Genomic Ancestry,Self-Rated Health and Its Association with Mortality in an Admixed Population: 10 Year Follow-Up of the Bambui-Epigen (Brazil) Cohort Study of Ageing

Background

Self-rated health (SRH) has strong predictive value for mortality in different contexts and cultures, but there is inconsistent evidence on ethnoracial disparities in SRH in Latin America, possibly due to the complexity surrounding ethnoracial self-classification.

Materials/Methods

We used 370,539 Single Nucleotide Polymorphisms (SNPs) to examine the association between individual genomic proportions of African, European and Native American ancestry, and ethnoracial self-classification, with baseline and 10-year SRH trajectories in 1,311 community dwelling older Brazilians. We also examined whether genomic ancestry and ethnoracial self-classification affect the predictive value of SRH for subsequent mortality.

Results

European ancestry predominated among participants, followed by African and Native American (median = 84.0%, 9.6% and 5.3%, respectively); the prevalence of Non-White (Mixed and Black) was 39.8%. Persons at higher levels of African and Native American genomic ancestry, and those self-identified as Non-White, were more likely to report poor health than other groups, even after controlling for socioeconomic conditions and an array of self-reported and objective physical health measures. Increased risks for mortality associated with worse SRH trajectories were strong and remarkably similar (hazard ratio ~3) across all genomic ancestry and ethno-racial groups.

Conclusions

Our results demonstrated for the first time that higher levels of African and Native American genomic ancestry—and the inverse for European ancestry—were strongly correlated with worse SRH in a Latin American admixed population. Both genomic ancestry and ethnoracial self-classification did not modify the strong association between baseline SRH or SRH trajectory, and subsequent mortality.     

Tolvaptan inhibits ERK-dependent cell proliferation, Cl⁻ secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin

In autosomal dominant polycystic kidney disease (ADPKD), arginine vasopressin (AVP) accelerates cyst growth by stimulating cAMP-dependent ERK activity and epithelial cell proliferation and by promoting Cl(-)-dependent fluid secretion. Tolvaptan, a V2 receptor antagonist, inhibits the renal effects of AVP and slows cyst growth in PKD animals. Here, we determined the effect of graded concentrations of tolvaptan on intracellular cAMP, ERK activity, cell proliferation, and transcellular Cl(-) secretion using human ADPKD cyst epithelial cells. Incubation of ADPKD cells with 10(-9) M AVP increased intracellular cAMP and stimulated ERK and cell proliferation. Tolvaptan caused a concentration-dependent inhibition of AVP-induced cAMP production with an apparent IC(50) of ～10(-10) M. Correspondingly, tolvaptan inhibited AVP-induced ERK signaling and cell proliferation. Basolateral application of AVP to ADPKD cell monolayers grown on permeable supports caused a sustained increase in short-circuit current that was completely blocked by the Cl(-) channel blocker CFTR(inh-172), consistent with AVP-induced transepithelial Cl(-) secretion. Tolvaptan inhibited AVP-induced Cl(-) secretion and decreased in vitro cyst growth of ADPKD cells cultured within a three-dimensional collagen matrix. These data demonstrate that relatively low concentrations of tolvaptan inhibit AVP-stimulated cell proliferation and Cl(-)-dependent fluid secretion by human ADPKD cystic cells.     

The cytotoxic and growth inhibitory effects of palladium(II) complexes on MDA-MB-435 cells

The antitumorigenic potential of two palladium(II) complexes, [Pd(ca(2)-o-phen)Cl(2)] - C1 and [Pd(dmba)(dppp)Cl] - C2, was evaluated, using MDA-MB-435 cells, a human breast adenocarcinoma cell-line that does not express the estrogen receptor α (ER-). Growth inhibition and induced alterations in cell-morphology were analyzed. The sulforhodamine B test showed that, compared to control cells, both C1 and C2 significantly inhibited (p < 0.5) cell growth. The maximum effect with both was achieved with 1 μM complexes, after 24 h of treatment. No further cell-growth inhibition was achieved by increasing concentration or incubation time. Cell morphology was analyzed after staining with hematoxylin-eosin (HE). The morphological changes noted in the treated cells were cell rounding-up, shrinkage, nuclear condensation and reduction of cell length (p < 0.05), thereby indicating that both C1 and C2 are cytotoxic to breast adenocarcinoma cells. All together, there was every indication that, by decreasing cell growth and inducing morphological changes, the tested complexes are cytotoxic, hence their potentiality as promising candidates for antineoplastic drug development.     

Role of IL-10 in a neonatal mouse listeriosis model.

This study was undertaken to test the hypothesis that altered IL-10 production plays a role in the increased susceptibility of neonates to listeriosis. Plasma IL-10 levels were measured in neonatal and adult mice at various times after infection with Listeria monocytogenes. Relative to adults, neonatal mice had markedly increased IL-10 levels early in the course of infection with Listeria using a 90% lethal dose. Higher neonatal IL-10 responses were also observed after injecting adults and pups with equal doses of killed organisms. Splenic macrophages from neonates produced higher IL-10 levels than those of adults after in vitro stimulation with killed bacteria, confirming in vivo observations. Moreover, IL-10 blockade had differential effects in neonates and adults infected with live Listeria. In adult mice, anti-IL-10 Abs decreased bacterial burden early in the course of infection, but were no longer effective at 6 days or later after challenge. In the pups, however, the same treatment had beneficial effects both early and late during infection and resulted in increased survival. Collectively, our data suggest that an overproduction of IL-10 by macrophages may at least partially explain the increased susceptibility of neonates to listeriosis, and provide further evidence that cytokine production is different in adults and neonates.     

Phylogeny and temporal diversification of Calomys (Rodentia, Sigmodontinae): implications for the biogeography of an endemic genus of the open/dry biomes of South America

A thorough analysis of character evolution and biogeography of a group is only possible with a comprehensive sampling of its diversity. The sigmodontine genus Calomys is particularly interesting for the study of neotropical biogeography as it occurs exclusively in the dry and grassland biomes: Cerrado, Caatinga, Chaco, Pampas, Venezuelan Llanos, Puna, and a diversity of dry forests biomes. Although Brazil encompasses a large part of the geographic distribution of the genus and at least three endemic species, the last published phylogeny of Calomys included only two specimens (both representing the same species) from a single locality in this country. In the present paper we add complete cytochrome b sequences of Brazilian karyomorphs to previously published sequences in order to provide a phylogenetic hypothesis including most of the genus diversity. The main objectives of this study were to clarify taxonomic issues related to Brazilian karyomorphs and to study the diversification processes of the genus by analyzing its biogeography in combination with cladogenesis dates estimated with a molecular clock. The phylogeny indicates that at least six different species inhabit the Brazilian territory, one of them still undescribed. Date estimates indicate that two sequential basal splits, the first separating Andean from lowland species and the second isolating species north and south of the Amazonia, took place in the Pliocene between 3 and 4 Ma. A large-bodied and speciose clade of lowland species associated with dry forests and ecotones of the core Cerrado and Chaco areas with adjacent biomes diversified in the Pleistocene. This indicates the importance of safeguarding ecotones and the Cerrado at a time where this biome is being rapidly destroyed.     

Adipokine levels are altered by shiftwork: a preliminary study

Shiftwork is often associated with metabolic diseases, and in the past few years, several cytokines have been postulated to contribute to various diseases, including insulin resistance. The aim of this study was to compare the concentrations of adiponectin, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in samples of young adult men exposed to a fixed (i) night shift (n = 9), working from 22:00 to 06:00 h; (ii) early morning shift (n = 6), working from 06:00 to 14:00 h; and (iii) day shift (n = 7), working from 08:00 to 17:00 h. The fixed night-shift and early-morning-shift samples were considered collectively as a shiftworker group given their work times. Blood samples were collected during the regular working day at 4-h intervals over the course of 24 h, thus totaling six samples. Morphological and physical activity parameters did not differ between the three groups. Total energy intake was lowest on the early morning shifts (p 相似文献   

Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases in hypertensive vascular remodeling

Structural vascular changes in two-kidney, one-clip (2K-1C) hypertension may result from increased matrix metalloproteinase (MMP)-2 activity. MMP-2 activation is regulated by other MMPs, including transmembrane-MMPs, and by tissue inhibitors of MMPs (TIMPs). We have investigated the localization of MMP-2, -9, -14, and TIMPs 1–4 in hypertensive aortas and measured their levels by zymography/Western blotting and immunohistochemistry. Gelatinolytic activity was assayed in tissues by in situ zymography. Sham-operated and 2K-1C hypertensive rats were treated with doxycycline (or vehicle) for 8 weeks, and the systolic blood pressure was monitored weekly. Doxycycline attenuated 2K-1C hypertension (165 ± 11.7 mmHg versus 213 ± 7.9 mm Hg in hypertensive controls, P < 0.01), and completely prevented increase in the thicknesses of the media and the intima in 2K-1C animals (P < 0.01). Increased amounts of MMP-2, -9, and -14 were found in hypertensive aortas, as well as enhanced gelatinolytic activity. A gradient in the localization of MMP-2, -9, and -14 was found, with increased amounts detected in the intima, at sites with higher gelatinolytic activity. Doxycycline attenuated hypertension induced increases in all the 3 investigated MMPs in both the media and the intima (all P < 0.05), but it did not change the amounts of TIMPs 1–4 (P > 0.05). Therefore, an imbalance between increased amounts of MMPs at the tissue level without a corresponding increase in the quantities of TIMPs, particularly in the intima and inner media layers, appears to account for the increased proteolytic activity found in 2K-1C hypertension-induced maladaptive vascular remodeling.     

Identification,classification and evolution of Owl Monkeys (<Emphasis Type="Italic">Aotus</Emphasis>, Illiger 1811)

Background  

Owl monkeys, belonging to the genus Aotus, have been extensively used as animal models in biomedical research but few reports have focused on the taxonomy and phylogeography of this genus. Moreover, the morphological similarity of several Aotus species has led to frequent misidentifications, mainly at the boundaries of their distribution. In this study, sequence data from five mitochondrial regions and the nuclear, Y-linked, SRY gene were used for species identification and phylogenetic reconstructions using well characterized specimens of Aotus nancymaae, A. vociferans, A. lemurinus, A. griseimembra, A. trivirgatus, A. nigriceps, A. azarae boliviensis and A. infulatus.     

Decreased GTP-stimulated adenylyl cyclase activity in HPRT-deficient human and mouse fibroblast and rat B103 neuroblastoma cell membranes

Defect of the purine salvage enzyme, hypoxanthine phosphoribosyl transferase (HPRT), results in Lesch-Nyhan disease (LND). It is unknown how the metabolic defect translates into the severe neuropsychiatric phenotype characterized by self-injurious behavior, dystonia and mental retardation. There are abnormalities in GTP, UTP and CTP concentrations in HPRT-deficient cells. Moreover, GTP, ITP, XTP, UTP and CTP differentially support Gs-protein-mediated adenylyl cyclase (AC) activation. Based on these findings we hypothesized that abnormal AC regulation may constitute the missing link between HPRT deficiency and the neuropsychiatric symptoms in LND. To test this hypothesis, we studied AC activity in membranes from primary human skin and immortalized mouse skin fibroblasts, mouse Neuro-2a neuroblastoma cells and rat B103 neuroblastoma cells. In B103 control membranes, GTP, ITP, XTP and UTP exhibited profound stimulatory effects on basal AC activity that approached the effects of hydrolysis-resistant nucleotide analogs. In HPRT- membranes, the stimulatory effects of GTP, ITP, XTP and UTP were strongly reduced. Similarly, in human and mouse skin fibroblast membranes we also observed a decrease in GTP-stimulated AC activity in HPRT-deficient cells compared with the respective controls. In mouse Neuro-2a neuroblastoma membranes, AC activity in the presence of GTP was below the detection limit of the assay. We discuss several possibilities to explain the abnormalities in AC regulation in HPRT deficiency that encompass various species and cell types.