Adverse Fetal and Neonatal Outcomes Associated with a Life-Long High Fat Diet: Role of Altered Development of the Placental Vasculature

Maternal obesity results in a number of obstetrical and fetal complications with both immediate and long-term consequences. The increased prevalence of obesity has resulted in increasing numbers of women of reproductive age in this high-risk group. Since many of these obese women have been subjected to hypercaloric diets from early childhood we have developed a rodent model of life-long maternal obesity to more clearly understand the mechanisms that contribute to adverse pregnancy outcomes in obese women. Female Sprague Dawley rats were fed a control diet (CON - 16% of calories from fat) or high fat diet (HF - 45% of calories from fat) from 3 to 19 weeks of age. Prior to pregnancy HF-fed dams exhibited significant increases in body fat, serum leptin and triglycerides. A subset of dams was sacrificed at gestational day 15 to evaluate fetal and placental development. The remaining animals were allowed to deliver normally. HF-fed dams exhibited a more than 3-fold increase in fetal death and decreased neonatal survival. These outcomes were associated with altered vascular development in the placenta, as well as increased hypoxia in the labyrinth. We propose that the altered placental vasculature may result in reduced oxygenation of the fetal tissues contributing to premature demise and poor neonatal survival

Expression of Barhl2 and its relationship with Pax6 expression in the forebrain of the mouse embryo

BACKGROUND: The transcription factor Barhl2 is an antiproneural transcription factor with roles in neuronal differentiation. The functions of its homologue in Drosophila development are better understood than its functions in mammalian brain development. Existing evidence suggests that its expression in the embryonic forebrain of the mouse is regional and may complement that of another transcription factor that is important for forebrain development, Pax6. The aim of this study is to provide a more detailed description of the Barhl2 expression pattern in the embryonic forebrain than is currently available, to relate its expression domains to those of Pax6 and to examine the effects of Pax6 loss on Barhl2 expression. RESULTS: We found that Barhl2 is expressed in the developing diencephalon from the time of anterior neural tube closure. Its expression initially overlaps that of Pax6 in a central region of the alar diencephalon but over the following days their domains of expression become complementary in most forebrain regions. The exceptions are the thalamus and pretectum, where countergradients of Pax6 and Barhl2 expression are established by embryonic day 12.5, before overall Pax6 levels in these regions decline greatly while Barhl2 levels remain relatively high. We found that Barhl2 expression becomes upregulated in specifically the thalamus and pretectum in Pax6-null mice. CONCLUSIONS: The region-specific expression pattern of Barhl2 makes it likely to be an important player in the development of region-specific differences in embryonic mouse forebrain. Repression of its expression in the thalamus and pretectum by Pax6 may be crucial for allowing proneural factors to promote normal neuronal differentiation in this region

The role and impact of comparison websites on the consumer search process in the US and German airline markets

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A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies

Purpose: This study evaluated the safety, toxicity, pharmacological properties and biological activity of PI-88, a heparanase endoglycosidase enzyme inhibitor, with fixed weekly docetaxel in patients with advanced solid malignancies. Experimental design: This was a phase I study to determine the maximal-tolerated dose of escalating doses of PI-88 administered subcutaneously for 4 days per week, along with docetaxel 30 mg/m given on days 1, 8, 15 of a 28-day schedule. Results: Sixteen patients received a total of 42 courses of therapy. No dose-limiting toxicities were observed despite escalation to the highest planned dose level of PI-88 (250 mg/day). Frequent minor toxicities included fatigue (38%), dysgeusia (28.5%), thrombocytopenia (12%), diarrhea (14%), nausea (12%), and emesis (10%) in the 42 courses. No significant bleeding complications were observed. One patient developed a positive anti-heparin antibody test/serotonin releasing assay with positive anti-platelet factor 4/PI-88 antibodies and grade 1 thrombocytopenia in cycle 5, and was withdrawn from the study without any sequelae. PI-88 plasma concentrations (mirrored by APTT) and urinary elimination were linear and dose-proportional. Docetaxel did not alter the pharmacokinetic (PK) profile of PI-88, nor did PI-88 affect docetaxel PK. No significant relationship was determined between plasma or urine FGF-2, or plasma VEGF levels and PI-88 dose/response. Although no objective responses were observed; 9 of the 15 evaluable patients had stable disease for greater than two cycles of therapy. Conclusion: PI-88 administered at 250 mg/day for 4 days each week for 3 weeks with docetaxel 30 mg/m on days 1, 8 and 15, every 28 days, was determined to be the recommended dose level for phase II evaluation. This combination was well tolerated without severe toxicities or PK interactions