Progestin enhances vasoconstrictor responses in postmenopausal women receiving estrogen replacement therapy.

Clinical and experimental evidence suggests that the cardioprotective effect of estrogen replacement is due to effects both on scrum lipids and on blood vessels. Current practice includes the use of a progestin in combination with estrogen if the patient still has her uterus: however, little is known about the effects of combination therapy on vascular reactivity. We therefore studied the effects of estrogen alone and with added progestin on forearm vascular resistance at rest, during reactive hyperemia, and after cold pressor stimulation using plethysmography in six healthy, postmenopausal women. Measurements were made before therapy: after giving conjugated estrogen i.v.; followed by a daily oral dose of 0.625 mg for 21 days; and sequentially after the addition of 10 mg of medroxyprogesterone acetate (MPA) for 10 days. Mean blood pressure did not change significantly. After 21 days of estrogen therapy, forearm blood flow, resting vascular resistance, and resistance after cold pressor stimulation did not change significantly. However, after addition of MPA, resting forearm vascular resistance rose significantly from baseline: 25.7 ±â€Š2.7 U (SE) versus 38.3 ±â€Š2.5 (p = 0.004). In addition, forearm vascular resistance rose to a higher level after cold pressor stimulus during combination therapy (32.3 ±â€Š5.9 vs. 58.4 ±â€Š5.7; p = 0.0057) than after estrogen replacement alone (32.3 ±â€Š5.9 vs. 37.7 ±â€Š5.3; p = NS). We conclude that combination hormone replacement therapy results in higher resting vascular resistance and increased pressor responsiveness than does estrogen replacement therapy alone.

Predictive Relationships Between Students' Evaluation Ratings and Course Satisfaction.

Objective. To assess the reliability and validity of course evaluation data. Methods. A correlation study was conducted using archival data from pharmacy student course evaluations. Bivariate relationships between eight course-rating items and overall rating item and the extent to which course type, level, and grade point average moderated these relationships were analyzed. Results. Significant bivariate relationships were found between the eight course evaluation rating variables and the overall course rating variable. Pharmacy practice course type significantly moderated the relationship between all predictor and criterion variables. Conclusion. Pharmacy school administrators should consider individual course evaluation item ratings when making decisions regarding course offerings or faculty promotion and tenure.

Can senior volunteers deliver reminiscence and creative activity interventions? Results of the legacy intervention family enactment randomized controlled trial.

CONTEXT: Palliative care patients and their family caregivers may have a foreshortened perspective of the time left to live, or the expectation of the patient's death in the near future. Patients and caregivers may report distress in physical, psychological, or existential/spiritual realms. OBJECTIVES: To conduct a randomized controlled trial examining the effectiveness of retired senior volunteers (RSVs) in delivering a reminiscence and creative activity intervention aimed at alleviating palliative care patient and caregiver distress. METHODS: Of the 45 dyads that completed baseline assessments, 28 completed postintervention and 24 completed follow-up assessments. The intervention group received three home visits by RSVs; control group families received three supportive telephone calls by the research staff. Measures included symptom assessment and associated burden, depression, religiousness/spirituality, and meaning in life. RESULTS: Patients in the intervention group reported a significantly greater reduction in frequency of emotional symptoms (P=0.02) and emotional symptom bother (P=0.04) than the control group, as well as improved spiritual functioning. Family caregivers in the intervention group were more likely than control caregivers to endorse items on the Meaning of Life Scale (P=0.02). Only improvement in intervention patients' emotional symptom bother maintained at follow-up after discontinuing RSV contact (P=0.024). CONCLUSION: Delivery of the intervention by RSVs had a positive impact on palliative care patients' emotional symptoms and burden and caregivers' meaning in life. Meaningful prolonged engagement with palliative care patients and caregivers, possibly through alternative modes of treatment delivery such as continued RSV contact, may be necessary for maintenance of therapeutic effects.

BH3 mimetic ABT-737 and a proteasome inhibitor synergistically kill melanomas through Noxa-dependent apoptosis.

The Bcl-2 family is important in modulating sensitivity to anticancer drugs in many cancers, including melanomas. The BH3 mimetic ABT-737 is a potent small molecule inhibitor of the anti-apoptotic proteins Bcl-2/Bcl-X(L)/Bcl-w. In this report, we examined whether ABT-737 is effective in killing melanoma cells in combination with the proteasome inhibitor MG-132, and further evaluated the mechanisms of action. Viability, morphological, and Annexin V apoptosis assays showed that ABT-737 alone exhibited little cytotoxicity, yet it displayed strong synergistic lethality when combined with MG-132. In addition, the detection of Bax/Bak activation indicated that the combination treatment synergistically induced mitochondria-mediated apoptosis. Furthermore, mechanistic analysis revealed that this combination treatment induced expression of the pro-apoptotic protein Noxa- and caspase-dependent degradation of the anti-apoptotic protein, Mcl-1. Finally, siRNA-mediated inhibition of Mcl-1 expression significantly increased sensitivity to ABT-737 in these cells, and knocking down Noxa expression protected the cells from cytotoxicity induced by the combination treatment. These findings demonstrate that ABT-737 combined with MG-132 synergistically induced Noxa-dependent mitochondrial-mediated apoptosis. In summary, this study indicates promising therapeutic potential of targeting anti-apoptotic Bcl-2 family members in treating melanoma, and it validates rational molecular approaches that target anti-apoptotic defenses when developing cancer treatments.

Hyperthermia induces endoplasmic reticulum-mediated apoptosis in melanoma and non-melanoma skin cancer cells.

Hyperthermia has been revived as a promising approach for cancer treatment. To understand the underlying mechanisms of hyperthermic killing of cancer cells, we examined the cytotoxic effects of hyperthermia on various skin cancer cell lines using cell viability, morphological analyses, and caspase activation assays. Hyperthermia induced cytotoxicity in a time- and temperature-dependent manner. At middle dose/time combinations, heat-induced apoptosis, whereas at higher doses, necrosis was the mechanism of cell death. To investigate the mechanisms of hyperthermia-induced apoptosis, we examined the activation of extrinsic (Caspase 8) and intrinsic (Caspase 9) apoptotic pathways. Hyperthermia did not activate Caspases 8 or 9, but did activate Caspase 3/7, suggesting a non-conventional apoptotic pathway. Last, analysis of Grp78 expression and Caspase 12 or 4 activation indicated that hyperthermia induced endoplasmic reticulum-mediated apoptosis. Thus, hyperthermia induced apoptosis in two types of skin cancer cells through endoplasmic reticulum-mediated apoptosis and not through the classical intrinsic or extrinsic apoptosis pathways. Hyperthermia may be a promising treatment for basal cell carcinoma and melanoma, bypassing the antiapoptotic defenses concentrated in the intrinsic and extrinsic apoptosis pathways. These results also raise the possibility that heat may be combined with other approaches for induction of apoptosis to achieve synergistic killing of skin cancers.

The prelamin A pre-peptide induces cardiac and skeletal myoblast differentiation.

Prelamin A processing is unique amongst mammalian proteins and results in the production of a farnesylated and carboxymethylated peptide. We examined the effect of pathogenic LMNA mutations on prelamin A processing, and of the covalently modified peptide on cardiac and skeletal myoblast differentiation. Here we report a mutation associated with dilated cardiomyopathy prevents prelamin A peptide production. In addition, topical application of the covalently modified C-terminal peptide to proliferating skeletal and cardiac myoblasts induced myotube and striated tissue formation, respectively. Western blot analysis revealed that skeletal and cardiac myoblasts are the first cell lines examined to contain unprocessed prelamin A, and immunostaining of peptide-treated cells revealed a previously unidentified role for prelamin A in cytoskeleton formation and intercellular organization. These results demonstrate a direct role for prelamin A in myoblast differentiation and indicate the prelamin A peptide may have therapeutic potential.