Temporal profiles of age-dependent changes in cytokine mRNA expression and glial cell activation after status epilepticus in postnatal rat hippocampus

<p>Abstract</p> <p>Background</p> <p>Status epilepticus (SE) is proposed to lead to an age-dependent acute activation of a repertoire of inflammatory processes, which may contribute to neuronal damage in the hippocampus. The extent and temporal profiles of activation of these processes are well known in the adult brain, but less so in the developing brain. We have now further elucidated to what extent inflammation is activated by SE by investigating the acute expression of several cytokines and subacute glial reactivity in the postnatal rat hippocampus.</p> <p>Methods</p> <p>SE was induced by an intraperitoneal (i.p.) injection of kainic acid (KA) in 9- and 21-day-old (P9 and P21) rats. The mRNA expression of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), glial-derived neurotrophic factor (GDNF), interferon gamma (IFN-γ), and transforming growth factor-beta 1 (TGF-β1) were measured from 4 h up to 3 days after KA injection with real-time quantitative PCR (qPCR). IL-1β protein expression was studied with ELISA, GFAP expression with western blotting, and microglial and astrocyte morphology with immunohistochemistry 3 days after SE.</p> <p>Results</p> <p>SE increased mRNA expression of IL-1β, TNF-α and IL-10 mRNA in hippocampus of both P9 and P21 rats, their induction being more rapid and pronounced in P21 than in P9 rats. MMP-9 expression was augmented similarly in both age groups and GDNF expression augmented only in P21 rats, whereas neither IFN-γ nor TGF-β1 expression was induced in either age group. Microglia and astrocytes exhibited activated morphology in the hippocampus of P21 rats, but not in P9 rats 3 d after SE. Microglial activation was most pronounced in the CA1 region and also detected in the basomedial amygdala.</p> <p>Conclusion</p> <p>Our results suggest that SE provokes an age-specific cytokine expression in the acute phase, and age-specific glial cell activation in the subacute phase as verified now in the postnatal rat hippocampus. In the juvenile hippocampus, transient increases in cytokine mRNA expression after SE, in contrast to prolonged glial reactivity and region-specific microglial activity after SE, suggest that the inflammatory response is changed from a fulminant and general initial phase to a more moderate and specific subacute response.</p

Isolation and purification of ent-pimara-8(14),15-diene from engineered Aspergillus nidulans by accelerated solvent extraction combined with HPLC

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Diet-induced obesity in mice overexpressing neuropeptide y in noradrenergic neurons

Neuropeptide Y (NPY) is a neurotransmitter associated with feeding and obesity. We have constructed an NPY transgenic mouse model (OE- mouse), where targeted overexpression leads to increased levels of NPY in noradrenergic and adrenergic neurons. We previously showed that these mice become obese on a normal chow. Now we aimed to study the effect of a Western-type diet in OE- and wildtype (WT) mice, and to compare the genotype differences in the development of obesity, insulin resistance, and diabetes. Weight gain, glucose, and insulin tolerance tests, fasted plasma insulin, and cholesterol levels were assayed. We found that female OE- mice gained significantly more weight without hyperphagia or decreased activity, and showed larger white and brown fat depots with no difference in UCP-1 levels. They also displayed impaired glucose tolerance and decreased insulin sensitivity. OE- and WT males gained weight robustly, but no difference in the degree of adiposity was observed. However, 40% of but none of the WT males developed hyperglycaemia while on the diet. The present study shows that female OE- mice were not protected from the obesogenic effect of the diet suggesting that increased NPY release may predispose females to a greater risk of weight gain under high caloric conditions.</p

MMP-13 Regulates Growth of Wound Granulation Tissue and Modulates Gene Expression Signatures Involved in Inflammation, Proteolysis, and Cell Viability

Proteinases play a pivotal role in wound healing by regulating cell-matrix interactions and availability of bioactive molecules. The role of matrix metalloproteinase-13 (MMP-13) in granulation tissue growth was studied in subcutaneously implanted viscose cellulose sponge in MMP-13 knockout (Mmp13−/−) and wild type (WT) mice. The tissue samples were harvested at time points day 7, 14 and 21 and subjected to histological analysis and gene expression profiling. Granulation tissue growth was significantly reduced (42%) at day 21 in Mmp13−/− mice. Granulation tissue in Mmp13−/− mice showed delayed organization of myofibroblasts, increased microvascular density at day 14, and virtual absence of large vessels at day 21. Gene expression profiling identified differentially expressed genes in Mmp13−/− mouse granulation tissue involved in biological functions including inflammatory response, angiogenesis, cellular movement, cellular growth and proliferation and proteolysis. Among genes linked to angiogenesis, Adamts4 and Npy were significantly upregulated in early granulation tissue in Mmp13−/− mice, and a set of genes involved in leukocyte motility including Il6 were systematically downregulated at day 14. The expression of Pdgfd was downregulated in Mmp13−/− granulation tissue in all time points. The expression of matrix metalloproteinases Mmp2, Mmp3, Mmp9 was also significantly downregulated in granulation tissue of Mmp13−/− mice compared to WT mice. Mmp13−/− mouse skin fibroblasts displayed altered cell morphology and impaired ability to contract collagen gel and decreased production of MMP-2. These results provide evidence for an important role for MMP-13 in wound healing by coordinating cellular activities important in the growth and maturation of granulation tissue, including myofibroblast function, inflammation, angiogenesis, and proteolysis

Geographic origin as a determinant of left ventricular mass and diastolic function - the Cardiovascular Risk in Young Finns Study

Aims: Eastern Finns have higher risk of coronary heart disease (CHD) and carotid intima-media thickness than western Finns although current differences in CHD risk factors are minimal. Left ventricular (LV) mass and diastolic function predict future cardiovascular events but their east-west differences are unknown. We examined the association of eastern/western baseline origin with LV mass and diastolic function. Methods : The study population included 2045 subjects of the Cardiovascular Risk in Young Finns Study with data from the baseline survey (1980) and the latest follow-up (2011) when echocardiography was performed at the age of 34-49 years. Results: Subjects with eastern baseline origin had in 2011 higher LV mass (139 +/- 1.0 vs. 135 +/- 1.0 g, p=0.006) and E/e-ratio indicating weaker LV diastolic function (4.86 +/- 0.03 vs. 4.74 +/- 0.03, p=0.02) than western subjects. Results were independent of age, sex, area of examination and CHD risk factors such as blood pressure and BMI (LV mass indexed with height: pPeer reviewe

A Survey on Continuous Time Computations

We provide an overview of theories of continuous time computation. These theories allow us to understand both the hardness of questions related to continuous time dynamical systems and the computational power of continuous time analog models. We survey the existing models, summarizing results, and point to relevant references in the literature

Hydroxysteroid (17 beta) dehydrogenase 12 is essential for metabolic homeostasis in adult mice

Hydroxysteroid 17-beta dehydrogenase 12 (HSD17B12) is suggested to be involved in the elongation of very long chain fatty acids. Previously, we have shown a pivotal role for the enzyme during mouse development. In the present study we generated a conditional Hsd17b12 knockout (HSD17B12cKO) mouse model by breeding mice homozygous for a floxed Hsd17b12 allele with mice expressing the tamoxifen-inducible Cre recombinase at the ROSA26 locus. Gene inactivation was induced by administering tamoxifen to adult mice. The gene inactivation led to a 20% loss of body weight within six days, associated with drastic reduction in both white (83% males, 75% females) and brown (65% males, 60% females) fat, likely due to markedly reduced food and water intake. Furthermore, the knockout mice showed sickness behavior and signs of liver toxicity, specifically microvesicular hepatic steatosis and increased serum alanine aminotransferase (4.6-fold in males, 7.7-fold in females). The hepatic changes were more pronounced in females than males. Pro-inflammatory cytokines, such as interleukin 6 (IL-6), IL-17 and granulocyte-colony stimulating factor were increased in the HSD17B12cKO mice indicating inflammatory response. Serum lipidomics study showed an increase in the amount of dihydroceramides, despite the dramatic overall loss of lipids. In line with the proposed role for HSD17B12 in the fatty acid elongation, we observed accumulation of ceramides, dihydroceramides, hexosylceramides and lactosylceramides with shorter than 18-carbon fatty acid side chains in the serum. The results indicate that HSD17B12 is essential for proper lipid homeostasis, and HSD17B12 deficiency rapidly results in fatal systemic inflammation and lipolysis in adult mice.Peer reviewe

Childhood Psychosocial Environment and Adult Cardiac Health : A Causal Mediation Approach

Introduction: This study used causal mediation analysis to assess the life-course associations of a favorable childhood psychosocial environment with left ventricular mass and diastolic function in adulthood and the extent to which adult health behaviors mediate these associations. Methods: The sample included 880 participants (56% women) from the Young Finns Study with data on the childhood environment from 1980, adult health behaviors (smoking, physical activity, diet, and BMI) from 2001 and an echocardiographic assessment of the left ventricular mass (g/m(2.7)) and diastolic function (E/e' ratio; higher values indicating a lower diastolic function) from 2011. The associations of the childhood environment with the left ventricular mass and E/e' ratio and mediation pathways through health behaviors were assessed using marginal structural models that were controlled for age, sex, and time-dependent confounding by adult socioeconomic position (measured as educational attainment) via inverse probability weighting. The data were analyzed in 2018-2019. Results: The mean age in 2011 was 41 (range 34-49) years. Those above versus below the median childhood score had a 1.28 g/m(2.7) lower left ventricular mass (95% CI = -2.63, 0.07) and a 0.18 lower E/e' ratio (95% CI = -0.39, 0.03). There was no evidence for indirect effects from childhood environments to left ventricular outcomes through adult health behaviors after controlling for time-dependent confounding by the adult socioeconomic position (indirect effect beta = -0.30, 95% CI = -1.22, 0.63 for left ventricular mass; beta = -0.04, 95% CI = -0.18, 0.11 for E/e' ratio). The results after multiple imputation were similar. Conclusions: A favorable childhood environment is associated with more optimal cardiac structure and function in adulthood. After accounting for socioeconomic positions, adult health behaviors explain little of the associations. (C) 2019 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.Peer reviewe

Ideal cardiovascular health in childhood-Longitudinal associations with cardiac structure and function : The Special Turku Coronary Risk Factor Intervention Project (STRIP) and the Cardiovascular Risk in Young Finns Study (YFS)

Background: Ideal cardiovascular health (CVH), defined by the American Heart Association, is associated with incident cardiovascular disease in adults. However, association of the ideal CVH in childhood with current and future cardiac structure and function has not been studied. Methods and results: The sample comprised 827 children participating in the longitudinal Special Turku Coronary Risk Factor Intervention Project (STRIP) and The Cardiovascular Risk in Young Finns Study (YFS). In STRIP, complete data on the seven ideal CVH metrics and left ventricular (LV) mass measured with echocardiography were available at the age of 15 (n= 321), 17 (n= 309) and 19 (n= 283) years. In YFS, the cohort comprised children aged 12-18 years (n = 506) with complete ideal CVH metrics data from childhood and 25 years later in adulthood, and echocardiography performed in adulthood. In STRIP, ideal CVH score was inversely associated with LV mass during childhood (P = 0.036). In YFS, childhood ideal CVH score was inversely associated with LV mass, LV end-diastolic volume, E/e' ratio, and left atrium end-systolic volume in adulthood (all P <0.01). In addition, improvement of the ideal CVH score between childhood and adulthood was inversely associated with LV mass, LV end-diastolic volume, E/e' ratio, and left atrium end-systolic volume (all P Conclusions: Childhood ideal CVH score has a long-lasting effect on cardiac structure and function, and the association is evident already in childhood. Our findings support targeting the ideal CVHmetrics as part of primordial prevention of cardiovascular diseases. (C) 2016 Elsevier Ireland Ltd. All rights reserved.Peer reviewe