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This paper reports the hydrolysis of several PBT materials (pigmented or not). Degradation was monitored by gel permeation chromatography (chain scission), DSC (crystalline morphology), tensile test (residual mechanical properties) and DVS (polymer-water interaction). The embrittlement comes from chain scission associated with a small chemicrystallization effect. Results lead to the proposal of a kinetic model for the chain scission rate aimed to describe the auto-acceleration effect induced by carboxylic acids (chain ends) and successfully compared to results both from this work or literature. The mixed “average molar mass – crystallinity” criterion proposed in a previous paper was specified. At last, the effect of pigments is illustrated and shows that carbon black (present in particular in one masterbatch) plays an aggravating role on hydrolysis.

La degenerescence maculaire liee a l’âge (DMLA) est la premiere cause de cecite legale chez les personnes âgees de plus de 65 ans dans les pays developpes. Le traitement de la forme exsudative a ete revolutionne par l’apparition des therapies anti-VEGF. L’aflibercept est le dernier anti-VEGF a avoir obtenu l’autorisation de mise sur le marche. Objectif : L’objectif de cette etude etait d’evaluer la reponse visuelle et anatomique en condition de vraie vie du traitement par aflibercept chez les patients naifs atteints de DMLA exsudative. Patients et methodes : Il s’agit d’une etude retrospective sur une serie de patients diagnostiques pour la DMLA exsudative et traite par aflibercept dans le service d’ophtalmologie du CHU de Bordeaux entre novembre 2013 a juillet 2015. Les patients ont beneficie d’une phase d’induction de 3 injections puis d’un suivi personnalise laisse a l’appreciation de quatre retinologues. Une mesure de l’acuite visuelle en score EDTRS, un fond d’œil et un examen OCT etaient realises a chaque visite de controle et les donnees ont ete recueillies a J0, 3 mois, 6 mois, 9 mois, 12 mois, 18 mois et 24 mois. Le nombre d’injections et de visites sur l’ensemble du suivi a ete evalue. Le critere de jugement principal etait l’evolution de l’acuite visuelle sur la periode de suivi. Resultats : 43 yeux de 40 patients, âges de 77,7 ans en moyenne, ont ete traites par aflibercept avec un suivi de minimum 3 mois. 25 yeux etaient suivis 1 an et 5 yeux deux ans. A l’inclusion la meilleure acuite visuelle avec correction moyenne etait de 55,7 lettres. Les patients ont recu une moyenne de 7,5 injections la premiere annee et 2,6 la 2ieme annee. Le gain moyen d’acuite visuelle etait de 7,3 lettres a 3 mois, de 6,2 lettres a 12 mois, et 6,8 lettres a 2 ans. Sur le plan anatomique, l’epaisseur maculaire centrale a diminue de 118,3μm a 3 mois, 136,4μm a 12 mois et 65,5μm a 2 ans. Conclusion : Le gain d’acuite visuelle a 3 mois etait maintenu a 12 mois et a 2 ans. Les parametres anatomiques montraient une evolution similaire. Nous pouvons obtenir pour nos patients des resultats se rapprochant des etudes pivotales malgre des protocoles differents, personnalises et l’allongement des intervalles de surveillance. Des etudes sur de plus gros echantillons, a plus long terme et evaluant les differents schemas therapeutiques seraient interessantes.

The dramatic increase in drug-related deaths in the last decade has presented fiduciary and logistical difficulties to medicolegal jurisdictions of all types and sizes. New Hampshire, with a centralized state medical examiner system of death investigation, has been confronted with the task of investigating these drug-related deaths against the backdrop of statutory hurdles inhibiting a nimble response to the situation. This has led to a collaborative approach with law enforcement and the state Department of Justice in terms of triaging drug deaths to full autopsy versus external examination with toxicology testing. Preliminary data suggest that between 11 and 13% of suspected drug deaths have an alternative cause of death revealed by autopsy. Positive toxicological findings were documented in 97.5% of cases in which only an external examination was performed; however, some of these cases may have had undetected, significant internal findings that could have accounted for an alternative cause of death if an autopsy had been performed. While the case triage system described has temporarily addressed the acute problem, the issue of the medical examiner's appropriate role in the adequate evaluation of public health and safety remains extant. Furthermore, noncompliance with the National Association of Medical Examiners inspection and accreditation standards puts this agency, and others facing the same issues, at risk of losing full accreditation status until such resource issues are addressed by legislators and other stakeholders in the quality of medicolegal death investigation in the United States.

Introduction Myocardial infarction (MI) is a severe ischemic disease precipitating long-term adverse remodeling and heart failure. The chemokine CXCL12/SDF-1 is essential for cardiovascular system development and plays a prominent role in physio-pathological processes such as inflammation, angiogenesis and tissue fibrosis. In addition to the binding to its cognate receptors CXCR4 and CXCR7, CXCL12 interacts with heparan-sulfates (HS) which coordinate its biological activity. We have previously highlighted the essential role of CXCL12/HS interactions in vascular growth and remodeling in the setting of critical limb ischemia. In addition, studies in experimental model of MI revealed a protective role for the CXCL12α isoform, through the regulation of cardiomyocyte survival and recruitment of inflammatory cells. However, in mice, three CXCL12 isoforms (α, β and γ) have been identified and, among them, the CXCL12γ isoform shows an unchallenged ability to cooperate with HS, suggesting a putative pivotal role in tissue repair. Objectives The aim of the study is to analyze the role of CXCL12γ isoform and the importance of CXCL12/HS interactions in post-ischemic cardiac remodeling in an acute model of MI. Methods MI was induced by permanent ligation of the left ascending coronary artery in mice carrying a Cxcl12 gene mutation that precludes interactions with HS (Cxcl12Gagtm) and in Cxcl12γ knock-in animals (Cxcl12γ-KI) harboring CXCL12γ deficiency. Alternatively, the impact of CXCL12γ overexpression and the importance of its interactions with HS was also evaluated in wild-type (WT) mice receiving transcutaneous echo-guided injections of adenovirus encoding WT Cxcl12γ or HS-binding-disabled Cxcl12γ in cardiac tissue. Cardiac function and remodeling have been assessed through echocardiography analysis, evaluation of infarct size, interstitial fibrosis, vascular growth (capillary and arteriole densities) and inflammatory cell infiltration into the cardiac tissue. Results After MI, Cxcl12Gagtm and Cxcl12γ-KI animals exhibit reduction in cardiac function and adverse left ventricular remodeling when compared to their respective WT littermates. Interestingly, overexpression of CXCL12γ in WT mice cardiac restored cardiac function by reducing the size of the infarcted area, interstitial fibrosis and promoting vascular growth. In sharp contrast, HS–binding disabled CXCL12gamma mutants failed to improve cardiac function and to abrogate adverse left ventricular remodeling. Conclusion We show that CXCL12γ isoform plays an important role in the regulation of post-ischemic cardiac function and remodeling and that its interactions with HS are essential for adequate cardiac repair in the setting of acute MI.

Background Activated cardiac fibroblasts produce extracellular matrix proteins that accumulate during cardiac fibrosis. We have recently shown that PW1 is expressed in a subset of cardiac stromal cells and that cardiac PW1+ cells represent a cellular source of fibroblasts in the ischemic hearts. Purpose We aimed to further identify new cell surface markers expressed by cardiac PW1+ cells and to investigate their role in the fibrogenic behavior of these cells. Methods and results We first performed transcriptomic and proteomic profiling of FACS-isolated cardiac PW1+ from normal and ischemic hearts. RNA-sequencing output files were processed with bioinformatics algorithms to identify 378 specific cell-surface markers for cardiac PW1+ cells. By comparing these candidates with the proteomic profile, we then cross-identified 9 cell surface proteins primarily involved in cell motility, adhesion to the matrix, inflammatory response and response to wounding. One of these candidates (i.e., aV-integrin or CD51) was expressed in almost all cardiac PW1+ cells (93±1%), and was predominantly found in cells expressing PW1 in the myocardium. Cardiac PW1+ cells showed a predominant expression of aVβ1 complex which is known to mediate fibrosis through TGF-beta activation in a number of tissues. The transfer of isolated cardiac PW1+CD51+ cells into ischemic hearts was associated with fibrosis development. We further demonstrated that inhibition of aV-integrin in cardiac PW1+ cells reduces their profibrotic gene expression profile and their ability to differentiate into fibroblasts. Lastly, a pharmacological blockade of aV-integrin improved cardiac function and animal survival following myocardial infarction coupled with a reduced infarct size and fibrotic lesion. Conclusions These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of aV-integrin leads to reduced pathological outcomes following cardiac ischemia. Acknowledgement/Funding Fondation Leducq (grant 13CVD01, CardioStemNet project), Fédération Française de Cardiologie and Era-CVD (ANR-16-ECVD-0011-03, Clarify project)

Background Myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Mature B lymphocytes have been shown to exacerbate tissue injury and deterioration of cardiac function after MI. However, the cellular and molecular mechanisms governing B cell deleterious effects in the ischemic milieu remain to be defined. Purpose In this study, we speculate that endogenous activation of the miR21/HIFα-related pathways mediates the effect of B lymphocytes on post-ischemic cardiac remodeling. Methods Acute MI was induced by permanent ligation of the left anterior descending artery in mice. Cardiac function and remodeling was determined by echocardiography and immunohistochemistry. Inflammatory cell number and phenotype were defined by FACS analysis. To evaluate the role of HIFα isoforms in B cells, we generated mice with B cell lineage specific (Cd79aCre/+) conditional deletion of HIF1α (HIF1αflox/flox), HIF2α (HIF2αflox/flox), or both isoforms (HIF1α-HIF2αflox/flox). Results Acute MI increased miR21 levels in B cells. miR21 deficient mice showed reduced B cell numbers in the spleen, blood and subsequently in the injured cardiac tissue. Transplantation of bone marrow derived cells isolated from miR21-deficient mice (miR21−/−) improved cardiac function and remodeling when compared to administration of wild-type (WT) bone marrow cells. Similarly, in Rag1−/− immunodeficient mice with acute MI, re-supplementation with miR21−/− B lymphocytes restored cardiac repair and function when compared to injection of WT B cells. miR21 abrogated PTEN contents and subsequently enhanced HIF1α levels in cultured B cells. B cell deletion of HIF1α, but not that of HIF2α, reduced B cell accumulation and improved cardiac function after MI. Mice, which were equally deficient in HIF1α and HIF2α, also exhibited abrogation of adverse ventricular remodeling and showed recovery of cardiac function after MI. Toll like receptor agonist, CpG, fostered the release of the monocyte chemo-attractant protein, Ccl7, in cultured WT B cells but not in miR21- or HIF1α- deficient B cells. Ccl7 circulating levels were also reduced in miR21−/− and Cd79aCre/+/HIF1α flox/flox animals after acute MI. Ccl7 down-regulation hampered Ly6Chigh monocyte infiltration in the ischemic myocardium, leading to decreased infarct size and interstitial fibrosis, supporting cardiac repair. Conclusion This work reveals a novel function for miR21/HIF1α related pathways in B lymphocyte dependent effect on cardiac function and remodeling in the setting of acute MI.

Objectives Endometrial cancer presents well-defined risk factors such as depth of myometrial invasion, histological subtype, tumour differentiation grade and lymphovascular space invasion (LVSI). The aim of this study was to investigate other clinical-pathological factors that might influence the recurrence of patients diagnosed with low and intermediate risk endometrial cancer. Methods Case-control study from a cohort retrospective of 196 patients diagnosed with low and intermediate risk endometrial cancer at a single institution between 2009 and 2014 was conducted. Medical records were reviewed to compare clinical (race, smoking, menopause, body mass index (BMI)) and pathological (histological subtype (endometrioid vs endometrioid with squamous differentiation), tumour differentiation grade, tumour localization, endocervical invasion, LVSI) carachteristics into patients with recurrence (case) and without recurrence (control) of disease. Three controls for each patient case was matched for age and staging. Results Twenty-one patients with recurrence was found (10.7%), of which 14 were stage IA and 7 were stage IB. We selected 63 patients without recurrence (controls). There were no significant differences in any clinical carachteristic between case and control patients. Among pathological variables, presence of squamous differentiation (28.6% vs. 4.8%, p=0.007), tumour differentiation grade 2 or 3 (57.1% vs. 30.2%, p=0.037) and presence of endocervical invasion (28.6% vs. 12.7%, p=0.103) were associated with disease recurrence from univariate analysis. On multivariable analysis, only squamous differentiation was a significant risk factor for recurrence (p=0.031). Conclusions Our data suggest that squamous differentiation may be a poor prognostic factor in patients with low and intermediate-risk endometrial carcinoma, had a 5.6 fold increased risk for recurrence.

This paper reports the study of embrittlement of PBT submitted either to thermal or hydrolytic ageing. All changes were followed up by tensile tests, rheometry in molten state and gel permeation chromatography for molar mass changes, SAXS and DSC experiments for crystallinity changes. Both kind of ageing were shown to induce predominant chain scissions with moderate crystallinity increase, in great part due to annealing. The combination of all results were used to establish a Mw - χc embrittlement window helping for a determination of an end of life criterion. The authors would like to thank the ANRT for granting this project (N °2019/1467). The authors would also like to thank V. Michel, RX manager at PIMM laboratory for helping in SAXS measurements and data treatment.

Introduction Cardiovascular disease (CVD) is the main cause of death in non-communicable diseases. In response to myocardial infarction (MI), extracellular vesicles (EVs), large (lEVs) and small (sEVs), are released within and from the heart to facilitate intercellular communication and maintain cardiac homeostasis, transferring their content such as miRNA, to recipient cells. Objective As diabetes increases the risk of CVD, the objective was to investigate how diabetes influences the release of cardiac EVs post-MI and to determine EV miRNA content. Methods B6J mice were fed chow diet or high-fat diet (HFD) for 3 months and subjected to MI by permanent ligation of the left anterior descending artery. Left ventricles were harvested at different timepoints post-MI and processed for EV extraction by differential centrifugation. EVs were analysed by Tunable Resistive Pulse Sensing (TRPS), flow cytometry and Western blot (WB). RNA sequencing of cardiac EVs was performed to reveal miRNAs of interest that were upregulated in cardiac EVs of MI mice and validated in HFD mice. Results In control mice, release of both lEVs and sEVs was increased at 24 h and 7 d post-MI. Similarly, in HFD mice, lEVs peaked at 24 h and 7 d post-MI and this increase was greater than in chow diet mice but there were no differences in sEV release between sham and MI HFD mice. TRPS analysis revealed that diabetes does not change EV size and flow cytometry showed that they are mainly of cardiomyocyte origin. Furthermore, EVs harboured cardiomyocyte marker (Troponin T) and sEVs carried tetraspanin markers as revealed by WB. Different miRNAs were also found to be upregulated in lEVs and sEVs in MI mice. Conclusion Our results show that diabetes modulates the release of both cardiac lEVs and sEVs post-MI. Furthermore, there is a difference in miRNA content between the 2 types of EVs post-MI. Further work is needed to investigate the functional impact of cardiac EVs in the diabetic heart post-MI.

Objective To evaluate the impact of surgical resection and adjuvant treatment on the course of patients after malignant progression of previously treated isocitrate dehydrogenase 1 (IDH1)–mutated World Health Organization (WHO) grade II astrocytoma. Methods This retrospective study explored 56 patients undergoing tumor resection for malignant progression after previously treated IDH1-mutated WHO grade II astrocytoma. We analyzed survival after malignant progression, analyzed overall survival (OS), and identified prognostic factors using Kaplan-Meier estimates and log-rank test. Results By the time of malignant transformation, median age was 44 years, and median Karnofsky Performance Status (KPS) score was 90. Complete resection of contrast-enhancing tissue was achieved in 18 (32.1%) patients. Median survival after re-resection was 33 months (95% confidence interval [CI], 20–46); median OS was 123 months (95% CI, 77–170). Gross total tumor resection, postoperative KPS score ≥80, adjuvant radiochemotherapy, and prior radiotherapy significantly correlated with post-malignant progression survival. Conclusions Patients in good clinical condition with malignant progression of previously treated low-grade gliomas should receive aggressive treatment, including re-resection.

Introduction Cardiovascular disease (CVD) is the main cause of death in non-communicable diseases. In response to myocardial infarction (MI), extracellular vesicles (EVs) including large (lEVs) and small (sEVs), are released within and from the heart to facilitate intercellular communication and maintaining cardiac homeostasis. Objective As diabetes increases the risk of CVD, the purpose of the study was to investigate how diabetes influences the release of intracardiac EVs after MI. Method C57BL/6 J male mice were fed normal chow diet or high-fat diet (HFD) for 3 months. HFD fed mice were glucose intolerant as attested by the measure of GTT above 200 mg/mL. Mice were subjected to MI by permanent ligation of the left anterior descending artery and sham animals underwent similar surgical procedure without ligation. Left ventricles from sham or MI mice were then harvested at either 15, 24, 48 or 72 hours after surgery (N = 5 per group at each time point) and processed for EV extraction by differential centrifugation. EVs were quantified and analyzed via Tunable Resistive Pulse Sensing Technology (TRPS), flow cytometry and Western blot. Results In chow diet fed mice, release of both lEVs and sEVs was increased at 24 h post-MI when compared to shams. These findings were in agreement with previous data obtained in younger control animals. In diabetic mice, lEVs peaked at 24 h post-MI and this increase was slightly greater than that observed in chow diet fed mice. However, there were no differences in sEV release between sham and MI diabetic mice. TRPS analysis revealed that diabetes does not change EV size and population. Furthermore, both control and diabetic derived EVs harboured cardiomyocyte marker (Troponin T) as revealed by Western blot. Conclusion Our results show that diabetes modulates the release of both intracardiac sEVs and lEVs after MI. Further work will be needed to fully investigate the functional impact of cardiac EVs in the diabetic heart after MI.

Introduction The chemokine CXCL12 is essential for cardiovascular system development and plays a major role in physio-pathological processes such as inflammation, angiogenesis but also tissue remodeling after an ischemic insult. In addition to the binding to its receptors, CXCR4 and CXCR7, CXCL12 interaction with heparan-sulfates (HS) commands its biological activity. Studies in experimental models of myocardial infarction (MI) revealed a protective role for CXCL12α. However, in mice, three CXCL12 isoforms (α, β and γ) have been identified and the CXCL12γ isoform shows an unchallenged ability to cooperate with HS, suggesting a pivotal role in tissue repair. Objective The aim of the study is to analyze the role of CXCL12γ isoform and the importance of CXCL12/HS interactions in post-ischemic cardiac remodeling in an acute model of MI. Method MI are induced in mice carrying a Cxcl12 gene mutation that precludes interactions with HS (Cxcl12Gagtm) and in Cxcl12γ knock-in animals (Cxcl12γ-KI), harboring CXCL12γ deficiency. Alternatively, the impact of CXCL12γ overexpression is also evaluated in wild-type (WT) mice receiving transcutaneous echo-guided injections of adenovirus encoding Cxcl12γ in cardiac tissue. Cardiac function and remodeling have been assessed through echocardiography analysis and evaluation of infarct size, interstitial fibrosis, capillary and arteriole densities and as well as inflammatory cell infiltration. Results After MI, Cxcl12Gagtm and Cxcl12γ-KI animals exhibit reduction in cardiac function and adverse left ventricular remodeling when compared to their respective WT littermates. Interestingly, overexpression of CXCL12γ in WT mice normalizes cardiac function by reducing the size of the infarcted area, interstitial fibrosis and promoting vascular growth. Conclusion We show that CXCL12γ isoform plays an important role in the regulation of cardiac function after MI and that its interactions with HS seems essential for adequate cardiac repair.

Data concerning treatment of secondary glioblastoma evolving from previously treated WHO II or III grade tumors are very scarce. The aim of this study was to evaluate the impact of surgical resection and adjuvant treatment on survival in patients with secondary glioblastoma. Thirty-nine patients with secondary glioblastoma evolving from previously treated lower grade gliomas between 2004 and 2015 were included. We evaluated the extent of resection, pathological parameters, adjuvant treatment, as well as survival after malignant transformation. The primary tumor grade was WHO II in 16 (41.0%) and WHO III in 23 (59.0%) patients. Median age was 43 years (range 23–67). Median KPS was 80 (range 60–100) before surgery, and 70 (range 50–100) after surgery. Gross total resection (GTR) of contrast-enhancing disease was achieved in 19 (48.7%) patients. Adjuvant treatment was radio-chemotherapy in 23 (59.0%), radiotherapy in three (7.7%), chemotherapy in five (12.8%) and none in eight (20.5%) patients. Median survival was 11 months (range 1–35) in the entire group. Time since initial diagnosis and previous treatment did not correlate with survival after glioblastoma. Failed GTR, poor KPS after surgery, and no adjuvant treatment were prognostic factors for shorter survival in univariate analysis (p

Anti-VEGF therapies have revolutionized the treatment of neovascular age-related macular degeneration (AMD).The goal of this study was to evaluate the "real life" visual and anatomical outcomes of aflibercept treatment for treatment-naive patients with exudative AMD.This was a retrospective study of patients treated with aflibercept in the department of Ophthalmology at the University Hospital of Bordeaux between November 2013 and July 2015. The follow-up period varied from 3months to 2years. All patients received an induction phase with 3monthly intravitreal injections (IVT) followed by personalized monitoring. ETDRS best-corrected visual acuity (BCVA), fundus examination and OCT were performed at each visit. Data were collected at day 0, 3 months, 6, 9, 12months, 18 and 24months.Forty-three eyes of forty patients, mean age 77.7years, were included, with a minimum of 3months follow-up. Twenty-five eyes were followed for 1year; 5 eyes for two years. At baseline, the mean BCVA was 55.7 letters. Patients received 7.5 injections on average the first year and 2.6 the 2nd year. The mean gain of visual acuity was +7.3 letters at 3 months, +6.2 letters at 12 months, and +6.8 letters at 2years. Anatomically, the OCT data showed a decline of all parameters. The central macular thickness decreased by 118.3μm at 3months, 136.4μm at 12months and 65.5μm at 2years.Aflibercept can achieve effective visual and anatomical outcomes with results, which approach the pivotal studies, despite the use of personalized protocols and longer monitoring intervals.

© 2012 Elsevier 0196-4399/00 (see frontmatter) 13 Introduction Arcanobacterium haemolyticum (formerly Corynebacterium haemolyticum) is a gram-positive bacillus that is mainly implicated in pharyngitis and skin infections. Most of these infections occur in the adolescent age group, sometimes mixed with other pathogens. This microorganism is sometimes overlooked in the clinical microbiology laboratory because it is rare. The colonies may be dismissed as insignificant or misidentified as Streptococcus or Corynebacterium species, resulting in a missed or delayed diagnosis. Endocarditis is rarely caused by the bacterium and has been reported in only three cases in the literature. In this case report, we present a fatal case of endocarditis associated with a congenital bicuspid aortic valve. We also describe the laboratory methods used for the identification of the organism, together with a brief review of the literature on reported cases of A. haemolyticum infection.

Background: The PI3K pathway plays a major role in cancer cell growth and survival and is the most frequently altered pathway in cancer. BEZ235 is a potent and highly specific oral PI3K/mTOR inhibitor. Administered as hard-gelatine capsule, BEZ235 was well tolerated with a favorable safety profile. Available data showed that BEZ235 led to PRs (1 patient (pt) with NSCLC [PTENnull], 1 pt with ER+ breast cancer [mutation unknown]) and prolonged disease stabilization (4 to >24 months) in pts with PI3K pathway dysregulated tumors (N=9/51), 5/9 with ER+, 1/9 with HER2+ breast cancer. Here, we present data from patients (pts) receiving treatment with a special drug delivery system of BEZ235 (SDS) with improved PK properties (Cao SABCS 2010). Results: 22 pts have been treated with BEZ235 SDS capsule at 3 dose levels (qd): 400 mg (5); 800 mg (6), 1000 mg (11). Median age was 56 years. The most common tumor types among pts enrolled were: breast cancer (4), CRC (4) and NSCLC (3). 2/22 pts were treated for >3 cycles, 16/22 pts progressed within the first three cycles of treatment. The maximum tolerated dose (MTD) is 1000 mg/d. Dose-limiting toxicities (DLTs) included: 2 Grade (G)3 fatigue (800 mg and 1000 mg) and 1 G3 skin rash (at 1000 mg). The most common treatment-related AEs included: fatigue, diarrhea, nausea, vomiting (G1-3). Preliminary PK data showed a slow absorption rate, Cmax at ∼6 h post-dose (range 2-8 h). The elimination halflife is ∼6 h across doses and visits. Steady state was reached after 8 days of treatment; the mean (SD) exposures at steady state (AUC, rss) for the dose of 400, 800, and 1000 mg/d were 8864 (12210), 19060 (19860), 46010 (36150) ng*h/mL, respectively. The exposure across dose levels (AUC0- 24, SS) was above the exposure required for tumor stasis in PI3K pathway dysregulated tumors, estimated based on CT measurements in patients(Bottino SABCS 2010). Currently, the efficacy of BEZ235 SDS, alone and in combination with trastuzumab, in patients with PIK3CA mutated breast cancer is investigated. As of today 1 clinical PR was observed with BEZ235+trastuzumab in a patient with breast cancer (HER2+, PIK3CA mutated, trastuzumab refractory) with brain and peripheral metastases. Conclusions: BEZ235 SDS treatment is well tolerated. The MTD is 1000 mg/d. Available PD and efficacy data show that BEZ235 is active in breast cancer (especially PI3K pathway dysregulated tumors). Phase II studies in breast cancer combining BEZ235 SDS with other agents will start soon. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-07.

Multiple self-inflicted gunshot wounds to the head are rare and usually present a challenge to the pathologist and to the police in determining the manner of death. We report a case of two suicidal gunshot wounds to the head. The literature is reviewed, and the pertinent findings, including location of the wounds, location of the brain injuries, types of weapons used, and criteria important to determine the manner of death, are discussed.

BACKGROUND: Glutathione S-transferases (GST) may prevent carcinogenesis through inactivation of reactive electrophiles by conjugation to reduced glutathione. Treatment directed at the induction or preservation of GST-pi expression in normal epithelium could have a profound impact on the prevention of prostate neoplasia. Finasteride, a 5-alpha-reductase inhibitor, is used as a chemopreventive agent because it blocks the conversion of testosterone to its byproduct which promotes prostate tumour growth. OBJECTIVE: To investigate GST-pi expression immunohistochemically in benign prostate tissue from untreated patients and from patients chronically treated with finasteride. MATERIALS: Immunostaining with anti-GST-pi antibody was performed on 10 (cysto-) prostatectomy, eight simple prostatectomy, and three transurethral prostatectomy specimens. The first set of 10 prostates was from untreated patients operated on for bladder cancer. The other cases were from patients with benign prostatic hyperplasia and chronically treated with finasteride. None of the specimens in either group showed prostatic cancer, prostatic intraepithelial neoplasia, urothelial carcinoma, or chronic prostatitis. Specimens were evaluated for the presence, intensity, and distribution of immunostaining. RESULTS: Diffuse cytoplasmic immunostaining was observed in the basal cell layer of the untreated specimens. Some variability in the expression of GST-pi was seen within each zone and also between the prostate zones. Only a minority of the secretory cells was stained weakly, mainly in the subnuclear region of the cells facing an uninterrupted basal cell layer. Staining was more homogeneously diffuse in the cytoplasm of the luminal cells facing the basement membrane directly. In the benign epithelium of the finasteride treated specimens the circumferential staining of the basal cells appeared to be more continuous than in the untreated cases, the gaps in the stained basal cell layer being fewer, shorter, or even absent in some ducts and acini. There was no variability in the intensity of staining of the basal cell layer, all the cells being intensely stained in a uniform way. The intensity of staining of the secretory cells was not influenced by finasteride treatment. CONCLUSIONS: Following chronic treatment with finasteride the immunohistochemical expression of pi class glutathione S-transferase in the benign prostate ducts and acini is upregulated in relation to an expanded basal cell layer. This could indicate that finasteride acts as a GST-pi inducer.

It is the aim of these studies to derive a numerically defined progression index for prostatic intraepithelial neoplasia (PIN) lesions.Histometric and karyometric features were automatically extracted from images of histopathologic sections by a machine vision system.Both histometric and karyometric measures lend themselves to the defining of a progression index. Karyometric features were found to be more sensitive. They allow the detection of very early change.It is possible to measure progression of PIN lesions with precision. The methodology would lend itself for measurement of regression due to chemopreventive intervention.

This work aimed to see whether (1) biofeedback is useful and (2) whether it needs to be combined with psychotherapy in sexually abused patients with anismus. Fifteen women aged 41.2±4.1 years who had experienced sexual abuse in childhood (9 cases) or adulthood (6 cases) and complained of symptoms of irritable bowel disease were studied. Anismus was recorded during anorectal manometry in all cases. Patients were free to choose biofeedback and/or group psychotherapy and/or individual psychotherapy. When necessary, psychoactive drugs were prescribed after a psychiatric evaluation. Initially all the patients chose biofeedback and none accepted psychotherapy. Eight patients accepted psychotherapy after several weeks of biofeedback. Thirteen patients completed the study: 5 treated by biofeedback alone, 5 with biofeedback and group therapy, and 3 with biofeedback and individual psychotherapy. Eight women recovered completely from their symptoms, only two of whom had had biofeedback without psychotherapy. Conclusion: Biofeedback alone was not always sufficient to cure abused patients, but was chosen initially by all the patients. It could initially be a middle path between somatic treatment and psychotherapy, at a time when patients are not yet ready to undertake the latter.

Here we report a case of sustentorial brain abscess due to Listeria monocytogenes. Blood culture and procalcitonine blood measurement were negative. L. monocytogenes was isolated from CSF after inoculation in Castañeda medium.

« Emee, 68 ans, dort beaucoup sauf quand sa fille est la. Elle pleure en silence, meme en dormant. Elle ne parle pas ou peu. » Telle est la presentation faite par l’equipe. Elle accepte l’entretien psychologique.

To develop a fast and reliable real time PCR technique for detecting plasmid-mediated quinolone resistance genes qnrA, qnrB and qnrS.A real-time PCR assay using SYBR Green I and Roche LightCycler(®) was developed to detect qnr genes. Detection of qnr genes was based on comparison of melting temperature differences with a positive control of each qnr genes. This assay was performed to study 138 isolates collected from diagnostic and screening samples in the Champagne-Ardenne region in 2004 (France).In optimized conditions, the three positive controls tested alone and with isolates confirmed the specificity of the PCR primers. Each PCR assay was able to test 30 strains in 60min for 1 qnr gene. Out of 138 isolates screened, 3.6 % isolates were positive for a qnrA1, 1.5 % for qnrS1 and no qnrB-like gene. Prevalence of qnr determinants was 5 % and reached 9.5 % in clinical isolates.Real-time PCR is a fast and reliable technique for screening of qnr-positive strains. This study shows a relatively high prevalence of qnr determinants (5 %) among ESBL-producing Enterobacteriaceae.

Forensic pathologists have historically found several characteristics of the entrance wound invaluable in determining range of fire in gunshot fatalities. Among these characteristics are the pattern and constituents of any deposited material such as soot and/or gun powder residues. We describe a case in which the application of previously described characteristics, in the absence of laboratory testing and examination of the crime scene, would have led to an erroneous conclusion with potentially grave consequences. We suggest that all attempts be made to use available laboratory tests and to perform detailed examination of crime scenes in determining the circumstances surrounding fatal gunshot injuries.

Sensorineural hearing defect and goiter are common features of Pendred's syndrome. The clinical diagnosis of Pendred's syndrome remains difficult because of the lack of sensitivity and specificity of the thyroid signs. The identification of PDS as the causative gene allowed molecular screening and enabled a re-evaluation of the syndrome to identify potential diagnostic characteristics. This report presents the clinical and genotypic findings of 30 French families, for whom a diagnosis of Pendred's syndrome had been made. Twenty-seven families had at least one mutated allele. Twenty-eight different mutations were identified, 11 of which had never been previously reported. The main clinical characteristics were: early hearing loss, fluctuation in terms of during deafness evolution, and the presence of an enlarged vestibular aqueduct.

Background.—Expression of cytokeratins 7 (CK7) and 20 (CK20) may help distinguish the site of origin for metastatic carcinomas. Little is known regarding their expression in biliary tract and pancreatic carcinomas. Our aim was to study the expression of CK7 and CK20 in these tumors. Design.—Fifty-three carcinomas of the extrahepatic bile ducts (n = 8), ampulla of Vater (n = 7), gallbladder (n = 11), and pancreas (n = 27), were retrieved from the surgical pathology files of the University of Massachusetts Medical Center. Formalin-fixed, paraffin-embedded sections were immunostained with mouse monoclonal antibodies to CK7 and CK20 using an avidin-biotin immunoperoxidase technique with microwave antigen retrieval. The percentage of cells positive for each antibody was assessed on a scale of 0 to 3 (0, 90%). Results.—The majority of carcinomas in all groups were positive for CK7 (CK7+) and negative for CK20 (CK20−). Of the CK7+ tumors, the majority of tumors in each group were 3+ positive. Conclusions.—(1) Carcinomas of the extrahepatic biliary tract and pancreas are strongly positive for CK7 and negative for CK20 and can be included in the differential diagnosis of other carcinomas with this profile in metastatic sites. (2) The CK7/CK20 immunostaining profile will not identify the site of origin for tumors with extensive growth in the porta hepatis region.

Separation of N16O and N18O has been measured in a thermal diffusion column heated by resonant absorption of CO laser photons. For the most part, the behavior of the laser‐heated column can be adequately explained as a simple thermal effect, although the separation efficiency at low‐input powers is higher in the laser‐heated column than in a comparable hot‐wire experiment.