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.     

A new quantitative measure of disc degeneration

Background Context

The ability to adequately measure a phenomenon is critical to studying and understanding it. Since 1957, a variety of subjective visual grading methods have been used to assess disc degeneration, but these have been limited by gross ordinal scales and imprecision, as well as suboptimal reliability. Conceptually sound, objective, precise measurements are needed to advance knowledge of disc degeneration and its causes, progression, and consequences.

Two-ring hybrid external fixation of distal tibial fractures: a review of 47 cases

BACKGROUND: The healing of a metaphyseal fracture line is a major problem in cases of distal tibial fracture treated with external fixation. METHODS: Forty-seven distal tibial fractures treated with two-ring Ilizarov hybrid external fixation (16 AO/OTA type A and 31 type C, 10 open) were followed up. Fracture reduction and union time was evaluated and IOWA and RAND 36-Item Health Survey scores were used to assess functional outcome. RESULTS: Thirty-five fractures united uneventfully in a median time of 20 weeks, but 12 fractures needed additional procedures because of delayed union. According to univariate analysis, the risk factors for a longer time needed for fracture union were translational displacement and current smoking, and the risk factors for reoperation because of delayed union translational displacement fibular fracture fixation, and the number of cigarettes smoked per day. In multivariate analysis, translational displacement was a risk factor for both longer time to fracture union and reoperation and fibular fracture fixation was a risk factor for reoperation. If the translational displacement was less than 3 mm, the reoperation rate was 6%, whereas if the displacement was more than 3 mm, it was 83%. Reoperation was performed on 50% of the patients who underwent fibular fixation and on 15% of the patients who did not undergo fibular fixation. There were only marginal decreases in the range of motion and arthritis scores in the AO/OTA fracture types other than type C3. There were no significant differences in RAND 36 scores between the general Finnish population aged 18 to 64 years and our patients. CONCLUSIONS: Hybrid external fixation of distal tibial fractures is associated with delayed union, which is closely related to the degree of residual translational displacement after reduction. Fixation of an associated fibular fracture does not help to achieve better contact in the tibial fracture and increases the risk of delayed union.     

DNA Flow Cytometry in Surgically Treated Lung Cancer: Prognostic Significance

Although DNA aneuploidy and high proliferative activity (S-phase fraction, SPF) of tumour cells, measured by flow cytometry, have proved to be indicators of poor prognosis in most solid tumours, there have been conflicting results in lung cancer studies. During a four-year period we studied the prognostic significance of DNA ploidy and SPF in 99 surgically treated lung cancer patients. Flow cytometric analysis was done from archival, formalin-fixed, paraffin-embedded tumour specimens. DNA index and SPF were determined, using MultiCycle software with sliced nuclear correction to compensate for debris. There were 61 DNA diploid and 38 DNA aneuploid tumours. The median SPF was 10.2%. Neither ploidy nor SPF was associated with previously known prognostic factors. Survival was poorer in patients with aneuploid tumours than in the other patients, but the difference was not statistically significant. DNA ploidy and SPF thus do not seem to be useful prognostic indicators in surgically treated lung cancer.     

Myocardial perfusion,oxidative metabolism,and free fatty acid uptake in patients with hypertrophic cardiomyopathy attributable to the Asp 175Asn mutation in the α-tropomyosin gene: A positron emission tomography study

Background  The relationship between myocardial metabolic changes and the severity of left ventricular (LV) hypertrophy in patients with hypertrophic cardiomyopathy (HCM) is largely unknown. We characterized metabolic abnormalities in patients with a genetically identical cause for HCM but with variable LV hypertrophy. Methods and Results  Eight patients with HCM attributable to the Asp175Asn mutation in the α-tropomyosin gene underwent myocardial perfusion, oxidative, and free fatty acid (FFA) metabolism measurements via positron emission tomography and oxygen 15-labeled water, carbon 11 acetate, and fluorine 14(R,S)-[18F] Fluoro-6-thia-heptadecanoic acid (18 FTHA). LV mass, work, and efficiency were assessed by echocardiography. Thirty-six healthy volunteers served as control subjects. Compared with control subjects, HCM patients had increased myocardial oxidative metabolism and FFA uptake (P<.05). However, in patients, LV mass was inversely related to global myocardial perfusion, oxidative metabolism, and FFA uptake (all P<.03), and regional wall thickness was inversely related to regional perfusion (P<.01), oxidative metabolism (P<.001), and FFA uptake (P<.01). Therefore patients with mild (LV mass less than median of 177 g) but not advanced LV hypertrophy were characterized by increased perfusion, oxidative metablism, and LV efficiency as compared with control subjects (P<.05). Conclusions  In HCM attributable to the Asp 175Asn mutation in the α-tropomyosin gene, myocardial oxidative metabolism and FFA metabolism are increased and inversely related to LV hypertrophy at both the whole heart and regional level. Increased metabolism and efficiency characterize patients with mild myocardial hypertrophy. These hypermetabolic alterations regress with advanced hypertrophy. Dis Tuunanen and Kuusisto contributed equally to this work This study was financially supported by an EVO grant (Kuopio University Hospital), as well as the Turunen Foundation, Instrumentarium Foundation, and Finish Cultural Foundation.