Disability trends among nonagenarians in 2001�C2007: Vitality 90+ Study

Substantial growth of the population aged 90 years or over has focused interest on trends in the functioning and disability of the oldest old, but research findings are scarce and they vary. In the Vitality 90+ Study, we evaluated overall, gender-specific, and age-specific trends in disability among total cohorts of people aged 90 years or older in the city of Tampere, Finland, in the years 2001, 2003, and 2007. The size of the target population ranged from 1113 to 1146 and the participation rate from 79 to 86%. The participants were asked whether they were able to get in and out of bed, dress and undress, move about indoors, walk 400 m, and use stairs. Independence was defined as being able to perform an activity without help. The aggregate outcome measures included independence in all five activities, dependence in one to four activities, dependence in all five activities (severe dependence), and a disability score. In analyses taking into account the within subject associations which resulted due to those who participated in several years, and proxy respondents, no overall or gender-specific trend was found in any of the independence or dependence estimates. In each year, independence decreased clearly by increasing age. Our results imply stable disability levels in nonagenarians in a population with increasing life expectancy and improving survival until the age of 90. Longer-time series are needed to confirm the trends.     

Valproic acid stimulates clusterin expression in human astrocytes: Implications for Alzheimer's disease

Clusterin is a secreted molecular chaperone, also called apolipoprotein J. Recent genetic studies have demonstrated that clusterin is a significant susceptibility gene for late-onset Alzheimer's disease (AD). Clusterin shares several properties with apolipoprotein E, a well-known risk gene for AD, i.e. they bind to amyloid-β peptides and are present in neuritic plaques, enhance the clearance of amyloid-β peptides in brain, and are included in lipid particles and thus regulate cholesterol traffic. Biochemical studies indicate that clusterin can prevent the progress of AD pathogenesis. We have observed earlier that histone deacetylase (HDAC) inhibitors can induce the expression of clusterin in several neuroblastoma and glioma cell lines. Recent studies have revealed that valproic acid, a common and well-tolerated drug for epilepsy and bipolar disorders, is a potent HDAC inhibitor. In this study, we examined whether valproic acid can induce the expression of clusterin in human astrocytes. Our results demonstrated that valproic acid is a potent inducer of clusterin expression and secretion in human astrocytes at the therapeutical concentrations. Another clinically used HDAC inhibitor, the cancer drug, Vorinostat (SAHA, suberoylanilide hydroxamic acid), also robustly stimulated the expression of clusterin in human astrocytes. One could postulate that valproic acid may be able to prevent amyloid-β aggregation in AD, as observed in transgenic AD mice, by increasing clusterin expression.     

Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer

The androgen receptor (AR) signaling pathway is involved in the emergence of castration-resistant prostate cancer (CRPC). Here, we identified several androgen-regulated microRNAs (miRNAs) that may contribute to the development of CRPC. Seven miRNAs, miR-21, miR-32, miR-99a, miR-99b, miR-148a, miR-221 and miR-590-5p, were found to be differentially expressed in CRPC compared with benign prostate hyperplasia (BPH) according to microarray analyses. Significant growth advantage for LNCaP cells transfected with pre-miR-32 and pre-miR-148a was found. miR-32 was demonstrated to reduce apoptosis, whereas miR-148a enhanced proliferation. Androgen regulation of miR-32 and miR-148a was confirmed by androgen stimulation of the LNCaP cells followed by expression analyses. The AR-binding sites in proximity of these miRNAs were demonstrated with chromatin immunoprecipitation (ChIP). To identify target genes for the miRNAs, mRNA microarray analyses were performed with LNCaP cells transfected with pre-miR-32 and pre-miR-148a. Expression of BTG2 and PIK3IP1 was reduced in the cells transfected with pre-miR-32 and pre-miR-148a, respectively. Also, the protein expression was reduced according to western blot analysis. BTG2 and PIK3IP1 were confirmed to be targets by 3'UTR-luciferase assays. Finally, immunostainings showed a statistically significant (P<0.0001) reduction of BTG2 protein in CRPCs compared with untreated prostate cancer (PC). The lack of BTG2 staining was also associated (P<0.01) with a short progression-free time in patients who underwent prostatectomy. In conclusion, androgen-regulated miR-32 is overexpressed in CRPC, leading to reduced expression of BTG2. Thus, miR-32 is a potential marker for aggressive disease and is a putative drug target in PC.     

Relationship of Modic type 1 change with disc degeneration: a prospective MRI study

Objective  The objective was to study the natural course of Modic type 1 change (M1) in relation to lumbar disc degeneration. Materials and methods  Twenty-four chronic low back pain (LBP) patients with M1 on lumbar spine were selected from 1,015 patients with magnetic resonance imaging from a follow-up study lasting for 18–74 months. Exclusion criteria were any other specific back disorder, age ≥60 years, or a recent spine operation. The association between the development of M1 and degenerative disc changes was studied using multivariate modeling (complex samples logistic regression). Results  At baseline, 20 of 28 (71%) disc spaces with M1 had a decreased disc height (DH) and 16 of 28 (57%) a dark nucleus pulposus, but ten of 28 (36%) a very dark annulus fibrosus and a paradoxically bright nucleus pulposus albeit decreased DH. During follow-up, DH decreased in 13 of 28 (46%) and signal intensity of nucleus pulposus (DSI) in eight of 28 (29%) disc spaces with M1, but it increased in four (14%) discs. In those without M1, only few changes occurred. The larger the M1, the more likely was the DH low or decreased further. Both the presence and changes in M1 were associated with a decrease in DH and changes in DSI and bulges. Conclusion  The degenerative process in discs with adjacent M1 seems to be accelerated and leads to advanced and deforming changes with special morphologic features. M1 may be a sign of a pathologic degenerative process in the discovertebral unit.