Biomedical subjects

D Dunbar

Publications and source records attributed to D Dunbar.

At least 19 recordsLinked to original sources

PubMed2004

Associations between blood pressure and overweight defined by new standards for body mass index in childhood.

BACKGROUND: Using data from a longitudinal study of young Australians, we applied recent international standards for overweight and obesity to examine associations with blood pressure (BP) and to determine the prevalence and degree of tracking of overweight and obesity. We also aimed to examine socioeconomic status in relation to these variables. METHODS: BP, height, and weight were measured at 3-year intervals from age 9 to 18, and then at 25 years of age in a Western Australian cohort. At these stages, data were available for 1,036, 1,310, 618, 615 and 600 individuals, respectively. RESULTS: We found 10% of 9-year-old males to be overweight or obese, while among 12-year-olds, 13% were overweight or obese; at age 15, and still at age 18, overweight or obesity was registered in 17% of this population and it rose to 42% among the 25-year-old young men. The percentage of overweight or obese females at these stages was initially 8, then 12 (at age 12), 11 (at age 15), 14 (at age 18) and finally 32. Overweight or obesity tracked to young adult life in 16% of those overweight or obese at 9, 24% at 12, 34% at 15 and 35% at 18 years. Systolic BP was significantly higher in the overweight or obese except in 12-year-olds. At the age of 25 years, 53% of men had high normal BP or were hypertensive. CONCLUSIONS: Increasing overweight or obesity in young Australians, consistent with international trends, has serious health implications. Overweight and obesity show tracking and are predictors of higher blood pressure, except in early adolescence.

Adolescent↗

PubMed2001

Induction of CYP1A by benzo[k]fluoranthene in human hepatocytes: CYP1A1 or CYP1A2?

While fresh human hepatocyte cultures are widely used to model hepatic cytochrome P450 (CYP) regulation and activity, their CYP1A subfamily composition induced by, e.g., polycyclic aromatic hydrocarbons is ambiguous. CYP1A1, CYP1A2, or both have been reported to be expressed, and their varied roles in chemical carcinogenesis makes resolution of which CYPs are expressed essential. We have used an immunoblot system with Bis-Tris-HCl-buffered polyacrylamide gel, which clearly resolves human CYP1A1 and CYP1A2, and polyclonal goat anti-human CYP1A1/CYP1A2 and rabbit anti-human CYP1A2 antibodies to probe the expressed CYP1A1 and CYP1A2 composition of seven individual human hepatocyte cultures induced with 5 microM benzo[k]fluoranthene (BKF) for 24 h. In six of the cultures only CYP1A1 was detected, and in the seventh both CYPs were detected. In most vehicle-treated hepatocyte cultures, neither CYP1A1 nor CYP1A2 was detected. In three additional hepatocyte cultures treated individually with BKF and 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD), the resultant induced CYP1A1/1A2 profiles were essentially not influenced by the nature of the inducing agents. To develop an activity-based assay to differentiate between CYP1A1 and CYP1A2 expression in human hepatocytes, our previously published R warfarin assay (Drug Metab. Disp. (1995) 23, 1339-1345) was applied to TCDD (10 nM)-treated hepatocyte culture. The low concentration of TCDD did not produce inhibition of the warfarin metabolism-such inhibition could confound the results. Based on the ratios of 6- to 8-hydroxywarfarin formed in two cultures, the ratios of CYP1A1/CYP1A2 expressed in these cultures were determined and they agreed with the ratios determined by immunoblot analysis. Thus each individual human hepatocyte culture must be characterized for induced CYP1A1 and CYP1A2 expression in studies of CYP1A activity. The warfarin assay provides a means of characterizing the cultures.

Adolescent↗

PubMed2001

Family lifestyle and parental body mass index as predictors of body mass index in Australian children: a longitudinal study.

OBJECTIVE: To investigate associations between body mass index (BMI) and family characteristics, including lifestyle, in parents and offspring from Australian families. DESIGN AND SUBJECTS: Longitudinal survey of 219 families of Australian children who had been surveyed 3-yearly between the ages of 9 and 18 y. MEASUREMENTS: Socio-economic status, weight and height, diet from 3 day records or food frequency questionnaires, alcohol consumption, smoking habits and physical fitness in offspring (bicycle ergometry in 18-y-olds). RESULTS: In 18-y-olds, in models examining offspring's lifestyle variables, BMI was predicted negatively by physical fitness (P=0.012), and positively by alcohol intake (P=0.046) in sons while, in daughters, only a negative association with physical fitness was significant. In models including parental characteristics, BMI in 18-y-old sons and daughters was significantly predicted by mothers' and fathers' BMI, independently of offsprings' alcohol intake, smoking, physical fitness and parents' education, and, in daughters, by fathers' alcohol intake. These models explained 48% of variance in daughters and 33% in sons. In both sons and daughters, BMI over the 9 y of the survey was consistently higher in offspring with overweight or obese fathers (P=0.033 for sons, P=0.024 for daughters) or mothers (P=0.031 for sons, P=0.037 for daughters). Physical fitness at the ages of 12, 15 and 18 y was negatively related to fathers' obesity in daughters and mothers' obesity in sons. Obesity in fathers was associated with a four-fold increase in risk of obesity at the age of 18 y in both sons and daughters with an independent eight-fold increase in risk for daughters if mothers were obese. Birthweight was unrelated to overweight or obesity in the 18-y-olds. Alcohol intake in sons related significantly to alcohol intake in either parent while, for daughters, there was a significant association only with fathers' alcohol consumption. In daughters, fat intake was positively associated with fat intake score in both fathers and mothers. CONCLUSION: Parental overweight or obesity may identify children at risk for a range of unhealthy behaviours. Promotion of a healthy lifestyle targeting overweight families, particularly in lower socio-economic groups, should be a priority.

Adolescent↗

PubMed2001

Tracking of blood pressure in Australian children.

OBJECTIVE: Tracking of blood pressure (BP) from childhood occurs in populations but, for individuals, prediction of adult BP from childhood levels is poor. We examined factors that may influence tracking of BP to identify better predictors of higher BP in early adult life. DESIGN: A prospective study of children recruited at the age of 9 years by random sampling of Perth metropolitan schools stratified by socio-economic status. SETTING: Community based with re-surveys 3-yearly for 9 years. PARTICIPANTS: A total of 516 boys and 520 girls at 9 years; 680 boys and 630 girls at 12 years; 318 boys and 300 girls at 15 years; 330 men and 326 women at 18 years. MAIN OUTCOME MEASURES: Systolic (SBP) and diastolic (DBP) BP. RESULTS: Persistence in the highest quartile for SBP between surveys was seen in 34-48% of subjects and in 37% between the ages of 9 and 18 years. The proportion increased to around 60% in those in the highest quartile for body mass index (BMI), to 70% in those in the highest quartile for change in BMI and to 60% if there was a family history of hypertension. In log-linear models, persistence in a quartile for SBP was significantly related to a family history of hypertension, previous SBP, BMI and change in BMI. Relationships were similar for DBP. CONCLUSIONS: Excessive weight gain in adolescence and a family history of hypertension substantially increase the risk of higher BP persisting into early adult life. Recognition of children at risk would allow early intervention emphasizing weight control with potential long-term benefits.

Adolescent↗

PubMed2001

Metabolic characterization of the major human small intestinal cytochrome p450s.

Human small intestine epithelial cells (enterocytes) provide the first site for cytochrome P450 (CYP)-catalyzed metabolism of orally ingested xenobiotics. CYP3A4 is the major form of CYP expressed in enterocytes and CYP2C is also expressed at a significant level. In this study, we further characterized the expression of CYP3A4 and CYP2C in human enterocytes and their interindividual variations by examining the metabolic activities from 10 individuals. CYP3A4 in human jejunum microsomes, as determined by 6beta-testosterone hydroxylase activity, varied from 0.36 to 2.46 nmol/min/mg. The apparent average K(m) and V(max) values from two representative individuals were 54 microM and 3.2 nmol/min/mg, respectively. CYP2C9 and CYP2C19 in human jejunum microsomes, as determined by diclofenac 4'-hydroxylase and mephenytoin 4'-hydroxylase activities, varied over an 18-fold range (7.3-129 pmol/min/mg) and 17-fold range (0.8-13.1 pmol/min/mg), respectively. The mean apparent K(m) for diclofenac 4'-hydroxylase was 9.9 microM , whereas the apparent mean K(m) for S-mephenytoin 4'-hydroxylase was 79.3 microM . The mean intrinsic clearance (V(max)/K(m)) was approximately 130-fold greater for diclofenac 4'-hydroxylase than for mephenytoin 4'-hydroxylase. The metabolic activities of CYP2C9 and CYP2C19 were confirmed by inhibition by sulfaphenazole for CYP2C9 and ticlopidine for CYP2C19. In addition, CYP2C9 activities did not correlate with CYP3A4 activities, while CYP2C19 activities had a significant but poor correlation with those of CYP3A4. Thus the major CYP activities in human enterocytes have large interindividual variabilities that are not strongly related.

Adult↗

PubMed2000

Human cytochrome P-450 metabolism of retinals to retinoic acids.

Retinoic acids have important pleiotropic biological effects and thus the potential for human cytochrome P-450s (CYPs) to mediate retinoic acid synthesis was investigated. We examined the retinoic acid synthetic activity of human cDNA-expressed CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A4+ cytochrome b(5) (b(5)), 3A5, and 4A11, expressed individually in insect cells together with NADPH-P-450 reductase. Only CYP1A1, 1A2, 1B1, and 3A4+b(5) converted all-trans-retinal (20 microM) to all-trans-retinoic acid with turnover numbers of 0.53, 0.18, 0.20, and 0.41 nmol/min/nmol P-450, respectively. With 9-cis-retinal as substrate, CYP1A2 exhibited a turnover number of 1.58 nmol/min/nmol P-450 whereas CYP1A1, 2C19, and 3A4+b(5) had turnover numbers of 0.40, 0.27, and 0.41 nmol/min/nmol P-450, respectively. For CYP3A4 activities with both retinals, b(5) was required. Kinetic analyses revealed that CYP1A1, 1A2, and 3A4+b(5) with all-trans-retinal had apparent K(m) values of 55, 356, and 255 microM, and V(max) values of 2.0, 8.3, and 6.3 nmol/min/nmol P-450, respectively, and with 9-cis-retinal had K(m) values of 77, 91, and 368 microM, and V(max) values of 2.7, 9.7, and 7.6 nmol/min/nmol P-450, respectively. The 9-cis retinoic acid synthetic activity of a group of 12 human liver microsomes correlated only with the CYP1A2 activity (r = 0.96), implicating CYP1A2 in human liver microsomal metabolism of 9-cis- retinal to 9-cis-retinoic acid. These studies have indicated that human CYPs are capable of catalyzing retinal to retinoic acid metabolism, but the physiological relevance of this metabolism is still unclear.

Animals↗

PubMed1999

Characterization of human small intestinal cytochromes P-450.

Human small intestine epithelial cells (enterocytes) provide the first site for cytochrome P-450 (CYP)-catalyzed metabolism of orally ingested xenobiotics. The CYP composition of enterocytes could thus affect the potential toxicity or therapeutic efficacy of xenobiotics by modifying systemic uptake. We have characterized human enterocyte CYP composition to enable assessment of its functional roles. An isolation method for enterocytes from human small intestine was developed using EDTA buffer-mediated elution. Villous enterocytes were isolated in high yield, separated from crypt cells. Reverse transcriptase-polymerase chain reaction of total RNA from enterocytes revealed that CYP1A1, 1B1, 2C, 2D6, 2E1, 3A4, and 3A5 mRNA were expressed, but only CYP2C and 3A4 were detectable by Western immunoblotting in enterocyte microsomes from 10 human small intestines, whereas CYP1A1 was weakly detectable in two of eight intestines tested. Microsomal protein content decreased markedly along the small intestine from the duodenum to the ileum, whereas total CYP content and CYP3A4 erythromycin N-demethylase activity increased slightly in progressing from the duodenum to the jejunum and then decreased markedly toward the ileum. Levels of CYP3A4 and 2C protein did not decrease in concert as a function of length along the intestine distally. Maximal CYP content for the 10 intestines varied from 0.06 to 0.18 nmol/mg microsomal protein and maximal CYP3A4 erythromycin N-demethylase activity varied from 0.30 to 0.76 nmol/min/mg microsomal protein. In conclusion, CYP3A4 is the major form of CYP expressed in human small intestine enterocytes, CYP3A5 expression was not detected, CYP2C and, in some intestines, CYP1A1 were expressed. The highest metabolic activity occurred in the proximal intestine.

Adolescent↗

PubMed1999

Induction of rat small intestinal cytochrome P-450 2J4.

Cytochrome P-450 (CYP) 2J4 is a member of the recently identified CYP2J subfamily-part of the CYP superfamily-and is primarily expressed in rat small intestinal epithelium (enterocytes). Studies to determine small intestinal CYP2J4 inducibility by prototypic CYP inducers have been undertaken. Immunoblot analysis of enterocyte microsomes from rats treated with beta-naphthoflavone, dexamethasone, or phenobarbital revealed unchanged, diminished, or slightly increased levels of CYP2J4 protein, respectively, relative to vehicle-treated rats, whereas rats treated with pyrazole (200 mg/kg) had 3- to 4-fold increased levels of CYP2J4. Pyrazole administration also increased CYP2J4 metabolic activity, as probed by retinoic acid formation from retinal, approximately 3-fold, and the activity was inhibited by 90% by a polyclonal anti-CYP2J4 antibody. CYP2J4 mRNA levels were increased 2.5-fold by pyrazole administration. The route of pyrazole administration-oral or i.p.-did not affect the extent or time course of intestinal CYP2J4 induction. However, at >300 mg/kg pyrazole, oral administration produced higher levels of CYP2J4 activity than i.p. administration. Pyrazole also produced increased hepatic and olfactory mucosal levels of CYP2J4. We speculate, based on our data and on published mechanisms of pyrazole induction, that pyrazole induces rat intestinal CYP2J4 by stabilization of mRNA primarily, and by stabilization of protein to a lesser extent. This study documents for the first time the induction of a CYP2J subfamily member by a xenobiotic and provides the basis for a mechanism by which xenobiotics could modulate biological processes.

Animals↗

PubMed1998

Characterization of the cytochrome P450 CYP2J4: expression in rat small intestine and role in retinoic acid biotransformation from retinal.

The sites of expression in the small intestine and the function of CYP2J4, a recently identified rat cytochrome (P450) isoform found to be predominantly expressed in the small intestine, were characterized. Immunoblot analysis with a polyclonal antibody to heterologously expressed CYP2J4 revealed that expression of CYP2J4 was at the highest level in the distal duodenum and jejunum and decreased toward the ileum. Villous cells expressed higher levels of CYP2J4 than crypt cells. Isoform-specific RNA polymerase chain reaction indicated that a related P450 isoform, CYP2J3, was only a minor form in rat small intestine. Since the intestinal mucosa is exposed to high levels of dietary nutrients, we hypothesized that CYP2J4 may be active toward diet-derived factors. We determined that purified, heterologously expressed CYP2J4 is active toward all-trans- and 9-cis-retinal in reconstituted systems, producing the corresponding retinoic acids as the major products. Apparent K(m) values for the formation of retinoic acids were 54 and 49 microM, respectively, and apparent Vmax values were 20 and 21 nmol/min/nmol P450, respectively. These activities were readily inhibited by a polyclonal anti-CYP2J4 antibody. Rat enterocyte microsomes were also active with all-trans-retinal to produce all-trans-retinoic acid in the presence of NADPH, and the majority of retinoic acid synthesis activity was inhibited by the polyclonal anti-CYP2J4 antibody. These findings suggest that CYP2J4 plays a major role in intestinal microsomal metabolism of retinal to retinoic acid and may be involved in the maintenance of retinoid homeostasis in the small intestine in vivo.

Animals↗

PubMed1998

A tRNA suppressor mutation in human mitochondria.

Mitochondrial mutations are associated with a wide spectrum of human diseases. A common class of point mutations affects tRNA genes, and mutations in the tRNA-leu(UUR) gene (MTTL1) are the most frequently detected. In earlier studies, we showed that lung carcinoma cybrid cells containing high levels (greater than 95%) of mutated mtDNA from a patient with the pathological nucleotide pair (np) 3243 tRNA-leu(UUR) mutation can remain genotypically stable over time, and exhibit severe defects in mitochondrial respiratory metabolism. From such a cybrid containing 99% mutated mtDNA, we have isolated a spontaneous derivative that retains mutant mtDNA at this level but which has nevertheless reverted to the wild-type phenotype, based on studies of respiration, growth in selective media, mitochondrial protein synthesis and biogenesis of mitochondrial membrane complexes. The cells are heteroplasmic for a novel anticodon mutation in tRNA-leu(CUN) at np 12300, predicted to generate a suppressor tRNA capable of decoding UUR leucine codons. The suppressor mutation represents approximately 10% of the total mtDNA, but was undetectable in a muscle biopsy sample taken from the original patient or in the parental cybrid. These results indicate that the primary biochemical defect in cells with high levels of np 3243 mutated mtDNA is the inability to translate UUR leucine codons.

Anticodon↗

PubMed1997

Induction of CYP1A1 by beta-naphthoflavone in IEC-18 rat intestinal epithelial cells and potentiation of induction by dibutyryl cAMP.

We have examined the inducibility of CYP1A1 by beta-naphthoflavone (BNF) in a rat intestinal epithelial cell line, IEC-18, and the associated interaction between cAMP and BNF. CYP1A1 was not constitutively expressed in IEC-18 cells. Upon treatment with BNF, CYP1A1 RNA, protein, and microsomal 7-ethoxyresorufin O-deethylase activity were detected. Treatment with dibutyryl cAMP resulted in a 2-fold increase in the extent of induction at both RNA and protein levels, with corresponding increases in CYP1A1 enzymatic activity. These results support the involvement of protein kinase A in Ah receptor-mediated induction of CYP1A1 and provide an in vitro model for further studies on the mechanisms underlying regional and cellular differences in the regulation of CYP1A1 gene expression in the small intestine.

Animals↗

PubMed1997

Health-related behaviours and psycho-social characteristics of 18 year-old Australians.

Psychosocial variables associated with health-related behaviours for diet, physical activity, alcohol consumption and smoking were examined in 18 year-old Australian men (n = 301) and women (n = 282). These psychosocial variables included Type A behaviour and depression, perceived self-efficacy for engaging in healthy behaviours and perceived barriers to performing these behaviours. Self-efficacy for following a healthy diet and moderating alcohol intake was greater in females but males had higher self-efficacy for physical activity. Self-efficacy for smoking did not differ according to gender. Lack of willpower was perceived as a barrier to desirable dietary, smoking and physical activity behaviours. Other perceived diet-related barriers included buying suitable foods when eating out, ignorance about appropriate foods and, in young women, perceived expense. Barriers for desirable levels of physical activity included planning time, tiredness, limiting social life and lack of social support. Social occasions were the main perceived barriers preventing both alcohol moderation and quitting smoking. Lack of family support, stress and concerns about weight gain, particularly in women, were perceived barriers to smoking cessation. Type A behaviour was associated with smoking and "unsafe" drinking in both men and women, generally unhealthy dietary choices in young women but with greater physical activity in young men. Depressive affect was significantly higher in female smokers and "unsafe" drinkers and tended to have an inverse relationship with physical activity in men and women. Depressive affect was inversely related to self-efficacy in both men and women for each of the health behaviours examined. Health promotion in young adults should therefore attempt to increase self-efficacy and address perceived barriers to change, taking into account gender-related differences in attitudes and the influence of depression and Type A characteristics on health-related behaviours.

Adolescent↗

PubMed1997

The three-dimensional passive support characteristics of ankle braces.

Studies of the passive support provided by ankle braces have focused primarily on inversion support. The goal of this study was to develop a technique to measure the support provided by ankle braces in all rotational directions and to use this technique to compare four common braces (Ascend, Swede-O, Aircast, and Active Ankle). For this purpose, a 6 degrees-of-freedom linkage was used to measure the flexibility of the ankle complex in 10 healthy subjects. Each subject was tested without brace support and with each of the four braces. Testing was repeated on each subject on two different occasions. The angular displacement at specified moment values and the four segmental flexibility values obtained from the loading portion of the moment-angular displacement data were used in the data analysis. Repeated measure analysis of variance followed by a Student Neuman-Keuls test at p < 0.05 was performed. This statistical analysis was used to identify significant differences among the braces and differences between each brace and the no brace condition. Each of the four braces provided significant support in inversion, eversion, and internal rotation, but the amount of support varied significantly among the braces. In external rotation, only the stirrup braces provided significant support. The braces also varied significantly in the amount of interference with dorsiflexion and plantar flexion. Clinicians may be assisted by objective data on the amount and nature of passive support when prescribing braces to their patients.

Adult↗

PubMed1997

Regulation of cytochrome P4501A1 expression in rat small intestine.

The predominant inducible cytochrome P450 (CYP) in rat small intestine is CYP1A1, which, when induced to elevated levels by xenobiotics or dietary constituents, has the potential to metabolize and consequently reduce the systemic uptake of low concentrations of orally ingested, bioactivatable polycyclic aromatic hydrocarbons and heterocyclic aromatic amines. We investigated the regulation of small intestinal CYP1A1 in an effort to develop its anticancer potential. The time courses of hepatic and intestinal CYP1A1 induction by beta-naphthoflavone (BNF) were compared quantitatively at the protein and mRNA levels by immunoblot and competitive RNA-polymerase chain reaction analyses. CYP1A1 mRNA levels in both organs increased sharply and were maximal at approximately 6 hr and returned to near basal levels by 12 hr after BNF treatment. In contrast, hepatic CYP1A2 mRNA levels increased much more gradually. Small intestinal CYP1A2 mRNA concentrations were insufficient to support translation of detectable protein. Maximal levels of intestinal and hepatic CYP1A1 protein occurred between 12 and 24 hr, and 24 and 48 hr, respectively, after BNF. Intestinal CYP1A1 protein was detectable earlier and for a shorter duration than hepatic CYP1A1. CYP1A1 induction was first detected in crypt cells 3 hr before the appearance of activity in villous cells, and maximal levels of activity were reached in crypt cells 12 to 18 hr before maximal and 1.5-fold (per mg protein) higher responses in villous cells-induction thus occurs in both villous and crypt cells. Previously detected decreases in CYP1A1 inducibility from duodenum to ileum correlated with decreases in immunoblot determined-Ah receptor levels. Intestinal CYP1A1 induction does not involve the glucocorticoid receptor in contrast to hepatic induction. These studies have revealed several novel features of small intestinal CYP1A1 regulation.

Animals↗

PubMed1996

Anesthetic efficacy of the intraosseous injection after an inferior alveolar nerve block.

The purpose of this study was to determine the contribution of the intraosseous (IO) injection to the inferior alveolar nerve (IAN) block in human first molars. Using a repeated-measures design, 40 subjects randomly received either a combination IAN block + IO injection (on the distal of the first molar) using 2% lidocaine with 1:100,000 epinephrine or an IAN block+mock IO injection (gingival penetration only) at two successive appointments. The first molar and adjacent teeth, and contralateral canine (+/-controls) were blindly tested with an Analytic Technology pulp tester at 2-min cycles for 60 min. An 80 reading was used as the criterion for pulpal anesthesia. One hundred percent of the subjects had lip numbness with the IAN block. For the first molar, anesthetic success, defined as achieving an 80 reading within 15 min and keeping this reading for 60 min, was 42% with the IAN and 90% with the IAN + IO. Anesthetic failure defined as never achieving two 80 readings during the 60 min was 32% with the IAN and 0% with the IAN + IO. The onset of anesthesia was immediate with the IO injection. Eighty percent of the subjects sampled had a subjective increase in heart rate with the IO injection. The IO injection and postinjection questionnaire recorded low pain ratings.

Adolescent↗

PubMed1996

Characterization of rat small intestinal cytochrome P450 composition and inducibility.

The composition and inducibility of cytochrome P450 (P450) in rat small intestinal epithelial cells were investigated with the use of RNA-polymerase chain reaction and immunoblot techniques. The complement of intestinal P450s is more restricted than hepatic forms. P450s 1A1, 2B1, and 3A1 were detected in enterocytes of untreated rats and were inducible by beta-naphthoflavone (BNF), phenobarbital, and pregnenolone-16alpha-carbonitrile or dexamethasone, respectively. In addition, P450s 2C6 and 2C11 were both constitutively expressed at low levels. In contrast, several P450 forms, which are found in the liver, were not detected in enterocytes of untreated or induced rats, including P450s 2A1, 2B2, 2E1, 3A2, and 4A1. P4501A2 mRNA was detected only in BNF-induced rat small intestine and at levels that did not result in its detectable translation. The most prominent inducible form in rat small intestine is P4501A1. Its inducibility diminishes markedly along the length of the small intestine from the duodenum to the ileum. Furthermore, the induction of P4501A1 in enterocytes was affected by the route of administration of the inducing agent. Thus, intestinal P4501A1 was more sensitive to orally administered BNF, whereas induction of hepatic P4501A1 was more sensitive to intraperitoneal administered BNF. Overall, the results demonstrate the differential regulation of P450s between the liver and small intestine, and provide a basis for further studies in assessing the potential of intestinal P450s to protect against orally ingested polycyclic aromatic hydrocarbon carcinogens.

Animals↗

PubMed1994

Low-energy transvenous cardioversion defibrillation of atrial tachyarrhythmias in the canine: an assessment of electrode configurations and monophasic pulse sequencing.

Prevention of recurrent atrial fibrillation and flutter remains a difficult clinical problem. Consequently, development of an easily implantable automatic atrial cardioverter defibrillator is appealing. In this context we have examined the feasibility of intracavitary low-energy shocks delivered via transvenously positioned electrodes for termination of induced atrial tachyarrhythmias in canine models. This study extends these observations with use of single-pathway (5 msec pulse duration) and dual-pathway sequential (5/5 msec, 0.2 msec separation) shocks of varying leading edge voltages (100 to 400 V) in a closed-chest canine talc-pericarditis model. Bipolar 9.5 French electrode catheters (electrode surface areas, 0.62 cm2) were positioned at the superior vena cava-right atrium (SVC-RA) junction (labeled SVC) and right ventricular (RV) apex, with a subcutaneous plate over the chest wall. For single-pathway shocks, overall treatment effectiveness was comparable among the three vectors tested (RV apex to SVC, 35%; RV apex to subcutaneous plate, 17%; and SVC to subcutaneous plate, 35%). Furthermore, there was no evident relationship between leading edge voltage and shock effectiveness. In contrast, although each of the dual-pathway shock vector combinations tested also showed similar overall effectiveness, there was an apparent dose-response effect as leading edge voltage increased. The SVC (common) to RV apex (pulse 1) and subcutaneous plate (pulse 2) achieved 60% effectiveness at 400 V (approximately 4 joules). Thus this study provides additional evidence favoring feasibility of low-energy transvenous atrial cardioversion defibrillation. However, further refinement of energy delivery is essential for the implantable automatic atrial cardioverter defibrillator concept to become clinically accepted.

Animals↗

PubMed1994

Rifampin-resistant Mycobacterium kansasii.

We identified 36 rifampin-resistant Mycobacterium kansasii isolates, including 17 (4%) of 464 isolates recovered in Texas between 1989 and 1992. Of 29 patients infected with rifampin-resistant M. kansasii whose history of medication was known, 90% had previously received rifampin, and 58% of these patients had been treated with one or two effective drugs. Thirty-two percent of rifampin-resistant isolates recovered since 1989 were from patients who were seropositive for human immunodeficiency virus (HIV) infection. Twenty courses of therapy with a four-drug regimen determined on the basis of in vitro susceptibilities were administered to 16 patients from whom rifampin-resistant isolates were recovered; the therapy did not include surgery. Sputum cultures converted to negative as the result of 90% of treatments (time to conversion: mean, 11 weeks; range, 4-20 weeks). Bacteriologic relapses occurred in four of five patients who withdrew from therapy after being culture negative for < or = 6 months of therapy and in one of 12 patients who were culture negative for at least 12 months of therapy (mean, 16.3 months). This study suggests that the prognosis for cure of infection due to rifampin-resistant M. kansasii with chemotherapy alone is excellent, although the number of cases appears to be increasing, in part because of the HIV disease epidemic.

Adult↗