Household economic resources, labour-market advantage and health problems - a study on causal relationships using prospective register data

Our aim was to find out whether the associations between health and both individual and household economic position reflected a causal effect on health of household affluence and consumption potential. We attempted to separate this effect from health-selection effects, in other words the potential effect of health on economic position, and from various effects related to occupational position and prestige that might correlate with the economic indicators. We made a distinction between individual labour-market advantage and household economic resources in order to reflect these theoretical definitions. Our aim was to test and compare two hypotheses: 1) low household economic resources lead to an increase in health problems later on, and 2) health problems are disadvantageous on the labour market, and consequently decrease the level of economic resources. We used prospective register data obtained from the databases of Statistics Finland and constituting an 11-per-cent random sample of the Finnish population in 1993-2006. Health problems were measured in terms of sickness allowance paid by the Finnish Social Insurance Institution, household economic resources in terms of household-equivalent disposable income and taxable wealth, and labour-market advantage in terms of individual taxable income and months of unemployment. We used structural equation models (n = 211,639) to examine the hypothesised causal pathways. Low household economic resources predicted future health problems, and health problems predicted future deterioration in labour-market advantage. The effect of economic resources on health problems was somewhat stronger. These results suggest that accumulated exposure to low economic resources leads to increasing health problems, and that this causal mechanism is a more significant source of persistent health inequalities than health problems that bring about a permanent decrease in economic resources.     

Reed beds may facilitate transfer of tributyltin from aquatic to terrestrial ecosystems through insect vectors in the Archipelago Sea, SW Finland

Due to their adsorptive behavior, organotin compounds (OTCs), such as tributyltin (TBT), are accumulated in aquatic sediments. They resist biodegradation and, despite a ban in 2008, are a potential source for future exposure. Sediment OTCs have mostly been measured from sites of known high concentrations such as ports, shipping lanes, and marine dredging waste sites. The possible flow of OTCs from marine to terrestrial ecosystems, however, has not been studied. In the present study, the authors assessed whether sediments in common reed beds (Phragmites australis) accumulate TBT and whether chironomid (Diptera: Chironomidae) communities developing in reed-bed sediments act as vectors in the transfer of TBT from aquatic to terrestrial ecosystems in the Airisto channel, Archipelago Sea. The authors also investigated whether distance from the only known source and depth and TBT concentration of the adjacent shipping lane affect reed-bed concentrations. Thirty-six sites along the Airisto channel were sampled at 2-km intervals with triplicate samples from reed beds and the adjacent shipping lane for sediment and seven reed-bed sites for chironomids, and these were analyzed with an solid phase extraction liquid chromatography tamdem mass spectrometry method. The closer to the source the sample site was, the higher the measured TBT concentrations were; and the deeper the shipping lane, the lower the concentration of TBT in reed-bed sediments. The chironomid TBT concentrations correlated with reed-bed sediment TBT concentrations and showed evidence of accumulation. Therefore, TBT may be transferred, through the food web, from aquatic to terrestrial ecosystems relatively close to a source through ecosystem boundaries, such as common reed beds, which are areas of high insect biomass production in the Archipelago Sea.     

Dietary fish oil supplements modify ruminal biohydrogenation, alter the flow of fatty acids at the omasum, and induce changes in the ruminal Butyrivibrio population in lactating cows

Four lactating cows fitted with ruminal cannulae and fed a grass silage-based diet were used in a 4 × 4 Latin square with 28-d periods to investigate the effects of incremental dietary fish oil (FO) supplementation (0, 75, 150, or 300 g/d) on the flow of fatty acids at the omasum and populations of rumen bacteria capable of biohydrogenation. FO decreased silage intake and ruminal volatile fatty acid concentrations and promoted an increase in molar butyrate and propionate proportions at the expense of acetate. Extensive ruminal biohydrogenation of 20:5(n-3) and 22:6(n-3) resulted in corresponding increases in numerous 20- and 22-carbon unsaturated fatty acids at the omasum. Omasal flow of several 20-, 21-, and 22-carbon all-cis (n-3) PUFA exceeded the intake from FO. Supplements of FO also induced a dose-dependent decrease in 18:0 and increased trans 18:1 and trans 18:2 flow at the omasum. Trans-11 was the major 18:1 intermediate in digesta, while FO induced quadratic increases in trans-10 18:1 flow, reaching a maximum of 300 g/d. FO had no substantial influence on omasal flow of CLA. Results suggest that one or more fatty acids in FO inhibit the reduction of trans-18:1 and trans-18:2 intermediates by ruminal microorganisms. qPCR based on 16S rRNA genes in omasal digesta indicated that key Butyrivibrio spp. declined linearly in response to FO. Dose-dependent increases in ruminal outflow of biohydrogenation intermediates containing one or more trans double bonds in response to FO has major implications for host metabolism and the nutritional quality of ruminant foods.     

TET2 mutations in B cells of patients affected by angioimmunoblastic T‐cell lymphoma

Angioimmunoblastic T‐cell lymphomas (AITLs) frequently carry mutations in the TET2 and IDH2 genes. TET2 mutations represent early genetic lesions as they had already been detected in haematopoietic precursor cells of AITL patients. We show by analysis of whole‐tissue sections and microdissected PD1⁺ cells that the frequency of TET2‐mutated AITL is presumably even higher than reported (12/13 cases in our collection; 92%). In two‐thirds of informative AITLs (6/9), a fraction of B cells was also TET2‐mutated. Investigation of four AITLs by TET2 and IGHV gene sequencing of single microdissected B cells showed that between 10% and 60% of polyclonal B cells in AITL lymph nodes harboured the identical TET2 mutations of the respective T‐cell lymphoma clone. Thus, TET2‐mutated haematopoietic precursor cells in AITL patients not only give rise to the T‐cell lymphoma but also generate a large population of mutated mature B cells. Future studies will show whether this is a reason why AITL patients frequently also develop B‐cell lymphomas. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses

Optimal angiogenic and lymphangiogenic gene therapy requires knowledge of the best growth factors for each purpose. We studied the therapeutic potential of human vascular endothelial growth factor (VEGF) family members VEGF-A, VEGF-B, VEGF-C, and VEGF-D as well as a VEGFR-3-specific mutant (VEGF-C156S) using adenoviral gene transfer in rabbit hindlimb skeletal muscle. The significance of proteolytic processing of VEGF-D was explored using adenoviruses encoding either full-length or mature (DeltaNDeltaC) VEGF-D. Adenoviruses expressing potent VEGFR-2 ligands, VEGF-A and VEGF-DDeltaNDeltaC, induced the strongest angiogenesis and vascular permeability effects as assessed by capillary vessel and perfusion measurements, modified Miles assay, and MRI. The most significant feature of angiogenesis induced by both VEGF-A and VEGF-DDeltaNDeltaC was a remarkable enlargement of microvessels with efficient recruitment of pericytes suggesting formation of arterioles or venules. VEGF-A also moderately increased capillary density and created glomeruloid bodies, clusters of tortuous vessels, whereas VEGF-DDeltaNDeltaC-induced angiogenesis was more diffuse. Vascular smooth muscle cell proliferation occurred in regions with increased plasma protein extravasation, indicating that arteriogenesis may be promoted by VEGF-A and VEGF-DDeltaNDeltaC. Full-length VEGF-C and VEGF-D induced predominantly and the selective VEGFR-3 ligand VEGF-C156S exclusively lymphangiogenesis. Unlike angiogenesis, lymphangiogenesis was not dependent on nitric oxide. The VEGFR-1 ligand VEGF-B did not promote either angiogenesis or lymphangiogenesis. Finally, we found a positive correlation between capillary size and vascular permeability. This study compares, for the first time, angiogenesis and lymphangiogenesis induced by gene transfer of different human VEGFs, and shows that VEGF-D is the most potent member when delivered via an adenoviral vector into skeletal muscle.     

Bursts of activity in collective cell migration

Dense monolayers of living cells display intriguing relaxation dynamics, reminiscent of soft and glassy materials close to the jamming transition, and migrate collectively when space is available, as in wound healing or in cancer invasion. Here we show that collective cell migration occurs in bursts that are similar to those recorded in the propagation of cracks, fluid fronts in porous media, and ferromagnetic domain walls. In analogy with these systems, the distribution of activity bursts displays scaling laws that are universal in different cell types and for cells moving on different substrates. The main features of the invasion dynamics are quantitatively captured by a model of interacting active particles moving in a disordered landscape. Our results illustrate that collective motion of living cells is analogous to the corresponding dynamics in driven, but inanimate, systems.Collective cell movement depends on intracellular biological mechanisms as well as environmental cues due to the extracellular matrix (1–5), mainly composed of collagen which is organized in hierarchical structures, such as fibrils and fibers. The mechanical properties of collagen fibril networks are essential to offer little resistance and high sensitivity to small deformations, allowing easy local remodeling and strong strain stiffening needed to ensure cell and tissue integrity (6). Wound healing is a typical biological assay to study collective migration of cells under controlled conditions in vitro and is a prototypical experimental method to study active matter (7–10). Experiments performed on soluble collagen (11) or other gels (12), micropatterned (13, 14) and deformable substrates (1) show that cell migration is guided by the substrate structure and stiffness (5, 15, 16).It has been argued that collective migration properties arise from stresses transmitted between neighboring cells (1) giving rise to long-ranged stress waves in the monolayer (17, 18). Hence the dynamics of an invading cell sheet is ruled by a combination of long-range internal stresses and interactions with the substrate, suggesting an analogy with driven elastic systems moving in a disordered medium such as cracks lines (19, 20), imbibition fronts (21), or ferromagnetic domain walls (22). The scaling laws in these systems are usually associated with a depinning critical point that has been widely studied by simple models for interface dynamics. Thanks to a combination of numerical simulations (23, 24) and renormalization group theory (23, 25–27), we now have a detailed picture of the nonequilibrium phase transitions and universality classes in these systems. Here we substantiate the analogy between collective cell migration and depinning by revealing and characterizing widely distributed bursts of activity in the collective migration of different types of cells (human cancer cells and epithelial cells, mouse endothelial cells) over different substrates (plastic, soluble, and fibrillar collagen) and experimental conditions [vascular endothelial (VE)-cadherin knockdown] and compare the experiments with simulations of a computational model of active particles (10). We find that in all these cases the statistical properties of the bursts follow universal scaling laws that are quantitatively similar to those observed in driven disordered systems (28).     

LMNA Mutation c.917T>G (p.L306R) Leads to Deleterious Hyper‐Assembly of Lamin A/C and Associates with Severe Right Ventricular Cardiomyopathy and Premature Aging

Mutations in the LMNA gene coding for the nuclear lamina proteins lamin A and its smaller splice form lamin C associate with a heterogeneous group of diseases collectively called laminopathies. Here, we describe a 2‐year‐old patient with a previously undescribed phenotype including right ventricular cardiomyopathy, progeroid features, and premature death. Sequencing of LMNA revealed a novel heterozygous de novo mutation p.L306R located in the α‐helical rod domain of A‐type lamins. Fibroblasts from the patient showed reduced proliferation and early premature replicative senescence, as characterized by progressive hyperlobulation of the nuclei, abnormally clustered centromeres, loss of lamin B1, and reorganization of promyelocytic leukemia nuclear bodies. Furthermore, the patient cells were more sensitive to double‐strand DNA breaks. Similar structural and phenotypic defects were observed in normal fibroblasts transfected with FLAG‐tagged p.L306R lamin A. Correspondingly, in vitro assembly studies revealed that the p.L306R generates a “hyper‐assembly” mutant of lamin A that forms extensive fiber arrays under physiological conditions where wild‐type lamin A is still largely soluble. In summary, we report a novel LMNA p.L306R mutation that leads to previously undescribed hyper‐assembly of lamin A, heavy distortion of nuclear shape and that manifests as right ventricular cardiomyopathy and premature aging.