Publications

The effects of hepatic uptake and efflux transporters on metabolism of digoxin were examined in isolated rat hepatocytes versus microsomes. The metabolic clearance estimated from microsomes was 4.59 +/- 0.69 ml/min/kg. However, the metabolic clearance estimated from hepatocytes was 15.9 +/- 3.0 ml/min/kg. The former did not correlate with in vivo clearance (12.9 ml/min/kg) for digoxin. Rifampin (an organic anion-transporting peptide 2 inhibitor) or GG918 [GF120918 (N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide)] (a potent P-glycoprotein inhibitor) were used to estimate effects of uptake or efflux transporters on digoxin metabolism. Whereas both inhibitors exerted minimal effects on metabolism in microsomes, rifampin and GG918 significantly decreased and increased digoxin metabolism in hepatocytes, respectively. Concentration-time course studies further demonstrated that, compared with the area under the curve (AUC) of control (15.6 +/- 0.1 microM . min), an increase of AUC (20.1 +/- 0.5 microM . min, p < 0.005) was observed when digoxin was coincubated with rifampin and a decrease of AUC (14.1 +/- 0.1 microM . min, p < 0.01) when GG918 was also present. Digoxin primary metabolite concentrations changed directionally in an inverse manner with parent drug concentrations, as would be expected. These results strongly suggest that the hepatic uptake and efflux transporters that are found in hepatocytes, but not in microsomes, modulate intracellular concentration of digoxin and thus affect metabolism. We conclude that the interplay of transporters and enzymes must be considered in defining the intrinsic metabolic clearance of the liver and in evaluating potential drug-drug interactions.

OBJECTIVE

To assess whether the specialty of a patient's primary care physician or being part of a gatekeeper plan influence breast and cervical cancer screening.

METHODS

Cross-sectional study of women in a national sample. For mammography, we studied women aged 40 and above, and for Papanicolaou (Pap) smear, women aged 18-65 years. Screening mammography or Pap smear within the previous two years was measured by patient self-report. The key independent variables were primary care physician specialty and whether the patient had a gatekeeper.

RESULTS

Among women seen by a family practice physician, there was a higher probability of being screened if the patient was part of a gatekeeper plan than if the patient was not part of a gatekeeper plan: mammography (OR = 1.35; 95% CI = 1.20-1.52) and Pap smear (OR = 1.60; 95% CI = 1.34-1.91). Among women seen by an internal medicine physician, cancer screening did not vary significantly by gatekeeper status.

CONCLUSIONS

The impact of gatekeeper plans upon cancer screening varies according to the primary care physician's specialty. Policy interventions designed to increase cancer screening should take into account different responses to gatekeeper requirements among different types of providers.

The objective of this study was to describe the relationship between attendance at conferences during residency training and residents' performance on the In-Training Examination (ITE) in Internal Medicine. Nineteen house officers participated in the study. Conference attendance records were retrospectively reviewed for the one-year period preceding the ITE (pre-ITE), and in the three-month period after house officers received their ITE scores (post-ITE). After receiving their scores, participants completed a questionnaire asking about study habits and opinions about conferences. Attendance was taken at 126/165 (76.4%) conferences pre-ITE and 32/42 (76.2%) conferences post-ITE. House officers attended a mean of 35% (range, 10-59) of the conferences pre-ITE and 32% (range, 9-75) post-ITE (p = 0.365). There was no correlation between prior conference attendance and ITE scores (Spearman correlation coefficient -0.230, p = 0.34), and no correlation between score and conference attendance post-ITE (Spearman correlation coefficient 0.174, p = 0.48). Participation in clinical rotations also failed to influence ITE scores in that content area (all p > 0.05). The findings of this study suggest conference attendance does not influence ITE scores. Medical educators may need to rethink and study how best to impart medical knowledge.

Ketosis-prone diabetes (KPD) is a rare form of type 2 diabetes, mostly observed in subjects of west African origin (west Africans and African-Americans), characterized by fulminant and phasic insulin dependence, but lacking markers of autoimmunity observed in type 1 diabetes. PAX4 is a transcription factor essential for the development of insulin-producing pancreatic beta-cells. Recently, a missense mutation (Arg121Trp) of PAX4 has been implicated in early and insulin deficient type 2 diabetes in Japanese subjects. The phenotype similarities between KPD and Japanese carriers of Arg121Trp have prompted us to investigate the role of PAX4 in KPD. We have screened 101 KPD subjects and we have found a new variant in the PAX4 gene (Arg133Trp), specific to the population of west African ancestry, and which predisposes to KPD under a recessive model. Homozygous Arg133Trp PAX4 carriers were found in 4% of subjects with KPD but not in 355 controls or 147 subjects with common type 2 or type 1 diabetes. In vitro, the Arg133Trp variant showed a decreased transcriptional repression of target gene promoters in an alpha-TC1.6 cell line. In addition, one KPD patient was heterozygous for a rare PAX4 variant (Arg37Trp) that was not found in controls and that showed a more severe biochemical phenotype than Arg133Trp. Clinical investigation of the homozygous Arg133Trp carriers and of the Arg37Trp carrier demonstrated a more severe alteration in insulin secretory reserve, during a glucagon-stimulation test, compared to other KPD subjects. Together these data provide the first evidence that ethnic-specific gene variants may contribute to the predisposition to this particular form of diabetes and suggest that KPD, like maturity onset diabetes of the young, is a rare, phenotypically defined but genetically heterogeneous form of type 2 diabetes.

UNLABELLED

Integrin alphavbeta5 is expressed on osteoclast precursors and is capable of recognizing the same amino acid motif as alphavbeta3. Three-month-old beta5(-/-) female OVX mice had increased osteoclastogenesis ex vivo, and microCT assessment of trabecular bone volume was 53% lower than WT-OVX animals. These preliminary data suggest alphavbeta5 integrin's presence on osteoclast precursors may inhibit of osteoclast formation.

INTRODUCTION

Osteoclasts are unique resorptive skeletal cells, capable of degrading bone on contact to the juxtaposed matrix. Integrin alphavbeta5 is expressed on osteoclast precursors, structurally similar to alphavbeta3, and capable of recognizing the same amino acid motif. Given the structural relationship and reciprocal regulation of alphavbeta3 and alphavbeta5, the purpose of this study was to evaluate how alphavbeta5 might contribute to osteoclast maturation and activity.

MATERIALS AND METHODS

Three-month-old wildtype (WT) and beta5(-/-) female mice had ovariectomy (OVX) or sham operations. The osteoclastogenic capacity of marrow-derived precursors, the kinetic, the circulating, and structural parameters of bone remodeling, was determined after 6 weeks of paired feeding.

RESULTS AND CONCLUSIONS

OVX increased osteoclastogenesis ex vivo and in vivo. Osteoclast formation and prolonged pre-osteoclast survival were substantially enhanced in cultures containing beta5(-/-) cells whether obtained from sham-operated or OVX mice. Expression of cathepsin K, beta3 integrin subunit, and calcitonin receptor were accelerated in cultured beta5(-/-)osteoclasts. beta5(-/-) osteoclasts from OVX animals showed a 3-fold enhancement of net resorptive activity, with quantitative muCT showing trabecular bone volume loss after OVX 53% greater in beta5(-/-) OVX compared with similarly treated WT OVX mice (p < 0.05). alpha5beta3 seems to be an inhibitor of osteoclast formation, in contrast to alphavbeta3. In addition, loss of alphavbeta5 seems to accelerate osteoclast formation in the OVX model. Further examination of alphavbeta5 signaling pathways may enhance our understanding of the activation of bone resorption.