Mitotic figure counts are overrated in resection specimen of invasive breast carcinoma

In order for some patients to benefit from aggressive chemotherapy for invasive breast carcinoma, many patients are currently being treated without little or no benefit. Enormous effort is hence being directed towards the identification of those patients who will need chemotherapy and those who will not. Since chemotherapy targets proliferating cells pathologists focus on the proliferative activity of tumors, as assessed by mitotic figure counts or by cell cycle specific immunohistochemical markers, such as Ki-67 and H3 histone. As far as the tumor grade is concerned, many of these studies have reported a tendency to up-grade carcinomas in resection specimen when compared to the initial diagnosis on the biopsy material, and most studies have noted that the upgrade in resection specimen is due solely or to a large extent to an increase in the mitotic figure count. In the present study, we propose a different explanation for the divergence in mitotic figure counts between biopsy and resection material. We assessed the proliferative activity of 52 invasive ductal carcinomas and confirm that the number of mitotic figures significantly increased by a factor of more than 3 in resection specimen over the biopsy material, while at the same time the pan-cell cycle specific marker MIB-1 yieldes comparable results. we propose that the delayed formalin fixation of resection specimen allows cell cycle activities to continue for a long time, up to many hours, and that this leads to an arrest of mitoses in metaphase where they are readily identified by the pathologist. We propose that the mitotic figure count in the rapidly fixed biopsy cores better represent the tumor biology and should be used as a basis for chemotherapy therapeutic decisions.

Temporal changes in mosquito abundance (Culex pipiens), avian malaria prevalence and lineage composition

Background: Knowledge on the temporal dynamics of host/vector/parasite interactions is a pre-requisite to further address relevant questions in the fields of epidemiology and evolutionary ecology of infectious diseases. In studies of avian malaria, the natural history of Plasmodium parasites with their natural mosquito vectors, however, is mostly unknown. Methods: Using artificial water containers placed in the field, we monitored the relative abundance of parous females of Culex pipiens mosquitoes during two years (2010-2011), in a population in western Switzerland. Additionally, we used molecular tools to examine changes in avian malaria prevalence and Plasmodium lineage composition in female C. pipiens caught throughout one field season (April-August) in 2011. Results: C. pipiens relative abundance varied both between years and months, and was associated with temperature fluctuations. Total Plasmodium prevalence was high and increased from spring to summer months (13.1-20.3%). The Plasmodium community was composed of seven different lineages including P. relictum (SGS1, GRW11 and PADOM02 lineages), P. vaughani (lineage SYAT05) and other Plasmodium spp. (AFTRU5, PADOM1, COLL1). The most prevalent lineages, P. vaughani (lineage SYAT05) and P. relictum (lineage SGS1), were consistently found between years, although they had antagonistic dominance patterns during the season survey. Conclusions: Our results suggest that the time window of analysis is critical in evaluating changes in the community of avian malaria lineages infecting mosquitoes. The potential determinants of the observed changes as well as their implications for future prospects on avian malaria are discussed.

High b-value Diffusion-weighted Imaging: A Sensitive Method to Reveal White Matter Changes in Schizophrenia

Background: b-value is the parameter characterizing the intensity of the diffusion weighting during image acquisition. Data acquisition is usually performed with low b value (b~1000 s/mm2). Evidence shows that high b-values (b>2000 s/mm2) are more sensitive to the slow diffusion compartment (SDC) and maybe more sensitive in detecting white matter (WM) anomalies in schizophrenia.Methods: 12 male patients with schizophrenia (mean age 35 +/-3 years) and 16 healthy male controls matched for age were scanned with a low b-value (1000 s/mm2) and a high b-value (4000 s/mm2) protocol. Apparent diffusion coefficient (ADC) is a measure of the average diffusion distance of water molecules per time unit (mm2/s). ADC maps were generated for all individuals. 8 region of interests (frontal and parietal region bilaterally, centrum semi-ovale bilaterally and anterior and posterior corpus callosum) were manually traced blind to diagnosis.Results: ADC measures acquired with high b-value imaging were more sensitive in detecting differences between schizophrenia patients and healthy controls than low b-value imaging with a gain in significance by a factor of 20- 100 times despite the lower image Signal-to-noise ratio (SNR). Increased ADC was identified in patient's WM (p=0.00015) with major contributions from left and right centrum semi-ovale and to a lesser extent right parietal region.Conclusions: Our results may be related to the sensitivity of high b-value imaging to the SDC believed to reflect mainly the intra-axonal and myelin bound water pool. High b-value imaging might be more sensitive and specific to WM anomalies in schizophrenia than low b-value imaging

Changes in arbuscular mycorrhizal fungal phenotypes and genotypes in response to plant species identity and phosphorus concentration.

* Arbuscular mycorrhizal fungi (AMF) are plant symbionts that improve floristic diversity and ecosystem productivity. Many AMF species are generalists with wide host ranges. Arbuscular mycorrhizal fungi individuals are heterokaryotic, and AMF populations are genetically diverse. Populations of AMF harbor two levels of genetic diversity on which selection can act, namely among individuals and within individuals. Whether environmental factors alter genetic diversity within populations is still unknown. * Here, we measured genetic changes and changes in fitness-related traits of genetically distinct AMF individuals from one field, grown with different concentrations of available phosphate or different host species. * We found significant genotype-by-environment interactions for AMF fitness traits in response to these treatments. Host identity had a strong effect on the fitness of different AMF, unearthing a specificity of response within Glomus intraradices. Arbuscular mycorrhizal fungi individuals grown in novel environments consistently showed a reduced presence of polymorphic genetic markers, providing some evidence for host or phosphate-induced genetic change in AMF. * Given that AMF individuals can form extensive hyphal networks colonizing different hosts simultaneously, contrasting habitats or soil properties may lead to evolution in the population. Local selection may alter the structure of AMF populations and maintain genetic diversity, potentially even within the hyphal network of one fungus.

Physiological changes during postharvest senescence of broccoli

The objective of this work was to determine the early physiological changes throughout shelf life of fresh broccoli (Brassica oleracea L. var. italica) cv. Piracicaba Precoce at 25ºC and relative humidity of 96% in the dark until complete senescence. Head inflorescences showed lack of turgidity and commercial value when weight loss reached up to 5%, coinciding with 48 hour after harvest. Chlorophyll content was stable until 24 hours after harvesting; afterwards, an intense degradation phase took place. At 72 hours, total head yellowing was observed when chlorophyll content dropped to 30% of its initial content. Peroxidase activity increased by 1.4 fold during the first six hours, dropping to its lowest level approximately 24 hours after harvesting. However, from this time on, an increment of activity was observed until 72 hours. At 24 hours after harvesting, respiration was reduced by 50%. At later stages of senescence, respiration of florets was stable, but in a lower level than that determined at harvest. Sharp reduction of starch and reducing sugars was observed within 24 hours after harvesting, followed by continuous period of decline in starch and non-reducing sugars.

"Suddenly I get into the zone": Examining discontinuities and nonlinear changes in flow experiences at work

Work-related flow is defined as a sudden and enjoyable merging of action and awareness that represents a peak experience in the daily lives of workers. Employees" perceptions of challenge and skill and their subjective experiences in terms of enjoyment, interest and absorption were measured using the experience sampling method, yielding a total of 6981 observations from a sample of 60 employees. Linear and nonlinear approaches were applied in order to model both continuous and sudden changes. According to the R2, AICc and BIC indexes, the nonlinear dynamical systems model (i.e. cusp catastrophe model) fit the data better than the linear and logistic regression models. Likewise, the cusp catastrophe model appears to be especially powerful for modelling those cases of high levels of flow. Overall, flow represents a nonequilibrium condition that combines continuous and abrupt changes across time. Research and intervention efforts concerned with this process should focus on the variable of challenge, which, according to our study, appears to play a key role in the abrupt changes observed in work-related flow.

Changes in insulin secretion and glucose metabolism induced by dexamethasone in lean and obese females

Résumé But: Chez les individus sveltes et en bonne santé, les modifications de la sensibilité à l'insuline secondaires à l'administration de dexaméthasone pendant deux jours sont compensées par une modification de la sécrétion d'insuline, permettant le maintien de l'homéostasie glucidique. Cette étude évalue les modifications du métabolisme glucidique et de la sécrétion d'insuline induites par une administration limitée de dexaméthasone chez les femmes obèses. Méthode de recherche: Onze femmes obèses ayant une tolérance au glucose normale ont été étudiées à deux reprises, 1° sans dexaméthasone et 2° après deux jours d'administration de dexaméthasone à faible dose. Un clamp hyperglycémique comportant deux plateaux (taux plasmatique de glucose à 7.5, respectivement 10 mM) avec du glucose marqué (6.6 ²H2 glc) a été utilisé pour déterminer la sécrétion d'insuline et le métabolisme du glucose du corps entier. Les résultats ont été comparés à ceux d'un groupe de huit femmes sveltes. Résultats : Sans dexaméthasone, les femmes obèses avaient un taux d'insuline plasmatique supérieur à jeun, durant le premier pic de sécrétion d'insuline, et aux deux plateaux hyperglycémiques. Elles avaient toutefois un métabolisme glucidique normal comparé à celui des femmes sveltes, ce qui indique une compensation adéquate. Après administration de la dexaméthasone, les femmes obèses avaient une augmentation du taux d'insuline plasmatique de 66 à 92%, mais une baisse de stockage du glucose de 15.4%. Ceci contrastait avec l'augmentation du taux d'insuline plasmatique de 91 à 113% chez les femmes sveltes et l'absence de changement de stockage du glucose du corps entier. Discussion : L'administration de dexaméthasone conduit à une baisse significative du stockage du glucose du corps entier pour une glycémie fixée chez les femmes obèses mais non chez les femmes sveltes. Ceci indique que les femmes obèses sont incapables d'accroître adéquatement leur sécrétion d'insuline. Abstract: Objective: In healthy lean individuals, changes in insulin sensitivity occurring as a consequence of a 2-day dexamethasone administration are compensated for by changes in insulin secretion, allowing glucose homeostasis to be maintained. This study evaluated the changes in glucose metabolism and insulin secretion induced by short-term dexamethasone administration in obese women. Research Methods and Procedures: Eleven obese women with normal glucose tolerance were studied on two occasions, without and after 2 days of low-dose dexamethasone administration. A two-step hyperglycemic clamp (7.5 and 10 mr1/1 glucose) with 6,6 2H2 glucose was used to assess insulin secretion and whole body glucose metabolism. Results were compared with those obtained in a group of eight lean women. Results: Without dexamethasone, obese women had higher plasma insulin concentrations in the fasting state, during the first phase of insulin secretion, and at the two hyperglycemic plateaus. However, they had normal whole body glucose metabolism compared with lean women, indicating adequate compensation. After dexamethasone, obese women had a 66% to 92% increase in plasma insulin concentrations but a 15.4% decrease in whole body glucose disposal. This contrasted with lean women, who had a 91% to 113% increase in plasma insulin concentrations, with no change in whole body glucose disposal. Discussion: Dexamethasone administration led to a significant reduction in whole body glucose disposal at fixed glycemia in obese but not lean women. This indicates that obese women are unable to increase their insulin secretion appropriately.

Age-related changes in the bimanual advantage and in brain oscillatory activity during tapping movements suggest a decline in processing sensory reafference

Deficits in the processing of sensory reafferences have been suggested as accounting for age-related decline in motor coordination. Whether sensory reafferences are accurately processed can be assessed based on the bimanual advantage in tapping: because of tapping with an additional hand increases kinesthetic reafferences, bimanual tapping is characterized by a reduced inter-tap interval variability than unimanual tapping. A suppression of the bimanual advantage would thus indicate a deficit in sensory reafference. We tested whether elderly indeed show a reduced bimanual advantage by measuring unimanual (UM) and bimanual (BM) self-paced tapping performance in groups of young (n = 29) and old (n = 27) healthy adults. Electroencephalogram was recorded to assess the underlying patterns of oscillatory activity, a neurophysiological mechanism advanced to support the integration of sensory reafferences. Behaviorally, there was a significant interaction between the factors tapping condition and age group at the level of the inter-tap interval variability, driven by a lower variability in BM than UM tapping in the young, but not in the elderly group. This result indicates that in self-paced tapping, the bimanual advantage is absent in elderly. Electrophysiological results revealed an interaction between tapping condition and age group on low beta band (14âeuro"20 Hz) activity. Beta activity varied depending on the tapping condition in the elderly but not in the young group. Source estimations localized this effect within left superior parietal and left occipital areas. We interpret our results in terms of engagement of different mechanisms in the elderly depending on the tapping mode: a âeuro~kinestheticâeuro? mechanism for UM and a âeuro~visual imageryâeuro? mechanism for BM tapping movement.

Biochemical changes associated to soybean seeds osmoconditioning during storage

A work was carried out with the purpose of verifying the biochemical changes associated to soybean (Glycine max (L.) Merrill) seeds osmoconditioning. Seeds of the UFV 10, IAC 8 and Doko RC cultivars harvested at R8 development stage and submitted to different treatments were used. The biochemical evaluations were performed during seed storage, after the hydration-dehydration process. Initially, seeds were osmoconditioned in a polyethylene glycol (PEG 6000) solution, with the osmotic potential of -0.8 MPa and 20ºC, for a period of four days. After that, seeds were dried back until the initial moisture content (10-11%) and stored in natural conditions for three and six months. Two controls were used: untreated seeds (dry seeds) and water soaked seeds. Seed changes in protein and lipid, hexanal accumulation and fatty acids contents were evaluated. The results showed that seed storage under laboratory natural conditions caused reduction in protein, lipid and polyunsaturated fatty acids content and promoted hexanal production. Storage periods reduced protein levels for all treatments, however the PEG 6000 treatment showed lower protein reduction. The soybean seed storage increased hexanal production, but hexanal levels were smaller with osmoconditioning comparing to the other imbibition treatments.

How are Spanish academics coping with changes? Responses from a life histories research.

[eng] This report is part of the research project, The effects of social changes in work and professional life of Spanish academics, partially financed by the Spanish Ministry of Science and Innovation (SEJ2006-01876), that has explored change in legislation, organisation, research schemes and so on, in the last thirty years. The main aim of this project is deepening our understanding of the impact of undergoing economic, social, cultural, technological and labour change in Spanish universities in the life and professional identity of the teaching and research staff, taking into account the national and european context. This paper gathers part of the results gained from the project, being its primary objective to contribute to an improved knowledge-base on professional knowledge and work experience in higher education institutions in Spain and, as a consequence, to understand how Spanish academics are coping with current changes.

Pregnancy-associated changes in host permissiveness to metastasis

THESIS SUMMARY : Metastasis is a multistep process involving tumour cell-autonomous features, the host tissue stroma of the primary tumour, the blood or lymphatic system as well as a receptive target organ. Most studies on factors influencing metastasis have concentrated on the characteristics of the disseminating tumour cell and on early steps of metastasis including invasion and angiogenesis. Although these steps are necessary for tumour cells to disseminate, it is the challenges encountered in the later steps of metastasis -survival while in the circulation and engraftment and outgrowth in the target organ -that account for the inefficiency of circulating tumour cells in establishing secondary lesions. Full understanding of the metastatic process therefore requires elucidation of the mechanisms that regulate these late steps, and in particular that determine what makes any given tissue permissive for metastatic tumour growth. To address this issue, we assessed the mechanisms whereby a physiological situation -pregnancy -can alter host permissiveness toward metastasis. We show that pregnant NOD/SCID mice -injected intravenously with tumour cells -develop more metastases than their non-pregnant counterparts irrespective of the tumour cell type. There was no direct effect of pregnancy-related circulating factors on tumour cell proliferation, and subcutaneous tumour growth does not vary between pregnant and nonpregnant animals. However, decreased elimination of tumour cells from the lung microvasculature was observed in pregnant mice, prompting us to assess whether pregnancy-related adaptations in innate immunity could account for this differential clearing. We found that natural killer (NK) cell fractions are decreased in blood and spleen of pregnant mice and that NK cell cytotoxicity is impaired, as reported previously. The use of NK-deficient mice or tumour cell lines resistant to NK killing abrogates the difference in metastasis load between pregnant and virgin mice. CD11 b+ Gr-1+ myeloid-derived suppressor cells (MDSC) have previously been shown to accumulate in tumour-bearing mice and to down-modulate NK activity. Accordingly, we show an increase in MDSC in pregnant mouse blood, spleen, lungs and liver. Depletion of MDSC prior to tumour cell injection decreased metastasis load in pregnant NOD/SCID mice but had no effect on virgin mice. Similarly, adoptive transfer of MDSC extracted from pregnant mice into virgin mice lead to increased metastasis take. In parallel, we investigated whether the lung and liver microenvironments are modified during pregnancy thereby providing a more "permissive soil" for the establishment of metastases. A comparative analysis of microarray data of pregnant mouse lungs and liver with "premetastatic niche" gene expression profiles of these organs shows that similar mechanisms could mediate an increase in lung and liver metastasis in pregnant mice and in mice harbouring an aggressive primary tumour. Several commonly up-regulated genes point towards the recruitment of myeloid cells, consistent with the accumulation of MDSC observed in pregnant mice. MDSC have never been evoked in the context of pregnancy before. Although the role of MDSC in pregnancy requires further investigation we suggest that MDSC accumulation constitutes an important and hitherto unrecognised common denominator of maternal immune tolerance and cancer immune escape. RESUME DE THESE : La métastatisation est un processus en plusieurs étapes qui implique des compétences particulières chez les cellules tumorales, le stroma de la tumeur primaire, les vaisseaux sanguins ou lymphatiques ainsi qu'un organe cible' réceptif. Jusqu'alors, la recherche s'est principalement intéressée aux facteurs qui influencent les étapes précoces de la métastatisation donc aux caractéristiques de la cellule métastatique, et aux processus tels que l'invasion et l'angiogenèse, tandis que peu d'études traitent des étapes tardives tel que la survie dans la circulation sanguine et l'établissement d'une lésion dans l'organe cible. En particulier, l'élucidation des facteurs qui déterminent la permissivité d'un tissu à la greffe de cellules disséminantes est indispensable à la compréhension de ce processus complexe qu'est la métastatisation. Nous proposons ici un modèle de souris récapitulant les étapes tardives de la métastatisation dans un contexte d'une permissivité accrue aux métastases chez la souris gravide, et nous évaluons les mécanismes impliqués. Les souris gestantes développent plus de métastases après l'injection intraveineuse de cellules tumorales, indépendamment du type de tumeur d'origine. Les taux élevés d'hormones et de facteurs de croissance chez la souris gravide n'inflúencent pas la prolifération des cellules tumorales et fa croissance de tumeurs sous-cutanées n'est pas non plus accélérée par la gestation. En revanche, une fois injectées, les cellules tumorales sont éliminées ` moins rapidement des vaisseaux pulmonaires chez la souris gravide que chez les contrôles. Cette observation est compatible avec un effet de la gestation sur l'immunité innée et nous avons mis en évidence une diminution des proportions de cellules NK (natural killer) dans le sang et la rate en particulier, ainsi qu'une cytotoxicité moindre envers des cellules tumorales. En utilisant des souris déficientes en cellules NK ou en injectant des cellules résistantes à l'attaqué par des cellules NK, la différence entre souris gestantes et non-gestantes disparaît. Il a été démontré chez des souris porteuses de tumeurs, que l'accumulation de cellules immunosuppressives de la lignée myélo-monocytaire (ou MDSC pour myeloid-derived suppressor tells) pouvait être responsable d'une inhibition de l'activité de cellules NK. Des nombres augmentés de ces cellules, caractérisées par les marqueurs de surface CD11b et Gr-1, ont été trouvés dans le sang, la rate, les poumons et le foie de souris gravides. Leur rôle dans la métastatisation est démontré par le fait que leur dépletion diminue le nombre de lésions secondaires chez la souris gestante, tandis que leur transfert dans des souris non-gestantes augmente le taux de métastases. L'utilisation de puces à ADN sur les foies et poumons de souris gravides a permis de mettre en évidence des différences d'expression génique proches de celles observées dans l'établissement de niches pré-métastatiques. Ceci suggère que des mécanismes similaires pourraient être responsables d'une permissivité accrue aux métastases chez la souris gravide et chez la souris porteuse d'une tumeur primaire agressive, telle que, en particulier, l'accumulation de cellules immunosuppressives dans les organes cibles. C'est la première fois que l'accumulation de MDSC est évoquée chez la souris gravide et nous proposons ici que celles-ci jouent un rôle dans la tolérance immunitaire envers le foetus et sont responsables de l'échappement de cellules tumorales injectées à la surveillance immunitaire par des cellules NK.

Deletion of mu- and kappa-opioid receptors in mice changes epidermal hypertrophy, density of peripheral nerve endings, and itch behavior.

The mu- (MOR) and kappa- (KOR) opioid receptors have been implicated in the regulation of homeostasis of non-neuronal cells, such as keratinocytes, and sensations like pain and chronic pruritus. Therefore, we have studied the phenotype of skin after deletion of MOR and KOR. In addition, we applied a dry skin model in these knockout mice and compared the different mice before and after induction of the dermatitis in terms of epidermal thickness, epidermal peripheral nerve ending distribution, dermal inflammatory infiltrate (mast cells, CD4 positive lymphocytes), and scratching behavior. MOR knockout mice reveal as phenotype a significantly thinner epidermis and a higher density of epidermal fiber staining by protein gene product 9.5 than the wild-type counterparts. Epidermal hypertrophy, induced by the dry skin dermatitis, was significantly less developed in MOR knockout than in wild-type mice. Neither mast cells nor CD4 T(h)-lymphocytes are involved in the changes of epidermal nerve endings and epidermal homeostasis. Finally, behavior experiments revealed that MOR and KOR knockout mice scratch less after induction of dry skin dermatitis than wild-type mice. These results indicate that MOR and KOR are important in skin homeostasis, epidermal nerve fiber regulation, and pathophysiology of itching.

Developmental changes in cardiac recovery from anoxia-reoxygenation.

The developing cardiovascular system is known to operate normally in a hypoxic environment. However, the functional and ultrastructural recovery of embryonic/fetal hearts subjected to anoxia lasting as long as hypoxia/ischemia performed in adult animal models remains to be investigated. Isolated spontaneously beating hearts from Hamburger-Hamilton developmental stages 14 (14HH), 20HH, 24HH, and 27HH chick embryos were subjected in vitro to 30 or 60 min of anoxia followed by 60 min of reoxygenation. Morphological alterations and apoptosis were assessed histologically and by transmission electron microscopy. Anoxia provoked an initial tachycardia followed by bradycardia leading to complete cardiac arrest, except for in the youngest heart, which kept beating. Complete atrioventricular block appeared after 9.4 +/- 1.1, 1.7 +/- 0.2, and 1.6 +/- 0.3 min at stages 20HH, 24HH, and 27HH, respectively. At reoxygenation, sinoatrial activity resumed first in the form of irregular bursts, and one-to-one atrioventricular conduction resumed after 8, 17, and 35 min at stages 20HH, 24HH, and 27HH, respectively. Ventricular shortening recovered within 30 min except at stage 27HH. After 60 min of anoxia, stage 27HH hearts did not retrieve their baseline activity. Whatever the stage and anoxia duration, nuclear and mitochondrial swelling observed at the end of anoxia were reversible with no apoptosis. Thus the embryonic heart is able to fully recover from anoxia/reoxygenation although its anoxic tolerance declines with age. Changes in cellular homeostatic mechanisms rather than in energy metabolism may account for these developmental variations.

Monitoring of Finnish arable land : changes in soil quality between 1987 and 1998

Selostus: Suomalaisten viljelymaiden tilan seuranta : muutoksia peltojen ominaisuuksissa aikavälillä 1987-1998