Conversion of cell-survival activity of Akt into apoptotic death of cancer cells by two mutations on the BIM BH3 domain.

Survival and proliferation of cancer cells are often associated with hyperactivity of the serine/threonine kinase, Akt. Herein, we show that prosurvival activity of Akt can be converted into prodeath activity by embedding an Akt recognition sequence in the apoptogenic BH3 domain of human BIM. The recognition sequence was created by introducing two mutations, I155R and E158S, into the core region of the BIM BH3 domain. Although a 21-mer BIM BH3 peptide containing these two mutations bound weakly to BCL-XL and BCL-2, this peptide with phosphorylation of Ser158 bound to these proteins with a dissociation constant of <10 nM. The crystal structure of the phosphorylated peptide bound to BCL-XL revealed that the phospho-Ser158 makes favorable interactions with two BCL-XL residues, which cannot be formed with unphosphorylated Ser158. Remarkably, the designed peptide showed a cytotoxic effect on PTEN-null PC3 tumor cells whose Akt activity is aberrantly high. The cell-killing activity disappeared when the cellular Akt activity was lowered by ectopic PTEN expression. Thus, these results lay a foundation for developing a peptide or protein agent that is dormant in normal cells but is transformed into a potent apoptogenic molecule upon phosphorylation by hyperactivity of Akt in cancer cells.

Influence of stereopsis and abnormal binocular vision on ocular and systemic discomfort while watching 3D television.

PURPOSE: To evaluate the degree of three-dimensional (3D) perception and ocular and systemic discomfort in patients with abnormal binocular vision (ABV), and their relationship to stereoacuity while watching a 3D television (TV). METHODS: Patients with strabismus, amblyopia, or anisometropia older than 9 years were recruited for the ABV group (98 subjects). Normal volunteers were enrolled in the control group (32 subjects). Best-corrected visual acuity, refractive errors, angle of strabismus, and stereoacuity were measured. After watching 3D TV for 20 min, a survey was conducted to evaluate the degree of 3D perception, and ocular and systemic discomfort while watching 3D TV. RESULTS: One hundred and thirty subjects were enrolled in this study. The ABV group included 49 patients with strabismus, 22 with amblyopia, and 27 with anisometropia. The ABV group showed worse stereoacuity at near and distant fixation (P<0.001). Ocular and systemic discomfort was, however, not different between the two groups. Fifty-three subjects in the ABV group and all subjects in the control group showed good stereopsis (60 s of arc or better at near), and they reported more dizziness, headache, eye fatigue, and pain (P<0.05) than the other 45 subjects with decreased stereopsis. The subjects with good stereopsis in the ABV group felt more eye fatigue than those in the control group (P=0.031). The subjects with decreased stereopsis showed more difficulty with 3D perception (P<0.001). CONCLUSIONS: The subjects with abnormal stereopsis showed decreased 3D perception while watching 3D TV. However, ocular and systemic discomfort was more closely related to better stereopsis.

Effectiveness of raloxifene on bone mineral density and serum lipid levels in post-menopausal women with low BMD after discontinuation of hormone replacement therapy.

OBJECTIVE: To evaluate the effect of raloxifene on bone mineral density (BMD) and serum lipid levels in post-menopausal women who had discontinued hormone replacement therapy (HRT). METHODS: Thirty-four post-menopausal women with low BMD who had taken 60 mg of raloxifene daily for 12 months after discontinuing HRT were evaluated retrospectively. Information about their demographics, fracture history, BMD, lipid profiles and adverse events were collected from medical records and intranet database. The outcome measures were changes in the spine (L2-L4) and femur BMD, serum lipid concentrations, fracture rate and tolerability. RESULTS: The post-menopausal women had a significant increase in their spine (L2-L4) and femur BMD from their baseline BMD [spine, 2.9 +/- 4.6% (P < 0.001); femur, 3.0 +/- 6.6% (P = 0.01)]. Serum low-density lipoprotein (LDL) cholesterol was significantly reduced by 22.6% below baseline after 12 months (P = 0.007). No fractures were observed during therapy. Raloxifene was well tolerated. The most common adverse event was hot flash, which was generally mild. CONCLUSIONS: Raloxifene increases BMD at important skeletal sites, and lowers LDL cholesterol with tolerable adverse events.

Thermosoftening treatment of the nasotracheal tube before intubation can reduce epistaxis and nasal damage.

UNLABELLED: We evaluated whether a thermosoftening treatment with warm saline of a nasotracheal preformed tube can improve navigability through the nasal passageways and reduce epistaxis and nasal damage. A total of 150 patients were randomly allocated to three groups: Group I (untreated tube group, n = 50), Group II (35 degrees C treated tube group, n = 50), and Group III (45 degrees C treated tube group, n = 50). In Groups II and III, the tubes were softened at 35 +/- 2 degrees C and 45 +/- 2 degrees C with warm saline, respectively. In Group I the tube was prepared at room temperature (25 +/- 2 degrees C). The incidence of epistaxis and nasal damage in Groups II and III was significantly less than that of Group I (P: < 0.05). Despite the more frequent incidence of smooth passage in Group III, no statistical difference was found among the groups. Logistic regression analysis also confirmed that epistaxis was more likely to be reduced when the tube had been thermosoftened (odds ratio = 1.46, 95% confidence interval = 1.02, 2.11). We conclude that simple thermosoftening treatment of the nasotracheal tube with warm saline helps to reduce epistaxis and nasal damage. IMPLICATIONS: Thermosoftening treatment of a nasotracheal tube with warm saline before intubation can effectively reduce epistaxis and nasal damage. This technique is safe, easy, and suitable for all types of tubes and does not require additional implements.

Paroxysmal tachycardia and hypertension with or without ventricular fibrillation during laparoscopic adrenalectomy: two case reports in patients with noncatecholamine-secreting adrenocortical adenomas.

We present two cases of sudden unanticipated cardiovascular complications in patients with noncatecholamine-secreting adrenocortical adenomas during laparoscopic adrenalectomy. In the first case, the patient developed paroxysmal tachycardia and hypertension followed by ventricular fibrillation shortly after clipping of the adrenal vein. In the second case, the patient suffered hypertension and bigeminy during manipulation of the adrenal gland just around the adrenal vein. Awareness of such complications during either conventional or laparoscopic adrenalectomy is important even if the operation is performed in a patient with an apparently noncatecholamine-secreting adrenocortical adenoma.