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P Jacob

Publications and source records attributed to P Jacob.

At least 55 records · Page 3Linked to original sources
PubMed2001

Comparative electron microscopic study of the surface structure of gold, Teflon, and titanium stapes prostheses.

HYPOTHESIS: The goal of this study was to compare stapes prostheses of different materials with respect to their surface structures and to discuss their suitability for their use in stapes surgery. BACKGROUND: The surface condition of a stapes prosthesis plays an important role in relation to the type of membrane that forms between the stapes piston and the bony edge of the stapedotomy opening. The quality of this membrane in thickness and mobility is one of the determinants for postoperative hearing improvement. METHODS: The surface conditions of gold, Teflon/steel, Teflon/platinum, and titanium stapes prostheses were examined with a scanning electron microscope. The loop, shaft, and end of each prosthesis were studied. RESULTS: The gold piston was the smoothest of the four pistons examined. When it was cut with a scalpel, a very smooth surface was achieved at the end area. The Teflon piston had the roughest surface. However, when it was cut, a smooth surface with a parallel arrangement of fibers resulted. Its steel loop was the smoothest, followed by gold and platinum. The titanium shaft had a scaly surface, which remained when the end of the shaft was shortened. CONCLUSION: Because a certain roughness of the piston surface is necessary for the development of a stable membrane between the piston and the edge of the stapedotomy opening, the titanium prosthesis is considered to be the most suitable for stapes surgery of the three pistons examined.

Gold↗
PubMed2001

Simulation of exon deletion mutations induced by low-LET radiation at the HPRT locus.

Friedland, W., Li, W. B., Jacob, P. and Paretzke, H. G. Simulation of Exon Deletion Mutations Induced by Low-LET Radiation at the HPRT Locus. Radiat. Res. 155, 703-715 (2001). The induction of HPRT mutants with exon deletions after irradiation with photons was simulated using the biophysical radiation track structure model PARTRAC. The exon-intron structure of the human HPRT gene was incorporated into the chromatin fiber model in PARTRAC. After gamma and X irradiation, simulated double-stranded DNA fragments that overlapped with exons were assumed to result in exon deletion mutations with a probability that depended on the genomic or the geometric distance between the breakpoints. The consequences of different assumptions about this probability of deletion formation were evaluated on the basis of the resulting fractions of total, terminal and intragenic deletions. Agreement with corresponding measurements was obtained assuming a constant probability of deletion formation for fragments smaller than about 0.1 Mbp, and a probability of deletion formation decreasing with increasing geometric or genomic distance between the end points for larger fragments. For these two assumptions, yields of mutants with exon deletions, size distributions of deletions, patterns of deleted exons, and patterns of deleted STS marker sites surrounding the gene were calculated and compared with experimental data. The yields, size distributions and exon deletion patterns were grossly consistent, whereas larger deviations were found for the STS marker deletion patterns in this comparison.

Chromosome Mapping↗
PubMed2001

Track structures and dose distributions from decays of (131)I and (125)I in and around water spheres simulating micrometastases of differentiated thyroid cancer.

The disintegration of the radionuclides (131)I and (125)I and the subsequent charged-particle tracks left behind in water (as a model substance for a biological cell) are simulated by the Monte Carlo track structure simulation code PARTRAC, using new inelastic electron scattering cross sections for condensed water. Every photon and electron emitted was followed in detail, event by event, down to 10 eV. From the spatial information on the track structures, absorbed dose distributions per (131)I and (125)I decay were calculated in and around water spheres simulating micrometastases as well as in the tissue surrounding such metastases. These radionuclides were assumed to be distributed uniformly inside spheres of different diameters (0.01, 0.03, 0.1, 0.3, 1.0 and 3.0 mm). The respective electron degradation spectra, the nearest-neighbor distance distributions between inelastic events, and the distance distributions for all activations for both iodine radionuclides were calculated. The absorbed fractions of the initial electron energies, absorbed doses and energy depositions, and single-event distributions, F(1)(epsilon), inside the six water spheres described above and in the surrounding tissue were also calculated. The absorbed doses per decay inside the six water spheres, i.e., the calculated S values (listed from 0.01 to 3.0 mm), were 6.8 x 10(-4), 7.2 x 10(-5), 5.5 x 10(-6), 4.9 x 10(-7), 3.1 x 10(-8) and 1.8 x 10(-9) Gy Bq(-1) s(-1) for (131)I, and 3.4 x 10(-3), 1.7 x 10(-4), 5.1 x 10(-6), 2.0 x 10(-7), 5.6 x 10(-9) and 2.2 x 10(-10) Gy Bq(-1) s(-1) for (125)I. It is concluded that, in the treatment of thyroid cancer, the geometrical track structure properties of (125)I might be superior to those of (131)I in micrometastases with diameters less than 0.1 mm; however, in this medical context, many other factors also have to be considered.

Humans↗
PubMed2001

Na+/HCO3- cotransport in normal and cystic fibrosis intestine.

In a search for the HCO(3)(-) supply mechanisms to the enterocyte we cloned and sequenced an intestinal subtype of the Na(+)HCO(3)(-) cotransporter isoform I (dNBC1), which turned out to be identical to the pancreatic NBC1 subtype (pNBC1). Within the intestine, we found particularly high NBC1 expression levels in the duodenum and proximal colon. Experiments with stripped rabbit duodenum in Ussing-chambers revealed that Na(+)HCO(3)(-) cotransport (NBC) and CO(2) hydration/Na(+)/H(+) exchange were equally important duodenal HCO(3)(-) supply pathways and were both upregulated during cAMP-mediated secretion. In the proximal colon, however, HCO(3)(-) secretion was low but NBC1 expression even higher than in the duodenum. Ussing-chamber experiments with an NBC-specific inhibitor revealed that NBC, coupled to basolateral Cl(-)/HCO(3)(-) exchange, was an important alternative Cl(-) supply pathway to Na(+)K(+)2Cl(-) cotransport (NKCC) during cAMP-stimulated colonic Cl(-) secretion. To investigate the functional integrity of anion uptake pathways in the absence of cystic fibrosis transmembrane conductance regulator (CFTR), we fluorometrically assessed NBC and NKCC transport rates and cell volume before and during forskolin-stimulation in isolated colonic crypts from normal and CFTR (-/-) mice. Although forskolin stimulation decreased cell volume only in normal, not in CFTR (-/-) crypts, it activated NBC and NKCC to a similar degree in both normal and CFTR (-/-) crypts. We conclude that, depending on the intestinal segment, NBC1 plays an important role in basolateral HCO(3)(-) or Cl(-) uptake. Expression and activation by cAMP is preserved in CFTR (-/-) intestine.

Animals↗
PubMed2000

Clinical pharmacology of oral cotinine.

Cotinine is the major proximate metabolite of nicotine. The aims of our study were to assess the pharmacokinetics of oral cotinine comparing the use of saliva and plasma concentrations, and to characterize the subjective and cardiovascular effects of oral cotinine in nonsmokers. The clearance and half-life of cotinine measured using plasma or saliva concentrations were similar. There was no change in heart rate or blood pressure, and no differences in subjective response with cotinine compared to placebo. We conclude that administration of oral cotinine with measurement in saliva samples is easy, safe, and provides an accurate estimate of systemic clearance and half-life of cotinine.

Adult↗
PubMed2000

Thyroid cancer risk in Belarus after the Chernobyl accident: comparison with external exposures.

Within the time period 1990-1993, childhood thyroid cancer incidence due to the Chernobyl accident increased dramatically in Belarus, especially with regard to the birth cohort January 1, 1971, to May 31, 1986. This rise subsequently slowed down, i.e. during the period 1994-1996. The respective data were analysed and compared with the results of an analysis on the time dependence of thyroid cancer incidence in a pooled cohort of persons who had been exposed during childhood to external radiation with high dose rates. Concerning the period of 5-10 years following exposure, the excess absolute cancer risk per unit thyroid dose in the latter (external) exposure group was found to exceed the one in the Belarus group by a factor of two. This difference, however, is not statistically significant. The age-adjusted average excess absolute risk per unit thyroid dose for the period of 5-50 years following external childhood exposure was found to be 8 female and 14 male cases per 10(4) person-year Gy, which is a factor about 2.5 times higher than for the non-adjusted risk in the pooled cohort, as reported by Ron et al. in 1995. Assessments of future excess thyroid cancer cases due to the Chernobyl accident were done on the basis of the time dependence of thyroid cancer risk following external exposure. The thyroid cancer incidence among the birth cohort considered in Belarus and for a period starting from the cessation of the available observation data (1 January 1997) and extending to 50 years after the Chernobyl accident has been estimated to be about 15,000 cases, with an uncertainty range of 5,000-45,000 cases. According to our calculations, 80% of these cases exceed the baseline risk under enhanced thyroid surveillance.

Adolescent↗
PubMed2000

Strontium metabolism in teeth and enamel dose assessment: analysis of the Techa river data.

People living on the banks of the Techa river were exposed to 90Sr in the early 1950s. Data obtained by radiochemical measurements of extracted permanent teeth, 90Sr autopsy measurements in bone and tooth samples, in vivo measurements of surface beta activity of the anterior teeth and whole-body counter (WBC) measurements of 90Sr in the skeleton have been analyzed. Surface beta activity measurements indicate a biological half-life of 90Sr of about 35 years in enamel. The WBC measurements have been performed since 1974 and a model for the age-dependent strontium retention in human bone has been used to extrapolate to previous time periods when the other measurement results were obtained. For the first decade after the intake, the ratio of the 90Sr concentrations in teeth and bones were found to decrease with age at the time of major intake, from about 10 for 1-year-old children to about 0.3 for adults. There was a considerable variability of individual data within each age group. For adults, the correlation between 90Sr in skeleton and teeth was not high at 0.47 according to radiochemical data for posterior teeth (molars and premolars) and 0.43 according to measurements of surface beta activity for anterior teeth. For children and adolescents there was no correlation between individual measurements in the skeleton and teeth. The absorbed dose in enamel due to 90Sr in dentine has been calculated by Monte Carlo simulations of the electron transport. The results are in agreement with EPR measurements of the absorbed dose in the enamel of persons exposed, mainly due to 90Sr ingestion.

Adolescent↗
PubMed2000

Stochastic aspects and uncertainties in the prechemical and chemical stages of electron tracks in liquid water: a quantitative analysis based on Monte Carlo simulations.

A new physical module for the biophysical simulation code PARTRAC has recently been developed, based on newly derived electron inelastic-scattering cross-sections in liquid water. In the present work, two modules of PARTRAC describing the production, diffusion and interaction of chemical species were developed with the specific purpose of quantifying the role of the uncertainties in the parameters controlling the early stages of liquid water radiolysis. A set of values for such parameters was identified, and time-dependent yields and frequency distributions of chemical species produced by electrons of different energies were calculated. The calculated yields were in good agreement with available data and simulations, thus confirming the reliability of the code. As the primary-electron energy decreases down to 1 keV, the *OH decay kinetics were found to get faster, reflecting variations in the spatial distribution of the initial energy depositions. In agreement with analogous works, an opposite trend was found for energies of a few hundred eV, due to the very small number of species involved. The spreading effects shown at long times by *OH frequency distributions following 1 keV irradiation were found to be essentially due to stochastic aspects of the chemical stage, whereas for 1 MeV tracks the physical and pre-chemical stages also were found to play a significant role. Relevant differences in the calculated e(aq) -yields were found by coupling the physics of PARTRAC with descriptions of the pre-chemical and chemical stages adopted in different models. This indicates a strict interrelation of the various stages, and thus a strong dependence of the parameter values on the assumptions made for the preceding and subsequent stages of the process. Although equally acceptable results can be obtained starting from different assumptions, it is necessary to keep control of such uncertainties, since they can significantly influence the modeling of radical attack on DNA and, more generally, radiobiological damage estimation. This study confirms the need for new, independently derived data on specific steps of water radiolysis, to be included in comprehensive biophysical simulation codes.

Algorithms↗
PubMed2000

Simultaneous determination of mecamylamine, nicotine, and cotinine in plasma by gas chromatography-mass spectrometry.

The nicotine receptor antagonist mecamylamine has been shown to increase the efficacy of transdermal nicotine as a pharmacotherapy for tobacco addiction. A product for simultaneous transdermal administration of nicotine and mecamylamine is undergoing clinical trials. In order to carry out pharmacokinetic studies, quantitation of low nanogram per milliliter levels of mecamylamine and nicotine was required. This paper describes a method for simultaneous determination of mecamylamine, nicotine, and the nicotine metabolite, cotinine, in human plasma using gas chromatography-mass spectrometry (GC-MS). Limits of quantitation for mecamylamine, nicotine and cotinine are 2, 1 and 2 ng/ml, respectively.

Cotinine↗
PubMed2000

Role of Na(+)HCO(3)(-) cotransporter NBC1, Na(+)/H(+) exchanger NHE1, and carbonic anhydrase in rabbit duodenal bicarbonate secretion.

BACKGROUND & AIMS: HCO(3)(-) supply to the enterocyte is rate limiting for duodenal HCO(3)(-) secretion (J(HCO3-)). This study defines the molecular nature of the major HCO(3)(-) uptake pathways in rabbit duodenocytes and investigates their physiologic significance and regulation during basal and stimulated J(HCO3-). METHODS & RESULTS: pH gradient-driven (22)Na(+) uptake into duodenal basolateral membrane vesicles was partly HCO(3)(-) dependent, stilbene sensitive, and therefore mediated by Na(+)HCO(3)(-) cotransport, and partly HCO(3)(-) independent, Hoechst 642 sensitive, and therefore mediated by the Na(+)/H(+) exchanger isoform NHE1. Semiquantitative polymerase chain reaction (PCR) revealed high duodenal expression levels for the NBC1 isoform of the Na(+)HCO(3)(-) cotransporter gene family and NHE1. Cloning and comparison of full-length rabbit with human gastrointestinal and kidney NBC1 subtype revealed a conserved protein kinase A consensus sequence in the cytoplasmic N-terminus of the gastrointestinal NBC1. Inhibition of either Na(+)HCO(3)(-) cotransport or carbonic anhydrase reduced ouabain-sensitive J(HCO3-) in in vitro rabbit duodenal mucosae by approximately 50%, but did not affect 8-Br-cAMP-induced DeltaJ(HCO3-), suggesting cAMP-mediated up-regulation of the alternative pathway. However, inhibition of both Na(+)HCO(3)(-) cotransport and either carbonic anhydrase or NHE1 strongly reduced DeltaJ(HCO3-). CONCLUSIONS: NBC1 and NHE1 are the major base importers in rabbit duodenocytes. Na(+)HCO(3)(-) cotransport and CO(2) hydration/Na(+)/H(+) exchange are equally important pathways for duodenal HCO(3)(-) supply and are up-regulated during cAMP-mediated stimulation.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

Nicotine metabolism and elimination kinetics in newborns.

OBJECTIVE: To characterize the presence of and elimination kinetics of nicotine and its metabolites in newborns. METHODS: Blood samples from 13 newborns were collected during the first day of life and analyzed for nicotine and cotinine. Single daily urine samples were collected from nine newborns for up to 7 days and analyzed by gas chromatography-mass spectrometry for nicotine, cotinine, 3'-hydroxycotinine, and their conjugates. NONMEM was used to determine population half-life values. RESULTS: Blood and urine data gave similar results for nicotine and cotinine elimination kinetics. The elimination half-life for nicotine was 11.2 hours (95% confidence interval [CI], 8.0 to 18.9) based on blood data and 9.0 hours (95% CI, 7.0 to 12.4) based on urine data. The elimination half-life for cotinine was 16.3 hours (95% CI, 12.4 to 23.9) based on blood data and was 22.8 hours (95% CI, 19.5 to 25.8) based on urine data. The elimination half-lives for the other metabolites were 13 hours for conjugated nicotine; 19.8 hours for conjugated cotinine; 18.8 hours for 3'-hydroxycotinine; and 19.4 hours for conjugated 3'-hydroxycotinine. The half-life of nicotine is three to four times longer in newborns than in adults, whereas the half-life of cotinine is similar in newborns and adults. CONCLUSIONS: In adults, CYP2A6 is the predominant enzyme responsible for the metabolism of both nicotine and cotinine. The prolonged elimination of nicotine but not of cotinine in the newborn compared with that in the adult may be a result of different newborn CYP2A6 enzymatic substrate specificity, low CYP2A6 activity with another enzyme that is primarily responsible for cotinine metabolism, or differences in tissue distribution.

Aryl Hydrocarbon Hydroxylases↗
PubMed2000

Effects of cigarette smoking and carbon monoxide on nicotine and cotinine metabolism.

OBJECTIVES: To examine the effects of cigarette smoking on the disposition kinetics of nicotine and cotinine, to determine the effects of cigarette smoking on pathways of nicotine and cotinine metabolism, and to test the hypothesis that carbon monoxide inhibits the metabolism of nicotine. STUDY DESIGN: Twelve cigarette smokers were studied in three treatment conditions, each lasting 7 days, during which they smoked cigarettes, breathed carbon monoxide to achieve carboxyhemoglobin levels similar to cigarette smoking, or breathed air. In each treatment condition, subjects received a combined infusion of deuterium-labeled nicotine (d2) and cotinine (d4), with measurement of disposition kinetics and urine metabolite profile. RESULTS: Cigarette smoking significantly inhibited the metabolism of nicotine but had no effect on cotinine metabolism. Cigarette smoking markedly induced the O-glucuronidation of trans-3'-hydroxycotinine but had no effect on the N-glucuronidation of nicotine or cotinine. Carbon monoxide had no effect on nicotine or cotinine kinetics or metabolic profile. CONCLUSIONS: This study confirms previous observations that cigarette smoking inhibits nicotine metabolism but disproves the hypothesis that this effect is due to carbon monoxide. Induction of glucuronidation must be considered in understanding the effects of cigarette smoking on drug metabolism.

Adult↗
PubMed2000

Nicotine-mecamylamine interactions.

OBJECTIVES: Mecamylamine blocks nicotinic cholinergic receptors and has been proposed, in combination with nicotine, as a novel therapy to aid smoking cessation. The objective of this study was to characterize the pharmacokinetic and pharmacodynamic interactions between transdermal mecamylamine and intravenous nicotine. STUDY DESIGN: Twelve cigarette smokers were studied while receiving transdermal mecamylamine 6 mg/24 h and placebo patches for 7 days each. On the fifth day of patch use, subjects received a combined infusion of deuterium-labeled nicotine and cotinine, with measurement of disposition kinetics of nicotine and cotinine, and cardiovascular and plasma catecholamine responses to nicotine. Half of the subjects were studied under alkaline urine conditions and the other half under acidic urine conditions. RESULTS: Steady-state plasma mecamylamine concentrations were twice as high (mean, 12.2 versus 6.3 ng/mL), consistent with lower renal clearance (2.1 versus 5.8 mL/min/kg) during alkaline compared with acidic urine conditions. Mecamylamine did not significantly affect the clearances of nicotine or cotinine. Mecamylamine significantly reduced the volume of distribution and inhibited the cardioacceleratory and epinephrine-releasing effects of nicotine. CONCLUSIONS: Mecamylamine has little effect on the clearance of nicotine and is not expected to affect steady-state levels during transdermal nicotine dosing. The reduction of the volume of distribution of nicotine by mecamylamine suggests that part of the antagonism of nicotinic central nervous system effects by mecamylamine may be due to a pharmacokinetic interaction-most likely decreased transport of nicotine into the brain or decreased binding to nicotine receptors. Mecamylamine may decrease the potential adverse cardiovascular effects of coadministered nicotine.

Administration, Cutaneous↗
PubMed2000

EPR dose reconstruction for Russian nuclear workers.

The present paper describes results of the first independent evaluation of the accuracy of the dose-reconstruction technique by electron paramagnetic resonance using tooth enamel. Each of twenty-four teeth donated by Mayak nuclear workers with known occupational radiation exposure histories was cut into two parts so that each tooth could be shared for blind electron paramagnetic resonance examination by at least two of the four laboratories participating in the study. The mean difference (+/- SD) between electron paramagnetic resonance estimates of the paired samples of each tooth shared by the two laboratories in best agreement was 0.02 +/- 0.15 Gy. Mayak workers can be classified into two groups: modern workers (after 1961) having reliable official dose information and earlier nuclear workers whose dose information is less reliable because they were exposed mainly before 1961. Film badges did not contain filters until 1954. Doses in this earlier group are much higher (up to 5 Gy). Comparison of the electron paramagnetic resonance results with tooth doses calculated from official film-badge doses showed a close agreement for the first group, whereas in the second group, official doses appeared to be slightly higher than the electron paramagnetic resonance doses. The results suggested a possibility that the official doses were somewhat overestimated among the high-dose-exposed workers. Consequently, cancer risks derived from this high-dose group might tend to be slightly underestimated.

Electron Spin Resonance Spectroscopy↗
PubMed2000

Internal exposure from the ingestion of foods contaminated by 137Cs after the Chernobyl accident--report 2. Ingestion doses of the rural population of Ukraine up to 12 y after the accident (1986-1997).

Doses from the ingestion of 134Cs and 137Cs during 12 y following the Chernobyl accident have been estimated for approximately 3 million persons living in rural areas of the Zhitomir, Rivne, and Kyiv Oblasts of northern Ukraine. This assessment is based upon an extensive monitoring campaign that provided measurements of 137Cs in more than 120,000 samples of milk and in more than 100,000 persons; such measurements were made in approximately 4,500 locations. Two approaches were used for the dose assessment. In the first approach a so-called reference dose is estimated for each settlement on the basis of measured 137Cs concentration in milk, determination of the milk equivalent of diet, and consumption rates; a further assumption is that a high fraction of the food consumed is produced locally. The reference dose is used as the official dose estimate, which is the basis for any decision on possible financial compensation and economic privileges. In a second step, the so-called real age-dependent dose is estimated from the results of whole body counter measurements and the kinetics of radiocesium in the human body. Real doses above 0.5, 5, and 50 mSv were received by about 40%, 10%, and 0.2%, respectively, of the considered population. With the exception of 1986, for which the monitoring results were limited, the real individual doses derived from whole-body counting are consistently lower than the reference doses. However, this difference declined from a factor of 3-4 in 1987-1989 to a factor of approximately 1.5 in the mid 1990's. The difference between reference and real doses is attributed to the effectiveness of countermeasures implemented after the accident. The effectiveness of these countermeasures decreased with time due to increasing economic problems in Ukraine. The collective reference and real doses of the rural population due to the intake of 134Cs and 137Cs are estimated to be 13,300 and 5,300 person-Sv, respectively. Thus, about 8,000 person-Sv is estimated to have been averted by countermeasures.

Age Factors↗
PubMed2000

Liver injury due to tetrabamate (Atrium): an analysis of 11 cases.

BACKGROUND: Tetrabamate (Atriums), widely used in the treatment of tremor and ethanol-withdrawal symptoms, has been incriminated as a potential cause of reversible acute hepatitis. OBJECTIVE: We report here on 11 patients who experienced tetrabamate-related liver injury, in order to evaluate their clinical, histopathological and evolutive features. PATIENTS AND METHODS: Between 1987 and 1998, 34 cases of tetrabamate-associated acute hepatitis were spontaneously reported to the regional pharmacovigilance center of Lyon. Eleven cases were considered probably to be drug-induced. RESULTS: There were three males and eight females aged 31-82 years (mean, 57 years). The duration of treatment ranged from 33 to 206 days, and indication for treatment was depressive disorders, tremor or prevention of alcohol withdrawal symptoms. Clinical symptoms were asthenia (n = 9), jaundice (n = 3) and/or diffuse rash (n = 3). The pattern of liver injury was cytolytic (n = 10) or cholestatic (n = 1). Three patients presented biological features of hepatic failure. A percutaneous liver biopsy was performed in six patients. Histological examination of the liver specimen showed a large spectrum of lesions: massive hepatocellular necrosis (n = 1), centrilobular and nonconfluent hepatocyte necrosis (n = 2), intracellular cholestasis (n = 3), and granulomatous hepatitis (n = 1). Tetrabamate was discontinued in all patients. In seven patients, a complete recovery was observed 3 weeks to 3 months after drug withdrawal. Two patients, despite a rapid improvement of liver function tests, died from unrelated causes. The remaining two patients died from irreversible hepatic failure. CONCLUSIONS: Our data strongly suggest that tetrabamate may induce acute liver injury, which may eventually result in life-threatening liver failure.

Adult↗