Involvement of the CXCR7/CXCR4/CXCL12 Axis in the Malignant Progression of Human Neuroblastoma.

Neuroblastoma (NB) is a typical childhood and heterogeneous neoplasm for which efficient targeted therapies for high-risk tumors are not yet identified. The chemokine CXCL12, and its receptors CXCR4 and CXCR7 have been involved in tumor progression and dissemination. While CXCR4 expression is associated to undifferentiated tumors and poor prognosis, the role of CXCR7, the recently identified second CXCL12 receptor, has not yet been elucidated in NB. In this report, CXCR7 and CXCL12 expressions were evaluated using a tissue micro-array including 156 primary and 56 metastatic NB tissues. CXCL12 was found to be highly associated to NB vascular and stromal structures. In contrast to CXCR4, CXCR7 expression was low in undifferentiated tumors, while its expression was stronger in matured tissues and specifically associated to differentiated neural tumor cells. As determined by RT-PCR, CXCR7 expression was mainly detected in N-and S-type NB cell lines, and was slightly induced upon NB cell differentiation in vitro. The relative roles of the two CXCL12 receptors were further assessed by overexpressing CXCR7 or CXCR4 receptor alone, or in combination, in the IGR-NB8 and the SH-SY5Y NB cell lines. In vitro functional analyses indicated that, in response to their common ligand, both receptors induced activation of ERK1/2 cascade, but not Akt pathway. CXCR7 strongly reduced in vitro growth, in contrast to CXCR4, and impaired CXCR4/CXCL12-mediated chemotaxis. Subcutaneous implantation of CXCR7-expressing NB cells showed that CXCR7 also significantly reduced in vivo growth. Moreover, CXCR7 affected CXCR4-mediated orthotopic growth in a CXCL12-producing environment. In such model, CXCR7, in association with CXCR4, did not induce NB cell metastatic dissemination. In conclusion, the CXCR7 and CXCR4 receptors revealed specific expression patterns and distinct functional roles in NB. Our data suggest that CXCR7 elicits anti-tumorigenic functions, and may act as a regulator of CXCR4/CXCL12-mediated signaling in NB.

A pilot assessment of alpha-stat vs pH-stat arterial blood gas analysis after cardiac arrest.

PURPOSE: Resuscitated cardiac arrest (CA) patients typically receive therapeutic hypothermia, but arterial blood gases (ABGs) are often assessed after adjustment to 37°C (alpha-stat) instead of actual body temperature (pH-stat). We sought to compare alpha-stat and pH-stat assessment of Pao2 and Paco2 in such patients. MATERIALS AND METHODS: Using ABG data obtained during the first 24 hours of intensive care unit admission, we determined the impact of measured alpha vs calculated pH-stat on Pao2 and Paco2 on patient classification and outcomes for CA patients. RESULTS: We assessed 1013 ABGs from 120 CA patients with a median age of patients 66 years (interquartile range, 50-76). Median alpha-stat Pao2 changed from 122 (95-156) to 107 (82-143) mm Hg with pH-stat and median Paco2 from 39 (34-46) to 35 (30-41) mm Hg (both P < .001). Using the categories of hyperoxemia, normoxemia, and hypoxemia, pH-stat estimation of Pao2 reclassified approximately 20% of patients. Using the categories of hypercapnia, normocapnia, and hypocapnia, pH stat estimation of Paco2 reclassified approximately 40% of patients. The mortality of patients in different Pao2 and Paco2 categories was similar for pH-stat and alpha-stat. CONCLUSIONS: Using the pH-stat method, fewer resuscitated CA patients admitted to intensive care unit were classified as hyperoxemic or hypercapnic compared with alpha-stat. These findings suggest an impact of ABG assessment methodology on Pao2, Paco2, and patient classification but not on associated outcomes.

Opéras suisses en voyage - de Bätely à Betly = Schweizer Opern en voyage - von Bätely zu Betly

En 1834, Eugène Scribe réécrit un Singspiel de Goethe qui se déroule en Suisse ('Jeri und Bätely', 1780) pour la scène de l'Opéra comique, avec la musique d'Adolphe Adam. Deux ans plus tard, Gaetano Donizetti traduit le livret de Scribe en italien. Ces migrations et traductions ont fait, entre autres, l'objet d'un projet de recherche dirigé par Marie Caffari à l'Institut Littéraire Suisse de Bienne. Bernard Banoun, Francesco Micieli et Raphael Urweider se sont confrontés dans leurs propres traductions avec ce texte stratifié. Le volume regroupe aussi des essais de traductologues et musicologues qui offrent différentes perspectives méthodologiques sur cet opéra en voyage.

Bilan préopératoire pour la chirurgie cardio-vasculaire en urgence [Preoperative assessment in emergency cardiovascular surgery].

In the emergency situation, preoperative patient work-up for cardio-vascular surgery is quite different from the elective setting. We have analyzed a consecutive series of 5576 cases out of which 823 underwent emergency procedures (14.8%). The most frequent problems requiring emergent intervention were peripheral vascular (186 cases; 22.6% of the emergent procedure), followed by coronary artery disease (156 cases; 19.0%), thoracic aortic aneurysms (86 cases; 10.4%), abdominal aortic aneurysms (54 cases; 6.6%), congenital heart disease (36 cases: 4.4%), heart and heart lung transplantation (31 cases; 3.8%), problems with cardiac rythm (25 cases: 3.0%), and others (267 cases: 32.4%). Classification by proportion of urgent procedures with reference to elective operations shows a different picture. As a matter of fact transplantations were always emergency procedures (100%), whereas repair of aortic dissections type A and B was an emergency procedure in 81.5%. Emergency thoracic and abdominal aortic aneurysm repair accounted for 30% and 20% respectively and the corresponding proportion for peripheral vascular surgery is 19%. However, emergency surgery for acute coronary ischemia, valvular and congenital heart disease accounted for somewhat less than 10% for each group of these pathologies. Systematic pre-operative diagnostic work-up is a recognized tool for procedure related risk assessment and superior management of diseases. However, hemodynamic instability and other time related events correlated with negative outcome, are the main driving forces for accelerated diagnostic pathways

Synorogenic extension: Quantitative constraints on the age and displacement of the Zanskar shear zone (northwest Himalaya)

subsequent extension-induced exhumation. Geochronological dating of various Structural, thermobarometric, and geochronological data place limits on the age and tectonic displacement along the Zanskar shear zone, a major north-dipping synorogenic extensional structure separating the high-grade metamorphic sequence of the High Himalayan Crystalline Sequence from the overlying low-grade sedimentary rocks of the Tethyan Himalaya, A complete Barrovian metamorphic succession, from kyanite to biotite zone mineral assemblages, occurs within the I-km-thick Zanskar shear zone. Thermobarometric data indicate a difference In equilibration depths of 12 +/- 3 km between the lower kyanite zone and the garnet zone, which is Interpreted as a minimum estimate for the finite vertical displacement accommodated by the Zanskar shear zone. For the present-day dip of the structure (20 degrees), a simple geometrical model shows that a net slip of 35 +/- 9 km is required to regroup these samples to the same structural level. Because the kyanite to garnet zone rocks represent only part of the Zanskar shear zone, and because its original dip may have been less than the present-day dip, these estimates fur the finite displacement represent minimum values. Field relations and petrographic data suggest that migmatization and associated leucogranite intrusion in the footwall of the Zanskar shear zone occurred as a continuous profess starting at the Barrovian metamorphic peak and lasting throughout the subsequent extension-induced exhumation. Geochronological dataing of various leucogranitic plutons and dikes in the Zanskar shear zone footwall indicates that the main ductile shearing along the structure ended by 19.8 Ma and that extension most likely initiated shortly before 22.2 Ma.

Prevalence of respiratory viruses among febrile children with or without acute respiratory symptoms in Tanzania

Background Respiratory viruses are the most frequent cause of febrile illnesses in infants and young children but few investigations have assessed their impact and epidemiology in Africa . We investigated their rate in febrile outpatient children attending in Tanzania. Methods Children aged 2 months -10 years with fever >38 _C were recruited prospectively between April and December 2008. Medical history and clinical examination were recorded in a standardized fashion and nasopharyngeal swabs analyzed for the presence of 12 viruses by real-time PCR (FLUAV, FLUBV, RSV, MPV, HPIV-1/3, four types of HCoV, HBoV, PIC and HAdV). Ct values were used to provide semi-quantitative viral loads.Results Of 1005 febrile children enrolled, 623 (62%) had respiratory symptoms (URTI in 66%, bronchiolitis in 7% and clinical pneumonia in 27%); 156 (16%) had febrile illness that remained of unspecified etiology and 226 (22%) had other infectious diseases and no ARI (62 malaria, 56 gastroenteritis, 36 urinary tract and 72 others). The proportions of patients with at least one respiratory virus were 70%, 61% and 47% (Pvalue < 0.001) in these three groups. When excluding picornavirus and adenovirus these proportions were 48%, 24% and 26% (P-value < 0.001). Apart from picornavirus and adenovirus, influenza A and B viruses were the most frequent followed by coronavirus and RSV. The proportion of children with presumably high viral titers (Ct < 25) was higher in the group with respiratory symptoms (31%) than in the two other groups (21% and 16%). Influenza genotyping revealed strains that were similar to the ones circulating elsewhere in the world.Conclusion In African children with febrile illness, the prevalence of respiratory viruses, especially influenza A and B, is high particularly in the presence of respiratory symptoms, but also, although less so, in those with unspecified etiology or other infectious diseases. This highlights that these viruses are commonly circulating in Tanzanian children.

Leukocyte-endothelial cell interaction is necessary for photodynamic therapy induced vascular permeabilization.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) affects vascular barrier function and thus increases vessel permeability. This phenomenon may be exploited to facilitate targeted drug delivery and may lead to a new clinical application of photodynamic therapy. Here, we investigate the role of leukocyte recruitment for PDT-induced vascular permeabilization. STUDY DESIGN/MATERIAL AND METHODS: Fluorescein isothiocyanate dextran (FITC-D, 2,000 kDa) was injected intravenously 120 minutes after focal PDT on striated muscle in nude mice bearing dorsal skinfold chambers (Visudyne® 800 µg/kg, fluence rate 300 mW/cm2 , light dose of 200 J/cm2). Leukocyte interaction with endothelial cells was inhibited by antibodies functionally blocking adhesion molecules ("MABS-PDT" group, n = 5); control animals had PDT but no antibody injection (group "PDT", n = 7). By intravital microscopy, we monitored leukocyte rolling and sticking in real-time before, 90 and 180 minutes after PDT. The extravasation of FITC-D from striated muscle vessels into the interstitial space was determined in vivo during 45 minutes to assess treatment-induced alterations of vascular permeability. RESULTS: PDT significantly increased the recruitment of leukocytes and enhanced the leakage of FITC-D. Neutralization of adhesion molecules before PDT suppressed the rolling of leukocytes along the venular endothelium and significantly reduced the extravasation of FITC-D as compared to control animals (156 ± 27 vs. 11 ± 2 (mean ± SEM, number of WBC/30 seconds mm vessel circumference; P < 0.05) at 90 minutes after PDT and 194 ± 21 vs. 14 ± 4 at 180 minutes after PDT). In contrast, leukocyte sticking was not downregulated by the antibody treatment. CONCLUSION: Leukocyte recruitment plays an essential role in the permeability-enhancing effect of PDT.

Restoration of anti-tetanus toxoid responses in patients initiating highly active antiretroviral therapy with or without a boost immunization: an INITIO substudy.

INITIO is an open-labelled randomized trial evaluating first-line therapeutic strategies for human immunodeficiency virus-1 (HIV-1) infection. In an immunology substudy a tetanus toxoid booster (TTB) immunization was planned for 24 weeks after initiation of highly active antiretroviral therapy (HAART). All patients had received tetanus toxoid immunization in childhood. Generation of proliferative responses to tetanus toxoid was compared in two groups of patients, those receiving a protease inhibitor (PI)-sparing regimen (n = 21) and those receiving a PI-containing (n = 54) regimen. Fifty-two participants received a TTB immunization [PI-sparing (n = 15), PI-containing (n = 37)] and 23 participants did not [PI-sparing (n = 6) or PI-containing (n = 17)]. Cellular responses to tetanus antigen were monitored by lymphoproliferation at time of immunization and every 24 weeks to week 156. Proportions with a positive response (defined as stimulation index > or = 3 and Delta counts per minute > or = 3000) were compared at weeks 96 and 156. All analyses were intent-to-treat. Fifty-two participants had a TTB immunization at median 25 weeks; 23 patients did not. At weeks 96 and 156 there was no evidence of a difference in tetanus-specific responses, between those with or without TTB immunization (P = 0.2, P = 0.4). There was no difference in the proportion with response between those with PI-sparing or PI-containing regimens at both time-points (P = 0.8, P = 0.7). The proliferative response to tetanus toxoid was unaffected by initial HAART regimen. Anti-tetanus responses appear to reconstitute eventually in most patients over 156 weeks when treated successfully with HAART, irrespective of whether or not a TTB immunization has been administered.

Mandatory infectious diseases consultation for MRSA bacteremia is associated with reduced mortality.

OBJECTIVES: Although infectious disease (ID) consultation has been associated with lower mortality in Staphylococcus aureus bloodstream infections, it is still not mandatory in many centers. This study aimed at assessing the impact of ID consultation on diagnostic and therapeutic management of methicillin-resistant S. aureus (MRSA) bacteremia. METHODS: Retrospective cohort study of all patients with MRSA bacteremia from 2001 to 2010. ID consultations were obtained on request between 2001 and 2006 and became mandatory since 2007. RESULTS: 156 episodes of MRSA bacteremia were included, mostly from central venous catheter (32%) and skin and soft tissue (19%) infections. ID consultation coverage was 58% between 2001 and 2006 and 91% between 2007 and 2010. ID consultation was associated with more echocardiography (59% vs. 26%, p < 0.01), vancomycin trough level measurements (99% vs. 77%, p < 0.01), follow-up blood cultures (71% vs. 50%, p = 0.05), deep-seated infections (43% vs. 16%, p < 0.01), more frequent infection source control (83% vs. 57%, p = 0.03), a longer duration of MRSA-active therapy (median and IQR: 17 days, 13-30, vs. 12, 3-14, p < 0.01) and a 20% reduction in 7-day, 30-day and in-hospital mortality. CONCLUSIONS: ID consultation was associated with a better management of patients with MRSA bacteremia and a reduced mortality.