tbuckley/cabot-search huggingface dataset:
Population-specific influence of<i>SLC2A9</i>genotype on the acute hyperuricaemic response to a fructose load
Authors: Nicola Dalbeth, Meaghan E House, Gregory D Gamble, Anne Horne, Bregina Pool, Lauren Purvis, Angela Stewart, Marilyn Merriman, Murray Cadzow, Amanda Phipps-Green, Tony R Merriman
Journal: Annals of the Rheumatic Diseases (2013)

SLC2A9 is a strong genetic risk factor for hyperuricaemia and gout. SLC2A9 (GLUT9) is a high capacity urate transporter and reportedly transports glucose and fructose. Intake of fructose-containing beverages is associated with development of hyperuricaemia and gout.To determine whether genetic variation in SLC2A9 influences the acute serum urate response to a fructose load.Following an overnight fast, 76 healthy volunteers (25 Māori, 26 Pacific, 25 European Caucasian) drank a solution containing 64 g fructose. Serum and urine were obtained immediately before and then 30, 60, 120 and 180 min after ingestion. The SLC2A9 single nucleotide polymorphism (SNP) rs11942223 was genotyped and data were analysed based on the presence or absence of the gout protective minor allele (C).The rs11942223 C allele was present in 17 participants (22%). In the entire group, fructose intake led to an increase in serum urate, which peaked 60 min following fructose ingestion (analysis of variance p=0.006). The presence of the C allele was associated with an attenuated hyperuricaemic response (p(SNP)<0.0001) and increased fractional excretion of uric acid (FEUA) (p(SNP)<0.0001) following the fructose load. The effects of rs11942223 variants on serum urate and FEUA in response to fructose were present only in Caucasian ancestral subgroups but not in the Māori and Pacific ancestral subgroup.Variation in SLC2A9 influences acute serum urate and FEUA responses to a fructose load. SLC2A9 genotype may influence the development of gout on exposure to fructose-containing beverages, particularly in European Caucasian populations.
Hypercholesterolaemia is not associated with early atherosclerotic lesions in primary biliary cirrhosis
Authors: M Allocca, A Crosignani, A Gritti, G Ghilardi, D Gobatti, D Caruso, M Zuin, M Podda, P M Battezzati
Journal: Gut (2006)

Hypercholesterolaemia often occurs in primary biliary cirrhosis (PBC) as a result of chronic cholestasis, but whether these patients are exposed to greater cardiovascular risk is unknown.To establish whether hypercholesterolaemia is associated with subclinical atherosclerosis in PBC.103 consecutive patients with PBC (37 with total cholesterol > or =6.21 mmol/l) and 37 controls with hypercholesterolaemia, and 141 matched controls with normocholesterolaemia.Ultrasound imaging of carotid artery to determine intima-media thickness (IMT) and stenosis.Controls with hypercholesterolaemia had higher IMT and prevalence of carotid stenosis compared with patients with hypercholesterolaemic PBC (mean (SD) 0.850 (0.292) mm v 0.616 (0.137) mm, p(c)<0.001; 43% v 19%, p(c) = 0.129) who, in turn, were similar to the 66 patients with normocholesterolaemic PBC (0.600 (0.136) mm; 5%). Compared with subjects with normocholesterolaemia, controls with hypercholesterolaemia, but not patients with hypercholesterolaemic PBC, had an increased risk of raised IMT (odds ratio (OR) 5.4, 95% confidence interval (CI) 2.5 to 11.9, p<0.001; and 0.7, 0.3 to 2.0, p = 0.543) or carotid stenosis (8.2, 3.4 to 20, p<0.001; and 2.5, 0.9 to 6.9, p = 0.075). In PBC, compared with younger patients without hypertension, the risk of increased IMT was OR (CI) 3.1 (0.6 to 17; p = 0.192) in patients with hypertension or old age, but not hypercholesterolaemia, and 4.6 (0.8 to 27; p = 0.096) in patients who also had hypercholesterolaemia. The corresponding figures for risk of stenosis were 3.6 (0.4 to 36; p = 0.277) and 15.8 (1.8 to 141; p = 0.014).Hypercholesterolaemia is not consistently associated with subclinical atherosclerosis in PBC, but should be treated if other risk factors for cardiovascular disease are also present. The search for factors that may protect patients with hypercholesterolaemic PBC against atherosclerosis should be encouraged.
Smooth muscle cells and vascular diseases
Authors: J.-B. Michel, Z. Li, P. Lacolley
Journal: Cardiovascular Research (2012)

Vascular smooth muscle cells (VSMCs) are the stromal cells of the vascular wall, and, due to their myosin/actin interactions, they are also responsible for arterial contractile tonus and regulating blood pressure and flow in relation to specific metabolic demands. VSMCs show considerable differences depending on their position in the arterial tree (large conduit vs. small resistance vessels), their embryologic origin, and their organ-dependent microenvironment; the heart, brain, kidney, etc. As the stromal cells of the arterial wall, VSMCs synthesize and secrete insoluble extracellular matrix (ECM) molecules that assume the function of withstanding the high pressure of the circulating blood in the arterial system. For example, totally decellularized aortic grafts, created using sodium dodecyl sulphate detergent, are experimentally able to resist arterial blood pressure in the aorta in vivo , without dilating.1 This mechanical function predominates in large vessels, since pressure-dependent stress of the wall is also dependent on the diameter.2 Therefore, cell–ECM interactions are of particular importance in these large arteries. The contractile tonus of VSMCs, dependent on sympathetic innervation, is responsible for the peripheral resistance to blood flow generated by the beating heart, leading to the genesis of blood pressure. This function is mainly the characteristic of resistance arteries and arterioles and involves cell–cell interactions.

Due to pressure-dependent radial hydraulic conductance, the arterial wall is constantly submitted to outward convection of circulating plasma molecules.3 This physiological outward convection of plasma peptides or macromolecules is the main source of extrinsic stimuli, which, with time, cause damage to arterial VSMCs (pressure-dependent strain, lipid overload, hyperglycaemia, zymogens). In response to changes in their plasma-dependent microenvironment, VSMCs may either die or adapt, modifying their phenotype through acute, ligand/receptor-dependent signalling pathways or chronic nuclear signalling involving epigenetic molecular remodelling of their nuclear chromatin. VSMCs can also be the target of intrinsic …
Lessons From Anti–Vascular Endothelial Growth Factor and Anti–Vascular Endothelial Growth Factor Receptor Trials in Patients With Glioblastoma
Authors: Christine Lu-Emerson, Dan G. Duda, Kyrre E. Emblem, Jennie W. Taylor, Elizabeth R. Gerstner, Jay S. Loeffler, Tracy T. Batchelor, Rakesh K. Jain
Journal: Journal of Clinical Oncology (2015)

Treatment of glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains a significant unmet need in oncology. Historically, cytotoxic treatments provided little durable benefit, and tumors recurred within several months. This has spurred a substantial research effort to establish more effective therapies for both newly diagnosed and recurrent GBM. In this context, antiangiogenic therapy emerged as a promising treatment strategy because GBMs are highly vascular tumors. In particular, GBMs overexpress vascular endothelial growth factor (VEGF), a proangiogenic cytokine. Indeed, many studies have demonstrated promising radiographic response rates, delayed tumor progression, and a relatively safe profile for anti-VEGF agents. However, randomized phase III trials conducted to date have failed to show an overall survival benefit for antiangiogenic agents alone or in combination with chemoradiotherapy. These results indicate that antiangiogenic agents may not be beneficial in unselected populations of patients with GBM. Unfortunately, biomarker development has lagged behind in the process of drug development, and no validated biomarker exists for patient stratification. However, hypothesis-generating data from phase II trials that reveal an association between increased perfusion and/or oxygenation (ie, consequences of vascular normalization) and survival suggest that early imaging biomarkers could help identify the subset of patients who most likely will benefit from anti-VEGF agents. In this article, we discuss the lessons learned from the trials conducted to date and how we could potentially use recent advances in GBM biology and imaging to improve outcomes of patients with GBM who receive antiangiogenic therapy.
Monocyte subpopulations and cardiovascular risk in chronic kidney disease
Authors: Gunnar H. Heine, Alberto Ortiz, Ziad A. Massy, Bengt Lindholm, Andrzej Wiecek, Alberto Martínez-Castelao, Adrian Covic, David Goldsmith, Gültekin Süleymanlar, Gérard M. London, Gianfranco Parati, Rosa Sicari, Carmine Zoccali, Danilo Fliser
Journal: Nature Reviews Nephrology (2012)
Cardiac metabolsim: its contributions to alcoholic heart disease and myocardial failure.
Authors: R J Bing
Journal: Circulation (1978)

Changes in cardiac metabolism in myocardial failure and after alcohol ingestion are discussed. The main effect of alcohol ingestion is loss of cardiac contractility. Since heart muscle does not contain alcohol dehydrogenase, its toxicity is probably the result of a direct toxic effect of ethanol and acetaldehyde on the myocardial cell, possibly involving various membrane systems. Alcohol inhibits mitochondrial respiration and the activity of enzymes in the tricarboxylic acid cycle, and its interferes with both mitochondrial calcium uptake and binding. Ethanol profoundly affects myocardial lipid metabolism. Acetaldehyde diminishes myocardial protein synthesis and inhibits Ca++-activated myofibrillar ATPase. In myocardial failure, a series of possibilities may be responsible for the loss of contractility. Excitation-contraction coupling could be disturbed at the level of the sarcolemma, at the sarcoplasmic reticulum, at the mitochondria, and between calcium and the regulatory proteins. Deficiencies in Ca++ delivery systems of excitation-contraction coupling on the myosin ATPase activity could be responsible for the dimunition in cardiac contractility. Mitochondrial function may also be involved, since mitochondria from failing human hearts are defective with respect to respiratory control and calcium accumulation. Under certain conditions, the relationship of mitochondria to calcium sequestration is very important in influencing contractility. The involvement of contractile and regulatory proteins in myocardial failure cannot be excluded.
Does allometry mask important brain structure residuals relevant to species-specific behavioral evolution?
Authors: Ralph L. Holloway
Journal: Behavioral and Brain Sciences (2001)

Despite the ontogenetic allometric size effects that explain much of phyletic variation in brain components, the residuals of some structures indicates that mosaic brain evolution was an important factor in hominid evolution, and that reorganization of the hominid brain may have occurred as early as 3+ MY. Finlay et al.'s allometric technique masks residual variation around allometric trends, and the patterns of residuals relevant to species-specific departures from strict allometric trends.
Adaptive Evolution of M3 Lysin—A Candidate Gamete Recognition Protein in the Mytilus edulis Species Complex
Authors: Thiago G. Lima, Michael A. McCartney
Journal: Molecular Biology and Evolution (2013)

Marine invertebrate gamete recognition proteins (GRPs) are classic examples of rapid adaptive evolution of reproductive proteins, and hybridizing Mytilus blue mussels allow us to study the evolution of GRPs during speciation following secondary contact. Even with frequent hybridization, positive selection drives divergence of M7 lysin, one of the three Mytilus egg vitelline envelope (VE) lysins. Mytilus trossulus and M. edulis form a broad hybrid zone in the Canadian Maritimes and eastern Maine, isolated by strong (but partial) gamete incompatibility. M7 lysin, however, is an unlikely GRP controlling this gametic incompativility, as earlier studies showed either weak or no positive selection and extensive introgression between the two species. We used reverse transcriptase-polymerase chain reaction and cloned several alleles of M3 lysin, a potent VE lysin encoded by a nonhomologous gene whose evolution has not been studied. McDonald–Kreitman and HKA tests reveal strong positive selection, which PAML branch-site models detect in 19.7% of the codons. Protein structure predictions show that replacements map exclusively to one face of the carbohydrate recognition domain (CRD) of this C-type lectin, with codons under positive selection localizing to CRD regions known to control ligand specificity. Polymorphism/divergence analyses show that selective sweep has purged M. edulis but not M. trossulus of polymorphism, and unique to M3 is an absence of fixed substitutions and broad haplotype sharing between M. edulis and Mediterranean M. galloprovincialis. Taken together, these results suggest that different lysins serve as GRPs in different Mytilus hybrid zones, with M3 likely co-opted to play this role in the western Atlantic.
TWO DISEASES DUE TO FASHION IN CLOTHING: CHLOROSIS AND CHRONIC ERYTHEMA OF THE LEGS
Authors: F. P. Weber
Journal: BMJ (1925)

It is interesting to note that it is not necessary to have a negative balance-that is, a greater excretion than intake-of calcium or plhosphorus before rickets develops.So long as there is enough calcium and phosphorus absorbed to satisfy the nminimal demand for ossification, rickets will not develop.When absorption falls below this level rickets develops.-Sincethese pages were written Steenbock and Black, and alsoHess, have published papers claiming that rickets can be pre- veinted in rats by radiating the diet with ultra-violet light.Steenbock and Black radiate the whole diet, and claim that feeding this to the animal prevents the development of rickets.Hess radiates an inactive oil-cottonseed oil-and claims that feeding a little of this with the daily ration prevents rickets.Independent confirmation of this important work seems necessary, so we have carried out some experiments with that Dbject in view.We adopted the technique we ha've used throughout this work.Four groups of rats were taken, each rat weighing about 40 grams.Group 1 were fed on Sherman and Pappenheimer's diet 84 previously described.The diet, after being made up into a stiff paste with distilled water, was spread on a clock glass in a tfiin layer and placed under a mercury vapour lamp twelve inches from the burner and radiated for half an hour.It was then given to the rats daily for twenty-eight days, when the rats were killed and x-rayed.They showed no signs of rickets.Group 2 were fed on the standard diet, and in addition received 0.5'gram daily of an inactive linseed oil that had been radiated half an hour twelve inches from the mercury vapour lamp.Fresh oil was radiated for each day's ration.The rats were killed after twenty-eight days and x-rayed.They also showed no signs of rickets.In Group 3 the patent flour portion of the diet'only was radiated as described above; after mixing with the other con- stituents it was given to the rats.At the end of twenty-eight days these rats proved to be free from rickets.Group 4 were fed on the standard diet, and in addition they received a daily dose of radiated hardened cottonseed oil.This Dil, which is really a solid fat, is a commercial product that we have used for other experiments on account of its complete freedom from fat-soluble vitamin A. It is the liquid cottonseed oil of commerce that has been hardened by the technical process of hydrogenation.It was radiated in the following way: the oil was melted into a transparent quartz flask; this flask was attached to a slow-running motor and slowly rotated between two mercury vapour lamps, six inches from each lamp, and radiated for a
Osteoarthritis in football: FIFA/F-MARC approach
Authors: Jiri Dvorak
Journal: British Journal of Sports Medicine (2011)

Centrosome positioning relative to the nucleus and cell shape is highly regulated across cell types, during cell migration and during spindle formation in cell division. Across most sexually reproducing animals, centrosomes are provided to the oocyte through fertilization and must be positioned properly to establish the zygotic mitotic spindle. How centrosomes are positioned in space and time through the concerted action of key mitotic entry biochemical regulators including Protein Phosphatase 2A (PP2A-B55/SUR-6), biophysical regulators including Dynein and the nuclear lamina is unclear. Here, we uncover a role for PP2A-B55/SUR-6 in regulating centrosome positioning. Mechanistically, PP2A-B55/SUR-6 regulates nuclear size prior to mitotic entry, in turn affecting nuclear envelope-based Dynein density and motor capacity. Using computational simulations, PP2A-B55/ SUR-6 regulation of nuclear size and nuclear envelope Dynein density were both predicted to be required for proper centrosome positioning. Conversely, compromising nuclear lamina integrity led to centrosome detachment from the nuclear envelope and migration defects. Removal of PP2A-B55/SUR-6 and the nuclear lamina simultaneously further disrupted centrosome positioning, leading to unseparated centrosome pairs dissociated from the nuclear envelope. Taken together, we propose a model in which centrosomes migrate and are positioned through the concerted action of nuclear envelope-based Dynein pulling forces and cen-trosome-nuclear envelope tethering.
Structure of Cerebral Arterioles in Mice Deficient in Expression of the Gene for Endothelial Nitric Oxide Synthase
Authors: Gary L. Baumbach, Curt D. Sigmund, Frank M. Faraci
Journal: Circulation Research (2004)

We examined effects of pharmacological inhibition of nitric oxide synthase (NOS) and genetic deficiency of the endothelial isoform of NOS (eNOS) on structure and mechanics of cerebral arterioles. We measured pressure, diameter, and cross-sectional area (CSA) of the vessel wall (histologically) in maximally dilated cerebral arterioles in mice that were untreated or treated for 3 months with the NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg per day in drinking water). Treatment with L-NAME increased systemic arterial mean pressure (SAP; 143+/-4 versus 121+/-4 mm Hg, P<0.05) and CSA (437+/-27 versus 310+/-34 microm2, P<0.05). These findings suggest that hypertension induced in mice by NOS inhibition is accompanied by hypertrophy of cerebral arterioles. To determine the role of the eNOS isoform in regulation of cerebral vascular growth, we examined mice with targeted disruption of one (heterozygous) or both (homozygous) genes encoding eNOS. Wild-type littermates served as controls. SAP and CSA were significantly increased in homozygous (SAP, 141+/-5 versus 122+/-3 mm Hg in wild-type mice, P<0.05; CSA, 410+/-18 versus 306+/-15 microm2 in wild-type mice, P<0.05), but not in heterozygous (SAP, 135+/-4 mm Hg; CSA, 316+/-32 microm2) eNOS-deficient mice. Carotid ligation normalized cerebral arteriolar pulse pressure did not prevent increases in CSA in homozygous eNOS-deficient mice. Thus, cerebral arterioles undergo hypertrophy in homozygous eNOS-deficient mice, even in the absence of increases in arteriolar pulse pressure. These findings suggest that eNOS plays a major role in regulation of cerebral vascular growth.
Associations between the PTPN22 1858C-&gt;T polymorphism and radiographic joint destruction in patients with rheumatoid arthritis: results from a 10-year longitudinal study
Authors: B. A Lie, M. K Viken, S. Odegard, D. van der Heijde, R. Landewe, T. Uhlig, T. K Kvien
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> To investigate whether the <i>PTPN22</i> 1858T risk variant is associated with the rate of radiographic progression in rheumatoid arthritis (RA). <h3>Methods:</h3> A longitudinally followed cohort of 238 Norwegian patients with RA (the EURIDISS cohort) was genotyped for the <i>PTPN22</i> 1858C→T polymorphism. Radiographic damage was assessed by hand radiographs at baseline and after 1, 2, 5 and 10 years, and the radiographs were scored with the Sharp method modified by van der Heijde (Sharp–van der Heijde score) by a single experienced reader. Baseline serum levels of rheumatoid factor and anti-cyclic citrullinated peptide autoantibodies were also examined. <h3>Results:</h3> The reported association between RA susceptibility and carriage of the T allele (34.4% in patients vs 21.4% in controls; odds ratio 1.92, 95% confidence interval 1.36 to 2.71, p = 0.0002) was confirmed. An association between annual progression rate of Sharp–van der Heijde score and T-allele carriers (p = 0.01),was also found, which was also present when only patients positive for the shared epitope were analysed (p = 0.03). This association was also maintained in multivariate analyses adjusting for shared epitope and demographic variables. <h3>Conclusions:</h3> An association between the <i>PTPN22</i> risk variant and increased progression rate for structural damage was found. The results indicate that the <i>PTPN22</i> gene may not only be associated with disease susceptibility, but also with disease progression.
OBSERVATIONS CONCERNING THE PRODUCTION AND EXCRETION OF CHOLESTEROL IN MAMMALS
Authors: Sanford O. Byers, Meyer Friedman, Max W. Biggs, Barbara Gunning
Journal: The Journal of Experimental Medicine (1953)

Accumulation of cholate in plasma is the immediate cause of hypercholesteremia in the rat with bile duct ligation and in the normal rat given intravenous sodium cholate. The hypercholesteremia induced by cholate administration does not appear to be dependent upon any preceding change in the rates of absorption, excretion, synthesis, or redistribution of cholesterol in the tissues of the animal. Cholate administration seems to induce hypercholesteremia by impeding the normal rate of passage of cholesterol from the plasma into the liver; this impedance is probably due to an alteration of the cholesterol-binding power of plasma proteins induced by cholate. The chemical and physiological implications of this finding are discussed.
survival with an asymmetrical brain: advantages and disadvantages of cerebral lateralization
Authors: giorgio vallortigara, lesley j. rogers
Journal: Behavioral and Brain Sciences (2005)

recent evidence in natural and semi-natural settings has revealed a variety of left-right perceptual asymmetries among vertebrates. these include preferential use of the left or right visual hemifield during activities such as searching for food, agonistic responses, or escape from predators in animals as different as fish, amphibians, reptiles, birds, and mammals. there are obvious disadvantages in showing such directional asymmetries because relevant stimuli may be located to the animal's left or right at random; there is no a priori association between the meaning of a stimulus (e.g., its being a predator or a food item) and its being located to the animal's left or right. moreover, other organisms (e.g., predators) could exploit the predictability of behavior that arises from population-level lateral biases. it might be argued that lateralization of function enhances cognitive capacity and efficiency of the brain, thus counteracting the ecological disadvantages of lateral biases in behavior. however, such an increase in brain efficiency could be obtained by each individual being lateralized without any need to align the direction of the asymmetry in the majority of the individuals of the population. here we argue that the alignment of the direction of behavioral asymmetries at the population level arises as an “evolutionarily stable strategy” under “social” pressures occurring when individually asymmetrical organisms must coordinate their behavior with the behavior of other asymmetrical organisms of the same or different species.