Physical and mental health predicts better adherence to exercise intervention in older women: A post-hoc analysis.

Background: Adherence to exercise is crucial for promoting health and maintaining functioning. Aims: To investigate predictors of adherence to exercise in the initially free supervised fall prevention RCT and its low-cost, self-sustained continuation among elderly women. Methods: In the 2-year Kuopio Fall Prevention Study RCT, 457 women (aged 71-84) were offered a free initial 6-month supervised weekly training program (gym, Tai Chi) in the municipal facilities. Women's adherence during this period was categorized into high (≥80 %) and low (<80 %). In the next six months, their free access to the premises continued without supervision. For the second year, low-cost access was offered with unsupervised independent training in these facilities. The second-year adherence was based on purchasing(yes/no) a gym card to continue exercising. Information on baseline health, functioning, and lifestyle was obtained by mailed questionnaires and physical tests. Results: For the first six months, over 60 % of the women had high adherence. Only 26 % continued into the second year. For both follow-up years, active training history was related to better adherence. Initial predictors were related to mental health i.e. having less often fear of falls limiting one's mobility, ability to cope with external, not internal hostility, and being in a loving relationship. In the second year, predictors were related to younger age, having less frequent fear of falls, better functional capacity i.e. better strengths (grip and leg extension) and faster Timed "Up and Go" -test. Conclusion: Better mental and physical health, better functional capacity and active training background were associated with higher adherence to exercise intervention in older women.

Long-term life satisfaction in ageing women with work disability due to mental and musculoskeletal disorders.

BACKGROUND: Mental disorders (MDs) and musculoskeletal disorders (MSDs) are the major causes of global disability and increase in prevalence with age. AIMS: To support healthy ageing, we studied how work disability due to MDs or MSDs is related to life satisfaction (LS) cross-sectionally and in 5- and 10-year follow-ups among ageing women. METHODS: In the population-based OSTPRE cohort (women aged 58-67 in 1999), data on lifetime permanent work disability pensions (DPs) due to 'MDs only' (n = 337), 'MSDs only' (n = 942) and 'MDs + MSDs' (n = 212) and 'no DP' (n = 6322) until 1999 was obtained from the Finnish national register. The OSTPRE postal enquiry included a four-item life satisfaction (LS) scale (range 4-20: satisfied 4-6, intermediate 7-11, dissatisfied 12-20) at 5-year intervals, in 1999-2004 (n = 6548) and in 1999-2009 (n = 5562). RESULTS: In 1999, the risks of belonging to the dissatisfied LS group (score 12-20) vs. the satisfied group (score 4-6) were higher in 'MDs only' (OR = 4.30; 95%CI 2.95-6.28), 'MSDs only' (OR = 2.69; 2.12-3.40) and 'MDs + MSDs' (OR = 2.72; 1.77-4.16) groups than in the 'no DP' group. In the follow-ups, these risks were OR5yr = 5.59 (3.54-8.84) and OR10yr = 4.94 (2.80-8.73) for 'MDs only', OR5yr = 3.36 (2.58-4.37) and OR10yr = 3.18 (2.40-4.21) for 'MSDs only', and OR5yr = 4.70 (2.75-8.05) and OR10yr = 6.84 (3.53-13.27) for 'MDs + MSDs' (all: p ≤ 0.001). Adjusting for baseline LS did not change the pattern (all p ≤ 0.001). CONCLUSION: Work disability due to MDs and MSDs undermines healthy ageing among women via life dissatisfaction.

Comorbidity of mental and musculoskeletal disorders in ageing women: A data linkage study using national registries.

BACKGROUND: Mental disorders (MDs) and musculoskeletal disorders (MSDs) are the main causes of disability. Yet, their comorbidity has not received the deserved attention. OBJECTIVE: To investigate the extent of the comorbidity between MDs and MSDs in ageing women using national registries on prescription medications and work disability pensions (DPs). METHODS: The study included 7,809 Finnish women, born during 1932-41, from the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) cohort, established in 1989. Lifetime permanent DPs due to: 1) 'MDs only' (n = 359), 2) 'MSDs only' (n = 954), 3) 'MDs + MSDs' (n = 227), were recorded till 2003. The reference group was 'no DP' (n = 6,269). Data from the OSTPRE questionnaires was obtained in 1994. Use of medications was recorded in 1995 and 2003. The use of musculoskeletal or psychotropic medications by women having a DP or medication due to MD, or MSD diagnoses, respectively, was considered as an indicator of comorbidity. RESULTS: In 1995, all DP groups had used psychotropic and musculoskeletal medications more often than the referents. Use of musculoskeletal medications was associated with a higher use of psychotropic medications, and vice versa (OR=2.45; 95% CI 2.17-2.77), compared with non-use. The 'MSDs only' group was more likely to use psychotropic (OR=1.79; 95% CI 1.50-2.12), and the 'MDs only' group musculoskeletal medications (OR=1.38; 95% CI 1.09-1.74), compared with those without DPs. The proportions of medication users were similar in 1995 and 2003; however, the amounts used increased. CONCLUSIONS: There was strong evidence for comorbidity between MDs and MSDs in ageing women. Further research concerning their longitudinal relationships is warranted.

Obesity is associated with early hip fracture risk in postmenopausal women: a 25-year follow-up.

Association of body mass index and hip fracture has been controversial. In this study, women with lowest and highest body weight had the highest fracture incidence. A 25-year follow-up indicated that obesity associates with early hip fracture risk and suggested increasing trend in normal-weight women at a later stage. INTRODUCTION: Obesity is a pandemic health issue. Its association with hip fracture risk remains controversial. We studied the long-term relationship of body mass index and hip fracture incidence in postmenopausal women. METHODS: The cohort of 12,715 Finnish women born in 1932-1941 was followed for 25 years, covering ages from 58 up to 83. Fractures and deaths were obtained from national registries. Women were investigated in deciles of BMI as well as in WHO weight categories (normal, overweight, or obese). The follow-up analysis was carried out in two age strata as "early" (58-70 years) and "late" (> 70 years). Body weight information was updated accordingly. Femoral neck BMD was recorded for a subsample (n = 3163). Altogether, 427 hip fractures were observed. RESULTS: A higher risk of early hip fracture was observed in obese and normal-weight compared with overweight women with hazard ratios (HRs) of 2.3 ((95% CI) 1.4-3.7) and 2.0 (1.3-3.1) while no difference was observed in late hip fracture risk between the three WHO categories (log rank p = 0.14). All-cause mortality during the follow-up was 19.3%. Compared with normal weight women, the obese women had a higher risk of death with an HR of 1.6 (1.4-1.8) and higher baseline BMD (p < 0.001). Faster bone loss was observed in the obese compared with other women (p < 0.001). CONCLUSION: Obesity associates with earlier hip fracture and higher postfracture mortality. The obese women with low BMD have clearly the highest risk of hip fracture. This combination increases hip fracture risk more than either of the factors alone. After 75 years of age, risk appears to increase more in normal weight women, but this trend is in need of further confirmation.

A fall in the previous 12 months predicts fracture in the subsequent 5 years in postmenopausal women.

PURPOSE: The purpose of this study was to evaluate if a history of falls predicts future postmenopausal fractures and if this prediction variesaccording to frequency, mechanism, and severity of falls and site of fractures. METHODS: This study used data from OSTPRE prospective cohort. Total study population consisted of 8744 postmenopausal women (mean age 62.2 years) who responded to postal enquiry in 1999 (baseline) and in 2004 (follow-up). RESULTS: Women were classified by frequency (non/occasional/frequent fallers), mechanism (slip/nonslip), and severity (injurious/ non-injurious) of falls and fractures by site (major osteoporotic/other). A total of 1693 (19.4%) women reported a fall during the preceding 12 months in 1999; 812 a slip fall, 654 a nonslip, 379 an injurious fall, and 1308 a non-injurious fall. A total of 811 women (9.3%) sustained a fracture during the 5-year follow-up period (1999-2004); 431 major osteoporotic fractures and 380 other fractures. Compared with non-fallers, earlier falls predicted subsequent fractures with an OR of 1.41 (95% CI 1.19-1.67, p ≤ 0.001), 1.43 (95% CI 1.14-1.80, p = 0.002) for earlier slip falls, and 1.35 (95% CI 1.04-1.74, p = 0.02) for earlier nonslip falls. Earlier injurious falls predicted future fractures (OR = 1.64, 95% CI 1.21-2.23, p ≤ 0.01), especially other fractures (OR = 1.86, 95% CI 1.24-2.80, p ≤ 0.01), but not major osteoporotic fractures (OR = 1.37, 95% CI 0.89-2.10, p = 0.151). Fracture risk predictions for earlier non-injurious falls was OR = 1.36, 95% CI 1.12-1.64, p = 0.002. These risk patterns remain same after adjustments. CONCLUSION: History of falls (especially injurious falls) predicts subsequent fractures (mainly other fractures compared with major osteoporotic fractures) inpostmenopausal women. We aimed to investigate if history of falls (frequency, mechanism, and severity) is a predictor of future fractures in postmenopausal women. Our results indicate that history of falls (especially injurious falls) appeared to be an indicator for subsequent fracture overall. Earlier injurious falls were stronger predictors for future other fractures than for typical major osteoporotic fractures.

Role of musculoskeletal disorders in falls of postmenopausal women.

We aimed to investigate the role of musculoskeletal disorders (MSDs) as risk factors for falls among postmenopausal women. Our results indicate that MSDs are common and are associated with increased falling risk, especially nonslip falls. Excess number of falls due to MSDs is greater than that due to any other disease class. PURPOSE: Falls are a major public health problem worldwide. The aim of the study was to investigate the role of MSDs as risk factors for falls among postmenopausal women. METHODS: This cohort study utilized data from a population-based, prospective cohort study (OSTPRE). The study population consisted of 8656 women aged 57-66 years (in 1999) living in Kuopio Province, Eastern Finland, who responded to postal enquiries in 1999 and 2004. Information on MSDs and other morbidities was obtained from the 1999 enquiry and information on falls from the 2004 enquiry. Women were classified as fallers or non-fallers according to their falling events in the preceding 12 months. The fallers were further divided into women with slip and nonslip falls. RESULTS: Of the study sample, 53.3% reported a MSD and 39.2% reported a fall during the preceding 12 months. MSDs predicted falls (OR = 1.38; 95% CI 1.26-1.50) and the association was stronger for nonslip (OR = 1.56; 95% CI 1.39-1.75) than slip falls (OR 1.22; 95% CI 1.08-1.38) compared to the women without MSDs. The risk of falls increased with increasing number (1, 2, ≥ 3) of MSDs: 1.25 (95%CI 1.13-1.38), 1.48 (95%CI 1.30-1.68), and 1.92 (95%CI 1.60-2.31), respectively. After adjustments, the risk of falling related to MSDs reduced by about 5% (adjusted p < 0.001). The population attributable fraction of falls due to MSDs was 10.3% of all falls, greater than that due to any other disease class. CONCLUSION: MSDs are common and an important risk factor for falls and especially nonslip falls among postmenopausal women. The number of excess falls due to MSDs in this population group is greater than that due to any other disease class.

Long-term effects of functional impairment on fracture risk and mortality in postmenopausal women.

Our findings imply that simple functional tests can predict both hip fracture risk and excess mortality in postmenopausal women. Since the tests characterize general functional capacity (one-legged stance, squatting down, and grip strength), these simple measures should have clinical utility in the assessment of women at risk of falls and fragility fracture. INTRODUCTION: Functional impairment is associated with the risk of fall, which is the leading cause of hip fracture. We aimed to determine how clinical assessments of functional impairment predict long-term hip fracture and mortality. METHODS: A population-based prospective cohort involved 2815 Caucasian women with the average baseline age of 59.1 years. The mean follow-up time in 1994-2014 was 18.3 years. Three functional tests and their combinations assessed at baseline were treated as dichotomous risk factors: (1) inability to squat down and touch the floor (SQ), (2) inability to stand on one leg for 10 s (SOL), and (3) having grip strength (GS) within the lowest quartile (≤ 58 kPa, mean 45.6 kPa). Bone mineral density (BMD) at the proximal femur was measured by DXA. Fractures and deaths were verified from registries. Hazard ratios were determined by using Cox proportional models. Age, body mass index (BMI), and BMD were included as covariates for fracture risk estimates. Age, BMI, and smoking were used for mortality. RESULTS: Altogether, 650 (23.1%) women had 718 follow-up fractures, including 86 hip fractures. The mortality during the follow-up was 16.8% (n = 473). Half of the women (56.8%, n = 1600) had none of the impairments and were regarded as the referent group. Overall, women with any of the three impairments (43.2%, n = 1215) had higher risks of any fracture, hip fracture, and death, with hazard ratios (HR) of 1.3 ((95% CI) 1.0-1.5, p < 0.01), 2.4 (1.5-3.4, p < 0.001), and 1.5 (1.3-1.8, p < 0.001), respectively. The strongest single predictor for hip fracture was failing to achieve a one-leg stand for 10 s (prevalence 7.1%, n = 200), followed by inability to squat down (27.0%, n = 759) and weak grip strength (24.4%, n = 688), with their respective HRs of 4.3 (2.3-8.0, p < 0.001), 3.1 (2.0-5.0, p < 0.001), and 2.0 (1.2-3.4, p < 0.001). In addition, age, lower BMD, BMI, and smoking were significant covariates. CONCLUSIONS: These findings suggest that functional tests provide long-term prediction of fracture and death in postmenopausal women. Whether reversal of these impairments is associated with a reduction in adverse outcomes is an area for future trials.

Relationship of body anthropometric measures with skeletal muscle mass and strength in a reference cohort of young Finnish women.

OBJECTIVES: 1) To study if limb length explains variability in appendicular and total muscle mass better than height and 2) if muscle mass adjusted for limb length rather than height correlates better with grip and knee extension strength. METHODS: 400 healthy women aged 20-40 were recruited as a reference population. Body composition, limb length, grip strength and knee extension strength were measured. New relative muscle mass indexes were computed by adjusting upper limb muscle mass for upper limb length (ULRSMI) and lower limb muscle mass for lower limb length (LLRSMI). RESULTS: Height correlated strongest with all muscle mass measures. Height had the highest R² values for predicting variability in appendicular skeletal muscle mass (0.33), upper limb skeletal muscle mass (0.20), lower limb skeletal muscle mass (0.34) and total skeletal muscle mass (0.36). Correlation of relative skeletal muscle mass index (RSMI) with grip and knee extension strength (r=0.47 and 0.43) was higher when compared with correlation of ULRSMI and LLRSMI with these measures. CONCLUSION: Compared to limb length, height correlates better with regional and total muscle mass. Muscle mass adjusted for height correlates better with grip strength and knee strength when compared with muscle mass adjusted for limb length.

Inclusion of Regional Body Composition Parameters Improves Bone Mineral Density Cross-Calibration Between GE Lunar Prodigy and iDXA Densitometers.

Since 1989, the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE, n = 14220) Study has followed long-term changes of bone mineral density (BMD) and body composition in women with GE Lunar devices. During the course of OSTPRE, the dual-energy X-ray absorptiometry device had to be replaced by a newer model. Then, it was essential to determine whether systematic measurement differences in BMD and body composition will occur. As a part of the OSTPRE study, BMD was measured in 54 women, whereas body composition was determined in 55 women, aged 27-71, by using both the GE Healthcare Lunar Prodigy and iDXA narrow-angle fan beam densitometers during the same visit. The total body fat mass (FM) and lean body mass (LBM) results of these scanners showed a high linear correlation (r = 0.981-0.994, p < 0.0001). However, the mean total body FM and LBM values measured by iDXA were on average 2.3% (0.5 kg, 95% confidence interval: 0.3-0.7 kg) higher and 0.8% (0.3 kg, 95% confidence interval: 0.1-0.6 kg) lower, respectively, than those measured by Prodigy. Inclusion of local soft tissue measurements (total body LBM, legs/android FM) improved the agreement of total body, total hip, and lumbar spine BMD values between the devices but not femoral neck BMD agreement. Equations, based on linear regression analyses, were derived to minimize differences between the instruments. Then, the differences in BMD and body composition measurements were negligible between Prodigy and iDXA. Using correction equations enables an objective comparison of longitudinal BMD and body composition measurements.

Cross-Calibration of GE Healthcare Lunar Prodigy and iDXA Dual-Energy X-Ray Densitometers for Bone Mineral Measurements.

In long-term prospective studies, dual-energy X-ray absorptiometry (DXA) devices need to be inevitably changed. It is essential to assess whether systematic differences will exist between measurements with the new and old device. A group of female volunteers (21-72 years) underwent anteroposterior lumbar spine L2-L4 (n = 72), proximal femur (n = 72), and total body (n = 62) measurements with the Prodigy and the iDXA scanners at the same visit. The bone mineral density (BMD) measurements with these two scanners showed a high linear association at all tested sites (r = 0.962-0.995; p < 0.0001). The average iDXA BMD values were 1.5%, 0.5%, and 0.9% higher than those of Prodigy for lumbar spine (L2-L4) (p < 0.0001), femoral neck (p = 0.048), and total hip (p < 0.0001), respectively. Total body BMD values measured with the iDXA were -1.3% lower (p < 0.0001) than those measured with the Prodigy. For total body, lumbar spine, and femoral neck, the BMD differences as measured with these two devices were independent of subject height and weight. Linear correction equations were developed to ensure comparability of BMD measurements obtained with both DXA scanners. Importantly, use of equations from previous studies would have increased the discrepancy between these particular DXA scanners, especially at hip and at spine.

Association of adipokines and estradiol with bone and carotid calcifications in postmenopausal women.

OBJECTIVES: Carotid artery calcifications (CAC) and high carotid artery intima-media thickness (cIMT) are associated with low bone mineral density (BMD) by unknown mechanisms in postmenopausal women. Leptin, adiponectin and estradiol may mediate these associations. Our aim was to study the relationships of the aforementioned factors to bone health (BMD) and carotid atherosclerosis (CAC and cIMT). METHOD: Participants (n = 290, mean age 73.6 years) for this cross-sectional OSTPRE-BBA study (Kuopio Osteoporosis Risk Factor and Prevention - Bone, Brain and Atherosclerosis) were randomly selected from the OSTPRE cohort in 2009. Femoral neck and total body BMDs, trunk and total body fat mass were measured with dual-energy X-ray absorptiometry, and cIMT (mm) and CAC (no/yes) were measured with B-type ultrasound. Free estradiol, adiponectin and leptin were measured from serum samples. RESULTS: Circulating estradiol levels were associated with leptin (ß = 0.131, p < 0.001), but not with adiponectin (p > 0.05), when adjusted for total body fat mass. There were no associations between estradiol tertiles and BMDs, or with cIMT or CAC. Adiponectin levels were inversely associated with femoral neck BMD (p = 0.019, ß = -0.138) and total body BMD (p = 0.009, ß = -0.142), adjusted for total body fat mass, age, current smoking and estradiol, but showed no relationship with CAC or cIMT. Leptin levels were not associated with BMDs or cIMT; but the odds ratio was 1.5 between the CAC and leptin quartiles (p = 0.014), adjusted for total body fat mass, age, statin use and calcium intake. CONCLUSION: The adipokines are associated with vascular calcification and low BMD. Moreover, estradiol was not independently associated with BMD or CAC.

The association between major depressive disorder, use of antidepressants and bone mineral density (BMD) in men.

OBJECTIVE: Both depression and use of antidepressants have been negatively associated with bone mineral density (BMD) but mainly in studies among postmenopausal women. Therefore, the aim of this study was to investigate these relationships in men. METHODS: Between 2006 and 2011, 928 men (aged 24-98 years) from the Geelong Osteoporosis Study completed a comprehensive questionnaire, clinical measurements and had BMD assessments at the forearm, spine, total hip and total body. Major depressive disorder (MDD) was identified using a structured clinical interview (SCID-I/NP). The cross-sectional associations between BMD and both MDD and antidepressant use were analyzed using multivariable linear regression. RESULTS: Of the study population, 84 (9.1%) men had a single MDD episode, 50 (5.4%) had recurrent episodes and 65 (7.0%) were using antidepressants at the time of assessment. Following adjustments, recurrent MDD was associated with lower BMD at the forearm and total body (-6.5%, P=0.033 and -2.5%, P=0.033, respectively compared to men with no history of MDD), while single MDD episodes were associated with higher BMD at the total hip (+3.4%, P=0.030). Antidepressant use was associated with lower BMD only in lower-weight men (<75-110 kg depending on bone site). CONCLUSIONS: Both depression and use of antidepressants should be taken into account as possible risk factors for osteoporosis in men.

Modeling the antiferromagnetic MnIIMnII system within the protein phosphatase-5 catalytic site.

Protein phosphatase-5 (PP5), a novel target for inhibition in a search for new antitumor drugs, contains a homobimetallic Mn(II)Mn(II) system in its catalytic site. The ground electronic state is an antiferromagnetically-coupled singlet. We report optimizations of a known inhibitor within a 42-residue model of the PP5 catalytic site under several two-level hybrid ONIOM computational models. Using the high-resolution crystal structure of a PP5/inhibitor complex as reference, we compare geometric parameters as the qualities of the "high-level" and "low-level" wavefunctions are successively improved by using the correct antiferromagnetic (AF) singlet state. We find that the UB3LYP AF wavefunction for the high-level region is necessary for experimental fidelity. A closed-shell semi-empirical method (RPM6) can be used for the low-quality part of the hybrid scheme to afford geometries which are qualitatively on par with that obtained using the more time-consuming open-shell UB3LYP AF wavefunction. As the AF state can be elusive for such a large system, the ferromagnetic (F) state can also be used in the low-quality calculations without impacting the geometry.

Genetic disruption of protein phosphatase 5 in mice prevents high-fat diet feeding-induced weight gain.

The role of serine/threonine protein phosphatase 5 (PP5) in the development of obesity and insulin resistance associated with high-fat diet-feeding (HFD) was examined using PP5-deficient mice (Ppp5c(-/-)). Despite similar caloric intake, Ppp5c(-/-) mice on HFD gained markedly less weight and did not accumulate visceral fat compared to wild-type littermates (Ppp5c(+/+)). On a control diet, Ppp5c(-/-) mice had markedly improved glucose control compared to Ppp5c(+/+) mice, an effect diminished by HFD. However, even after 10 weeks of HFD glucose control in Ppp5c(-/-) mice was similar to that observed in Ppp5c(+/+) mice on the control diet. Thus, PP5 deficiency confers protection against HFD-induced weight gain in mice.

Serine/threonine protein phosphatase 5 regulates glucose homeostasis in vivo and apoptosis signalling in mouse pancreatic islets and clonal MIN6 cells.

AIMS/HYPOTHESIS: During the development of type 2 diabetes mellitus, beta cells are often exposed to a high glucose/hyperlipidaemic environment, in which the levels of reactive oxygen species (ROS) are elevated. In turn, ROS can trigger an apoptotic response leading to beta cell death, by activating mitogen-activated protein kinase (MAPK) signalling cascades. Here we test the hypothesis that serine/threonine protein phosphatase 5 (PP5) acts to suppress proapoptotic c-Jun N-terminal kinase (JNK) signalling in beta cells. METHODS: Ppp5c(-/-) and Ppp5c(+/+) mice were subjected to intraperitoneal glucose (IPGTT) or insulin tolerance tests. Pancreatic islets from Ppp5c(-/-) and Ppp5c(+/+) mice or MIN6 cells treated with short-interfering RNA targeting PP5 were exposed to palmitate or H(2)O(2) to activate MAPK signalling. Changes in protein phosphorylation, mRNA expression, apoptosis and insulin secretion were detected by western blot analysis, quantitative RT-PCR or ELISA. RESULTS: Ppp5c(-/-) mice weighed less and exhibited reduced fasting glycaemia and improved glucose tolerance during IPGTT, but retained normal insulin sensitivity and islet volume. Comparison of MAPK signalling in islets from Ppp5c(-/-) mice and MIN6 cells revealed that the lack of PP5 was associated with enhanced H(2)O(2)-induced phosphorylation of JNK and c-Jun. Cells with reduced PP5 also showed enhanced JNK phosphorylation and apoptosis after palmitate treatment. PP5 suppression in MIN6 cells correlated with hypersecretion of insulin in response to glucose. CONCLUSIONS/INTERPRETATION: PP5 deficiency in mice is associated with reduced weight gain, lower fasting glycaemia, and improved glucose tolerance during IPGTT. At a molecular level, PP5 helps suppress apoptosis in beta cells by a mechanism that involves regulation of JNK phosphorylation.

DNAJB6 chaperones PP2A mediated dephosphorylation of GSK3ß to downregulate ß-catenin transcription target, osteopontin.

Elevated levels of the oncoprotein, osteopontin (OPN), are associated with poor outcome of several types of cancers including melanoma. We have previously reported an important involvement of DNAJB6, a member of heat-shock protein 40 (HSP40) family, in negatively impacting tumor growth. The current study was prompted by our observations reported here which revealed a reciprocal relationship between DNAJB6 and OPN in melanoma specimens. The 'J domain' is the most conserved domain of HSP40 family of proteins. Hence, we assessed the functional role of the J domain in activities of DNAJB6. We report that the J domain of DNAJB6 is involved in mediating OPN suppression. Deletion of the J domain renders DNAJB6 incapable of impeding malignancy and suppressing OPN. Our mechanistic investigations reveal that DNAJB6 binds HSPA8 (heat-shock cognate protein, HSC70) and causes dephosphorylation of glycogen synthase kinase 3ß (GSK3ß) at Ser 9 by recruiting protein phosphatase, PP2A. This dephosphorylation activates GSK3ß, leading to degradation of ß-catenin and subsequent loss of TCF/LEF (T cell factor1/lymphoid enhancer factor1) activity. Deletion of the J domain abrogates assembly of this multiprotein complex and renders GSK3ß inactive, thus, stabilizing ß-catenin, a transcription co-activator for OPN expression. Our in-vitro and in-vivo functional analyses show that silencing OPN expression in the background of deletion of the J domain renders the resultant tumor cells less malignant despite the presence of stabilized ß-catenin. Thus, we have uncovered a new mechanism for regulation of GSK3ß activity leading to inhibition of Wnt/ß-catenin signaling.

Self-reported life satisfaction and alcohol use: a 15-year follow-up of healthy adult twins.

AIMS: To study the bidirectional relationships between life satisfaction (LS) and alcohol use. METHODS: Health questionnaires were administered in 1975, 1981 and 1990 to a population-based sample of healthy Finnish twins aged 18-45 at baseline (n = 14,083). These included a LS scale and three indicators for adverse alcohol use: binge drinking, passing out and high consumption (women/men ≥400/800 g/month). In longitudinal analyses, logistic regression, pair-wise case-control analyses and growth models were applied. RESULTS: All alcohol indicators increased the age-adjusted risk of becoming dissatisfied regardless of study period [binge drinking odds ratio (OR)(1975-1990 )= 1.29; 95% confidence interval (CI) 1.12-1.50; high consumption OR(1975-1990 )= 1.60; 1.29-1.99 and passing out OR(1981-1990 )= 2.01; 1.57-2.57]. Also, the dissatisfied had an increased subsequent risk for adverse alcohol use. The risk for passing out due to drinking (OR(1975-1990 )= 1.50; 1.22-1.86) was increased regardless of study period, while high consumption (OR(1975-1981 )= 1.97; 1.40-2.77; OR(1981-1990 )= 2.48; 1.50-4.12) and binge drinking (OR(1975-1981 )= 1.37; 1.12-1.67) showed some variation by the study period. Predictions remained after multiple adjustments. Longitudinally, high consumption predicted dissatisfaction somewhat more strongly than vice versa. The change/levels within the whole range of LS and alcohol consumption were only slightly associated in the entire study population. CONCLUSION: Life dissatisfaction and adverse alcohol use reciprocally predict each other prospectively. The heavier the alcohol use the stronger the relationship.

Body fat distribution is associated with lumbar spine bone density independently of body weight in postmenopausal women.

OBJECTIVE: To assess the association between the body fat distribution and axial bone mineral density (BMD) in postmenopausal women with or without hormone replacement therapy (HRT). DESIGN: Cross-sectional population-based study. SETTING: University of Eastern Finland, Bone and Cartilage Research Unit, Kuopio, Finland. POPULATION: 198 postmenopausal women, mean age 67.5 (1.9 SD), mean BMI 27.1 (3.9 SD). METHODS: Regional body composition and BMD assessed by dual X-ray absorptiometry (DXA, Prodigy). MAIN OUTCOME MEASURES: Spinal and Femoral BMD. RESULTS: Out of the body composition parameters, FM was the main determinant of postmenopausal bone mass. Only the lumbar spine (L2-L4) BMD, not the femoral neck BMD, was positively associated with the trunk FM. Positive trends for association were revealed between the spinal BMD and the trunk FM regardless of the use of HRT. Adjustments did not change the results. CONCLUSIONS: Higher trunk fat mass was associated with the spinal BMD, but not with the hip BMD in postmenopausal women, irrespective of the HRT use. In addition to biological factors, uncertainties related to DXA measurements in patients with varying body mass may contribute to this phenomenon.

Bone health-related factors and the use of bisphosphonates in community setting--15-year follow-up study.

UNLABELLED: The present study investigated the bone health related factors that were associated with the use of bisphosphonates (BP) among 2,050 postmenopausal Finnish women. Low BMD + low trauma energy fracture was the strongest determinant of BP use, while other secondary causes of osteoporosis were less strongly related with BP use. BP use was associated with reduced femoral neck (FN) and lumbar spine (LS) bone loss rate. INTRODUCTION: The aim was to identify bone health related factors associated with the use of BP in a community setting. METHODS: A population-based sample of 2,050 Finnish postmenopausal women was measured with dual X-ray absorptiometry at the FN and LS in 1989, 1994, 1999 and 2004, and information on osteoporosis risk factors, including low-trauma energy fractures, were collected with postal inquiries. Self-reported use of BP in 2004 was considered as the end point variable. RESULTS: Among BP users, 12% had T-score > -2.0 SD and no fracture during follow-up (FU). In women without any bone medication, 26% had T-score < -2.0 SD or low-trauma energy fracture or both during the FU. In BP users, a significant reduction in FN and LS bone loss rate, cumulative with duration of use, was observed in ANCOVA (p < 0.001). Among BP users, there was a significantly higher proportion of women with several independent risk factors for osteoporosis and more spine and humerus fractures but less ankle fractures. T-score < -2 SD combined with low-trauma energy fracture was significantly related to the use of BPs (p < 0.001, OR = 15.96) and T-score < -2 SD was a stronger predictor of BP use (p < 0.001, OR = 13.29) than fracture (p > 0.05, OR = 1.35) in multivariate logistic regression. Other factors related with BP use were vitamin D use (p = 0.001, OR = 2.27), high number of medications (p < 0.001, OR = 1.26) and rheumatoid arthritis (p < 0.05, OR 2.55). CONCLUSIONS: These findings reveal the recent bone health-related indications for BP prescription.