tbuckley/cabot-search huggingface dataset:
Circulating Estradiol and Mortality in Men With Systolic Chronic Heart Failure
Authors: Ewa A. Jankowska
Journal: JAMA (2009)

Androgen deficiency is common in men with chronic heart failure (HF) and is associated with increased morbidity and mortality. Estrogens are formed by the aromatization of androgens; therefore, abnormal estrogen metabolism would be anticipated in HF.To examine the relationship between serum concentration of estradiol and mortality in men with chronic HF and reduced left ventricular ejection fraction (LVEF).A prospective observational study at 2 tertiary cardiology centers (Wroclaw and Zabrze, Poland) of 501 men (mean [SD] age, 58 [12] years) with chronic HF, LVEF of 28% (SD, 8%), and New York Heart Association [NYHA] classes 1, 2, 3, and 4 of 52, 231, 181, and 37, respectively, who were recruited between January 1, 2002, and May 31, 2006. Cohort was divided into quintiles of serum estradiol (quintile 1, < 12.90 pg/mL; quintile 2, 12.90-21.79 pg/mL; quintile 3, 21.80-30.11 pg/mL; quintile 4, 30.12-37.39 pg/mL; and quintile 5, > or = 37.40 pg/mL). Quintile 3 was considered prospectively as the reference group.Serum concentrations of estradiol and androgens (total testosterone and dehydroepiandrosterone sulfate [DHEA-S]) were measured using immunoassays.Among 501 men with chronic HF, 171 deaths (34%) occurred during the 3-year follow-up. Compared with quintile 3, men in the lowest and highest estradiol quintiles had increased mortality (adjusted hazard ratio [HR], 4.17; 95% confidence interval [CI], 2.33-7.45 and HR, 2.33; 95% CI, 1.30-4.18; respectively; P < .001). These 2 quintiles had different clinical characteristics (quintile 1: increased serum total testosterone, decreased serum DHEA-S, advanced NYHA class, impaired renal function, and decreased total fat tissue mass; and quintile 5: increased serum bilirubin and liver enzymes, and decreased serum sodium; all P < .05 vs quintile 3). For increasing estradiol quintiles, 3-year survival rates adjusted for clinical variables and androgens were 44.6% (95% CI, 24.4%-63.0%), 65.8% (95% CI, 47.3%-79.2%), 82.4% (95% CI, 69.4%-90.2%), 79.0% (95% CI, 65.5%-87.6%), and 63.6% (95% CI, 46.6%-76.5%); respectively (P < .001).Among men with chronic HF and reduced LVEF, high and low concentrations of estradiol compared with the middle quintile of estradiol are related to an increased mortality.
Glioma cancer stem cells induce immunosuppressive macrophages/microglia
Authors: Adam Wu, Jun Wei, Ling-Yuan Kong, Yongtao Wang, Waldemar Priebe, Wei Qiao, Raymond Sawaya, Amy B. Heimberger
Journal: Neuro-Oncology (2010)

Macrophages (MΦs)/microglia that constitute the dominant tumor-infiltrating immune cells in glioblastoma are recruited by tumor-secreted factors and are induced to become immunosuppressive and tumor supportive (M2). Glioma cancer stem cells (gCSCs) have been shown to suppress adaptive immunity, but their role in innate immunity with respect to the recruitment and polarization of MΦs/microglia is unknown. The innate immunosuppressive properties of the gCSCs were characterized based on elaborated MΦ inhibitory cytokine-1 (MIC-1), transforming growth factor (TGF-β1), soluble colony-stimulating factor (sCSF), recruitment of monocytes, inhibition of MΦ/microglia phagocytosis, induction of MΦ/microglia cytokine secretion, and the inhibition of T-cell proliferation. The role of the signal transducer and activator of transcription 3 (STAT3) in mediating innate immune suppression was evaluated in the context of the functional assays. The gCSCs produced sCSF-1, TGF-β1, and MIC-1, cytokines known to recruit and polarize the MΦs/microglia to become immunosuppressive. The gCSC-conditioned medium polarized the MΦ/microglia to an M2 phenotype, inhibited MΦ/microglia phagocytosis, induced the secretion of the immunosuppressive cytokines interleukin-10 (IL-10) and TGF-β1 by the MΦs/microglia, and enhanced the capacity of MΦs/microglia to inhibit T-cell proliferation. The inhibition of phagocytosis and the secretion of IL-10 were reversed when the STAT3 pathway was blocked in the gCSCs. The gCSCs modulate innate immunity in glioblastoma by inducing immunosuppressive MΦs/microglia, and this capacity can be reversed by inhibiting phosphorylated STAT3.
Exacerbations of chronic obstructive pulmonary disease
Authors: B. R. Celli, P. J. Barnes
Journal: European Respiratory Journal (2007)

Exacerbations of chronic obstructive pulmonary disease are of major importance in terms of their prolonged detrimental effects on patients, the acceleration in disease progression and high healthcare costs. There is still debate about how exacerbations should be defined and graded, and their mechanisms are poorly understood. The major causal agents are either bacteria or viral infections, or a combination of the two. Noninfective causes include air pollution and pulmonary embolus but, in some patients, no cause is identified. Exacerbations represent an increase in the inflammation that is present in the stable state, with increased numbers of inflammatory cells (particularly neutrophils), cytokines, chemokines and proteases in the airways, and increased concentrations of certain cytokines and C-reactive protein in the blood. There are presently no reliable biomarkers with which to predict exacerbations. Exacerbations have a long-lasting adverse influence on health status. High doses of bronchodilators are the mainstay of treatment and systemic corticosteroids have some benefit. The routine use of antibiotics remains controversial but they are of benefit with exacerbations of a bacterial origin. Noninvasive ventilation is beneficial in preventing the need for intubation and its important complications but it is not certain whether its use in stable patients prevents exacerbations. Although important advances have been made, more effective treatments are needed in the future for prevention and treatment of exacerbations.
Cardiovascular fitness modifies the associations between physical activity and abdominal adiposity in children and adolescents: the European Youth Heart Study
Authors: F B Ortega, J R Ruiz, A Hurtig-Wennlöf, G Vicente-Rodríguez, N S Rizzo, M J Castillo, M Sjöström
Journal: British Journal of Sports Medicine (2008)

Objective To examine the associations between physical activity (PA) and abdominal adiposity, as measured by waist circumference, in children and adolescents, and to test whether cardiovascular fitness (CVF) modifies these associations. Methods PA components were measured by accelerometry in 1075 individuals aged 9 or 15 years old. CVF was measured by a maximal cycling test. Self-reported maternal educational level, body mass index, children's birth weight and television viewing were used as confounders. Results Linear regression did not show any association between the PA variables and waist circumference, after controlling for sex, age and height. When stratifying by CVF level (low/high), time spent at vigorous PA was inversely associated with waist circumference (p≤0.05) in the low CVF group. Unexpectedly, in the high CVF group, the PA variables were positively associated with waist circumference (p≤0.05). In both groups, the results were unchanged after controlling for the confounders. CVF was inversely associated with waist circumference, after controlling for all PA variables (p≤0.01) and confounders (p≤0.01). Conclusion CVF is inversely associated with abdominal adiposity and seems to modify the associations between PA and abdominal adiposity. In low-fit children and adolescents, time spent in vigorous PA seems to be the key component linked to abdominal adiposity. This finding should be considered in further development of lifestyle intervention strategies. The results found in the high-fit group need to be confirmed.
c-Fos protein as a target of anti-osteoclastogenic action of vitamin D, and synthesis of new analogs
Authors: H. Takasu
Journal: Journal of Clinical Investigation (2006)

Although active vitamin D drugs have been used for the treatment of osteoporosis, how the vitamin D receptor (VDR) regulates bone cell function remains largely unknown. Using osteoprotegerin-deficient mice, which exhibit severe osteoporosis due to excessive receptor activator of NF-κB ligand/receptor activator of NF-κB (RANKL/RANK) stimulation, we show herein that oral treatment of these mice with 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] inhibited bone resorption and prevented bone loss, suggesting that VDR counters RANKL/RANK signaling. In M-CSF–dependent osteoclast precursor cells isolated from mouse bone marrow, 1α,25(OH)2D3 potently and dose-dependently inhibited their differentiation into multinucleate osteoclasts induced by RANKL. Among signaling molecules downstream of RANK, 1α,25(OH)2D3 inhibited the induction of c-Fos protein after RANKL stimulation, and retroviral expression of c-Fos protein abrogated the suppressive effect of 1α,25(OH)2D3 on osteoclast development. By screening vitamin D analogs based on their c-Fos–suppressing activity, we identified a new analog, named DD281, that inhibited bone resorption and prevented bone loss in ovariectomized mice, more potently than 1α,25(OH)2D3, with similar levels of calcium absorption. Thus, c-Fos protein is an important target of the skeletal action of VDR-based drugs, and DD281 is a bone-selective analog that may be useful for the treatment of bone diseases with excessive osteoclastic activity.
Update in Sleep and Control of Ventilation 2007
Authors: Richard L. Horner, T. Douglas Bradley
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

with cognitive deficits and behavioral abnormalities, but this does not occur in all children and is not fully accounted for by OSA severity. Gozal and colleagues (3) hypothesized that C-reactive protein levels may identify children with OSA who have high susceptibility for cognitive abnormalities. In a community-based study of snoring and nonsnoring school-aged children (5–7 yr, n 5 278 subjects), C-reactive protein levels were measured in the morning after full polysomnography, and a battery of neurocognitive tests were also performed. C-reactive protein levels were nearly double in the children with OSA compared with control subjects (0.36 6 0.11 vs. 0.19 6 0.07 mg/dl). Importantly, these levels were further elevated in the children with OSA who also exhibited neurocognitive deficits compared with the children with OSA who had normal cognitive assessments, again with the difference being approximately twofold (0.48 6 0.12 vs. 0.21 6 0.08 mg/dl). Although cause and effect were not proven in this study, the results highlight that the level of systemic inflammation in pediatric sleepdisordered breathing, as indicated by C-reactive protein, is associated with adverse neurobehavioral outcomes. The effects of OSA on behavioral outcomes may relate to recent findings that exposure to long-term intermittent hypoxia in a mouse model of OSA causes irreversible impairments in the neuronal systems regulating wakefulness, especially selective loss of catecholaminergic arousal neurons via NADPH oxidase–mediated neuronal injury (4).
Suppressive effect of oestradiol on chemical hepatocarcinogenesis in rats
Authors: I Shimizu, M Yasuda, Y Mizobuchi, Y-R Ma, F Liu, M Shiba, T Horie, S Ito
Journal: Gut (1998)

Aims —To examine the effects of oestradiol and testosterone on the early carcinogenic changes expressed in rat liver from the diethylnitrosamine (DEN), 2-acetylaminofluorene (AAF), partial hepatectomy (PH) model of hepatocarcinogenesis. Methods —Preneoplastic liver lesions were evaluated using immunohistochemical analysis of glutathione-S-transferase placental form (GST-P) expression; oestrogen and androgen receptor levels were measured by radioimmunoassay. Results—Oestradiol administration to non-castrated DEN-AAF-PH treated males resulted in a decrease in the area of GST-P positive foci, while testosterone increased the serum oestradiol level and reduced the area. In males, castration alone and castration with oestradiol replacement significantly reduced the GST-P positive area, and increased the hepatic oestrogen receptor level. In DEN-AAF-PH treated females, castration with testosterone replacement was associated with a significant increase in the GST-P positive area and the hepatic androgen receptor level. Conclusion —These findings suggest that exogenous and endogenous oestradiol can suppress chemical hepatocarcinogenesis. It appears that oestrogen receptors may be involved in the inhibition of malignant transformation of preneoplastic liver cells, while androgens and androgen receptors are involved in hepatocarcinogenesis.
Presentation of rheumatoid arthritis and its relation to prognosis.
Authors: F D Hart
Journal: BMJ (1977)

A review of published reports in an attempt to relate the way rheumatoid arthritis presents to its manner of progression and prognosis has provided few positive answers. Certain, but not all, studies indicate that cases with an acute explosive onset do better than those of more insidious onset, but the latter have almost certainly lasted longer by the time they come under medical supervision. Cases of monarthritis and palindromic (remittent) arthritis do better than polyarthritic and persistent cases, but true diagnosis of the former is often uncertain. Undoubtedly persistent high-titre seropositivity and nodule formation are bad prognostic pointers. A plea is made for a more intensive study of the early case: if any therapeutic agent now or in the future can reverse the inflammatory process this is surely the time it is most likely to do so. This is the curable end of what is now an incurable disease.
Creating Order from Chaos: Cellular Regulation by Kinase Anchoring
Authors: John D. Scott, Carmen W. Dessauer, Kjetil Taskén
Journal: The Annual Review of Pharmacology and Toxicology (2012)

Second messenger responses rely on where and when the enzymes that propagate these signals become active. Spatial and temporal organization of certain signaling enzymes is controlled in part by A-kinase anchoring proteins (AKAPs). This family of regulatory proteins was originally classified on the basis of their ability to compartmentalize the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (also known as protein kinase A, or PKA). However, it is now recognized that AKAPs position G protein-coupled receptors, adenylyl cyclases, G proteins, and their effector proteins in relation to protein kinases and signal termination enzymes such as phosphodiesterases and protein phosphatases. This arrangement offers a simple and efficient means to limit the scope, duration, and directional flow of information to sites deep within the cell. This review focuses on the pros and cons of reagents that define the biological role of kinase anchoring inside cells and discusses recent advances in our understanding of anchored second messenger signaling in the cardiovascular and immune systems.
Identification of <i>cis</i> - and <i>trans</i> -Acting Genetic Variants Explaining Up to Half the Variation in Circulating Vascular Endothelial Growth Factor Levels
Authors: Stephanie Debette, Sophie Visvikis-Siest, Ming-Huen Chen, Ndeye-Coumba Ndiaye, Ci Song, Anita Destefano, Radwan Safa, Mohsen Azimi Nezhad, Douglas Sawyer, Jean-Brice Marteau, Vanessa Xanthakis, Gerard Siest, Lisa Sullivan, Michele Pfister, Holly Smith, Seung-Hoan Choi, John Lamont, Lars Lind, Qiong Yang, Peter Fitzgerald, Erik Ingelsson, Ramachandran S. Vasan, Sudha Seshadri
Journal: Circulation Research (2011)

Vascular endothelial growth factor (VEGF) affects angiogenesis, atherosclerosis, and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings.Our aim was to identify genetic variants associated with circulating VEGF levels, using an unbiased genome-wide approach, and to explore their functional significance with gene expression and pathway analysis.We undertook a genome-wide association study of serum VEGF levels in 3527 participants of the Framingham Heart Study, with preplanned replication in 1727 participants from 2 independent samples, the STANISLAS Family Study and the Prospective Investigation of the Vasculature in Uppsala Seniors study. One hundred forty single nucleotide polymorphism (SNPs) reached genome-wide significance (P<5×10(-8)). We found evidence of replication for the most significant associations in both replication datasets. In a conditional genome-wide association study, 4 SNPs mapping to 3 chromosomal regions were independently associated with circulating VEGF levels: rs6921438 and rs4416670 (6p21.1, P=6.11×10(-506) and P=1.47×10(-12)), rs6993770 (8q23.1, P=2.50×10(-16)), and rs10738760 (9p24.2, P=1.96×10(-34)). A genetic score including these 4 SNPs explained 48% of the heritability of serum VEGF levels. Six of the SNPs that reached genome-wide significance in the genome-wide association study were significantly associated with VEGF messenger RNA levels in peripheral blood mononuclear cells. Ingenuity pathway analyses showed found plausible biological links between VEGF and 2 novel genes in these loci (ZFPM2 and VLDLR).Genetic variants explaining up to half the heritability of serum VEGF levels were identified. These new insights provide important clues to the pathways regulating circulating VEGF levels.
Patterns of sequence conservation in presynaptic neural genes.
Authors: Dexter Hadley, Tara Murphy, Otto Valladares, Sridhar Hannenhalli, Lyle Ungar, Junhyong Kim, Maja Bućan
Journal: Genome biology (2006)

Abstract Background The neuronal synapse is a fundamental functional unit in the central nervous system of animals. Because synaptic function is evolutionarily conserved, we reasoned that functional sequences of genes and related genomic elements known to play important roles in neurotransmitter release would also be conserved. Results Evolutionary rate analysis revealed that presynaptic proteins evolve slowly, although some members of large gene families exhibit accelerated evolutionary rates relative to other family members. Comparative sequence analysis of 46 megabases spanning 150 presynaptic genes identified more than 26,000 elements that are highly conserved in eight vertebrate species, as well as a small subset of sequences (6%) that are shared among unrelated presynaptic genes. Analysis of large gene families revealed that upstream and intronic regions of closely related family members are extremely divergent. We also identified 504 exceptionally long conserved elements (≥360 base pairs, ≥80% pair-wise identity between human and other mammals) in intergenic and intronic regions of presynaptic genes. Many of these elements form a highly stable stem-loop RNA structure and consequently are candidates for novel regulatory elements, whereas some conserved noncoding elements are shown to correlate with specific gene expression profiles. The SynapseDB online database integrates these findings and other functional genomic resources for synaptic genes. Conclusion Highly conserved elements in nonprotein coding regions of 150 presynaptic genes represent sequences that may be involved in the transcriptional or post-transcriptional regulation of these genes. Furthermore, comparative sequence analysis will facilitate selection of genes and noncoding sequences for future functional studies and analysis of variation studies in neurodevelopmental and psychiatric disorders.
Towards a unified science of cultural evolution
Authors: Alex Mesoudi, Andrew Whiten, Kevin N. Laland
Journal: Behavioral and Brain Sciences (2006)

We suggest that human culture exhibits key Darwinian evolutionary properties, and argue that the structure of a science of cultural evolution should share fundamental features with the structure of the science of biological evolution. This latter claim is tested by outlining the methods and approaches employed by the principal subdisciplines of evolutionary biology and assessing whether there is an existing or potential corresponding approach to the study of cultural evolution. Existing approaches within anthropology and archaeology demonstrate a good match with the macroevolutionary methods of systematics, paleobiology, and biogeography, whereas mathematical models derived from population genetics have been successfully developed to study cultural microevolution. Much potential exists for experimental simulations and field studies of cultural microevolution, where there are opportunities to borrow further methods and hypotheses from biology. Potential also exists for the cultural equivalent of molecular genetics in "social cognitive neuroscience," although many fundamental issues have yet to be resolved. It is argued that studying culture within a unifying evolutionary framework has the potential to integrate a number of separate disciplines within the social sciences.
The Paradox of the Low-Renin State in Diabetic Nephropathy
Authors: DEBORAH A. PRICE, LISA E. PORTER, MICHAEL GORDON, NAOMI D. L. FISHER, JOSE MARIO F. DE'OLIVEIRA, LORI M. B. LAFFEL, DIANE R. PASSAN, GORDON H. WILLIAMS, NORMAN K. HOLLENBERG
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Although diabetic nephropathy is often a low renin state, the renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal renin system. PRA and renal vascular responses (inulin and para-aminohippurate clearance) to graded doses of an angiotensin II (AngII) antagonist, irbesartan, were assessed in eight healthy volunteers and 12 patients with type 2 diabetes mellitus and nephropathy on a 10 mmol Na intake, to activate the renin system. Basal PRA was suppressed in type 2 diabetes mellitus compared with the healthy subjects (0.58 ± 0.14 versus 1.58 ± 0.28 ng/L per s, mean ± SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to irbesartan in type 2 diabetes mellitus (714 ± 83 to 931 ± 116 ml/min; P = 0.002) than normal (624 ± 29 to 772 ± 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to irbesartan more gradually in the patients with type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus. This increase could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.