Relationship between physical activity and stiff or painful joints in mid-aged women and older women: a 3-year prospective study

This prospective study examined the association between physical activity and the incidence of self-reported stiff or painful joints (SPJ) among mid-age women and older women over a 3-year period. Data were collected from cohorts of mid-age (48–55 years at Time 1; n = 4,780) and older women (72–79 years at Time 1; n = 3,970) who completed mailed surveys 3 years apart for the Australian Longitudinal Study on Women's Health. Physical activity was measured with the Active Australia questions and categorized based on metabolic equivalent value minutes per week: none (<40 MET.min/week); very low (40 to <300 MET.min/week); low (300 to <600 MET.min/week); moderate (600 to <1,200 MET.min/week); and high (1,200+ MET.min/week). Cohort-specific logistic regression models were used to examine the association between physical activity at Time 1 and SPJ 'sometimes or often' and separately 'often' at Time 2. Respondents reporting SPJ 'sometimes or often' at Time 1 were excluded from analysis. In univariate models, the odds of reporting SPJ 'sometimes or often' were lower for mid-age respondents reporting low (odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.63–0.94), moderate (OR = 0.82, 95% CI = 0.68–0.99), and high (OR = 0.75, 95% CI = 0.62–0.90) physical activity levels and for older respondents who were moderately (OR = 0.80, 95% CI = 0.65–0.98) or highly active (OR = 0.83, 95% CI = 0.69–0.99) than for those who were sedentary. After adjustment for confounders, these associations were no longer statistically significant. The odds of reporting SPJ 'often' were lower for mid-age respondents who were moderately active (OR = 0.71, 95% CI = 0.52–0.97) than for sedentary respondents in univariate but not adjusted models. Older women in the low (OR = 0.72, 95% CI = 0.55–0.96), moderate (OR = 0.54, 95% CI = 0.39–0.76), and high (OR = 0.61, 95% CI = 0.46–0.82) physical activity categories had lower odds of reporting SPJ 'often' at Time 2 than their sedentary counterparts, even after adjustment for confounders. These results are the first to show a dose–response relationship between physical activity and arthritis symptoms in older women. They suggest that advice for older women not currently experiencing SPJ should routinely include counseling on the importance of physical activity for preventing the onset of these symptoms.

Active Notch1 confers a transformed phenotype to primary human melanocytes

The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf, yet clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions showed that Notch activity is significantly higher in melanomas than their nontransformed counterparts. The use of a constitutively active, truncated Notch transgene construct (N(IC)) was exploited to determine if Notch activation is a "driving" event in melanocytic transformation or instead a "passenger" event associated with melanoma progression. N(IC)-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma, such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. N(IC)-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth, suggesting that Notch alone is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene. This new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease.

Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats

Abstract RATIONALE: Previous studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking. MATERIALS AND METHODS: Rats were trained to self-administer either 10% ethanol or 5% sucrose (30 min/day). The orexin-1 receptor antagonist SB334867 (0, 5, 10, 15, 20 mg/kg, i.p.) was administered 30 min before the operant self-administration sessions. After these experiments, the operant self-administration behaviors were extinguished in both the ethanol and sucrose-trained rats. Upon reaching extinction criteria, SB334867 (0, 5, 10 mg/kg, i.p.) was administered 30 min before yohimbine (0 or 2 mg/kg, i.p.). In a separate experiment, the effect of SB334867 (0, 15, or 20 mg/kg, i.p.) on general locomotor activity was determined using the open-field test. RESULTS: The orexin-1 receptor antagonist, SB334867 (10, 15 and 20 mg/kg) decreased operant self-administration of 10% ethanol but not 5% sucrose self-administration. Furthermore, SB334867 (5 and 10 mg/kg) significantly decreased yohimbine-induced reinstatement of both ethanol and sucrose seeking. SB334867 did not significantly affect locomotor activity measured using the open-field test. CONCLUSIONS: The results suggest that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.