T-box 3 negatively regulates osteoblast differentiation by inhibiting expression of osterix and runx2.

T-box (Tbx)3, a known transcriptional repressor, is a member of a family of transcription factors, which contain a highly homologous DNA binding domain known as the Tbx domain. Based on the knowledge that mutation of the Tbx3 gene results in limb malformation, Tbx3 regulates osteoblast proliferation and its expression increases during osteoblast differentiation, we predicted that Tbx3 is an important regulator of osteoblast cell functions. In this study, we evaluated the consequence of transgenic overexpression of Tbx3 on osteoblast differentiation. Retroviral overexpression increased Tbx3 expression >100-fold at the mRNA and protein level. Overexpression of Tbx3 blocked mineralized nodule formation (28 +/- 8 vs. 7 +/- 1%) in MC3T3-E1 cells. In support of these data, alkaline phosphatase (ALP) activity was reduced 33-70% (P < 0.05) in both MC3T3-E1 cells and primary calvaria osteoblasts overexpressing Tbx3. In contrast, Tbx3 overexpression did not alter ALP activity in bone marrow stromal cells. Tbx3 overexpression blocked the increase in expression of key osteoblast marker genes, ALP, bone sialoprotein, and osteocalcin that occurs during normal osteoblast differentiation, but had little or no effect on expression of proliferation genes p53 and Myc. In addition, Tbx3 overexpression abolished increased osterix and runx2 expression observed during normal osteoblast differentiation, but the change in Msx1 and Msx2 expression over time was similar between control and Tbx3 overexpressing cells. Interestingly, osterix and runx2, but not Msx1 and Msx2, contain Tbx binding site in the regulatory region. Based on these data and our previous findings, we conclude that Tbx3 promotes proliferation and suppresses differentiation of osteoblasts and may be involved in regulating expression of key transcription factors involved in osteoblast differentiation.

Clinical pharmacokinetics of toremifene.

Toremifene is a chlorinated triphenylethylene derivative of tamoxifen approved for use in the treatment of patients with metastatic breast cancer. Toremifene is well tolerated in patients, and common adverse effects of this drug include vasomotor symptoms such as hot flashes and vaginal discharge. This compound is administered to patients orally at a dose of 60 mg/day, although alternative methods of administration have been investigated. Oral bioavailability is estimated to be approximately 100%. At steady state, toremifene and its metabolites are highly protein bound (>95%). Toremifene is metabolised in the liver by cytochrome P450 enzymes, and it is eliminated primarily in the faeces following enterohepatic circulation. The half-life of toremifene is approximately 5 days, and steady state is reached by 6 weeks depending on the dose given. The pharmacokinetics of toremifene have been shown to be altered by certain liver conditions, but age and kidney function do not appear to be as significant.

Abnormal coagulation and fibrinolysis in eclampsia. A clinical and laboratory correlation study.

This study evaluated the existence of abnormally increased coagulation and fibrinolysis in 33 severely toxemic and eclamptic women by means of a combined hemotologic profile with clinical and morphologic correlations. The dominant findings were: different degrees of thrombocytopenia, abnormal levels of blood fibrinogen, prolonged thrombin time, and positive protamine sulfate test. Altered activated partial thromboplastin time and positive ethanol gelation test were slightly less frequent, and only few cases showed prolonged prothrombin time or early lysis of euglobulins. These abnormalities seemed to be more numerous and more pronounced in the worst cases of the series and their severity seemed to be associated with the age of the patient and the presence of previous underlying disease. These variously handicapped pregnant women exhibited worse hematologic hematologic abnormalities, and provided most of the fatal cases in the series. Finally, the main findings were discussed and commented upon.

Factors that influence maternal mortality in eclampsia.

Three hundred sixty-five cases of eclampsia, including 49 women who died, were analyzed in order to determine factors which led to death. The age of the patient was clearly the most important factor. Older women tended to have coexisting renal and vascular disease and also manifested more hematologic abnormalities, in particular, disseminated intravascular coagulation. Other important factors leading to death were twin pregnancies, delay in hospitalization, failure to terminate the pregnancy, and the physician's unawareness of the severity of the mother's disease. The mortality after cesarean section was the same as in women delivered vaginally.