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Evaluation of pharmacodynamic (PD) markers in vivo.

Supplemental Table S1. IC50 values for Nultin-3a, Carboplatin, and 1:1 Combination; Supplemental Material and Methods; Supplemental Figure Legends

Evidence of the effectiveness of rehabilitation interventions in spinocerebellar ataxia is scarce and variable. OBJECTIVES: The aim of this systematic review was to gather the existing evidence on the effectiveness of these interventions. MATERIAL AND METHODS: To do this, we analysed all the clinical trials published to date and assessed their results in terms of improved balance, gait, and performance of daily activities after treatment. Significant improvements were found for posture (P

This work was trigerred by the earlier achivements of Yarman et al, aiming to bridge themordynamics and quantum mechanics, whence, Planck constant came to replace Boltzmann constant, and “average quantum level number” came to replace “temperature”. This evoked that the classical Maxwell energy probability distribution p(E) with respect to energy E of gas molecules might be taken care of, by the “energy probability distribution of the quantum levels” of a particle imprisoned in a given volume, assuming that in the case we have many particles, following Pauli exclusion principle, no pair of particles can sit at the same level. Thereby, the energy probability distribution of the quantum levels of a particle imprisoned in three dimensions, will be the subject of this essay. Such an outlook becomes interesting from several angles: i) It looks indeed very much like a classical Maxwellian distribution. ii) In the case we have as many free particles in the box as the number of levels depicted by the number of quantum levels in between the predetermined lower bound energy level and the upperbound energy level, all the while assuming that the Pauli principle holds, the distribution we disclose becomes the energy probability distribution of the ensemble of particles imprisoned in the given box. iii) It can even be guessed that, if elastic collisions between the free particles were allowed, and still assuming quantization and the Pauli principle, the outcome we disclose should be about the same as that of the energy probability distribution, molecules in a room would display in equilibrium. iv) The quantized energy being proportional to the sum of three squared integers associated with respectively, each of the spatial dimensions; the property we reveal certainly becomes remarkable from the point of view of mathematics of integer numbers. All the more, we further disclose that, to the probability distribution outlook remains the same, be this qualitatively for higher dimensions than 3.

The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+/HER2− and ER+/HER2+ subtypes. However, a subset of triple-negative breast cancer (TNBC) cell lines with intact Rb signaling were also found to be responsive. Equivalent levels of tumor growth inhibition were observed in ER+/HER2−, ER+/HER2+ as well as biomarker selected TNBC xenografts in response to abemaciclib. In addition, abemaciclib combined with hormonal blockade and/or HER2-targeted therapy induced significantly improved antitumor activity. CDK4/6 inhibition with abemaciclib combined with antimitotic agents, both in vitro and in vivo, did not antagonize the effect of either agent. Finally, we identified a set of Rb/E2F-regulated genes that consistently track with growth inhibitory response and constitute potential pharmacodynamic biomarkers of response to abemaciclib. Taken together, these data represent a comprehensive analysis of the preclinical activity of abemaciclib, used alone or in combination, in human breast cancer models. The subtypes most likely to respond to abemaciclib-based therapies can be identified by measurement of a specific set of biomarkers associated with increased dependency on cyclinD:CDK4/6:Rb signaling. These data support the clinical development of abemaciclib as monotherapy or as a combination partner in selected ER+/HER2−, HER2+/ER+, and TNBCs. Mol Cancer Ther; 17(5); 897–907. ©2018 AACR.

Infection during pregnancy is common and the developing fetal brain is vulnerable to vertical transmission due to immaturity of the fetal immune system. Infection is a major cause of multiple organ abnormalities, including the neuraxis, due to the neurotropism of the infectious agents. This review sets out to give an overview of fetal infection, review the general principles of the nature and timing of the infectious insult with respect to outcomes, review the neuroimaging of infection by ultrasound and magnetic resonance imaging (MRI), and review the various pathogens involved, including the two most common, cytomegalovirus (CMV) and Toxoplasma, and also other common viral and nonviral infections.

Evidence of the effectiveness of rehabilitation interventions in spinocerebellar ataxia is scarce and variable. OBJECTIVES: The aim of this systematic review was to gather the existing evidence on the effectiveness of these interventions. MATERIAL AND METHODS: To do this, we analysed all the clinical trials published to date and assessed their results in terms of improved balance, gait, and performance of daily activities after treatment. Significant improvements were found for posture (P.008) and gait (P.02), as well as a reduction in the scores for the SARAgp subscale (gait and posture) and SCAFI 8MW index (gait speed) (P=.02). We also observed improvements in speech disorders (P=.02), depressive symptoms (P.0001) and accidental falls (P.005).

The treatment of superficial cancerous tumors with heat alone or in various combinations with ionizing radiations is not a new idea and dates back to the beginning of the century. The history of the use of microwave heating in cancer therapy is simpler because of the late development of high power generators which necessitate high technology. The most important ultrasound interaction with biological structures is heat dissipation, and to a lesser extent, cavitation effects creating “microstreaming”. The experimental and clinical data demonstrate that ultrasound fields perturb standard ternperature probes to a very small extent. The temperature of the water cooling system can be changed during the treatment to decrease the inverted skin thermal gradient. The efficiency of hyperthermia alone in the treatment of these superficial tumors is low, but there is scientific evidence in the literature and from our own clinical data that hyperthermia combined with radiation therapy has a synergistic effect on tumor response.

Resume Introduction La derivation ventriculo-peritoneale (DVP) est un traitement de l’hydrocephalie, susceptible de dysfonctionner. La presentation clinique des dysfonctionnements est variable. Nous avons souhaite realiser une mise au point sur la semiologie des dysfonctionnements de DVP chez l’enfant, en raison du caractere urgent de sa prise en charge et du caractere parfois trompeur que peut prendre l’hypertension intracrânienne chez un enfant valve. Materiels et methodes Nous avons effectue une recherche PubMed (PubMed US National Library of Medicine ; National Institutes of Health ; http://www.ncbi.nlm.nih.gov/pubmed ) avec les sequences de mots clefs suivantes : ( dysfunction OR blockage ) AND shunting AND hydrocephalus ; shunt complications AND hydrocephalus ; hydrocephalus AND shunt AND malfunction . Les articles traitant de la derivation ventriculo-atriale n’ont pas ete retenus. Au total, 79 articles ont ete retenus (en langue anglaise et francaise). Les cas cliniques ont ete exclus. Resultats La presentation clinique est variable selon l’âge : les vomissements et la somnolence sont plus frequents chez les grands enfants, tandis que les nourrissons se presentent plus volontiers avec un tableau d’hypertension intracrânienne associant nausees, vomissements, irritabilite et fontanelle bombante. La somnolence est un bon indicateur predictif de dysfonctionnement de DVP. Le caractere totalement asymptomatique est rare mais possible. Un tableau abdominal est egalement possible, allant de l’inconfort abdominal a un tableau de peritonite. La fievre, le delai court depuis la derniere intervention et l’irritabilite seraient de bons facteurs predictifs d’infection de DVP. Pomper le reservoir de la DVP semble avoir une faible valeur predictive positive (12 %). Un dysfonctionnement de DVP peut conduire au deces, avec un taux de mortalite estime a 1 % par an les premieres annees. Conclusion Il est essentiel de connaitre la variabilite de la semiologie des dysfonctionnements de DVP, du fait de leur potentiel gravite. Il est important d’etre attentifs aux observations des parents, en particulier si cet enfant a deja presente un dysfonctionnement de DVP.

Introduction Nasal dermal sinus in children (NDSC) is a rare malformation (1/20,000 to 1/40,000). Apart from local infection, they present as median nasal lump or pit on the dorsum and their diagnosis and treatment are often delayed. Consequences of untreated NDSC are: local infection, meningitis, and empyema, due to their frequent intracranial extension. Patients and methods Six cases of NDSC were retrospectively reviewed (5 boys and one girl), all treated between 2006 and 2012 in our institution (Nancy University Hospital). All patients underwent a brain and facial CT-scan and MR imaging to check any bony lesions, skull base extension by foramen caecum, course of the sinus and the possible associated brain malformations. Evolution, treatment and follow-up (FU) were conducted by the same multidisciplinary team (neurosurgeon, ENT surgeon, and plastic surgeon). Children were operated on by a conjoined approach (cranial and facial) for removal of the sinus and its intracranial extension. Results Mean age at diagnosis was 12 months (birth–36 months). Initial presentation consisted of three local infections, one dorsum nasal lump, one CSF leakage, and one asymptomatic child. Five children presented with a skull base extension. There were no associated brain malformations. We observed only one surgical complication (bleeding from the anterior part of the superior sagittal sinus during dissection) leading to blood transfusion. Pathology results confirmed three dermoid cysts, one epidermoid cyst, one cyst with granulation tissue, and negative in one case. Average FU was 30.8 months (4–84 months). Two recurrences (same child) occurred, leading to two re-operations. There were no recurrences or complications at the end of FU. Conclusion NDSC are rare malformations, mostly diagnosed before the age of three years, due to an infectious complication. The aim of the treatment is complete removal to avoid recurrence, and a multidisciplinary strategy is required.

Objectif L’objectif de l’etude est d’estimer et de decrire l’evolution tout au long de la vie des couvertures vaccinales des vaccins combines de rappels comprenant les valences Diphterie, Tetanos et Poliomyelite, eventuellement associees a la valence Coqueluche (DTCaP, dTcaP et dTP), en France, entre 2013 et 2017. Methode Les couvertures vaccinales ont ete calculees pour chaque rendez-vous vaccinal, entre 2013 et 2017, a partir de l’Echantillon generaliste de beneficiaires de l’Assurance maladie. Deux populations ont ete definies : une population analysee selon l’application « stricte » du calendrier vaccinal en vigueur, et une population refletant une couverture cumulee « pratique courante » afin de prendre en compte le decalage potentiel du rendez-vous vaccinal. Pour cette population en « pratique courante », l’analyse a ete menee sur des classes d’âges plus larges de moins 1 an et plus 2 ans pour les rendez-vous de vaccination de 6 ans et 11–13 ans, et de plus ou moins 4 ans pour les autres rendez-vous de vaccination a l’âge adulte. Resultats En pratique « stricte », la couverture vaccinale par un vaccin combine de rappels DTCaP, dTcaP ou dTP etait, en moyenne sur la periode 2013 a 2017, de 27,0 % a 6 ans, 22,8 % a 11–13 ans, 3,7 % a 25 ans, 3,0 % a 45 ans, 2,9 % a 65 ans, 2,2 % a 75 ans, 1,6 % a 85 ans et 0,9 % a 95 ans. La couverture vaccinale en « pratique courante » etait en moyenne de 70,3 % a 8 ans, 75,3 % a 15 ans, 46,1 % a 29 ans, 40,3 % a 49 ans, 33,1 % a 69 ans, 28,2 % a 79 ans, 20,1 % a 89 ans et 10,6 % a 99 ans. Sur la periode d’etude de 2013 a 2017, la couverture vaccinale Coqueluche etait en augmentation a tous les rendez-vous de vaccination, et principalement a ceux des 6 ans et des 11–13 ans, conformement au nouveau calendrier vaccinal introduit en 2013. Entre 2013 et 2017, la couverture vaccinale Coqueluche cumulee en « pratique courante » est passee de 16,4 % a 63,8 % a 8 ans, et de 50,3 % a 61,2 % a 15 ans. Conclusion L’etude montre que les couvertures vaccinales restent insuffisantes pour l’ensemble des rendez-vous vaccinaux (

Introduction Spinal cord tumors in children (SCTC) are rare with a frequent diagnostic delay. Its management is multidisciplinary and challenging due to functional implications. The position of surgery is now better established but the role and timing of chemotherapy (CT) and radiotherapy (RT) still remains under debate. Adverse effects of treatments are important to be taken into account, in the follow-up of these children. The aim of this paper was to present a series of 21 cases of SCTC treated at the same institution, to briefly present clinical features, treatments and outcome, with a special focus on spinal deformities in children with this condition. Material and Methods Twenty-one consecutive SCTC were referred to our institution from 1990 to 2014. Data regarding age, sex, diagnostic delay, clinical examination, MRI, surgery, pathology, other treatment (CT and RT), orthopedic issues and follow-up of these children were retrospectively recorded. Results Mean age was 8 years (standard deviation: 5.2 years) (range: 4 months–17 years). Mean diagnosis delay was 5.5 months (standard deviation: 6.5 months) (range: 0 days–18 months). All children (10 girls, 11 boys) were operated on (10 partial removals, 7 subtotal and 4 gross total removals) as first-line treatment. Pathological results showed 12 juvenile pilocytic astrocytomas, 1 grade III astrocytoma, 1 grade IV astrocytoma, 3 oligodendrogliomas, 2 ependymomas, 1 glioblastoma and 1 rhabdoid tumor. Fourteen children (66.7%) received additional treatment: 12 CT and 7 RT. Ten children had postoperative spinal deformities. Mean follow-up (FU) was 71 months (5 months–180 months), with a median FU at 60 months, where 8 tumor progressions and 4 deaths were observed. Overall, survival (at 5 years) was 81% and progression free survival (at 5 years) was 67%. Conclusion Surgery is the goal standard for SCTC and the only appropriate treatment in cases of a low-grade lesion with stable disease on MR follow-up. Additional treatment must be reserved for high-grade lesions or tumor progression not attainable by a second look surgery. Spinal deformities are a frequent complication. Overall, survival and event free survival primarily depends on the pathology. Studies involving more centers are obligatory with the aim of collecting more cases and drawing more definitive conclusions regarding the management of these tumors.

Donor blood sampling performed once prior to transplant. Recipient blood sampling performed daily while inpatient and processed in MDC as per protocol Institution review board approved study RESULTS: 1 or more informative INDELs detected in 9 of 10 recipients post transplant. Where the informative INDEL was multiplexed with an INDEL present in both donor and recipient DNA, percentages of the former can be calculated The cfdDNA levels rose sharply to peak at post operative Day 1-2 and decreased to a trough by Day 3-6(refer to chart) CONCLUSIONS: INDEL polymorphism is a plausible mechanism to detect cfdDNA in recipient plasma post renal transplant cfdDNA has been shown to spike with insults to donor graft. Current results have achieved a proof of concept and demonstrate ability of the this novel technique to potentially monitor graft health Future directions include correlation of cfDNA with long term graft outcome and peak level with various graft insults

Background Ductal carcinoma in situ is defined as breast cancer confined to the ducts of the breast without evidence of penetration of the basement membrane. Local treatment quality represents one of the most prognostic factors as half of recurrences are invasive diseases. The main goal of adjuvant radiotherapy after conservative surgery is to decrease local recurrences and to permit breast conservation with low treatment-induced sequelae. Several randomized trials have established the impact of 50 Gy to the whole breast (WB) in terms of local control. Nevertheless, no randomized trial is still available concerning the role of the boost in this disease. The phase III randomized trial “BONBIS” is elaborated to evaluate the impact of a 16-Gy boost after 50 Gy delivered to the whole breast in 25 fractions and 33 days. Methods: A total of 1950 patients DCIS breast cancer patients are planned to be enrolled in this trial. Patients will receive the following treatment: (A) WB radiotherapy of 50 Gy in 25 fractions vs. (B) WB radiotherapy of 50 Gy in 25 fractions plus a localized 16-Gy boost in 8 fractions. The primary endpoint is local-relapse free survival (LRFS). This trial is designed to detect an expected rate in control arm of 7% and 4 % in experimental arm. With 90% power and a=0.05, 137 events are necessary to achieve the main goal. An interim analysis is planned after 50% of observed event. Stratifications are made based on recognized prognostic factors: age, hormonal treatment, differentiation, circumstance of diagnosis, surgical margin, centre. Secondary endpoints are relapse free survival, overall survival, acute and late toxicities, cosmetic results, and quality of life. Translational researches are also planned to identify intrinsic radiosensitivity of normal tissues (radiation-induced apoptosis assay, genome-wide association study) but also predictive models of tumor recurrences. Inclusions have started in November 2008 and are not so far than the planned estimation. This trial is granted by the French National Cancer Institute (PHRC 2008) and supported by the French National Society of Radiation Oncology (SFRO). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-06-01.

We document a biphasic effect of Rac2 on the activation and inhibition of PLD2. Cells overexpressing Rac2 and PLD2 simultaneously show a robust initial (10 min) response toward a chemoattractant that is later (30 min) greatly diminished over PLD2-only controls. The first phase is due to the presence of a Rac2-PLD2 positive-feedback loop. To explain the mechanism for the Rac2-led PLD2 inhibition (the second phase), we used leukocytes from wild-type (WT) and Rac2(-/-) knockout mice. Rac2(-/-) cells displayed an enhanced PLD2 (but not PLD1) enzymatic activity, confirming the inhibitory role of Rac2. Late inhibitory responses on PLD2 due to Rac2 were reversed in the presence of phosphatidylinositol 4,5-bisphosphate (PIP(2)) both in vitro (purified GST-PH-PLD2, where GST is glutathione S-transferase and PH is pleckstrin homology) and in vivo. Coimmunoprecipitation and immunofluorescence microscopy indicated that PLD2 and Rac2 remain together. The presence of an "arc" of Rac2 at the leading edge of leukocyte pseudopodia and PLD2 physically posterior to this wave of Rac2 was observed in late chemotaxis. We propose Rac-led inhibition of PLD2 function is due to sterical interference of Rac with PLD2's PH binding site to the membrane and deprivation of the PIP(2). This work supports the importance of functional interactions between PLD and Rac in the biological response of cell migration.

"Orbital tumors (OT) are neoplasms of the bony orbit and contents except for the eyeball." Given this definition, we exclude the retinoblastomas, which are the most frequent tumors of this anatomical area in the pediatric population. Although these tumors are rare, there is a great variety of etiologies. Among them, the most frequent OTs in childhood are rhabdomyosarcomas and metastatic tumors: metastatic neuroblastomas and leukemias (chloromas). Moreover, adult and pediatric varieties of OT are made up of two clusters of distinctive histological entities. Examination must be careful: measurement, direction of proptosis, impairment of ocular motility, compressive optic neuropathy, strabismus, etc. Age at onset as well as unilateral or bilateral proptosis are important features. Benign tumors such as dermoid cysts or hemangiomas grow slowly, whereas rapid growth suggests a malignant tumor. Fundi and visual acuity should be checked. The general examination focuses especially on cutaneous abnormalities such as cafe au lait spots and subcutaneous nodules in neurofibromatosis type 1 (NF1), a hemangioma that often involves the cutaneous portion of the eyelid. When a metastatic tumor is suspected, abdominal palpation and ultrasonography must be performed. Ultrasonography leaves the posterior third of the orbit inaccessible to exploration. The depth to which it can penetrate the orbit is limited (20mm). Most of the time, standard x-rays, CT, and MR imaging allow for an adequate assessment and usually provide a diagnosis. In children, CT and MRI sometimes require anesthesia to be properly performed.

Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91phox and p22phox, which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47phox and p67phox. A fifth subunit, p40phox, plays an important role in phagocytosis-induced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40phox, in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40phoxR105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40phox-deficient granulocytes, with premature loss of p40phoxR105Q from phagosomes. Thus, p40phox binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease.

Trojan asteroids undergo very large perturbations because of their resonance with Jupiter. Fortunately the secular evolution of quasi circular orbits remains simple—if we neglect the small short period perturbations. That study is done in the approximation of the three dimensional circular restricted three-body problem, with a small mass ratio μ—that is about 0.001 in the Sun Jupiter case. The Trojan asteroids can be defined as celestial bodies that have a “mean longitude”, M + ω + Ω, always different from that of Jupiter. In the vicinity of any circular Trojan orbit exists a set of “quasi-circular orbits” with the following properties: (A) Orbits of that set remain in that set with an eccentricity that remains of the order of the mass ratio μ. (B) The relative variations of the semi-major axis and the inclination remain of the order of \({\sqrt{\mu}}\) . (C) There exist corresponding “quasi integrals” the main terms of which have long-term relative variations of the order of μ only. For instance the product c(1 – cos i) where c is the modulus of the angular momentum and i the inclination. (D) The large perturbations affect essentially the difference “mean longitude of the Trojan asteroid minus mean longitude of Jupiter”. That difference can have very large perturbations that are characteristics of the “horseshoes orbit”. For small inclinations it is well known that this difference has two stable points near ±60° (Lagange equilibrium points L4 and L5) and an unstable point at 180° (L3). The stable longitude differences are function of the inclination and reach 180° for an inclination of 145°41′. Beyond that inclination only one equilibrium remains: a stable difference at 180°.

Introduction Benign intracranial hypertension (BIH) is a rare condition, especially in childhood. The aim of this study was to analyze retrospectively pediatric cases that were diagnosed and managed in the same institution during the 2002–2006 period. Patients and methods Eight children (four girls and four boys) with a diagnosis of BIH were reviewed. The mean age at diagnosis was 10.5 years. Follow-up lasted a mean two years. The clinical features were those of intracranial hypertension. One child had previously had optic nerve sheath fenestration and another one occipitocervical decompression because of an associated Chiari I malformation. Results One child had a bilateral transverse sinus stenosis on angio-MRI. Seven children had a cerebrospinal fluid (CSF) pressure monitoring. Seven children were treated with acetazolamide. Three children are free of symptoms with the association of acetazolamide and depletive lumbar puncture (LP). For three others, a lumboperitoneal shunt had to be inserted. One child is in complete remission after depletive LP only. The clinical symptoms of BIH disappeared for all eight children, including normalization of the visual loss present in three children. Conclusion BIH is a condition that threatens visual prognosis. Diagnosis is assessed by clinical, radiological, and raised CSF pressure criteria. First-line treatment is medical (acetazolamide at first intention) and surgery is recommended for refractory cases. The relationship between BIH and obesity is less clear than for adulthood. Depletion of CSF by LP is an important therapeutic factor.

Polymorphisms of the genes 5'-10'-methylenetetrahydrofolate reductase (MTHFR, 677CT and 1298AC), methionine synthase (MTR, 2756AC) and methionine synthase reductase (MTRR, 66AC) provoke variations in enzyme activity, which can lead to alterations in the metabolism of folates and in the synthesis of S-adenosyl-methionine (SAM), the most active methyl donor in the body. This could play an important role in carcinogenesis through the degree of DNA methylation and of nucleotide synthesis. In the present study, four polymorphisms were studied, two of the methylenetetrahydrofolate reductase gene, and the other two of methionine synthase and methionine synthase reductase. Our aim was to study the association between prostate carcinoma susceptibility and these polymorphisms. A hospital-based case-control study was conducted in 182 patients (mean age: 70.7+/-7.29 years) with histologically confirmed prostate carcinoma and in 205 control subjects (mean age: 70.3+/-7.82 years) diagnosed with benign prostatic hyperplasia (BPH). Genomic DNA was extracted from peripheral leukocytes. Comparison of the MTHFR CT and TT genotypes in patients and the controls revealed significant differences (0.57 vs 0.38) (OR: 2.19, 95% CI: 1.46-3.30) and (0.06 vs 0.15) (OR: 0.36, 95% CI: 0.17-0.73), respectively. No statistically significant differences were found between patients and controls with respect to the MTHFR 1298AC, the MTR 2756AC and the MTRR 66AC polymorphisms. However, among the patients, the MTR 2756 allele C was related to a high Gleason score. We conclude that the polymorphism MTHFR C677T is clearly related to prostatic carcinogenesis, on the contrary to the other polymorphisms studied, although the MTR 2756 allele C acts as a factor of tumor aggressiveness, this being found in tumors with high carcinogenic potential.

Background and purpose Germ cell tumors (GCT) of the central nervous system are rare (2% of all brain tumors in children). Although originating from germ cells, GCT cover a spectrum of different tumors with different management and prognosis, depending on whether they secrete tumor markers or not. The aim of this study is to present a series of children with GCT and comment on overall management practices . Methods We retrospectively reviewed 13 children under the age of 18 years (nine boys and four girls), treated in the same institution between 1986 and 2006 for one or more primitive GCT of the central nervous system. Results Median age at diagnosis is 12.9 years (7–17 years). Tumor markers (alpha foetoprotein [αFP], human chorionic gonadotrophin [βHCG]) were assessed 11 times in blood as well as cerebrospinal fluid (CSF). Tumors were located as follows: pineal region (10 cases), hypothalamus (eight cases), basal ganglia (one case) and corpus callosum (one case). Six were bifocal (pineal region and hypothalamus). Clinical signs were mostly dominated by diabetes insipidus and intracranial hypertension. Seven children required surgery for hydrocephalus. Tumor markers were positive in three cases and these children subsequently received chemotherapy followed by radiotherapy, except one child. Eventually, the three patients with positive markers required surgery because of a residual lesion. The eight other patients had a stereotactic biopsy for diagnosis. At the end of follow-up, treatment morbidity appears to be low and neither death nor recurrence was observed. Mean follow-up is 8.85 years (2–20 years). Conclusions The prognosis of cerebral GCTs in children is excellent because of their pronounced chemo- and radiosensitivity. Surgery is crucial for diagnosis in the event of negative markers, or if there is evidence of residual tumor with normalization of tumor markers at the end of chemotherapy. Tumor markers must be monitored to check the diagnosis and for follow-up. The place of tumor biopsy during endoscopic third ventriculostomy (performed if hydrocephalus is present) is still debated.

Introduction Des 1998, un groupe de travail d’experts, mis en place par la Federation nationale des centres de lutte contre le cancer (FNCLCC), a publie puis a mis a jour regulierement des recommandations pour l’indication de l’agent stimulant l’erythropoiese (ASE) en cancerologie. A l’issue d’un processus de veille realise en 2006, de nouvelles donnees, non concordantes avec la derniere actualisation de 2003, ont ete identifiees, conferant ainsi des indices suffisants pour envisager des modifications dans les recommandations existantes. Ce travail a ete realise en collaboration avec l’Institut national du cancer et avec des partenaires des secteurs publics (CHU, CHG) et prive. Cet article presente une version abregee du document integral consultable sur le site Internet du programme des « Standards, Options: Recommandations » (SOR): www.sor-cancer.fr.

Resume Contexte La stimulation du nerf vague (SNV) est proposee dans le traitement des epilepsies pharmacoresistantes. Materiel et methode Les donnees cliniques et chirurgicales des patients ayant beneficie d’une SNV entre 1999 et 2010 aux CHU de Bordeaux et Toulouse ont ete collectees et analysees. Resultats Un total de 101 patients ont ete inclus dont 57 hommes. L’âge median de revelation de l’epilepsie etait de 7,5 ans, ecart interquartile (EI) [2,5–12,5] et le delai median entre le debut de l’epilepsie et l’implantation etait de 21,1 ans, EI [11,9–29,5]. Quatre-vingt-cinq patients etaient en vie et avaient une stimulation vagale fonctionnelle a la date de fin d’etude. La probabilite d’avoir une stimulation vagale fonctionnelle a 1, 2 et 5 ans est respectivement de : 99 %, IC95 % [97,1,100]; 96,49 %, IC95 % [92,7, 100] et de 88,2 %, IC95 % [79,9,97,4]. Parmi les patients de notre serie, 41,6 % presentaient une diminution de plus de 50 % de la frequence des crises. Le nombre de crises a diminue en moyenne de 5,7 par semaine. Nous n’avons pas pu mettre en evidence de facteur predictif d’une efficacite de la stimulation. Conclusion La stimulation vagale procure une amelioration de la frequence des crises, mais aussi une reduction de leur intensite et un effet favorable sur le psychisme des patients. La morbidite est faible et l’effet therapeutique de la stimulation est durable. L’indication de la mise en place d’une stimulation vagale meriterait d’etre discutee plus tot dans l’evolution d’une epilepsie severe non chirurgicale.

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Ventriculoperitoneal shunting (VPS) is a treatment of the hydrocephalus that may dysfunction. The clinical presentation of shunt dysfunction is variable. We therefore decided to focus on the clinical presentation of VPS malfunction in children, as this condition requires immediate emergency treatment and because of the sometimes confusing signs of intracranial hypertension in a shunted child.We searched PubMed with the following groups of keywords: (dysfunction OR blockage) AND shunting AND hydrocephalus; shunt complications AND hydrocephalus; hydrocephalus AND shunt AND malfunction. Articles dealing with ventriculo-atrial shunt were excluded. A total of 79 articles were retained for analysis (English and French). Case reports were excluded.The clinical presentation varies by age: vomiting and alterated level of consciousness are the most frequent signs in older children, whereas infants present more often with raised intracranial pressure symptoms such as nausea, vomiting, irritability and bulging fontanel. Drowsiness is a good predictor of VPS dysfunction. An asymptomatic presentation is rare but possible. Abdominal presentation is also possible, ranging from abdominal discomfort to peritonitis. Fever, occurring a short time after the last intervention, and irritability are good predictors of shunt infection. Pumping the chamber of the VPS has a weak positive predictive value (12%). Shunt dysfunction can lead to death, with an estimated mortality rate at 1% per year during the first years.It is essential to be aware of the variability of the clinical presentation of VPS dysfunction, because of the potential severity of this condition. Also it is important to pay attention to the comments of the parents, especially if the child experienced a previous shunt malfunction.

Resume L’exerese complete d’une lesion responsable d’une epilepsie permet la disparition ou la reduction importante des crises dans 85 % des cas. Cependant, le pronostic semble moins favorable dans les epilepsies temporales lesionnelles car les structures temporo-mesiales peuvent participer a la genese des crises sans etre le siege de ces lesions. L’analyse electro-clinique et radiologique des patients peut apporter des elements d’orientation en faveur d’une telle implication mais ne semble pas toujours suffisante. Afin d’evaluer les criteres nous ayant conduits au choix de la strategie chirurgicale, nous rapportons une serie retrospective consecutive de 47 patients traites pour une epilepsie temporale pharmaco-resistante symptomatique d’une lesion temporale extra-hippocampique traites soit par lesionectomie seule (groupe 1, n = 17), soit par lesionectomie associee a une resection des structures temporo-mesiales (groupe 2, n = 30). Les cas presentant une sclerose hippocampique associee a la lesion (double pathologie) ont ete exclus de cette etude. Les resultats de cette etude montrent qu’avec un recul moyen de 72 mois, 84 % des patients du groupe 2 ont ete liberes de leur crise (grade Ia de Engel) contre seulement 47 % des patients du groupe 1. L’analyse statistique a identifie le type de chirurgie comme le facteur pronostique preponderant. En conclusion, les criteres electro-cliniques retenus pour evoquer une participation temporo-mesiale dans l’elaboration des crises sont insuffisants pour preciser la strategie chirurgicale. Compte tenu de sa valeur pronostique, l’evaluation de cette participation, parfois complexe, apparait importante a realiser. L’existence d’une double pathologie « fonctionnelle » acquise est evoquee pour expliquer ce resultat.

Resume Au cours des traitements des cancers du col uterin, l'anemie est un facteur relativement frequent et son determinisme est multifactoriel, associant souvent hemorragie, carence martiale, inflammation et infection. Il y a une correlation entre le stade tumoral et la frequence de cette anemie, definie par une concentration d'hemoglobine inferieure a 12 g/dl. La frequence de l'anemie varie en effet dans les series publiees de 25 % en cas de cancer de stade I, a 33 % en cas de cancer de stade II et jusqu'a 40 % en cas de cancer de stade III. Il y a aussi une correlation entre l'anemie et la survie des patientes et c'est l'un des facteurs pronostiques les plus importants apres le stade et la taille tumorale. L'anemie est donc un facteur de pronostic defavorable, souvent lie au stade et a la taille tumorale, mais ce n'est pas un facteur independant. L'anemie aggrave l'hypoxie des tumeurs du col uterin et l'hypoxie est un facteur pronostique independant pour les patientes atteintes de cancer classe N0. Par ailleurs, on sait que l'oxygenation de ces tumeurs est directement liee a la concentration d'hemoglobine. La compensation de l'anemie par transfusion permet certainement de modifier le pronostic chez les patientes initialement anemiques ou celles le devenant en cours d'irradiation. Pour les patientes fumeuses, l'anemie est probablement plus profonde que celle appreciee par les seuls chiffres de concentration d'hemoglobine, du fait de la presence de carboxyhemoglobine. Les chimiotherapies concomitantes a base de sels de platine, qui sont maintenant devenues un standard, majorent notoirement ce risque d'anemie et c'est pourquoi plus de 50 % des patientes seront concernees au cours de leurs traitements. Si sa compensation plutot par transfusion est recommandee dans les SOR (Standards Options et Recommandations de la Federation nationale des centres de lutte contre le cancer) en dessous de 10 g/dl, l'utilisation des erythropoietines recombinantes est une option therapeutique entre 10 et 12 g/dl. Elles sont fortement conseillees apres une compensation rapide de l'anemie initiale par la transfusion sanguine. Chez les 70 % de patientes dont l'anemie repond aux erythropoietines recombinantes, un meilleur controle de la concentration d'hemoglobine est obtenu. L'impact de cette anemie sur la qualite de vie et l'observance des traitements justifie l'utilisation des erythropoietines, surtout dans cette pathologie tumorale ou les traitements sont particulierement astheniants et ou leur tolerance est parfois un facteur limitant.

The Rho family GTPase Rac acts as a molecular switch for signal transduction to regulate various cellular functions. Mice deficient in the hematopoietic-specific Rac2 isoform exhibit agonist-specific defects in neutrophil chemotaxis and superoxide production, despite expression of the highly homologous Rac1 isoform. To examine whether functional defects in rac2–/– neutrophils reflect effects of an overall decrease in total cellular Rac or an isoform-specific role for Rac2, retroviral vectors were used to express exogenous Rac1 or Rac2 at levels similar to endogenous. In rac2–/– neutrophils differentiated from transduced myeloid progenitors in vitro, increasing cellular Rac levels by expression of either exogenous Rac1 or Rac2 increased formylmethionylleucylphenylalanine- or phorbol ester-stimulated NADPH oxidase activity. Of note, placement of an epitope tag on the N terminus of Rac1 or Rac2 blunted reconstitution of responses in rac2–/– neutrophils. In rac2–/– neutrophils isolated from mice transplanted with Rac-transduced bone marrow cells, superoxide production and chemotaxis were fully reconstituted by expression of exogenous Rac2, but not Rac1. A chimeric Rac1 protein in which the Rac1 C-terminal polybasic domain, which contains six lysines or arginines, was replaced with that of the human Rac2 polybasic domain containing only three basic residues, also reconstituted superoxide production and chemotaxis, whereas expression of a Rac2 derivative in which the polybasic domain was replaced with that of Rac1 did not and resulted in disoriented cell motility. Thus, the composition of the polybasic domain is sufficient for determining Rac isoform specificity in the production of superoxide and chemotaxis in murine neutrophils in vivo.

Preparation of molybdenyl and vanadyl acidic salts of [PMo 12 O 40 ] 3− has been achieved by cationic exchange between solid heteropolyacid and acetylacetonate complexes in toluene. Ammonium vanadyl salts were prepared by solid-state reaction between acidic vanadyl salts and urea at 250 °C. Importance of hydration state or exposure to water vapor on the preparation and structure of acidic vanadyl salts was revealed. Solid solution of acidic vanadyl salts with cubic Fd 3 ¯ m lattice can be obtained. Exposure of ammonium vanadyl salts to water vapor gives rise to a rebuilding of at least the surface of the particles leading to segregation into a pure ammonium Pn 3 ¯ m phase and a pure highly hydrated vanadyl Fd 3 ¯ m phase. Catalytic behavior of bulk solids for oxidative dehydrogenation of isobutyric acid at 320 °C was determined in presence of water. For ammonium vanadyl salts, the yield in methacrylic acid increases as the proportion of vanadyl phase increases until 0.75 VO 2+ per polyanion and then a plateau is reached. This observation is consistent with the characterizations suggesting that these salts are composed of a core of ammonium salt embedded in hydrated vanadyl salt. Presence of molybdenyl in cationic position neither allows an increase of the catalytic performances nor stabilizes the catalysts.

The Rho family GTPase Rac is a crucial participant in numerous cellular functions and acts as a molecular switch for signal transduction. Mice deficient in hemopoietic-specific Rac2 exhibited agonist-specific defects in neutrophil functions including chemoattractant-stimulated filamentous actin polymerization and chemotaxis, and superoxide production elicited by phorbol ester, fMLP, or IgG-coated particles, despite expression of the highly homologous Rac1 isoform. In this study, functional responses of Rac2-null murine macrophages were characterized to examine whether Rac2 also has nonredundant functions in this phagocytic lineage. In contrast to murine neutrophils, in which Rac1 and Rac2 are present in similar amounts, Rac1 was ∼4-fold more abundant than Rac2 in both bone marrow-derived and peritoneal exudate macrophages, and macrophage Rac1 levels were unchanged by the absence of Rac2. Accumulation of exudate macrophages during peritoneal inflammation was reduced in rac2−/− mice. FcγR-mediated phagocytosis of IgG-coated SRBC was also significantly decreased in Rac2-null macrophages, as was NADPH oxidase activity in response to phorbol ester or FcγR stimulation. However, phagocytosis and oxidant production stimulated by serum-opsonized zymosan was normal in rac2−/− macrophages. Macrophage morphology was also similar in wild-type and Rac2-null cells, as was actin polymerization induced by FcγR-mediated phagocytosis or M-CSF. Hence, Rac2-null macrophages have selective defects paralleling many of the observed functional defects in Rac2-null neutrophils. These results provide genetic evidence that although Rac2 is a relatively minor isoform in murine macrophages, it plays a nonoverlapping role with Rac1 to regulate host defense functions in this phagocyte lineage.

Resumen Cambios En La Frecuentacion De Patologias En Consulta Externa. Analisis De La Evolucion En 6 Anos Introduccion En 1996 realizamos un analisis de la tasa de frecuentacion de patologias atendidas en la consulta externa. lo largo de estos anos hemos realizado diversas estrategias de actuacion sobre algunas patologias o entidades como la HBP y la contracepcion masculina. Objetivo Conocer el resultado de dichas medidas pasados 6 anos, en el ano 2002. Material y metodo Se analiza el porcentaje de las distintas patologias vistas en consulta externa de la Unidad de Urologia en el ano 2002, y se comparan los resultados con los obtenidos antes de haber realizado el rediseno de la actuacion sobre los casos mencionados. Resultados El rediseno en el manejo de la contracepcion masculina y de la HBP ha permitido disponer de un 15% y un 1,2% mas de primeras visitas en consulta externa respectivamente, mientras que se ha incrementado un 25% la consulta por sospecha de cancer prostatico. Se aprecian importantes incrementos de consultas por patologias como la hematuria (56,4%), crisis renoureteral (51,9%), sindrome miccional (61,1%) e impotencia (17,8%). Conclusiones El rediseno de la actuacion sobre patologias es una herramienta eficaz en la gestion de una Unidad de Urologia. Su analisis permite valorar los beneficios conseguidos y detectar nuevos problemas que surgen.

The solid-state behavior of (NH 4 ) 4 [PMo 11 V V O 40 ], crystallized from a water/dioxane solution, has been studied. Decomposition of one of the four ammonium cations occurs easily and a thermal treatment in air at 220 °C leads to (NH 4 ) 3 H[PMo 11 VO 40 ]. Further ammonium decomposition was observed between 220 and 300 °C up to (NH 4 ) 0.8 H 3.2 [PMo 11 VO 40 ]. Only one cubic phase was evident and the lattice parameter increases as ammonia is eliminated. Rietveld refinement of X-ray patterns of all samples is better with an occupancy of 3 4 for anionic sites, as previously proposed for Cs 4 [PMo 11 VO 40 ]. Solid-state substitution of cesium for ammonium cations has been performed by thermal treatments at 300 °C of the ammonium salt impregnated by cesium nitrate. Only three ammonium cations can be substituted. The catalytic behavior of these salts for the oxidative dehydrogenation of isobutyric acid reveals high catalytic activity and selectivity to methacrylic acid for all the samples up to three cesium cations but fall down hereafter.

Does a rapidly rotating body fall slower than a non-rotating body? This difficult question requires the choice of suitable relativistic generalizations. The vertical free fall of a rotating dumb-bell in a Schwarzschild field and that of an horizontal rotating ring are both integrable. Their differences with the free fall of non-rotating bodies are extremely small. Notice that this effect differs from the precession of their spin.

Defects in myeloid cell function in Rac2 knockout mice underline the importance of this isoform in activation of NADPH oxidase and cell motility. However, the specific role of Rac1 in neutrophil function has been difficult to assess since deletion of Rac1 results in embryonic lethality in mice. To elucidate the specific role of Rac1 in neutrophils, we generated mice with a conditional Rac1 deficiency restricted to cells of the granulocyte/monocyte lineage. As observed in Rac2-deficient neutrophils, Rac1-deficient neutrophils demonstrated profound defects in inflammatory recruitment in vivo, migration to chemotactic stimuli, and chemoattractant-mediated actin assembly. In contrast, superoxide production is normal in Rac1-deficient neutrophils but markedly diminished in Rac2 null cells. These data demonstrate that although Rac1 and Rac2 are both required for actin-mediated functions, Rac2 is specifically required for activation of the neutrophil NADPH oxidase.

Resume Objectifs. – Le cancer du sein survenant chez la femme tres jeune est rare et son diagnostic et sa prise en charge sont parfois difficiles. L’objectif de l’etude etait d’en analyser les caracteristiques epidemiologiques et clinicopathologiques et surtout d’evaluer les resultats des therapeutiques instaurees. Patientes et methodes. – Les dossiers de trente patientes âgees de 30 ans ou moins, chez qui un diagnostic de cancer invasif du sein a ete porte entre 1986 et 2001, ont fait l’objet d’une etude retrospective dans le service de radiotherapie du centre Alexis-Vautrin. Resultats. – Six patientes (20 %) avaient un antecedent familial de cancer mammaire. Dans 90 % des cas, le signe revelateur etait un nodule cliniquement palpable, de taille moyenne de 3,5 cm. Il s’agissait de 11 cancers de stade I, 11 de stade II, de 6 de stade III et de deux de stade IV. Cinq cancers ont ete decouverts au decours d’une grossesse (taille clinique moyenne = 5,8 cm). Une chimiotherapie neoadjuvante a ete prescrite chez 11 patientes. Vingt trois fois sur 28 (82 %), le sein a pu etre conserve. Il s’agissait d’un carcinome canalaire infiltrant de grade III dans 13/27 cas et une fois sur deux, il s’accompagnait d’une atteinte ganglionnaire axillaire. Les recepteurs œstrogeniques etaient absents dans 11/26 cas. Apres un suivi post-therapeutique median de 5 ans, on a constate six recidives locales (20 %), quatre cancers du sein controlateral et trois cancers secondaires. Dix patientes (38 %) sont decedees dans un tableau d’evolution metastatique ulterieure. Le taux de survie globale a 5 ans etait de 78 %. Conclusion. – Ces resultats rejoignent les donnees de la litterature qui soulignent le pronostic defavorable du cancer du sein chez les femmes tres jeune et incitent a adapter en fonction de l’ensemble des facteurs pronostiques les indications des therapeutiques locales et des traitements adjuvants systemiques et hormonaux.

Resume Afin de faire le point sur l’activite et les techniques d’irradiation corporelle totale en France, le groupe des radiotherapeutes de centres a adresse un questionnaire a tous les services de radiotherapie des Centres de lutte contre le cancer ou des hopitaux publics effectuant ce type d’irradiation. Trente-six questionnaires ont ete envoyes et 31 centres ont repondu. Trois n’en pratiquent pas. Cinq centres n’ont pas repondu. Les resultats portent sur l’activite des 28 centres qui ont accepte de nous repondre de facon claire et detaillee. Ces resultats ont ete presentes a la reunion des radiotherapeutes de centres en janvier 2000. Un total de 10 630 irradiations corporelles totales a ete repertorie ; entre 850 et 900 irradiations corporelles totales sont realisees chaque annee depuis 1995. Les irradiations corporelles totales non fractionnees, dont la frequence diminue, ne sont actuellement utilisees que dans cinq centres. Pour les irradiations corporelles totales fractionnees, les techniques commentees ici sont celles pratiquees en 1999, au moment de l’envoi du questionnaire. La majorite (78 %) des equipes utilisent des accelerateurs lineaires. Les resultats de la synthese de ces donnees sont presentes sous forme de tableaux. En 2002, les irradiations corporelles totales non fractionnees sont d’indication exceptionnelle et les irradiations corporelles totales sont generalement fractionnees en six seances a raison de 2 Gy j –1 avec ajout de protections pulmonaires limitant la dose entre 6 et 11 Gy selon les centres et la pathologie.

Resume Des benevoles interviennent depuis 6 ans dans un service de reanimation pediatrique. Ils ont pour objectif principal d’apporter un soutien aux parents. Les regles de fonctionnement sont definies par une convention passee entre l’hopital et l’association a laquelle appartiennent ces benevoles. Le benevole a un role d’ecoute essentiel grâce a son regard exterieur et a sa totale disponibilite. Dans cet univers completement etranger aux parents et si peu accueillant qu’est un service de reanimation, le benevole participe a creer un environnement moins hostile. Il peut egalement les informer des differents types d’aide qui leur sont proposees et les orienter vers une assistante sociale ou une psychologue. La presence des benevoles peut aider a prevenir ou a desamorcer les tensions entre les parents et les soignants et a maintenir ainsi un climat favorable. A la phase initiale l’acceptation des benevoles par une equipe soignante n’est jamais simple. Ulterieurement, les principales difficultes rencontrees sont : a) d’etre confronte a la mort d’enfant, soulignant l’importance d’une formation de qualite et d’une supervision ; b) la preservation de la confidentialite de la relation etablie avec les parents. L’introduction de benevoles dans un service necessite une reflexion multidisciplinaire prealable sur les differentes modalites d’accueil et de soutien des parents.

Unilateral hydronephrosis can complicate a far from negligible number of patients with Crohn´s disease. Bilateral hydronephrosis associated with Crohn´s disease is a much more unusual entity. In the other hand, the treatment for this condition is still controversial. We present the case of a 44 year old female with several bowel obstruction episodes caused by ileocolic Crohn´s disease. During the last episode she was also diagnosed of bilateral hydroureter and hydronephrosis. After the resolution of the bowel obstruction and the placement of a double J catheter in both ureters, the patient was operated. Ileocolic resection and bilateral ureterolisis with omental wrapping were performed. Although urinary and wound infection complicated the postoperative course, and a enterocutaneous fistula had to be medically treated one year later, the patient is now free of symptoms and her renal function is normal.