The Peroxisomal 3-keto-acyl-CoA thiolase B Gene Expression Is under the Dual Control of PPARα and HNF4α in the Liver.

PPARα and HNF4α are nuclear receptors that control gene transcription by direct binding to specific nucleotide sequences. Using transgenic mice deficient for either PPARα or HNF4α, we show that the expression of the peroxisomal 3-keto-acyl-CoA thiolase B (Thb) is under the dependence of these two transcription factors. Transactivation and gel shift experiments identified a novel PPAR response element within intron 3 of the Thb gene, by which PPARα but not HNF4α transactivates. Intriguingly, we found that HNF4α enhanced PPARα/RXRα transactivation from TB PPRE3 in a DNA-binding independent manner. Coimmunoprecipitation assays supported the hypothesis that HNF4α was physically interacting with RXRα. RT-PCR performed with RNA from liver-specific HNF4α-null mice confirmed the involvement of HNF4α in the PPARα-regulated induction of Thb by Wy14,643. Overall, we conclude that HNF4α enhances the PPARα-mediated activation of Thb gene expression in part through interaction with the obligate PPARα partner, RXRα.

Global carbon sinks and their variability inferred from atmospheric O2 and delta13C.

Recent time-series measurements of atmospheric O2 show that the land biosphere and world oceans annually sequestered 1.4 +/- 0.8 and 2.0 +/- 0.6 gigatons of carbon, respectively, between mid-1991 and mid-1997. The rapid storage of carbon by the land biosphere from 1991 to 1997 contrasts with the 1980s, when the land biosphere was approximately neutral. Comparison with measurements of delta13CO2 implies an isotopic flux of 89 +/- 21 gigatons of carbon per mil per year, in agreement with model- and inventory-based estimates of this flux. Both the delta13C and the O2 data show significant interannual variability in carbon storage over the period of record. The general agreement of the independent estimates from O2 and delta13C is a robust signal of variable carbon uptake by both the land biosphere and the oceans.

A pharmacokinetic and pharmacodynamic study of the potential drug interaction between tasosartan and atenolol in patients with stage 1 and 2 essential hypertension.

The primary objective of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of tasosartan and atenolol administered alone and concomitantly under steady-state conditions in 17 patients ages 18 to 65 years diagnosed with stage 1 to 2 essential hypertension. After a 3- to 14-day qualification period, all patients received placebo tasosartan on days--1 through 5 and 25 through 34, atenolol alone (50 mg) on days 1 through 5, atenolol (50 mg) + tasosartan (50 mg) on days 6 through 19, and tasosartan (50 mg) alone on days 20 through 24. A PK and PD evaluation of atenolol alone was performed on study day 5. On study day 19, PK and PD of both tasosartan and atenolol were assessed. PK and PD evaluation for tasosartan alone was assessed on study day 24. The coadministration of atenolol + tasosartan did not affect the pharmacokinetics of tasosartan, its major metabolite (enoltasosartan), or atenolol when compared with tasosartan or atenolol administered separately. For area under the change in diastolic blood pressure curve, the reduction was significantly greater after tasosartan + atenolol compared with that after atenolol alone (336 +/- 85 and 190 +/- 71 mmHg.24 h; p < 0.05 for combination and atenolol alone, respectively; mean +/- SEM). Combination therapy also caused a maximal reduction in diastolic blood pressure that is significantly more than with monotherapy with atenolol (-27 +/- 2 mmHg and -20 +/- 2 mmHg, respectively, p < 0.05). The additive effects of tasosartan and atenolol in decreasing diastolic blood pressure may provide a rationale for combination antihypertensive therapy.

Acute promyelocytic leukemia in a HIV seropositive patient.

Acute myeloid leukemia (AML) is infrequent in patients with human immunodeficiency virus (HIV) infection. Among AML, acute promyelocytic leukemia (APL) has been rarely described in such patients, with only one case being published. We report a 30 years-old intravenous drug abuser HIV-infected male with APL who attained complete clinical, morphological, and molecular remission after differentiation therapy with all-trans-retinoic acid (ATRA) followed by intensive chemotherapy. The results of treatment in this patient and in other AML published cases suggest that therapy for AML should not be modified because of HIV infection if patients have an adequate performance status.

Pharmacokinetics of the aldose reductase inhibitor tolrestat: studies in healthy young and elderly male and female subjects and in subjects with diabetes.

Tolrestat is an aldose reductase inhibitor undergoing clinical trials in diabetic subjects that may reduce the severity of chronic tissue damage associated with hyperglycemia. These studies were conducted to evaluate the pharmacokinetics of tolrestat in healthy young and elderly male and female subjects and in young and elderly subjects with diabetes. The drug was administered in a multiple-dose regimen, and steady-state parameters were obtained. There were no important gender-related differences, but mean values for apparent oral clearance, renal clearance, and corresponding unbound parameters were significantly lower for the elderly healthy subjects than for the young healthy subjects. The drug is highly bound to plasma proteins, and the unbound fraction (0.75%) did not differ among the subjects. The results from young and elderly diabetic subjects suggest that diabetes per se has no influence on tolrestat disposition but that there is an age-related reduction in apparent oral clearance (30 versus 18 ml/hr/kg) and a corresponding increase in the minimum steady-state plasma concentration (1.2 versus 1.9 micrograms/ml). These data indicate a possible need to reduce the dose of tolrestat in elderly subjects, assuming the same concentration-response relationship.

Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study.

Fluoride stimulates trabecular bone formation, whereas bisphosphonates reduce bone resorption and turnover. Fracture prevention has not been convincingly demonstrated for either treatment so far. We compared the effects of 1-yr treatment of 9-mo-old minipigs with sodium fluoride (NaF, 2 mg/kg/d p.o.) or alendronate (ALN, 4 amino-1-hydroxybutylidene bisphosphonate monosodium, 1 mg/kg/d p.o.) on the biomechanical and histomorphometric properties of pig bones. As expected, NaF increased and ALN decreased bone turnover, but in these normal animals neither changed mean bone volume. NaF reduced the strength of cancellous bone from the L4 vertebra, relative to control animals, and the stiffness (resistance to deformation) of the femora, relative to the ALN group. In the ALN-treated animals, there was a strong positive correlation between bone strength and L5 cancellous bone volume, but no such correlation was observed in the NaF group. Furthermore, the modulus (resistance to deformation of the tissue) was inversely related to NaF content and there was a relative decrease in bone strength above 0.25 mg NaF/g bone. Moreover, within the range of changes measured in this study, there was an inverse correlation between bone turnover, estimated as the percentage of osteoid surface, and modulus. These findings have relevant implications regarding the use of these agents for osteoporosis therapy.

Healing of large segmental defects in rat femurs is aided by RhBMP-2 in PLGA matrix.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) can be used to enhance the repair of congenital or acquired bone pathologies when formulated in the appropriate carrier. Poly [D,L-(lactide-co-glycolide)] (PLGA) has been shown to be an effective carrier of rhBMP-2. We investigated several particle sizes PLGA and several doses of rhBMP-2 in a rat orthotopic model. We also investigated the effects of a fibrinolytic inhibitory agent, epsilon aminocaproic acid (EACA), on the healing response. Our data indicate that higher doses of rhBMP-2 resulted in increased failure torque (408 +/- 70 N-mm or 60% of the intact value) and higher incidence of union (100%). The induced bone in femurs treated with the smaller particle size PLGA achieved the greatest torsional stiffness and strength. The presence of rhBMP-2 was necessary for new bone to form, but the presence of EACA did not change these results; the use of the PLGA carrier appeared to increase bone strength and stiffness. In fact, with higher doses of rhBMP-2 in PLGA, the stiffness of the new bone was equal to that of intact controls (64 +/- 20 N-mm/deg [intact femurs] versus 45 +/- 10 N-mm/degree [medium dose in small PLGA], 61 +/- 17 N-mm/degree [high dose in small PLGA], and 36 +/- 11 N-mm/degree [medium dose in large PLGA]; P > .05). In conclusion, PLGA implanted with rhBMP-2 effectively aided in healing large segmental defects in rat femurs.

Long-term follow-up of 85 patients with obsessive-compulsive disorder.

In this study, long-term outcome for patients with obsessive-compulsive disorder treated with serotonin reuptake inhibitor medications was examined. The records of 85 patients who had first been evaluated at least 1 year previously (the mean follow-up period was 773 days) were reviewed. Information was collected on age at onset of symptoms, time since first evaluation, and scores on several scales measuring symptom severity, including the Yale-Brown Obsessive Compulsive Scale. Comparison of these baseline data with Yale-Brown scale scores at the most recent follow-up visit showed that 74 (87%) of the patients had responded to treatment. No predictors of improvement were found.