Genetics University of Toronto Thrombophilia Study in Women (GUTTSI): genetic and other risk factors for venous thromboembolism in women

BACKGROUND: Women may be at increased risk for venous thromboembolism (VTE) as compared with men. We studied the effects of genetic and biochemical markers of thrombophilia in women, in conjunction with other established risk factors for VTE. METHOD: The present retrospective case-control study was conducted in a thrombosis treatment programme at a large Toronto hospital. The cases were 129 women aged 16-79 years with objectively confirmed VTE. Age-matched control individuals were women who were free of venous thrombosis. Neither cases nor control individuals had known cardiovascular disease. Participants were interviewed regarding personal risk factors for VTE, including smoking, history of malignancy, pregnancy, and oestrogen or oral contraceptive use. Blood specimens were analyzed for common single nucleotide polymorphisms of prothrombin, factor V and methylenetetrahydrofolate reductase (MTHFR; C677T, A1298C and T1317C), and the A66G polymorphism for methionine synthase reductase (MTRR).Fasting plasma homocysteine was also analyzed. RESULTS: Women with VTE were significantly more likely than female control individuals to carry the prothrombin polymorphism and the factor V polymorphism, or to have fasting hyperhomocysteinaemia. Homozygosity for the C677T MTHFR gene was not a significant risk factor for VTE, or were the A1298C or T1317C MTHFR homozygous variants. Also, the A66G MTRR homozygous state did not confer an increased risk for VTE. CONCLUSION: Prothrombin and factor V polymorphisms increased the risk for VTE in women, independent from other established risk factors. Although hyperhomocysteinaemia also heightens this risk, common polymorphisms in two genes that are responsible for homocysteine remethylation do not. These findings are consistent with previous studies that included both men and women

A titanium-nitride near-infrared kinetic inductance photon-counting detector and its anomalous electrodynamics

We demonstrate single-photon counting at 1550 nm with titanium-nitride (TiN) microwave kinetic inductance detectors. Energy resolution of 0.4 eV and arrival-time resolution of 1.2 microseconds are achieved. 0-, 1-, 2-photon events are resolved and shown to follow Poisson statistics. We find that the temperature-dependent frequency shift deviates from the Mattis-Bardeen theory, and the dissipation response shows a shorter decay time than the frequency response at low temperatures. We suggest that the observed anomalous electrodynamics may be related to quasiparticle traps or subgap states in the disordered TiN films. Finally, the electron density-of-states is derived from the pulse response.Comment: 4 pages, 3 figure

Monopoles and Knots in Skyrme Theory

We show that the Skyrme theory actually is a theory of monopoles which allows a new type of solitons, the topological knots made of monopole-anti-monopole pair,which is different from the well-known skyrmions. Furthermore, we derive a generalized Skyrme action from the Yang-Mills action of QCD, which we propose to be an effective action of QCD in the infra-red limit. We discuss the physical implications of our results.Comment: 4 pages. Phys. Rev. Lett. in pres

Color Reflection Invariance and Monopole Condensation in QCD

We review the quantum instability of the Savvidy-Nielsen-Olesen (SNO) vacuum of the one-loop effective action of SU(2) QCD, and point out a critical defect in the calculation of the functional determinant of the gluon loop in the SNO effective action. We prove that the gauge invariance, in particular the color reflection invariance, exclude the unstable tachyonic modes from the gluon loop integral. This guarantees the stability of the magnetic condensation in QCD.Comment: 28 pages, 3 figures, JHEP styl

Effect of diverse supercritical extraction procedures on the odour profile of chía (Salvia hispanica L.) oil

La semilla (Salvia hispanica L.) de chía contiene alrededor de 32-39% de aceite, con un alto contenido de ácido a-linolénico (C18:3) (61–70%). La extracción mediante fluidos supercríticos (EFSC) utilizando CO2 es una alternativa interesante para la extracción de aceites vegetales ya que no presenta los inconvenientes asociados al empleo de disolventes orgánicos logrando un producto de mayor calidad. Por ello, es importante la determinación de las condiciones de presión y temperatura operativas óptimas de este proceso. Así, los valores aplicados de estos parámetros pueden afectar el perfil de olor (atributo de calidad organoléptica) del producto obtenido. El objetivo del presente trabajo fue evaluar el perfil de olor de aceite de chía obtenido por EFSC en función de las condiciones de extracción empleadas. La EFSC fue llevada cabo a presiones operativas de 250 y 450 bar, temperaturas de 40 y 60ºC, con y sin la adición de etanol como co-solvente, flujo másico de fluido supercrítico de 8 kg/h. El perfil de olor se analizó mediante una Nariz Electrónica acoplada a un Espectrómetro de Masa (NE-MS) (a-Prometheus, Alpha MOS, Francia) utilizando la metodología de espacio de cabeza estático y 18 sensores semiselectivos frente a los distintos grupos de compuestos volátiles pertenecientes al alimento. La señal generada en cada sensor es el valor de la resistencia eléctrica causada por adsorción de los compuestos volátiles. El conjunto de respuestas obtenidas en cada sensor produce un patrón característico del perfil de olor de la matriz alimenticia en estudio. Se analizaron 2,0±0,1ml de muestra previamente incubada a 35ºC durante 90s. Para el análisis, se consideró la relación entre el máximo de la variación en la resistencia de cada sensor y su resistencia base El rango de relaciones masa/carga analizados con el MS fue 50-200amu, utilizando impacto electrónico como técnica de ionización y un cuadrupolo como analizador. Los perfiles de olor determinados por NE-MS se analizaron mediante Análisis de Componentes Principales (PCA) con selección de variables (Alphasoft V8®), obteniéndose 2 componentes, los cuales explicaron el 50,3 y el 43,1% de la varianza total, respectivamente. Se observó que la tecnología NE-MS es capaz de discriminar los aceites provenientes en función de sus respectivos tratamientos, por lo que las condiciones operativas de obtención de aceite por EFSC pueden ejercer su influencia sobre el olor de un producto. A través de la tecnología NE-MS es posible diferenciar el perfil de olor de los aceites de chía obtenidos bajo diferentes condiciones operativas por lo que resulta primordial la selección y el control de las variables aplicadas al proceso.Chia seed (Salvia hispanica L.) contains about 32-39% of oil by weight, with a high content of a- linolenic acid (C18:3) (61–70%). The extraction with supercritical fluids (EFSC) using CO2 results an interesting alternative to the extraction of vegetable oils because it does not present the problems associated with the use of organic solvents, obtaining a high quality product. Therefore, the selection of the optimum pressure and temperature conditions of this process is important. Thus, the values of these parameters can affect the smell profile (organoleptic quality parameter) of the final product. The objective of this work was to evaluate the smell profile of the chia oil obtained by EFSC depending on the extraction conditions used. The EFSC was carried out under the following operative conditions: pressure (250 and 450 bar), temperatures (40 and 60ºC), with and without the use of ethanol as cosolvent, with a flow rate of 8 kg/h CO2. The smell profile was analyzed with an Electronic Nose coupled with a Mass Spectrometer (NE-MS) (a-Prometheus, Alpha MOS, France) using the methodology of the static head space and 18 semi selective sensors against to the different groups of volatile compounds of the food. The signal generated in each sensor is the value of the electric resistance caused by adsorption of the volatile compounds. The set of responses obtained in each sensor produces a characteristic pattern of the smell profile of the food matrix assayed. Samples of 2.0 ± 0.1 ml previously incubated at 35 ºC for 90 s were analyzed. For the study, the ratio between the maximum variation of the resistance of each sensor and its base resistance was considered. Mass/charge ratio assayed with the MS was 50-200 amu, using electronic impact as ionization technique and a quadrupole analyzer. The smell profiles determined by NE-MS were analyzed by Principal Component Analyses (PCA) with a selection of variables (Alphasoft V8®), obtaining 2 components that explained 50.3 and 43.1% of total variance, respectively. It was observed that NE-MS technology could discriminate the oils according to the different treatments, so the operative conditions of the oil extraction by EFSC influence the smell of the product. Therefore, the selection and control of the applied variables in the EFSC is very relevant.Centro de Investigación y Desarrollo en Criotecnología de Alimento

Re-evaluating Adjuvant Breast Cancer Trials: Assessing Hormone Receptor Status by Immunohistochemical Versus Extraction Assays

Background: Tumor levels of steroid hormone receptors, a factor used to select adjuvant treatment for early-stage breast cancer, are currently determined with immunohistochemical assays. These assays have a discordance of 10%-30% with previously used extraction assays. We assessed the concordance and predictive value of hormone receptor status as determined by immunohistochemical and extraction assays on specimens from International Breast Cancer Study Group Trials VIII and IX. These trials predominantly used extraction assays and compared adjuvant chemoendocrine therapy with endocrine therapy alone among pre- and postmenopausal patients with lymph node-negative breast cancer. Trial conclusions were that combination therapy provided a benefit to pre- and postmenopausal patients with estrogen receptor (ER)-negative tumors but not to ER-positive postmenopausal patients. ER-positive premenopausal patients required further study. Methods: Tumor specimens from 571 premenopausal and 976 postmenopausal patients on which extraction assays had determined ER and progesterone receptor (PgR) levels before randomization from October 1, 1988, through October 1, 1999, were re-evaluated with an immunohistochemical assay in a central pathology laboratory. The endpoint was disease-free survival. Hazard ratios of recurrence or death for treatment comparisons were estimated with Cox proportional hazards regression models, and discriminatory ability was evaluated with the c index. All statistical tests were two-sided. Results: Concordance of hormone receptor status determined by both assays ranged from 74% (κ = 0.48) for PgR among postmenopausal patients to 88% (κ = 0.66) for ER in postmenopausal patients. Hazard ratio estimates were similar for the association between disease-free survival and ER status (among all patients) or PgR status (among postmenopausal patients) as determined by the two methods. However, among premenopausal patients treated with endocrine therapy alone, the discriminatory ability of PgR status as determined by immunohistochemical assay was statistically significantly better (c index = 0.60 versus 0.51; P = .003) than that determined by extraction assay, and so immunohistochemically determined PgR status could predict disease-free survival. Conclusions: Trial conclusions in which ER status (for all patients) or PgR status (for postmenopausal patients) was determined by immunohistochemical assay supported those determined by extraction assays. However, among premenopausal patients, trial conclusions drawn from PgR status differed—immunohistochemically determined PgR status could predict response to endocrine therapy, unlike that determined by the extraction assa

The Self Model and the Conception of Biological Identity in Immunology

The self/non-self model, first proposed by F.M. Burnet, has dominated immunology for sixty years now. According to this model, any foreign element will trigger an immune reaction in an organism, whereas endogenous elements will not, in normal circumstances, induce an immune reaction. In this paper we show that the self/non-self model is no longer an appropriate explanation of experimental data in immunology, and that this inadequacy may be rooted in an excessively strong metaphysical conception of biological identity. We suggest that another hypothesis, one based on the notion of continuity, gives a better account of immune phenomena. Finally, we underscore the mapping between this metaphysical deflation from self to continuity in immunology and the philosophical debate between substantialism and empiricism about identity

A 6-week, multicentre, randomised, double-blind, double-dummy, active-controlled, clinical safety study of lumiracoxib and rofecoxib in osteoarthritis patients

<p>Abstract</p> <p>Background</p> <p>Lumiracoxib is a selective cyclooxygenase-2 inhibitor effective in the treatment of osteoarthritis (OA) with a superior gastrointestinal (GI) safety profile as compared to traditional non-steroidal anti-inflammatory drugs (NSAIDs, ibuprofen and naproxen). This safety study compared the GI tolerability, the blood pressure (BP) profile and the incidence of oedema with lumiracoxib and rofecoxib in the treatment of OA. Rofecoxib was withdrawn worldwide due to an associated increased risk of CV events and lumiracoxib has been withdrawn from Australia, Canada, Europe and a few other countries following reports of suspected adverse liver reactions.</p> <p>Methods</p> <p>This randomised, double-blind study enrolled 309 patients (aged greater than or equal to 50 years) with primary OA across 51 centres in Europe. Patients were randomly allocated to receive either lumiracoxib 400 mg od (four times the recommended dose in OA) (<it>n </it>= 154) or rofecoxib 25 mg od (<it>n </it>= 155). The study was conducted for 6 weeks and assessments were performed at Weeks 3 and 6. The primary safety measures were the incidence of predefined GI adverse events (AEs) and peripheral oedema. The secondary safety measures included effect of treatment on the mean sitting systolic and diastolic blood pressure (msSBP and msDBP). Tolerability of lumiracoxib 400 mg was assessed by the incidence of AEs.</p> <p>Results</p> <p>Lumiracoxib and rofecoxib displayed similar GI safety profiles with no statistically significant difference in predefined GI AEs between the two groups (43.5% <it>vs</it>. 37.4%, respectively). The incidence and severity of individual predefined GI AEs was comparable between the two groups. The incidence of peripheral oedema was low and identical in both the groups (<it>n </it>= 9, 5.8%). Only one patient in the lumiracoxib group and three patients in the rofecoxib group had a moderate or severe event. At Week 6 there was a significantly lower msSBP and msDBP in the lumiracoxib group compared to the rofecoxib group (<it>p </it>< 0.05). A similar percentage of patients in both groups showed an improvement in target joint pain and disease activity. The tolerability profile was similar in both the treatment groups.</p> <p>Conclusion</p> <p>Lumiracoxib 400 mg od (four times the recommended dose in OA) provided a comparable GI safety profile to rofecoxib 25 mg od (therapeutic dose). However, lumiracoxib was associated with a significantly better BP profile as compared to rofecoxib.</p> <p>Trial registration number -</p> <p>NCT00637949</p

'Sink or swim': an evaluation of the clinical characteristics of individuals with high bone mass.

SUMMARY: High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. INTRODUCTION: High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. METHODS: Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. RESULTS: Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m(2), p < 0.001). CONCLUSION: Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass