K-ras is essential for the development of the mouse embryo.

ras genes encode members of the small GTP-binding proteins. Ras protein in highly conserved in various species from yeast to humans and plays a key role in signal transduction. Ras is related to cell proliferation and differentiation. While, in addition, mutations in the ras genes are implicated in a variety of tumors. However, the physiological functions and specific roles of each ras gene, H-ras, K-ras and N-ras, are still not fully understood. To clarify the role of the K-Ras in vivo, we generated K-ras mutant mice by gene targeting. In contrast to the findings that H-Ras-deficient mice and N-Ras-deficient mice are born and grow normally, the K-Ras-deficient embryos die progressively between embryonic day 12.5 and term. At embryonic day 15.5, their ventricular walls are extremely thin. Besides, at embryonic day 11.5, they demonstrate increased cell death of motoneurons in the medulla and the cervical spinal cord. Our results thus indicate K-Ras to be essential for normal development in mice and residual Ras composed of H-Ras and N-Ras cannot compensate for the loss of K-Ras function in the mutant mice.

Combination of intermittent cyclical etidronate and hormone replacement therapy for postmenopausal non-responders to estrogen.

OBJECTIVE: To investigate whether the addition of etidronate to conventional hormone replacement therapy (HRT) is effective against bone loss in postmenopausal women whose lumbar bone mineral density (BMD) cannot be maintained by HRT. DESIGN: Single-centre, placebo-controlled randomised study. PATIENTS: Among 1138 patients on conventional HRT, 30 postmenopausal women were considered to be non-responders to estrogen, since their BMDs continued to decrease by more than 1% per year in spite of the HRT. The BMD of all the included patients was less than 70% of the young adult mean. INTERVENTIONS: PATIENTS were randomly divided into two groups: group A (n = 15) treated with conventional HRT and placebo, and group B (n = 15) treated with combined intermittent cyclical etidronate therapy (ICT-etidronate) and conventional HRT. Measurement of lumbar BMD was performed at baseline and at 6 and 12 months using dual energy x-ray absorptiometry (DEXA). Biochemical markers of bone resorption and formation were also measured during the visits. RESULTS: ICT-etidronate combined with HRT increased the lumbar BMD at 6 months (p < 0.05) and 12 months (p < 0.05) compared with baseline. Lumbar BMDs of the combined treatment group were significantly increased at 12 months (p < 0.05) compared with the HRT-only group. Bone resorption was suppressed by combined therapy at 6 months (p < 0.05). Bone formation did not change in either group. CONCLUSIONS: ICT-etidronate combined with HRT seems to be effective in preventing loss of BMD in postmenopausal women who do not respond to estrogen, and may be useful in preventing fractures in this group.

Changes in coagulation factors and fibrinolytic components of postmenopausal women receiving continuous hormone replacement therapy.

OBJECTIVE: The effect of hormone replacement therapy (HRT) on coagulation factors and fibrinolytic components in postmenopausal women was studied for 6 months to elucidate whether continuous HRT has an influence on thrombosis. METHODS: One hundred and thirty-four postmenopausal women were divided into three groups according to treatment: 39 women who had undergone hysterectomy and oophorectomy received 0.625 mg/day of conjugated equine estrogen (CEE) continuously (CEE therapy), 48 postmenopausal women received both 0.625 mg/day of CEE and 2.5 mg/day of medroxyprogesterone acetate (MPA) continuously (CEE/MPA therapy) and 47 postmenopausal women received placebo as control. The following variables were measured before treatment as well as after 1, 3 and 6 months of treatment: factor VII activity, protein C activity, fibrinogen level, antithrombin III activity, plasminogen activator inhibitor-1 (PAI-1) level and the plasma concentration of tissue-type plasminogen activator (t-PA). RESULTS: After 1 month of treatment, protein C activity increased by 9.6% and 11.4% of the initial value (p < 0.05), fibrinogen level decreased by 7.8% and 6.1% of the initial value (p < 0.05) and PAI-1 decreased by 19.4% and 14.3% of the initial value (p < 0.05) in the CEE therapy group and the CEE/MPA therapy group, respectively. Factor VII activity increased by 10.1% of the initial value (p < 0.05) in the CEE therapy group only. Antithrombin III and t-PA levels did not change throughout either treatment. CONCLUSION: Except for an increase in factor VII activity in the case of continuous CEE therapy, continuous HRT had no unfavorable effects on either coagulation factors or fibrinolytic components.