer incidence. The excess absolute risk per unit thyroid dose (EARPD) for the birth cohort 1971-1985 by the MC analysis was 2.1 (95% CI 1.0-4.5) cases per 10(4) person-year Gy. The point estimate is lower by a factor of two than that observed in a pooled study of thyroid cancer risk after external exposures. The excess relative risk per unit thyroid dose was 23 (95% CI 8.6-82) Gy(-1). No significant differences between countries or cities and rural areas were found. In the lowest dose group of the settlements with an average thyroid dose of 0.05 Gy the risk was statistically significantly elevated. Dependencies of risks on age-at-exposure and on gender are consistent with findings after external exposures.

Child↗
PubMed1999

Ca2+/calmodulin-dependent protein kinase II isoenzymes gamma and delta are both present in H+/K+-ATPase-containing rabbit gastric tubulovesicles.

Ca2+/calmodulin-dependent protein kinase II is thought to participate in M3 muscarinic receptor-mediated acid secretion in gastric parietal cells. During acid secretion tubulovesicles carrying H+/K+-ATPase fuse with the apical membrane. We localized Ca2+/calmodulin-dependent protein kinase II from highly purified rabbit gastric tubulovesicles using Ca2+/calmodulin-dependent protein kinase II isoform-specific antibodies, in vitro phosphorylation and pharmacological inhibition of Ca2+/calmodulin-dependent protein kinase II activity by the potent Ca2+/calmodulin-dependent protein kinase II inhibitor KN-62. The presence of Ca2+/calmodulin-dependent protein kinase II in tubulovesicles was shown by immunoblot detection of both Ca2+/calmodulin-dependent protein kinase II-gamma (54 kDa) and Ca2+/calmodulin-dependent protein kinase II-delta (56.5 kDa). The immunoprecipitated Ca2+/calmodulin-dependent protein kinase II from tubulovesicles showed Ca2+/calmodulin-dependent protein kinase activity by phosphorylating autocamtide-II, a specific synthetic Ca2+/calmodulin-dependent protein kinase II substrate. KN-62 inhibited the in vitro autophosphorylation of tubulovesicle-associated Ca2+/calmodulin-dependent protein kinase II (IC50 = 11 nM). During the search for potential Ca2+/calmodulin-dependent protein kinase II substrates we identified different proteins associated with tubulovesicles, such as synaptophysin and beta-tubulin immunoreactivity, which were identified using specific antibodies. These targets are known to participate in intracellular membrane traffic. Ca2+/calmodulin-dependent protein kinase II is thought to play an important role in regulating tubulovesicular motor activity and therefore in acid secretion.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

Disposition kinetics and effects of menthol.

BACKGROUND: Menthol is widely used in a variety of commercial products and foods, but its clinical pharmacology is not well studied. To determine the disposition kinetics and to examine subjective and cardiovascular effects of menthol, we conducted a crossover placebo-controlled study that compared pure menthol versus placebo, along with an uncontrolled exposure to menthol in food or beverage. A novel assay for the measurement of menthol in biological fluids was also developed. METHODS: Twelve subjects were studied; each received a 100 mg l-menthol capsule, a placebo capsule, and 10 mg menthol in mint candy or mint tea on three different occasions. Plasma and urine levels of menthol and conjugated menthol (glucuronide), cardiovascular measurements, and subjective effects were measured at frequent intervals. RESULTS: Menthol was rapidly metabolized, and only menthol glucuronide could be measured in plasma or urine. The plasma half-life of menthol glucuronide averaged 56.2 minutes (95% confidence interval [CI], 51.0 to 61.5) and 42.6 minutes (95% CI, 32.5 to 52.7) in menthol capsule and mint candy/mint tea conditions, respectively (P < .05). The plasma area under the plasma concentration-time curve ratios for menthol capsule to mint candy/mint tea treatment averaged 9.2 (95% CI, 8.2 to 10.1). Urinary recovery of menthol as the glucuronide averaged 45.6 and 56.6% for menthol capsule and mint candy/tea, respectively (difference not significant). After menthol capsule dosing, the decrease in heart rate was less than the decrease after placebo administration (P < .05). Menthol reduced subjective vigor value at 30 minutes. CONCLUSIONS: We conclude that pure menthol and menthol in food or beverages have a similar systemic bioavailability and that menthol has a small cardioaccelerating effect.

Adult↗
PubMed1999

Model validation for external doses due to environmental contaminations by the Chernobyl accident.

The objective of the present paper is to validate the deterministic JSP5 model for external exposures to population groups living in the areas contaminated with radionuclides after the Chernobyl accident. For this purpose inhabitants of contaminated areas wore TL-dosimeters for about 1 mo in the spring/summer periods of the years 1989 to 1994. External doses due to the Chernobyl accident were determined from the dosimeter readings by subtracting the natural background. 2,342 results for rural inhabitants and 420 results for inhabitants of the town Novozybkov passed reliability checks. These data show that the average dose in inhabitants of a rural settlement predicted by the model is in the range 0.69-1.55 of the measured values with a confidence level of 95%. Differences are attributed to settlement specific location factors, which are supported by the very good agreement of model and measurements in Novozybkov. In this case location factors of the model were obtained from Novozybkov directly.

Adult↗
PubMed1999

Minor tobacco alkaloids as biomarkers for tobacco use: comparison of users of cigarettes, smokeless tobacco, cigars, and pipes.

OBJECTIVES: This study (1) determined levels of various tobacco alkaloids in commercial tobacco products. (2) determined urinary concentrations, urinary excretion, and half-lives of the alkaloids in humans; and (3) examined the possibility that urine concentrations of nicotine-related alkaloids can be used as biomarkers of tobacco use. METHODS: Nicotine intake from various tobacco products was determined through pharmacokinetic techniques. Correlations of nicotine intake with urinary excretion and concentrations of anabasine, anatabine, nornicotine, nicotine, and cotinine were examined. By using urinary excretion data, elimination half-lives of the alkaloids were calculated. RESULTS: Alkaloid levels in commercial tobacco products, in milligrams per gram, were as follows: nicotine, 6.5 to 17.5; nornicotine, 0.14 to 0.66; anabasine, 0.008 to 0.030; and anatabine, 0.065 to 0.27. Measurable concentrations of all alkaloids were excreted in the urine of most subjects smoking cigarettes, cigars, and pipes and using smokeless tobacco. Correlations between nicotine intake and alkaloid concentrations were good to excellent. CONCLUSIONS: Anabasine and anatabine, which are present in tobacco but not in nicotine medications, can be used to assess tobacco use in persons undergoing nicotine replacement therapy.

Adult↗
PubMed1999

Time trends of thyroid cancer incidence in Belarus after the Chernobyl accident.

The rates of childhood thyroid cancer incidence observed in Belarus during the period 1986 to 1995 are described as a function of time after exposure, age at exposure, and sex. Conclusions are drawn for the excess absolute risk function. After a minimum latent period of about 3 years after exposure, this risk function has a linear increase with time for at least 6 years. After correction for the dependence of average doses on age, the radiation-induced absolute thyroid risk in Gomel is about a factor of 3 higher for children up to age 10 at exposure compared to older ones; this may be due in part to different case-collection quality. In addition, in the group up to 10 years at exposure, the thyroid of girls is more sensitive to radiation by a factor of about 1.5 than the thyroid of boys on an absolute scale. Risk estimates from external exposure are consistent with risk estimates from Gomel assuming that the increase in excess cases reaches a plateau soon.

Adolescent↗
PubMed1999

Ethnic differences in N-glucuronidation of nicotine and cotinine.

We previously reported that the metabolism of cotinine, the proximate metabolite of nicotine, is significantly slower in black than in white cigarette smokers. To understand why the metabolism of nicotine and cotinine might differ between blacks and whites, we studied the pattern of nicotine metabolism in blacks and whites. One hundred eight healthy smokers (51 blacks and 57 whites), of similar age, gender distribution, and smoking history, received an i.v. infusion of deuterium-labeled nicotine and cotinine. The clearance of cotinine, the fractional conversion of nicotine to cotinine, and the metabolic clearance of nicotine to cotinine were significantly lower in blacks than in whites. Blacks excreted significantly less nicotine as nicotine-N-glucuronide and less cotinine as cotinine-N-glucuronide than whites, but there was no difference in the excretion of 3'-hydroxycotinine-O-glucuronide. Nicotine and cotinine glucuronidation appeared to be polymorphic, with evidence of slow and fast N-glucuronide formers among blacks but was unimodal with fast conjugators only among whites. Other findings of note included the demonstration of a significant correlation between the distribution volumes of nicotine and cotinine with lean body mass: there was a smaller distribution volume and a shorter half-life for cotinine in women than in men and a smaller volume of distribution of cotinine in blacks than in whites. We conclude that the metabolism of cotinine is slower in blacks than in whites because of both slower oxidative metabolism of nicotine to cotinine (presumably via cytochrome P-450 2A6) and slower N-glucuronidation. Ethnic differences in the metabolism of other drugs undergoing N-glucuronidation should be studied.

Adult↗
PubMed1999

Two-step model for the risk of fatal and incidental lung tumors in rats exposed to radon.

Data from 4276 rats with radon exposures up to 10,000 WLM at rates up to 1000 WL are analyzed with a two-step clonal expansion model. The age dependences of the hazard for the risks for fatal and for incidental tumors are very different. Therefore, two different parameterizations of the model are used in the two cases. In both cases radiation acts only on the initiating mutation and the clonal expansion, but not on the second mutation. Average exposure rates of 5 WL for fatal tumors and 0.5 WL for incidental tumors double the rate of spontaneous mutations. While the fatal tumors show a linear increase in the effective clonal expansion rate up to about 100 WL average exposure rate and a saturation at higher exposure rates, the incidental tumors follow a step-like behavior of this parameter. It is proposed that only the fatal lung tumors among the rats be used for generalizations to models for lung cancer in humans. The fitted model for fatal tumors shows an inverse dose-rate effect at average exposure rates above 20 WL. However, below 10 WL the lung cancer risk per unit exposure decreases with increasing duration of exposure. Between 10 and 20 WL, the difference in ERR/WLM between acute and protracted exposure is small.

Age Factors↗
PubMed1998

Nicotine metabolism and intake in black and white smokers.

CONTEXT: Racial differences in tobacco-related diseases are not fully explained by cigarette-smoking behavior. Despite smoking fewer cigarettes per day, blacks have higher levels of serum cotinine, the proximate metabolite of nicotine. OBJECTIVE: To compare the rates of metabolism and the daily intake of nicotine in black smokers and white smokers. DESIGN: Participants received simultaneous infusions of deuterium-labeled nicotine and cotinine. Urine was collected for determination of total clearance of nicotine and cotinine, fractional conversion of nicotine to cotinine, and cotinine elimination rate. Using cotinine levels during ad libitum smoking and clearance data, the daily intake of nicotine from smoking was estimated. SETTING: Metabolic ward of a university-affiliated public hospital. PARTICIPANTS: A total of 40 black and 39 white smokers, average consumption of 14 and 14.7 cigarettes per day, respectively, of similar age (mean, 32.5 and 32.3 years, respectively) and body weight (mean, 73.3 and 68.8 kg, respectively). MAIN OUTCOME MEASURES: Clearance (renal and nonrenal), half-life, and volume of distribution of nicotine and cotinine and the calculated daily intake of nicotine. RESULTS: The total and nonrenal clearances of nicotine were not significantly different, respectively, in blacks (17.7 and 17.2 mL x min(-1) x kg(-1)) compared with whites (19.6 and 18.9 mL x min(-1) x kg(-1)) (P=.11 and .20). However, the total and nonrenal clearances of cotinine were significantly lower, respectively, in blacks (0.56 and 0.47 mL x min(-1) x kg(-1)) than in whites (0.68 vs 0.61 mL x min(-1) x kg(-1); P=.009 for each comparison). The nicotine intake per cigarette was 30% greater in blacks compared with whites (1.41 vs 1.09 mg per cigarette, respectively; P=.02). Volume of distribution did not differ for the 2 groups, but cotinine half-life was higher in blacks than in whites (1064 vs 950 minutes, respectively; P = .07). CONCLUSIONS: Higher levels of cotinine per cigarette smoked by blacks compared with whites can be explained by both slower clearance of cotinine and higher intake of nicotine per cigarette in blacks. Greater nicotine and therefore greater tobacco smoke intake per cigarette could, in part, explain some of the ethnic differences in smoking-related disease risks.

Adult↗
PubMed1998

Thyroid dose and thyroid cancer incidence after the Chernobyl accident: assessments for the Zhytomyr region (Ukraine).

In the Zhytomyr region, about 52,000 measurements of the 131I activity in thyroids were performed. On the basis of these measurements, individual doses have been assessed for the people monitored and age-dependent average doses have been estimated for those settlements with more than 11 direct measurements. In order to estimate the pattern of thyroid exposure in the Zhytomyr region, these doses have been interpolated or extrapolated to population groups who were not monitored during May-June 1986. For this purpose, a model has been developed based on a correlation between thyroid dose estimates with the 137Cs deposition and the co-ordinates of the settlements relative to Chernobyl. Collective doses of people who were born in the years 1968 to 1986 were calculated. The radiation-induced thyroid cancer incidence in the period 1991 to 1995 was assessed by subtracting the spontaneous incidence from the observed incidence. The result is considerably lower than that observed in longer periods after external exposures. Possible reasons for this difference are discussed.

Adolescent↗