Age-related increases in parathyroid hormone may be antecedent to both osteoporosis and dementia

<p>Abstract</p> <p>Background</p> <p>Numerous studies have reported that age-induced increased parathyroid hormone plasma levels are associated with cognitive decline and dementia. Little is known about the correlation that may exist between neurological processing speed, cognition and bone density in cases of hyperparathyroidism. Thus, we decided to determine if parathyroid hormone levels correlate to processing speed and/or bone density.</p> <p>Methods</p> <p>The recruited subjects that met the inclusion criteria (n = 92, age-matched, age 18-90 years, mean = 58.85, SD = 15.47) were evaluated for plasma parathyroid hormone levels and these levels were statistically correlated with event-related P300 potentials. Groups were compared for age, bone density and P300 latency. One-tailed tests were used to ascertain the statistical significance of the correlations. The study groups were categorized and analyzed for differences of parathyroid hormone levels: parathyroid hormone levels <30 (n = 30, mean = 22.7 ± 5.6 SD) and PTH levels >30 (n = 62, mean = 62.4 ± 28.3 SD, p ≤ 02).</p> <p>Results</p> <p>Patients with parathyroid hormone levels <30 showed statistically significantly less P300 latency (P300 = 332.7 ± 4.8 SE) relative to those with parathyroid hormone levels >30, which demonstrated greater P300 latency (P300 = 345.7 ± 3.6 SE, p = .02). Participants with parathyroid hormone values <30 (n = 26) were found to have statistically significantly higher bone density (M = -1.25 ± .31 SE) than those with parathyroid hormone values >30 (n = 48, M = -1.85 ± .19 SE, p = .04).</p> <p>Conclusion</p> <p>Our findings of a statistically lower bone density and prolonged P300 in patients with high parathyroid hormone levels may suggest that increased parathyroid hormone levels coupled with prolonged P300 latency may become putative biological markers of both dementia and osteoporosis and warrant intensive investigation.</p

IL-1α Mediated Chorioamnionitis Induces Depletion of FoxP3+ Cells and Ileal Inflammation in the Ovine Fetal Gut

Endotoxin induced chorioamnionitis increases IL-1 and provokes an inflammatory response in the fetal ileum that interferes with intestinal maturation. In the present study, we tested in an ovine chorioamnionitis model whether IL-1 is a major cytokine driving the inflammatory response in the fetal ileum.Sheep bearing singleton fetuses received a single intraamniotic injection of recombinant ovine IL-1α at 7, 3 or 1 d before caesarian delivery at 125 days gestational age (term = 150 days).3 and 7 d after IL-1α administration, intestinal mRNA levels for IL-4, IL-10, IFN-γ and TNF-α were strongly elevated. Numbers of CD3+ and CD4+ T-lymphocytes and myeloidperoxidase+ cells were increased whereas FoxP3+ T-cells were detected at low frequency. This increased proinflammatory state was associated with ileal mucosal barrier loss as demonstrated by decreased levels of the intestinal fatty acid binding protein and disruption of the tight junctional protein ZO-1.Intraamniotic IL-1α causes an acute detrimental inflammatory response in the ileum, suggesting that induction of IL-1 is a critical element in the pathophysiological effects of endotoxin induced chorioamnionitis. A disturbed balance between T-effector and FoxP3+ cells may contribute to this process

The Role of the Multiple Banded Antigen of Ureaplasma parvum in Intra-Amniotic Infection: Major Virulence Factor or Decoy?

The multiple banded antigen (MBA) is a predicted virulence factor of Ureaplasma species. Antigenic variation of the MBA is a potential mechanism by which ureaplasmas avoid immune recognition and cause chronic infections of the upper genital tract of pregnant women. We tested whether the MBA is involved in the pathogenesis of intra-amniotic infection and chorioamnionitis by injecting virulent or avirulent-derived ureaplasma clones (expressing single MBA variants) into the amniotic fluid of pregnant sheep. At 55 days of gestation pregnant ewes (n = 20) received intra-amniotic injections of virulent-derived or avirulent-derived U. parvum serovar 6 strains (2×104 CFU), or 10B medium (n = 5). Amniotic fluid was collected every two weeks post-infection and fetal tissues were collected at the time of surgical delivery of the fetus (140 days of gestation). Whilst chronic colonisation was established in the amniotic fluid of animals infected with avirulent-derived and virulent-derived ureaplasmas, the severity of chorioamnionitis and fetal inflammation was not different between these groups (p>0.05). MBA size variants (32–170 kDa) were generated in vivo in amniotic fluid samples from both the avirulent and virulent groups, whereas in vitro antibody selection experiments led to the emergence of MBA-negative escape variants in both strains. Anti-ureaplasma IgG antibodies were detected in the maternal serum of animals from the avirulent (40%) and virulent (55%) groups, and these antibodies correlated with increased IL-1β, IL-6 and IL-8 expression in chorioamnion tissue (p<0.05). We demonstrate that ureaplasmas are capable of MBA phase variation in vitro; however, ureaplasmas undergo MBA size variation in vivo, to potentially prevent eradication by the immune response. Size variation of the MBA did not correlate with the severity of chorioamnionitis. Nonetheless, the correlation between a maternal humoral response and the expression of chorioamnion cytokines is a novel finding. This host response may be important in the pathogenesis of inflammation-mediated adverse pregnancy outcomes

Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome

Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5(pasireotide, or SOM230) or D2(cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin-dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D2receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases

Synthesis of carboxylated derivatives of poly(isobutylene-co-isoprene) by azide–alkyne “click” chemistry

The final publication is available at Springer via https://dx.doi.org/10.1038/s41428-018-0130-yThe synthesis of carboxylated derivatives of poly(isobutylene-co-isoprene) (isobutylene–isoprene rubber, IIR) with substitution levels ranging from 1 to 4 mol% and different spacer lengths was accomplished through azide–alkyne Huisgen cycloaddition. Azido-functionalized IIR was first prepared by reacting brominated IIR with sodium azide to full conversion in a 90:10 tetrahydrofuran/N,N-dimethylacetamide mixture. The click reaction of azido-functionalized IIR with acetylenic acids, which was carried out using the copper(I) bromide/N,N,N′,N″,N″-pentamethyldiethylenetriamine catalyst system in tetrahydrofuran, yielded carboxylated IIRs. The products were characterized by 1H NMR and FT-IR spectroscopy, and their molecular weight was determined by size exclusion chromatography analysis. The conversion to carboxylated groups reached up to 100% as determined by NMR spectroscopy but was highly dependent on the type of solvent and the amounts of catalysts and reactants used in the procedures.ARLANXEO Canada Inc.Natural Sciences and Engineering Research Council (NSERC) of Canad

Unravelling the relationship between animal growth and immune response during micro-parasitic infections

Background: Both host genetic potentials for growth and disease resistance, as well as nutrition are known to affect responses of individuals challenged with micro-parasites, but their interactive effects are difficult to predict from experimental studies alone. Methodology/Principal Findings: Here, a mathematical model is proposed to explore the hypothesis that a host's response to pathogen challenge largely depends on the interaction between a host's genetic capacities for growth or disease resistance and the nutritional environment. As might be expected, the model predicts that if nutritional availability is high, hosts with higher growth capacities will also grow faster under micro-parasitic challenge, and more resistant animals will exhibit a more effective immune response. Growth capacity has little effect on immune response and resistance capacity has little effect on achieved growth. However, the influence of host genetics on phenotypic performance changes drastically if nutrient availability is scarce. In this case achieved growth and immune response depend simultaneously on both capacities for growth and disease resistance. A higher growth capacity (achieved e.g. through genetic selection) would be detrimental for the animal's ability to cope with pathogens and greater resistance may reduce growth in the short-term. Significance: Our model can thus explain contradicting outcomes of genetic selection observed in experimental studies and provides the necessary biological background for understanding the influence of selection and/or changes in the nutritional environment on phenotypic growth and immune response. © 2009 Doeschl-Wilson et al