Extracapsular tumor spread and the risk of local, axillary and supraclavicular recurrence in node-positive, premenopausal patients with breast cancer.

BACKGROUND: Extracapsular tumor spread (ECS) has been identified as a possible risk factor for breast cancer recurrence, but controversy exists regarding its role in decision making for regional radiotherapy. This study evaluates ECS as a predictor of local, axillary, and supraclavicular recurrence. PATIENTS AND METHODS: International Breast Cancer Study Group Trial VI accrued 1475 eligible pre- and perimenopausal women with node-positive breast cancer who were randomly assigned to receive three to nine courses of classical combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. ECS status was determined retrospectively in 933 patients based on review of pathology reports. Cumulative incidence and hazard ratios (HRs) were estimated using methods for competing risks analysis. Adjustment factors included treatment group and baseline patient and tumor characteristics. The median follow-up was 14 years. RESULTS: In univariable analysis, ECS was significantly associated with supraclavicular recurrence (HR = 1.96; 95% confidence interval 1.23-3.13; P = 0.005). HRs for local and axillary recurrence were 1.38 (P = 0.06) and 1.81 (P = 0.11), respectively. Following adjustment for number of lymph node metastases and other baseline prognostic factors, ECS was not significantly associated with any of the three recurrence types studied. CONCLUSIONS: Our results indicate that the decision for additional regional radiotherapy should not be based solely on the presence of ECS.

Cardio-pulmonary interaction in premature newborn with nasal continuous positive airways pressure (n-CPAP) respiratory assistance evaluated with echocardiography

Introduction: Nasal continuous positive airways pressure (n-CPAP) is an effective treatment in premature infants with respiratory distress. The cardio-pulmonary interactions secondary to n-CPAP are well studied in adults, but less well described in premature infants. We postulated that there could be important interactions with regard to the patent ductus arteriosus (PDA). Methods: Prospective study, approved by the local ethic committee. Premature infants less than 32 weeks gestation, _7 days-old, needing n-CPAP for respiratory distress, but without the need of additional oxygen were included in the study. Every patient had a first echocardiography with n-CPAP and then n-CPAP was retrieved. 3 hours later the echocardiography was repeated by the same investigator and then the patient replaced on n-CPAP. Results: 14 premature newborn were included, mean gestational age of 28 _ 2 weeks, mean weight 1.1 _ 0.3 Kg and height 39 _ 3 cm. Echocardiographic measurements are depicted in Table 1. Significant finding were observed between measurement on n- CPAP or without n-CPAP: on end diastolic left ventricular diameter (12.8 _ 1.6 mm vs. 13.5 _ 2 mm), on end systolic left ventricular diameter (8.4 _ 1.3 mm vs. 9.1 _ 1.5 mm), left atrium diameter (8.9 _ 2.2 mm vs. 10.4 _ 2.5 mm), maximal velocity on tricuspid valve (46 _ 10 cm/s vs. 51 _ 9 cm/s), calculated Qp (3.7 _ 0.8 L/min/m2 vs. 4.3 _ 0.8 L/min/m2). Only three patients have demonstrated a PDA during the study. Conclusion: Positive end expiratory pressure (Peep) has hemodynamic effects which are: reduction of systemic and pulmonary venous return as shown by the changes on tricuspid valve inflow,on the calculated Qp and finally on the diameter of the left atrium and left ventricle.We found in premature infants the same hemodynamic effects than those described in adults but with lower Peep values. This could be due to the particular elasticity and weakness of the thoracic wall of premature infants. Interestingly the flow through a PDA seems also to be diminished with Peep, but the number of patients is insufficient to conclude. Further investigation will be needed to better understand these interactions. Table 1. Echocardiographic measurement (mean (SD)). With n-CPAP Without n-CPAP p value RV ED diameter (mm) 6.3 (1.7) 6.04 (1.1) NS LV ED diameter (mm) 12.8 (1.6) 13.5 (2.0) _0.05 LV ES diameter (mm) 8.4 (1.3) 9.1 (1.5) _0.05 SF (%) 34 (5) 33 (6) NS Ao valve diameter (mm) 7.4 (1.3) 7.4 (1.2) NS LA diameter (mm) 8.9 (2.2) 10.4 (2.5) _0.05 Vmax Ao (cm/s) 70 (16) 71 (18) NS Vmax PV (cm/s) 69 (15) 72 (16) NS Vmax TV (cm/s) 46 (10) 51 (9) _0.05 Vmax MV (cm/s) 53 (17) 54 (18) NS Qp (L/min/m2) 3.7 (0.8) 4.3 (0.8) _0.05 Qs (L/min/m2) 4.0 (0.8) 4.0 (0.7) NS Qp/Qs 0.92 (0.14) 1.09 (0.23) _0.05 RV: right ventricle, LV: left ventricle, ED: end diastolic, ES: end systolic, SF: shortening fraction,Ao: aortic valve, LA: left atrium,Vmax: maximum Doppler Velocity, Qp: pulmonary output, Qs: systemic output, NS: non significant.

The implementation of liquid chromatography tandem mass spectrometry for the official control of lipophilic toxins in seafood: Single-laboratory validation under four chromatographic conditions

We performed a comprehensive study to assess the fit for purpose of four chromatographic conditions for the determination of six groups of marine lipophilic toxins (okadaic acid and dinophysistoxins, pectenotoxins, azaspiracids, yessotoxins, gymnodimine and spirolides) by LC-MS/MS to select the most suitable conditions as stated by the European Union Reference Laboratory for Marine Biotoxins (EURLMB). For every case, the elution gradient has been optimized to achieve a total run-time cycle of 12 min. We performed a single-laboratory validation for the analysis of three relevant matrices for the seafood aquaculture industry (mussels, pacific oysters and clams), and for sea urchins for which no data about lipophilic toxins have been reported before. Moreover, we have compared the method performance under alkaline conditions using two quantification strategies: the external standard calibration (EXS) and the matrix-matched standard calibration (MMS). Alkaline conditions were the only scenario that allowed detection windows with polarity switching in a 3200 QTrap mass spectrometer, thus the analysis of all toxins can be accomplished in a single run, increasing sample throughput. The limits of quantification under alkaline conditions met the validation requirements established by the EURLMB for all toxins and matrices, while the remaining conditions failed in some cases. The accuracy of the method and the matrix effects where generally dependent on the mobile phases and the seafood species. The MMS had a moderate positive impact on method accuracy for crude extracts, but it showed poor trueness for seafood species other than mussels when analyzing hydrolyzed extracts. Alkaline conditions with EXS and recovery correction for OA were selected as the most proper conditions in the context of our laboratory. This comparative study can help other laboratories to choose the best conditions for the implementation of LC-MS/MS according to their own necessities.

Positive and negative regulation of cellular immune responses in physiologic conditions and diseases.

The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences both in vitro and in vivo suggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer.

Rethinking the triggering inflammatory processes of chronic periaortitis.

Chronic periaortitis (CP) is an uncommon inflammatory disease which primarily involves the infrarenal portion of the abdominal aorta. However, CP should be regarded as a generalized disease with three different pathophysiological entities, namely idiopathic retroperitoneal fibrosis (RPF), inflammatory abdominal aortic aneurysm and perianeurysmal RPF. These entities share similar histopathological characteristics and finally will lead to fibrosis of the retroperitoneal space. Beside fibrosis, an infiltrate with variable chronic inflammatory cell is present. The majority of these cells are lymphocytes and macrophages as well as vascular endothelial cells, most of which are HLA-DR-positive. B and T cells are present with a majority of T cells of the T-helper phenotype. Cytokine gene expression analysis shows the presence of interleukin (IL)-1alpha, IL-2, IL-4, interferon-gamma and IL-2 receptors. Adhesion molecules such as E-selectin, intercellular adhesion molecule-1 and the vascular cell adhesion molecule-1 were also found in aortic tissue, and may play a significant role in CP pathophysiology. Although CP pathogenesis remains unknown, an exaggerated inflammatory response to advanced atherosclerosis (ATS) has been postulated to be the main process. Autoimmunity has also been proposed as a contributing factor based on immunohistochemical studies. The suspected allergen may be a component of ceroid, which is elaborated within the atheroma. We review the pathogenesis and the pathophysiology of CP, and its potential links with ATS. Clinically relevant issues are summarized in each section with regard to the current working hypothesis of this complex inflammatory disease.

Missed opportunities among HIV-positive women to control viral replication during pregnancy and to have a vaginal delivery.

INTRODUCTION: Most national guidelines for the prevention of mother-to-child transmission of HIV in Europe updated between 2001 and 2010 recommend vaginal deliveries for women with undetectable or very low viral load (VL). Our aim was to explore the impact of these new guidelines on the rates of vaginal deliveries among HIV-positive women in Europe. METHODS: In a pooled analysis of data on HIV-positive pregnant women enrolled in the Swiss Mother & Child HIV Cohort Study and the European Collaborative Study 2000 to 2010, deliveries were classified as occurring pre- or postpublication of national guidelines recommending vaginal delivery. RESULTS: Overall, 2663 women with 3013 deliveries were included from 10 countries; 28% women were diagnosed with HIV during pregnancy. Combination antiretroviral therapy was used in most pregnancies (2020, 73%), starting during the first or second trimester in 78% and during the third trimester in 22%; in 25% pregnancies, the woman conceived on combination antiretroviral therapy. Overall, in 86% pregnancies, a VL < 400 copies per milliliter was achieved before delivery. The proportion of vaginal deliveries increased from 17% (414/2377) before the change in guidelines to 52% (313/600) after; elective Caesarean section rates decreased from 65% to 27%. The proportion of women with undetectable VL having a Caesarean section was 55% after implementation of new guidelines. We observed a decrease of late preterm deliveries from 16% (377/2354) before to 7% (42/599) after the change in guidelines (P < 0.001). CONCLUSION: There are still missed opportunities for women with HIV to fully suppress their VL and to deliver vaginally in Europe.

Retrovirus-mediated gene transfer in polyclonal T cells results in lower apoptosis and enhanced ex vivo cell expansion of CMV-reactive CD8 T cells as compared with EBV-reactive CD8 T cells.

To modulate alloreactivity after hematopoietic stem cell transplantation, "suicide" gene-modified donor T cells (GMCs) have been administered with an allogeneic T-cell-depleted marrow graft. We previously demonstrated that such GMCs, generated after CD3 activation, retrovirus-mediated transduction, and G418 selection, had an impaired Epstein-Barr virus (EBV) reactivity, likely to result in an altered control of EBV-induced lymphoproliferative disease. To further characterize the antiviral potential of GMCs, we compared the frequencies of cytomegalovirus (CMV)-specific CD8+ T (CMV-T) cells and EBV-specific CD8+ T (EBV-T) cells within GMCs from CMV- and EBV-double seropositive donors. Unlike anti-EBV responses, the anti-CMV responses were not altered by GMC preparation. During the first days of culture, CMV-T cells exhibited a lower level of CD3-induced apoptosis than did EBV-T cells. In addition, the CMV-T cells escaping initial apoptosis subsequently underwent a higher expansion rate than EBV-T cells. The differential early sensitivity to apoptosis could be in relation to the "recent activation" phenotype of EBV-T cells as evidenced by a higher level of CD69 expression. Furthermore, EBV-T cells were found to have a CD45RA-CD27+CCR7- effector memory phenotype, whereas CMV-T cells had a CD45RA+CD27-CCR7- terminal effector phenotype. Such differences could be contributive, because bulk CD8+CD27- cells had a higher expansion than did bulk CD8+CD27+ cells. Overall, ex vivo T-cell culture differentially affects apoptosis, long-term proliferation, and overall survival of CMV-T and EBV-T cells. Such functional differences need to be taken into account when designing cell and/or gene therapy protocols involving ex vivo T-cell manipulation.

gcodeml: A Grid-enabled Tool for Detecting Positive Selection in Biological Evolution

One of the important questions in biological evolution is to know if certain changes along protein coding genes have contributed to the adaptation of species. This problem is known to be biologically complex and computationally very expensive. It, therefore, requires efficient Grid or cluster solutions to overcome the computational challenge. We have developed a Grid-enabled tool (gcodeml) that relies on the PAML (codeml) package to help analyse large phylogenetic datasets on both Grids and computational clusters. Although we report on results for gcodeml, our approach is applicable and customisable to related problems in biology or other scientific domains.

Ecology and evolution of soil nematode chemotaxis.

Plants influence the behavior of and modify community composition of soil-dwelling organisms through the exudation of organic molecules. Given the chemical complexity of the soil matrix, soil-dwelling organisms have evolved the ability to detect and respond to these cues for successful foraging. A key question is how specific these responses are and how they may evolve. Here, we review and discuss the ecology and evolution of chemotaxis of soil nematodes. Soil nematodes are a group of diverse functional and taxonomic types, which may reveal a variety of responses. We predicted that nematodes of different feeding guilds use host-specific cues for chemotaxis. However, the examination of a comprehensive nematode phylogeny revealed that distantly related nematodes, and nematodes from different feeding guilds, can exploit the same signals for positive orientation. Carbon dioxide (CO(2)), which is ubiquitous in soil and indicates biological activity, is widely used as such a cue. The use of the same signals by a variety of species and species groups suggests that parts of the chemo-sensory machinery have remained highly conserved during the radiation of nematodes. However, besides CO(2), many other chemical compounds, belonging to different chemical classes, have been shown to induce chemotaxis in nematodes. Plants surrounded by a complex nematode community, including beneficial entomopathogenic nematodes, plant-parasitic nematodes, as well as microbial feeders, are thus under diffuse selection for producing specific molecules in the rhizosphere that maximize their fitness. However, it is largely unknown how selection may operate and how belowground signaling may evolve. Given the paucity of data for certain groups of nematodes, future work is needed to better understand the evolutionary mechanisms of communication between plant roots and soil biota.

Clinical and radiographic findings in two brothers affected with a novel mutation in matrix metalloproteinase 2 gene.

The two well-described osteolysis syndromes associated with matrix metalloproteinase-2 deficiency and mutations in the metalloproteinase-2 gene are Torg-Winchester syndrome and nodulosis-arthropathy-osteolysis variant. They are characterized by carpal-tarsal destruction, subcutaneous nodules, and generalized osteoporosis and show autosomal recessive inheritance. Herein, we report two siblings affected with a novel mutation in matrix metalloproteinase 2 gene and discuss their clinical and radiographic findings.

Characterization of fecal indicator bacteria in sediments cores from the largest freshwater lake of Western Europe (Lake Geneva, Switzerland)

This study characterized the fecal indicator bacteria (FIB), including Escherichia coli (E. coli) and Enteroccocus (ENT), disseminated over time in the Bay of Vidy, which is the most contaminated area of Lake Geneva. Sediments were collected from a site located at similar to 500 m from the present waste water treatment plant (WWTP) outlet pipe, in front of the former WWTP outlet pipe, which was located at only 300 m from the coastal recreational area (before 2001). E. coil and ENT were enumerated in sediment suspension using the membrane filter method. The FIB characterization was performed for human Enterococcus faecalis (E. faecalis) and Enterococcus faecium (E. faecium) and human specific bacteroides by PCR using specific primers and a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Bacterial cultures revealed that maximum values of 35.2 x 10(8) and 6.6 x 10(6) CFU g(-1) dry sediment for E. coil and ENT, respectively, were found in the sediments deposited following eutrophication of Lake Geneva in the 1970s. whereas the WWTP started operating in 1964. The same tendency was observed for the presence of human fecal pollution: the percentage of PCR amplification with primers ESP-1/ESP-2 for E. faecalis and E. faecium indicated that more than 90% of these bacteria were from human origin. Interestingly, the PCR assays for specific-human bacteroides HF183/HF134 were positive for DNA extracted from all isolated strains of sediment surrounding WWPT outlet pipe discharge. The MALDI-TOF MS confirmed the presence of general E. coli and predominance E. faecium in isolated strains. Our results demonstrated that human fecal bacteria highly increased in the sediments contaminated with WWTP effluent following the eutrophication of Lake Geneva. Additionally, other FIB cultivable strains from animals or adapted environmental strains were detected in the sediment of the bay. The approaches used in this research are valuable to assess the temporal distribution and the source of the human fecal pollution in aquatic environments. (C) 2011 Elsevier Inc. All rights reserved.

Combined radiohormonotherapy in node positive lymph node prostate cancer

Purpose: Pelvic radiation therapy (RT) represents a therapeutic option in the treatment of node-positive prostate cancer but it remains controversial, because of its high rate toxicities. New radiation technique such as IMRT may reduce these complications. In this study, we aimed to assess the rate of toxicities according to CTC-NCI.v3 in such patients treated with either 3DCRT or IMRT (Tomotherapy).Methods and Materials: From January 2008 to December 2010, data were analyzed from 30 consecutive patients including 29 node-positive prostate cancer undergoing definitive or adjuvant RT (IMRT and/or 3DCRT) after radical prostatectomy and lymphadenectomy combined to hormonal therapy. Median age was 66 years (range : 52-83). Median preoperative PSA value was 12 ng/ml (range: 2.72-165). According to the pT-classification, there were 4 pT2, 7 pT3a, 10 pT3b, and 1 pT4 patients. Pathologic positive lymph nodes were found in 23 patients. Radiologic positive lymph nodes were found in 5 patients. Two patients were node negative. Gleason score was ranging between 7 to 10. Twelve patients were treated by Tomotherapy including 4 with simultaneous integrated boost (SIB). Eighteen patients were treated by Tomotherapy including 2 with SIB to the whole pelvis and 3DCRT boost to the prostate. V50% for bladder and rectum were recorded. Acute and late toxicities were assessed according to CTC-NCI.v3 classification.Results: With a median follow-up of 17 months, only one patient presented nodal and metastatic failure. Urinary incontinence was graded 1 after surgery for 6 patients and grade 2 in two. Sexual impuissance was noted in 3 patients. Acute toxicities during RT were proctitis grade 0 in 23 patients (76.5%), grade 1 in 7 (23.5%). Nocturia grade 1 in 9 patients. Interruption of treatment was seen in only case because of grade 3 urinary incontinence. Late effects included erectile dysfunction in 5 patients (83%) and one patient had grade 3proctitis requiring colostomy 3 months after RT. Median Dose-Volume Histogram according to radiation techniques V50% bladder V50% rectum Tomotherapy (IMRT) 36.25 Gy 39 Gy Tomotherapy + 3DCRT 41.26 Gy 39.18 GyConclusion: Based on our above-mentioned findings, there is no a significant difference in morbidity in patients treated with Tomotherapy or Tomotherapy with 3DCRT boost.

De viles rurals a indrets de la regió metropolitana de Barcelona: transformacions històriques del paisatge a la Vall del Congost (Figaró-Montmany, l’Ametlla del Vallès i la Garriga, 1850-2010)

El projecte ha assolit la majoria d’objectius, ajustats a la reducció d'una quarta part de l'import concedit: 1) caracteritzar la transformació del paisatge agro-forestal i urbà a dos municipis de la vall del Congost, La Garriga i Figaró-Montmany, reconstruint amb SIG els mapes d'ús del sòl de 1854, 1949, 1956 i 2005, obtenint per intersecció de cobertes les matrius dels canvis d'ús; i 2) avaluar amb l’índex de connectivitat ecològica l'impacte ambiental d'aquells canvis des del punt de vista de la biodiversitat i la resiliència del paisatges, amb un especial èmfasi en la reforestació induïda per l'abandonament rural i la pèrdua de paisatges en mosaic, en un àmbit més gran pel període 1956-1993-2005. Aquests resultats han permès preparar varis articles per publicar en co-autoría a revistes com Landscape History, Environment and History o Landscape and Urban Planning. Ja és a punt de poder-se lliurar el primer amb el títol de "Looking backwards into a Mediterranean edge environment: Landscape changes and ecological connectivity in El Congost Valley (province of Barcelona, Catalonia) 1850-2005", incloent dos objectius esmentats a la memòria: identificar les principals forces motores d'aquells canvis en el paisatge relacionant els usos del sòl amb les formes d'ordenació del territori, caracteritzar-ne les forces rectores econòmico-socials i el paper jugat per la protecció del Parc Natural del Montseny i els Cingles de Bertí. Els resultats també permetran abordar en el futur altres aspectes, com per exemple estimar el potencial energètic de la biomassa local tot cercant que el seu aprofitament generi sinèrgies territorials positives per a l'ecologia del paisatge amb la recuperació d’una ramaderia extensiva i una agricultura ecològica que facin possible la restauració dels paisatges en mosaic. L'estudi ha pogut incorporar un aspecte inicialment no previst, el cens d'orquídies mediterrànies a Figaró-Montmany elaborat pel naturalista Paul Wilcox