The genetic liability to disability retirement: a 30-year follow-up study of 24,000 Finnish twins

Background

No previous studies on the effect of genetic factors on the liability to disability retirement have been carried out. The main aim of this study was to investigate the contribution of genetic factors on disability retirement due to the most common medical causes, including depressive disorders.

Methods

The study sample consisted of 24 043 participants (49.7% women) consisting of 11 186 complete same-sex twin pairs including 3519 monozygotic (MZ) and 7667dizygotic (DZ) pairs. Information on retirement events during 1.1.1975–31.12.2004, including disability pensions (DPs) with diagnoses, was obtained from the Finnish nationwide official pension registers. Correlations in liability for MZ and DZ twins and discrete time correlated frailty model were used to investigate the genetic liability to age at disability retirement.

Results

The 30 year cumulative incidence of disability retirement was 20%. Under the best fitting genetic models, the heritability estimate for DPs due to any medical cause was 0.36 (95% CI 0.32–0.40), due to musculoskeletal disorders 0.37 (0.30–0.43), cardiovascular diseases 0.48 (0.39–0.57), mental disorders 0.42 (0.35–0.49) and all other reasons 0.24 (0.17–0.31). The effect of genetic factors decreased with increasing age of retirement. For DP due to depressive disorders, 28% of the variance was explained by environmental factors shared by family members (95% CI 21–36) and 58% of the variance by the age interval specific environmental factors (95% CI 44–71).

Conclusions

A moderate genetic contribution to the variation of disability retirement due to any medical cause was found. The genetic effects appeared to be stronger at younger ages of disability retirement suggesting the increasing influence of environmental factors not shared with family members with increasing age. Familial aggregation in DPs due to depressive disorders was best explained by the common environmental factors and genetic factors were not needed to account for the pattern of familial aggregation.     

Geographical trends in the yolk carotenoid composition of the pied flycatcher (Ficedula hypoleuca)

Carotenoids in the egg yolks of birds are considered to be important antioxidants and immune stimulants during the rapid growth of embryos. Yolk carotenoid composition is strongly affected by the carotenoid composition of the female??s diet at the time of egg formation. Spatial and temporal differences in carotenoid availability may thus be reflected in yolk concentrations. To assess whether yolk carotenoid concentrations or carotenoid profiles show any large-scale geographical trends or differences among habitats, we collected yolk samples from 16 European populations of the pied flycatcher, Ficedula hypoleuca. We found that the concentrations and proportions of lutein and some other xanthophylls in the egg yolks decreased from Central Europe northwards. The most southern population (which is also the one found at the highest altitude) also showed relatively low carotenoid levels. Concentrations of ??-carotene and zeaxanthin did not show any obvious geographical gradients. Egg yolks also contained proportionally more lutein and other xanthophylls in deciduous than in mixed or coniferous habitats. We suggest that latitudinal gradients in lutein and xanthophylls reflect the lower availability of lutein-rich food items in the northern F. hypoleuca populations and in montane southern populations, which start egg-laying earlier relative to tree phenology than the Central European populations. Similarly, among-habitat variation is likely to reflect the better availability of lutein-rich food in deciduous forests. Our study is the first to indicate that the concentration and profile of yolk carotenoids may show large-scale spatial variation among populations in different parts of the species?? geographical range. Further studies are needed to test the fitness effects of this geographical variation.     

Opsin gene sequence variation across phylogenetic and population histories in Mysis (Crustacea: Mysida) does not match current light environments or visual-pigment absorbance spectra

The hypothesis that selection on the opsin gene is efficient in tuning vision to the ambient light environment of an organism was assessed in 49 populations of 12 Mysis crustacean species, inhabiting arctic marine waters, coastal littoral habitats, freshwater lakes ('glacial relicts') and the deep Caspian Sea. Extensive sequence variation was found within and among taxa, but its patterns did not match expectations based on light environments, spectral sensitivity of the visual pigment measured by microspectrophotometry or the history of species and populations. The main split in the opsin gene tree was between lineages I and II, differing in six amino acids. Lineage I was present in marine and Caspian Sea species and in the North American freshwater Mysis diluviana, whereas lineage II was found in the European and circumarctic fresh- and brackish-water Mysis relicta, Mysis salemaai and Mysis segerstralei. Both lineages were present in some populations of M. salemaai and M. segerstralei. Absorbance spectra of the visual pigment in nine populations of the latter three species showed a dichotomy between lake (λ(max) =554-562 nm) and brackish-water (Baltic Sea) populations (λ(max) = 521-535 nm). Judged by the shape of spectra, this difference was not because of different chromophores (A2 vs. A1), but neither did it coincide with the split in the opsin tree (lineages I/II), species identity or current light environments. In all, adaptive evolution of the opsin gene in Mysis could not be demonstrated, but its sequence variation did not conform to a neutral expectation either, suggesting evolutionary constraints and/or unidentified mechanisms of spectral tuning.     

Substituted salicylaldehydes as potential antimicrobial drugs: minimal inhibitory and microbicidal concentrations

Substituted salicylaldehydes are potent antibacterial and antifungal agents and may have chemotherapeutic potential. In the clinical setting, the minimal inhibitory concentration (MIC) as well as the minimal bactericidal and fungicidal concentrations (MBC and MFC, respectively) are of fundamental interest. Therefore, we have now, using a panel of five microbial species (Bacillus cereus, Candida albicans, Escherichia coli, Saccharomyces cerevisiae, and Staphylococcus aureus), determined the MIC and MBC/MFC values of a total of 22 aromatic aldehydes, including 19 substituted salicylaldehydes and the unsubstituted parent compounds benzaldehyde and salicylaldehyde (2-hydroxybenzaldehyde). The results clearly indicate that both of the yeasts studied are remarkably sensitive to various salicylaldehydes and, especially, to halogenated ones. Some congeners clearly merit consideration as potential therapeutic agents for Candida infections. The MIC values of the most potent congeners are of roughly the same magnitude as that of amphotericin B, and the results of the MFC measurements indicate that the compounds are fungicidal. All of the bacteria studied are also sensitive to at least some of the compounds tested but, clearly, this class of antimicrobials has superior activity against yeasts. Structure-activity relationships are discussed for each microbial species and compared with each other. The comparison of the results of MIC and MBC/MFC measurements with those of agar diffusion tests revealed aspects that are of interest concerning the methodology of antimicrobial activity screening. Unexpectedly, it was found that some compounds that are completely devoid of activity in agar diffusion tests had potent activity in MIC tests, indicating that if only agar diffusion methodology is used in drug discovery, some highly active compounds may be missed.     

Genes involved in systemic and arterial bed dependent atherosclerosis--Tampere Vascular study

Background

Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed.

Methodology/Principal Findings

We characterized the genes generally involved in human advanced atherosclerotic (AHA type V–VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25).

Conclusions

This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds.     

Melanoma cell-derived factors stimulate hyaluronan synthesis in dermal fibroblasts by upregulating HAS2 through PDGFR-PI3K-AKT and p38 signaling

In many cancers hyaluronan content is increased, either by tumor cells or the surrounding stromal cells and this increased hyaluronan content correlates with unfavorable clinical prognosis. In the present work, we studied the effects of melanoma cell (aggressive melanoma cell line C8161)-derived factors on fibroblast hyaluronan synthesis, intracellular signaling, MMP expression and invasion. Treatment of the fibroblast cultures with melanoma cell conditioned medium (CM) caused accumulation of hyaluronan in the culture medium and formation of thick pericellular hyaluronan coat and hyaluronan cables. The expression of Has2 was increased approximately 20-fold by the C8161 melanoma cell CM, while Has1 and Has3 were increased twofold. Knock-down of Has2 expression with siRNA showed that Has2 was responsible for the increased hyaluronan synthesis induced by the melanoma cell CM. To find out the signaling routes, which led to Has2 upregulation, the phosphorylation profiles of 46 kinases were screened with phosphokinase array kit. Melanoma cell CM treatment strongly induced a rapid phosphorylation of p38, JNK, AKT, CREB, HSP27, STAT3 and cJUN. Treatment of the fibroblasts with specific inhibitors of PI3K, AKT and p38 reduced the melanoma cell CM-induced hyaluronan secretion, while the inhibitor of PDGFR totally blocked it. In addition, siRNA for PDGFRα/β inhibited Has2 upregulation in melanoma cell CM-treated fibroblasts. In parallel with the increased hyaluronan synthesis the melanoma cell CM-treated fibroblasts showed spindle shape, numerous long cell protrusions, enhanced MMP expression and increased invasion into collagen-Cultrex matrix. siRNA blocking of Has2 or PDGFRα/β expression reversed the stimulatory effect of melanoma cell CM on fibroblast invasion. PDGF secreted by melanoma cells thus mediated fibroblasts activation, with HAS2 upregulation as a major factor in the fibroblast response. This effect on stromal matrix is suggested to favor tumor growth.     

EMG recurrence quantifications in dynamic exercise

This study was designed to evaluate the suitability of nonlinear recurrence quantification analysis (RQA) in assessing electromyograph (EMG) signals during dynamic exercise. RQA has been proven to be effective in analyzing nonstationary signals. The subject group consisted of 19 male patients diagnosed with low back pain. EMG signals were recorded from left and right paraspinal muscles during isoinertial exercise both before and after 12 weeks of regimented physical therapy. Autorecurrence analysis was performed between the left and right EMG signals individually, and cross-recurrence analysis was performed on the left-right EMG pairs. Spectral analysis of the EMG signals was employed as an independent, objective measure of fatigue. Increase in the RQA variable % determinism during the 90-s dynamic tests was found to be a good marker for fatigue. Before physical therapy, this nonlinear marker revealed simultaneous increases in motor unit recruitment within each pool and between left and right pools. After physical therapy, the motor unit recruitment was less within and between pools, indicative of increased fatigue resistance. Finally, fatigue resistance (less increase in % determinism) correlated well with subjective scores of pain relief. Taken together, these latter results indicate that recurrence analysis may be useful in charting the efficacy of a specific exercise therapy program in reducing low back pain by elevating the fatigue threshold.     

Muscle use during double poling evaluated by positron emission tomography

Due to the complexity of movement in cross-country skiing (XCS), the muscle activation patterns are not well elucidated. Previous studies have applied surface electromyography (SEMG); however, recent gains in three-dimensional (3D) imaging techniques such as positron emission tomography (PET) have rendered an alternative approach to investigate muscle activation. The purpose of the present study was to examine muscle use during double poling (DP) at two work intensities by use of PET. Eight male subjects performed two 20-min DP bouts on separate days. Work intensity was ～ 53 and 74% of peak oxygen uptake (Vo(2peak)), respectively. During exercise 188 ± 8 MBq of [(18)F]fluorodeoxyglucose ([(18)F]FDG) was injected, and subsequent to exercise a full-body PET scan was conducted. Regions of interest (ROI) were defined within 15 relevant muscles, and a glucose uptake index (GUI) was determined for all ROIs. The muscles that span the shoulder and elbow joints, the abdominal muscles, and hip flexors displayed the greatest GUI during DP. Glucose uptake did not increase significantly from low to high intensity in most upper body muscles; however, an increased GUI (P < 0.05) was seen for the knee flexor (27%) and extensor muscles (16%), and for abdominal muscles (21%). The present data confirm previous findings that muscles of the upper limb are the primary working muscles in DP. The present data further suggest that when exercise intensity increases, the muscles that span the lumbar spine, hip, and knee joints contribute increasingly. Finally, PET provides a promising alternative or supplement to existing methods to assess muscle activation in complex human movements.     

Higher Free Fatty Acid Uptake in Visceral Than in Abdominal Subcutaneous Fat Tissue in Men

Visceral adipose tissue has been shown to have high lipolytic activity. The aim of this study was to examine whether free fatty acid (FFA) uptake into visceral adipose tissue is enhanced compared to abdominal subcutaneous tissue in vivo. Abdominal adipose tissue FFA uptake was measured using positron emission tomography (PET) and [¹⁸F]‐labeled 6‐thia‐hepta‐decanoic acid ([¹⁸F]FTHA) and fat masses using magnetic resonance imaging (MRI) in 18 healthy young adult males. We found that FFA uptake was 30% higher in visceral compared to subcutaneous adipose tissue (0.0025 ± 0.0018 vs. 0.0020 ± 0.0016 µmol/g/min, P = 0.005). Visceral and subcutaneous adipose tissue FFA uptakes were strongly associated with each other (P < 0.001). When tissue FFA uptake per gram of fat was multiplied by the total tissue mass, total FFA uptake was almost 1.5 times higher in abdominal subcutaneous than in visceral adipose tissue. In conclusion, we observed enhanced FFA uptake in visceral compared to abdominal subcutaneous adipose tissue and, simultaneously, these metabolic rates were strongly associated with each other. The higher total tissue FFA uptake in subcutaneous than in visceral adipose tissue indicates that although visceral fat is active in extracting FFA, its overall contribution to systemic metabolism is limited in healthy lean males. Our results indicate that subcutaneous, rather than visceral fat storage plays a more direct role in systemic FFA availability. The recognized relationship between abdominal visceral fat mass and metabolic complications may be explained by direct effects of visceral fat on the liver.