Citations

Estrogen receptors are found on vascular endothelial and smooth muscle cells; their expression is influenced by exposure to the hormone. Estrogen receptors influence non-genomic events, which are rapid in onset and genomic events, which are longer acting responses. Estrogens affect vascular tone indirectly by modulating release of endothelium-derived vasoactive factors and directly by modulating intracellular calcium in vascular smooth muscle cells. Estrogens indirectly affect thrombotic events and inflammation by altering platelet aggregation and leukocyte adherence and migration, respectively. Estrogens also influence production of mitogens which, when released at sites of vascular injury, affect vascular remodeling. Although estrogens initiate vascular responses, genomic sex may influence and/or limit expression of estrogen receptors and therefore actions of sex steroid hormones throughout the vasculature.

Premenopausal women have a significant reduction in coronary artery disease compared to age matched males. Little is known about the mechanism underlying this cardio protective effect of estrogen. Contradictory evidence has been published and our lack of basic understanding of hormone interactions and bioavailability of different estrogens prevents definitive interpretation of these data. We demonstrate gender-specific effects in the proliferation of coronary artery vascular smooth muscle cells obtained from a sexually mature animal model. Vascular smooth muscle cells are an integral component of the atherosclerotic plaque, and inhibition of cell proliferation by estrogen may be one mechanism by which estrogen exerts its cardio protective effect. Various types of estrogen may also have different mechanistic actions on the vascular system. No differences are demonstrated in overall estradiol binding in vascular smooth muscle cells obtained from male or female animals; however, differences in c-jun, c-fos and TIEG gene expression were gender related. Inhibition of vascular smooth muscle cell proliferation may have important implications in the prevention of atherosclerotic disease and these studies may provide evidence for the cardio protective effect of estrogen.

Hormones and purine nucleosides and nucleotides induced cultured bone cells to transform transiently from a spherical to a stellate shape. Cytochalasin B also induced the transformation. The change was blocked by colchicine and vinblastine, but not by lumicolchicine or cycloheximide. This morphologic transformation may provide a dynamic model of hormone action and bone cell modulation in vitro.

Purpose The purpose of this study was to determine whether an algorithm that recommended individualized changes in therapy would help providers to change therapy appropriately and improve glycemic control in their patients. Methods The algorithm recommended specific doses of oral agents and insulin based on a patient's medications and glucose or A1C levels at the time of the visit. The prospective observational study analyzed the effect of the algorithm on treatment decisions and A1C levels in patients with type 2 diabetes. Results The study included 1250 patients seen in pairs of initial and follow-up visits during a 7-month baseline and/or a subsequent 7-month algorithm period. The patients had a mean age of 62 years, body mass index of 33 kg/m2, duration of diabetes of 10 years, were 94% African American and 71% female, and had average initial A1C level of 7.7%. When the algorithm was available, providers were 45% more likely to intensify therapy when indicated (P = .005) and increased therapy by a 20% greater amount (P < .001). A1C level at follow-up was 90% more likely to be <7% in the algorithm group, even after adjusting for differences in age, sex, body mass index, race, duration of diabetes and therapy, glucose, and A1C level at the initial visit (P < .001). Conclusions Use of an algorithm that recommends patient-specific changes in diabetes medications improves both provider behavior and patient A1C levels and should allow quantitative evaluation of provider actions for that provider's patients.

Background and Purpose— Women have poorer outcomes from stroke than men. Women also have risk factors that are unique, including pregnancy and hormone therapy. Hormone therapy for postmenopausal replacement increased the risk of ischemic stroke according to results of the Women’s Health Initiative clinical trials. Based on the current understanding of the mechanisms of action of estrogen, the reasons for this increased risk are uncertain. One method to better understand the reasons for this increased risk is to re-evaluate estrogen’s role in the neurovascular unit, simplistically comprised of the neurons, glia, and endothelial cells, as well as the processes of inflammation, and hemostasis/thrombosis. Besides the role of estrogen there are many gaps of knowledge about issues specific to women and stroke. Summary of Review— A multidisciplinary workshop was held in August 2005 to summarize the current evidence for estrogen and, more generally, stroke in women, and to provide recommendations for future basic, preclinical, and clinical research studies. Conclusions— These studies may ultimately change the approach to stroke prevention and treatment in women.

AbstractPurpose: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule.Experimental Design: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 × institutional upper limit of normal (IULN) and ALT/AST ≤5.0 × IULN; Group 2 (n = 7): total bilirubin 3.1 to 5.0 × IULN and ALT/AST ≤5.0 × IULN; Group 3 (n = 6): total bilirubin ≤1.5 × IULN and ALT/AST 5.1 to 20.0 × IULN; Group 4 (n = 10): total bilirubin 1.5 to 3.0 × IULN and ALT/AST 5.1 to 20.0 × IULN. Irinotecan was given as a 90-minute i.v. infusion weekly for the first 4 weeks in each 6-week cycle at starting doses which escalated from 40 to as much as 75 mg/m2. After the first treatment, doses were adjusted based on individual patient toxicities. Starting doses for patients with hepatic dysfunction were derived from the maximum tolerated doses noted in the four hepatic dysfunction groups.Results: Forty-two patients were treated. Among the most frequent adverse events were neutropenia (41%, grades 3/4), diarrhea (15%, grades 3/4), nausea (10%, grade 3), and vomiting (5%, grades 3/4). Two patients died from drug-induced neutropenic sepsis. Two patients had objective tumor responses (complete response, liver metastases from unknown primary; partial response, colon cancer). Hepatic dysfunction reduced irinotecan clearance while increasing relative exposure to the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). SN-38 exposures in patients receiving doses of 40 to 75 mg/m2 were comparable to exposures in patients with normal liver function treated with a starting dose of 125 mg/m2.Conclusions: Irinotecan starting doses that seem to be safe for hepatically impaired patients treated with the weekly schedule are 60, 50, 60, and 40 mg/m2 for groups 1 to 4, respectively. At these starting doses, exposure to SN-38 and the adverse event profile are similar to that observed in patients with normal liver function and antitumor activity can be observed.

Fluorescence spectroscopic studies are powerful tools for the evaluation of receptor structure and the dynamic changes associated with receptor activation. Here, we have developed two chemically distinct fluorescent probes of the cholecystokinin (CCK) receptor by attaching acrylodan or a nitrobenzoxadiazole moiety to the amino terminus of a partial agonist CCK analogue. These two probes were able to bind to the CCK receptor specifically and with high affinity, and were able to elicit only submaximal intracellular calcium responses typical of partial agonists. The fluorescence characteristics of these probes were compared with those previously reported for structurally-related full agonist and antagonist probes. Like the previous probes, the partial agonist probes exhibited longer fluorescence lifetimes and increased anisotropy when bound to the receptor than when free in solution. The receptor-bound probes were not easily quenched by potassium iodide, suggesting that the fluorophores were protected from the extracellular aqueous milieu. The fluorescence characteristics of the partial agonist probes were quite similar to those of the analogous full agonist probes and quite distinct from the analogous antagonist probes. These data suggest that the partially activated conformational state of this receptor is more closely related to its fully active state than to its inactive state.