Breast imaging technology: Imaging biochemistry - applications to breast cancer

The use of magnetic resonance spectroscopy (MRS) to investigate breast tumour biochemistry in vivo is reviewed. To this end, results obtained both from patients in vivo and from tumour extracts and model systems are discussed. An association has been observed between transformation and an increase in phosphomonoesters (PMEs) detected in the (31)P MRS spectrum, as well as an increase in choline-containing metabolites detected in the (1)H spectrum. A decrease in PME content after treatment is associated with response to treatment as assessed by tumour volume. Experiments in model systems aimed at understanding the underlying biochemical processes are presented, as well as data indicating the usefulness of MRS in monitoring the uptake and metabolism of some chemotherapeutic agents

Piccolo genotype modulates neural correlates of emotion processing but not executive functioning

Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene—involved in monoaminergic neurotransmission—as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD

Homocysteine, vitamin B12 and folate levels in premature coronary artery disease

BACKGROUND: Hyperhomocysteinemia is known as an independent risk factor of atherosclerosis, but the probable role of hyperhomocysteinemia in premature Coronary Artery Disease (CAD) is not well studied. The aim of this study was to assess the role of hyperhomocysteinemia, folate and Vitamin B12 deficiency in the development of premature CAD. METHODS: We performed an analytical case-control study on 294 individuals under 45 years (225 males and 69 females) who were admitted for selective coronary angiography to two centers in Tehran. RESULTS: After considering the exclusion criteria, a total number of 225 individuals were enrolled of which 43.1% had CAD. The mean age of participants was 39.9 +/- 4.3 years (40.1 +/- 4.2 years in males and 39.4 +/- 4.8 years in females). Compared to the control group, the level of homocysteine measured in the plasma of the male participants was significantly high (14.9 +/- 1.2 versus 20.3 +/- 1.9 micromol/lit, P = 0.01). However there was no significant difference in homocysteine level of females with and without CAD (11.8 +/- 1.3 versus 11.5 ± 1.1 micromol/lit, P = 0.87). Mean plasma level of folic acid and vitamin B12 in the study group were 6.3 +/- 0.2 and 282.5 +/- 9.1 respectively. Based on these findings, 10.7% of the study group had folate deficiency while 26.6% had Vitamin B12 deficiency. Logistic regression analysis for evaluating independent CAD risk factors showed hyperhomocysteinemia as an independent risk factor for premature CAD in males (OR = 2.54 0.95% CI 1.23 to 5.22, P = 0.01). Study for the underlying causes of hyperhomocysteinemia showed that male gender and Vitamin B12 deficiency had significant influence on incidence of hyperhomocysteinemia. CONCLUSION: We may conclude that hyperhomocysteinemia is an independent risk factor for CAD in young patients (bellow 45 years old) – especially in men -and vitamin B12 deficiency is a preventable cause of hyperhomocysteinemia

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Commercial chicken breeds exhibit highly divergent patterns of linkage disequilibrium

The analysis of linkage disequilibrium (LD) underpins the development of effective genotyping technologies, trait mapping and understanding of biological mechanisms such as those driving recombination and the impact of selection. We apply the Malécot-Morton model of LD to create additive LD maps that describe the high-resolution LD landscape of commercial chickens. We investigated LD in chickens (Gallus gallus) at the highest resolution to date for broiler, white egg and brown egg layer commercial lines. There is minimal concordance between breeds of fine-scale LD patterns (correlation coefficient &lt;0.21), and even between discrete broiler lines. Regions of LD breakdown, which may align with recombination hot spots, are enriched near CpG islands and transcription start sites (P&lt;2.2 × 10?16), consistent with recent evidence described in finches, but concordance in hot spot locations between commercial breeds is only marginally greater than random. As in other birds, functional elements in the chicken genome are associated with recombination but, unlike evidence from other bird species, the LD landscape is not stable in the populations studied. The development of optimal genotyping panels for genome-led selection programmes will depend on careful analysis of the LD structure of each line of interest. Further study is required to fully elucidate the mechanisms underlying highly divergent LD patterns found in commercial chickens

A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects

BACKGROUND: Periconceptional use of vitamin supplements containing folic acid reduces the risk of a neural tube defect (NTD). In November 1998, food fortification with folic acid was mandated in Canada, as a public health strategy to increase the folic acid intake of all women of childbearing age. We undertook a comprehensive population based study in Newfoundland to assess the benefits and possible adverse effects of this intervention. METHODS: This study was carried out in women aged 19–44 years and in seniors from November 1997 to March 1998, and from November 2000 to March 2001. The evaluation was comprised of four components: I) Determination of rates of NTDs; II) Dietary assessment; III) Blood analysis; IV) Assessment of knowledge and use of folic acid supplements. RESULTS: The annual rates of NTDs in Newfoundland varied greatly between 1976 and 1997, with a mean rate of 3.40 per 1,000 births. There was no significant change in the average rates between 1991–93 and 1994–97 (relative risk [RR] 1.01, 95% confidence interval [CI] 0.76–1.34). The rates of NTDs fell by 78% (95% CI 65%–86%) after the implementation of folic acid fortification, from an average of 4.36 per 1,000 births during 1991–1997 to 0.96 per 1,000 births during 1998–2001 (RR 0.22, 95% CI 0.14–0.35). The average dietary intake of folic acid due to fortification was 70 μg/day in women aged 19–44 years and 74 μg/day in seniors. There were significant increases in serum and RBC folate levels for women and seniors after mandatory fortification. Among seniors, there were no significant changes in indices typical of vitamin B(12 )deficiencies, and no evidence of improved folate status masking haematological manifestations of vitamin B(12 )deficiency. The proportion of women aged 19–44 years taking a vitamin supplement containing folic acid increased from 17% to 28%. CONCLUSIONS: Based on these findings, mandatory food fortification in Canada should continue at the current levels. Public education regarding folic acid supplement use by women of childbearing age should also continue

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes

Linking direct and indirect pathways mediating earthworms, deer, and understory composition in Great Lakes forests

Ahistorical drivers such as nonnative invasive earthworms and high deer densities can have substantial impacts on ecosystem processes and plant community composition in temperate and boreal forests of North America. To assess the roles of earthworm disturbance, deer, and environmental factors in the understory, we sampled 125 mixed temperate-boreal forest sites across the western Great Lakes region. We utilized structural equation modeling (SEM) to address the hypothesis that earthworm disturbance to the upper soil horizons and selective herbivory by deer are associated with depauperate understory plant communities dominated by graminoid and nonnative species. Evidence of earthworm activity was found at 93 % of our sites and 49 % had high to very high severity earthworm disturbance. The SEM fit the data well and indicated that widespread nonnative earthworm disturbance and high deer densities had similar magnitudes of impact on understory plant communities and that these impacts were partially mediated by environmental characteristics. One-third of the variation in earthworm disturbance was explained by soil pH, precipitation, and litter quality. Deer density and earthworm disturbance both increased graminoid cover while environmental variables showed direct and indirect relationships. For example, the positive relationship between temperature and graminoids was indirect through a positive temperature effect on deer density. This research characterizes an integrated set of key environmental variables driving earthworm disturbance and deer impacts on the forest understory, facilitating predictions of the locations and severity of future change in northern temperate and boreal forest ecosystems

A quantitative synthesis of the medicinal ethnobotany of the Malinké of Mali and the Asháninka of Peru, with a new theoretical framework

<p>Abstract</p> <p>Background</p> <p>Although ethnomedically and taxonomically guided searches for new medicinal plants can improve the percentage of plants found containing active compounds when compared to random sampling, ethnobotany has fulfilled little of its promise in the last few decades to deliver a bounty of new, laboratory-proven medicinal plants and compounds. It is quite difficult to test, isolate, and elucidate the structure and mechanism of compounds from the plethora of new medicinal plant uses described each year with limited laboratory time and resources and the high cost of clinical trials of new drug candidates.</p> <p>Methods</p> <p>A new quantitative theoretical framework of mathematical formulas called "relational efficacy" is proposed that should narrow down this search for new plant-derived medicines based on the hypothesis that closely related plants used to treat closely related diseases in distantly related cultures have a higher probability of being effective because they are more likely to be independent discoveries of similar plant compounds and disease mechanisms. A prerequisite to this hypothesis, the idea that empirical testing in traditional medicine will lead to choosing similar medicinal plants and therefore the medicinal flora of two distant cultures will prove to be more similar than their general flora, is tested using resampling statistics on cross-cultural field data of the plants used by the Malinké of Mali and the Asháninka of Peru to treat the diseases malaria, African sleeping sickness, Chagas' disease, leishmaniasis, diabetes, eczema, asthma, and uterine fibroids.</p> <p>Results</p> <p>In this case, the similarity of the medicinal floras is found to be significantly greater than the similarity of the general floras, but only when the diseases in question are grouped into the categories of parasitic and autoimmune diseases.</p> <p>Conclusion</p> <p>If the central theoretical framework of this hypothesis is shown to be true, it will allow the synthesis of medicinal plant information from around the world to pinpoint the species with the highest potential efficacy to take into the laboratory and analyze further, ultimately saving much field and laboratory time and resources.</p> <p><b>Spanish abstract</b></p> <p>Las búsquedas que utilizan la etnomedicina y la taxonomía para descubrir nuevas plantas medicinales, pueden aumentar la probabilidad de éxito de encontrar compuestos químicos activos en plantas, en comparación con las búsquedas aleatorias. A pesar de lo anterior, en las últimas décadas, la etnobotánica no ha cumplido con las expectativas de proveer numerosas plantas medicinales y químicos nuevos una vez examinados en el laboratorio. Cada año se describen una plétora de plantas medicinales y sus usos, sin embargo las limitaciones de tiempo y recursos en los laboratorios, unidos al alto coste de los ensayos clínicos de las drogas potenciales, hacen muy difícil probar, aislar, y elucidar la estructura y el mecanismo de los compuestos de estas plantas. Se propone un nuevo marco teórico cuantitativo cuyo fin es focalizar la búsqueda de nueva plantas medicinales. Este marco teórico está basado en la hipótesis que las plantas cercanamente relacionadas, usadas para tratar enfermedades cercanamente relacionadas en culturas distantemente relacionadas, tienen una eficacia potencial más alta, debido a que es más probable que estos hallazgos sean descubrimientos independientes de compuestos químicos similares. Parte de esta hipótesis, que las escogencias racionales se hacen para elegir plantas medicinales similares y que la flora medicinal de dos culturas distantes es más similar que su flora general, se probó usando métodos estadísticos de remuestreo con datos de campo de la comunidad Malinké de Malí y de la Asháninka de Perú, y las enfermedades de paludismo, enfermedad africana del sueño, enfermedad de Chagas, leishmania, diabetes, eczema, asma, y fibromas uterinos. Se encontró, en este caso, que la similitud de las floras medicinales es significativamente mayor a la similitud de las floras generales, solamente cuando las enfermedades analizadas se agruparon en las categorías de enfermedades parasitarias y enfermedades autoinmunes. Si se demostrara que las otras partes de esta hipótesis son ciertas, se podría sintetizar la información sobre plantas medicinales alrededor del mundo, para establecer así las plantas potencialmente más eficaces para llevarlas al laboratorio y analizarlas más profundamente.</p> <p><b>French abstract</b></p> <p>Par rapport aux recherches menées de façon aléatoire, les recherches effectuées par des critères ethnobotaniques et taxonomiques ont de meilleures chances à découvrir de nouvelles plantes médicinales à produit chimique actifs. Pendant les dernières décennies pourtant, l'ethnobotanique a réalisé peu de ces promesses à révéler un grand nombre de plantes médicinales et de nouveaux produits chimiques, testés au laboratoire. Avec les ressources limitées pour la recherche au laboratoire et le coût élevé des épreuves cliniques pour trouver de nouveaux candidats aux médicaments, il est difficile d'étudier, d'isoler et d'élucider la structure et le mécanisme des produits chimiques de chacune des nombreuses plantes médicinales (et les utilisations de ces plantes) décrites chaque année. Nous proposons une nouvelle technique théorique et quantitative pour préciser la recherche de nouvelles plantes médicinales; elle est basée sur l'hypothèse que les plantes étroitement apparentées, employées pour traiter les maladies étroitement apparentées dans les cultures très éloignées les unes des autres, ont une potentialité d'efficacité supérieure parce qu'elles représentent la découverte indépendante des propriétés chimiques semblables des plantes. Une partie de cette hypothèse-qui démontre que la sélection des plantes médicinales semblables est un choix rationnel et qu'il y a davantage de ressemblance dans la flore médicinale de deux cultures éloignées que dans leur flore générale-est examinée par un re-échantillonnage des données de recherches effectuées parmi les Malinké au Mali et les Asháninka au Pérou, en particulier sur la malaria, la maladie africaine du sommeil, la maladie de Chagas, la leishmania, le diabète, l'eczéma, l'asthme et les fibromes utérins. Dans ces cas précis, la similitude de la flore médicinale s'avère sensiblement plus grande que la similitude de la flore générale, mais seulement quand les maladies en question sont regroupées ensemble comme maladies parasitaires et auto-immunitaires. Si cette hypothèse est prouvée, elle permettra la synthèse des informations recueillies sur les plantes médicinales du monde entier pour en sélectionner de façon plus précise celles qui sont les plus efficaces et qui méritent analyse plus approfondie au laboratoire.</p> <p><b>Asháninka abstract</b></p> <p>Aayiantyarori iròpero aavintane, ontzimatye ancovacovatero ayotero ovaqueraripaye incashi iyoyetziri ashaninka, ayotzityaro aajatzi iyotane viracocha paitachari "quimica" ancantero aaca oshintsinka inchashipaye. Atziri yotacotzirori cametsa, ishtoriajacotzirori iyotane ashaninkapaye te iroñàrantero maaroni ocaratzi yamenacotaqueri laboratorioki. Aaviantyarori cametsa, ayotacotero aavintarontsiyetatsiri osamani antzimaventero ishtoriatacotaro, aajatzi osheki opinata ampinaventero aparopaye inchashi, acoviriqui ayotacotero, osaretsikipaye. Tzimatsi ovaquerari quenquishiriantsitatsiri ero opinata osheki ashitoriatacotero aparopaye inchashi, asampiyetatyrey pashinipaye atziri saicatsiri intaina puitarika inchasshi yavintari, ajatzirica oshiyaro ayotzi aaca, quemetachari atziri saikatsiri nampitsiki malinke aajatzi ishiyari ashaninka saicatsiri peruki, tzimatsi inchashi aajatzi yaavintari osheki okamètsatzi aririka anteri mantsiyarentsi icantaitziri ompetarentsi catsirentsi, pochokirentsi, patsarontsi(matatsi) ashipetate maaroni, ampochavathate, ancainikentsite, oncatsithakite tsinani. Aririka añaker aajatzi ahiyaro inchashi yaavintayetari pashinipaye atziri intainasatzi irdotake ahitoriatacoperoteri anàashityard aavintarontsi ovamairiri shithanentsi, onàshitaavintarontsi tzicaacoventairi ero antane mantsiyarentsi. Omanperotatyarica iròperotzi avintarontsi, oshitovake laboratorioki aritaque iyoitanaquero maaroni quipatsiki iroperori avintarontsi.</p