Successful intergeneric transfer of a major apple scab resistance gene (Rvi6) from apple to pear and precise comparison of the downstream molecular mechanisms of this resistance in both species.

BACKGROUND: Scab is the most important fungal disease of apple and pear. Apple (Malus x domestica Borkh.) and European pear (Pyrus communis L.) are genetically related but they are hosts of two different fungal species: Venturia inaequalis for apple and V. pyrina for European pear. The apple/V. inaequalis pathosystem is quite well known, whereas knowledge about the pear/V. pyrina pathosystem is still limited. The aim of our study was to analyse the mode of action of a major resistance gene of apple (Rvi6) in transgenic apple and pear plants interacting with the two scab species (V. inaequalis and V. pyrina), in order to determine the degree of functional transferability between the two pathosystems. RESULTS: Transgenic pear clones constitutively expressing the Rvi6 gene from apple were compared to a scab transgenic apple clone carrying the same construct. After inoculation in greenhouse with V. pyrina, strong defense reactions and very limited sporulation were observed on all transgenic pear clones tested. Microscopic observations revealed frequent aborted conidiophores in the Rvi6 transgenic pear / V. pyrina interaction. The macro- and microscopic observations were very comparable to the Rvi6 apple / V. inaequalis interaction. However, this resistance in pear proved variable according to the strain of V. pyrina, and one of the strains tested overcame the resistance of most of the transgenic pear clones. Comparative transcriptomic analyses of apple and pear resistant interactions with V. inaequalis and V. pyrina, respectively, revealed different cascades of molecular mechanisms downstream of the pathogen recognition by Rvi6 in the two species. Signal transduction was triggered in both species with calcium (and G-proteins in pear) and interconnected hormonal signaling (jasmonic acid in pear, auxins in apple and brassinosteroids in both species), without involvement of salicylic acid. This led to the induction of defense responses such as a remodeling of primary and secondary cell wall, lipids biosynthesis (galactolipids in apple and cutin and cuticular waxes in pear), systemic acquired resistance signal generation (in apple) or perception in distal tissues (in pear), and the biosynthesis of phenylpropanoids (flavonoids in apple but also lignin in pear). CONCLUSION: This study is the first example of a successful intergeneric transfer of a resistance gene among Rosaceae, with a resistance gene functioning towards another species of pathogen.

Progestin-associated shift of meningioma mutational landscape.

Background: Meningiomas are the most common primary tumor of the central nervous system. The relationship between meningioma and progestins is frequently mentioned but has not been elucidated. Patients and methods: We identified 40 female patients operated for a meningioma after long-term progestin therapy and performed targeted next generation sequencing to decipher the mutational landscape of hormone-related meningiomas. A published cohort of 530 meningiomas in women was used as a reference population. Results: Compared with the control population of meningiomas in women, progestin-associated meningiomas were more frequently multiple meningiomas [19/40 (48%) versus 25/530 (5%), P < 10-12] and located at the skull base [46/72 (64%) versus 241/481 (50%), P = 0.03]. We found a higher frequency of PIK3CA mutations [14/40 (35%) versus 18/530 (3%), P < 10-8] and TRAF7 mutations [16/40 (40%) versus 140/530 (26%), P < 0.001] and a lower frequency of NF2-related tumors compared with the control population of meningiomas [3/40 (7.5%) versus 169/530 (32%), P < 0.001]. Conclusion: This shift in mutational landscape indicates the vulnerability of certain meningeal cells and mutations to hormone-induced tumorigenesis. While the relationship between PIK3CA mutation frequency and hormone-related cancers such as breast and endometrial cancer is well-known, this hormonally induced mutational shift is a unique feature in molecular oncology.

A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up.

Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

Mortality and histopathology in sheepshead minnow (Cyprinodon variegatus) larvae exposed to pectenotoxin-2 and Dinophysis acuminata.

Toxic species of the dinoflagellate genus Dinophysis can produce diarrheic toxins including okadaic acid (OA) and dinophysistoxins (DTXs), and the non-diarrheic pectenotoxins (PTXs). Okadaic acid and DTXs cause diarrheic shellfish poisoning (DSP) in human consumers, and also cause cytotoxic, immunotoxic and genotoxic effects in a variety of mollusks and fishes at different life stages in vitro. The possible effects of co-produced PTXs or live cells of Dinophysis to aquatic organisms, however, are less understood. Effects on an early life stage of sheepshead minnow (Cyprinodon variegatus), a common finfish in eastern USA estuaries, were evaluated using a 96-h toxicity bioassay. Three-week old larvae were exposed to PTX2 concentrations from 50 to 4000 nM, live Dinophysis acuminata culture (strain DAVA01), live cells resuspended in clean medium or culture filtrate. This D. acuminata strain produced mainly intracellular PTX2 (≈ 21 pg cell-1), with much lower levels of OA and dinophysistoxin-1. No mortality or gill damages were observed in larvae exposed to D. acuminata (from 5 to 5500 cells mL-1), resuspended cells and culture filtrate. However, exposure to purified PTX2 at intermediate to high concentrations (from 250 to 4000 nM) resulted in 8 to 100% mortality after 96 h (24-h LC50 of 1231 nM). Histopathology and transmission electron microscopy of fish exposed to intermediate to high PTX2 concentrations revealed important gill damage, including intercellular edema, necrosis and sloughing of gill respiratory epithelia, and damage to the osmoregulatory epithelium, including hypertrophy, proliferation, redistribution and necrosis of chloride cells. Tissue damage in gills is likely caused by the interaction of PTX2 with the actin cytoskeleton of the affected gill epithelia. Overall, the severe gill pathology observed following the PTX2 exposure suggested death was due to loss of respiratory and osmoregulatory functions in C. variegatus larvae.

Effect of water temperature increase on HO-1 expression in European sea bass (Dicentrarchus labrax L.) tissues.

One of the most pertinent environmental factors influencing the marine organism life is temperature. It has been demonstrated that an increase of temperature is able to induce the synthesis of heat shock proteins (HSP). In this study we investigated the expression of HO-1 mRNA, also referred to as HSP32, in different tissues of European sea bass (Dicentrarchus labrax, L.) at several time points after increased temperature exposure (from 12degC to 30degC). Our results showed that HO-1 was not expressed in gills, heart, muscle and brain while it was expressed at a basal level in intestine. In liver, spleen and kidneys, HO-1 expression was influenced by temperature increases. In the spleen, we found a significant decrease of the HO-1 expression at the end of 4 weeks. In kidneys a very fast collapse of HO-1 expression level was recorded reaching null value as soon as one hour after exposure to 30degC. In liver, HO-1 expression increased from one hour of exposure to 30degC confirming HO-1 involvement to heat shock response in this organ. This increasing trend reached a 4.5-fold higher value than the initial level after 4 weeks.

Children with poor access to healthcare in emergencies: standpoint and practices of pediatricians in France.

Many children with poor access to healthcare are finally admitted in emergency departments. This study describes the knowledge, attitudes, and practice of 161 pediatricians caring for these children. Among the pediatricians, 84 (52.8%) felt under-informed about the performance of the various health insurances, 107 (68.6%) lacked systematic information on the health insurance cover of the children they cared for, and many were unaware of appropriate local resources. Admission to emergency departments can be a way of linking up the healthcare pathway, once provided: systematic assessment of children's access to healthcare, better information and coordination of healthcare professionals' interventions, and several partnerships including social support.

The Dural Dark-Side Approach for falcine and tentorial meningioma: A surgical series of five patients.

INTRODUCTION: Falcine or tentorial meningioma can be complex to resect. When large meningiomas are located in eloquent areas, a direct ipsilateral surgical approach may cause brain injury and postoperative neurological deficits. In this series, 5 patients were surgically treated using a contralateral transfalcine or transtentorial approach to minimize brain retraction. This strategy was called the Dural Dark-Side Approach (DDSA). The aim was to analyze the quality of tumor resection and postoperative outcome. MATERIAL AND METHODS: In our department, from June 2018 to January 2020, 5 patients underwent microsurgical DDSA for resection of 4 falcine and 1 tentorial meningioma. All tumors were selected on the following two criteria: large>40mm diameter tumor, with surrounding functional cortex. Clinical and radiologic data were retrospectively analyzed. RESULTS AND DISCUSSION: Mean follow-up was 20 months. No patients required use of a rigid retractor during surgery. Gross total resection was performed in 3 patients and near-total resection in 2. All patients had favorable neurologic outcome. Postoperative MRI showed no ipsilateral or contralateral brain lesions. CONCLUSION: This series suggested that meticulous DDSA allows excellent resection in selected large falcine or tentorial meningioma. The approach offered a safe and effective surgical corridor without injuring the surrounding healthy parenchyma.

Developing a More Tailored Approach to Patient and Public Involvement with Children and Families in Pediatric Clinical Research: Lessons Learned.

Listening to, and acting on, the voices of children and families during clinical research and innovation is fundamental to ensuring enhanced pediatric health care, medicines development, and technological advances. While this is often discussed as an important step in ensuring patient-centered care, involving children and families across the life cycle of clinical research is not currently routine. The pediatric research community needs to address how to meaningfully involve children and families if they are to succeed in designing clinical research that suits the needs of pediatric patients and their families. This paper describes how an international community working under the umbrella International Children's Advisory Network (iCAN) and European Young Person's Advisory Group Network (eYPAGnet) has involved children and families in the design and delivery of pediatric clinical research. It offers practical solutions through various case studies assessed against seven patient engagement quality criteria within the Patient Engagement Quality Guidance (PEQG) tool, highlighting some of the lessons learnt from involving and engaging with children and families across different stages of clinical research, including pediatric trials for drug development programs.

Effects of water temperature increase and heavy metals contamination on WAP65 gene expression in sea bass (Dicentrarchus labrax) liver.

It has been previously demonstrated that "Warm temperature Acclimation-related 65 kD Protein" (WAP65) is involved in temperature acclimation, response to intoxication and infection, as well as in development. The expression of wap65-1 was investigated in the liver of European sea bass (Dicentrarchus labrax) during exposure to the increased temperature (from 12 deg C to 30 deg C) and during intoxication with four heavy metals: lead, cadmium, copper and zinc. Post temperature increase wap65 expression was highest after one hour at 30 deg C. After 1 to 4 weeks at 30 deg C wap65 transcript levels did not differ from the 12 deg C control group, similar to observations regarding the heat shock protein, hsp70. Upregulation of wap65 was detected after treatment (intoxication) with cadmium (0.5 µg/l). In contrast, a slight, but significant down regulation of wap65 was seen after copper (5 µg/l) intoxication. These data indicate that functional analyses of WAP65 are needed to understand the differential regulation of this gene by metals. The role of WAP65 may be similar to that of HSP70, which has generalized functions in responding to certain stressors and maintaining normal cell physiology.

[A new program of therapeutic education for obese patients]. / Un nouveau programme d'éducation thérapeutique pour les patients obèses.

Obesity is a chronic disease which is increasing over the past thirty years. This disease is complex and its treatment is difficult and generally frustrating for the patients and the medical team because of a high risk of relapse. Indeed, a dietetic approach alone is most of the time not good enough to obtain a long-lasting weight loss; the few drugs on the market should also be prescribed as a part of a more global approach. A multidisciplinary approach with a long-standing follow-up including a cognitive-behavioral therapy coupled to a diet and physical activity is mandatory to avoid any weight regain. We propose a new multidisciplinary program of two years with in hospital-stay and ambulatory follow-up which is showing some promising results (90% of success at one year).

A unique case of pure lateral spinal cord herniation.

BACKGROUND: Spinal cord herniation (SCH) remains a challenging diagnosis for neuroradiologists and may require treatment challenging for neurosurgeons. Most cord herniations are usually found at anterior thoracic levels. CLINICAL PRESENTATION: A 28-year-old woman presented at our department with a 7-year history of progressive myelopathy. MR analysis showed a displacement of the spinal cord in a lateral thoracic dural defect. The herniated cord was released using a microscope and the patient significantly recovered 6 months after surgery. CONCLUSION: We present a unique case of pure lateral SCH. In the light of reviewed literature and operative findings, the underlying pathophysiological mechanisms are discussed.

Determination of the optimal dose of ephedrine in the treatment of arterial hypotension due to general anesthesia in neonates and infants below 6 months old: the ephedrine study protocol for a randomized, open-label, controlled, dose escalation trial.

BACKGROUND: Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age. METHODS: The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia. DISCUSSION: This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old. TRIAL REGISTRATION: ClinicalTrials.gov NCT02384876 . Registered on March 2015.

Enhanced isochoric heating from fast electrons produced by high-contrast, relativistic-intensity laser pulses.

Thin, mass-limited targets composed of V/Cu/Al layers with diameters ranging from 50 to 300 microm have been isochorically heated by a 300 fs laser pulse delivering up to 10 J at 2x10{19} W/cm{2} irradiance. Detailed spectral analysis of the Cu x-ray emission indicates that the highest temperatures, of the order of 100 eV, have been reached when irradiating the smallest targets with a high-contrast, frequency-doubled pulse despite a reduced laser energy. Collisional particle-in-cell simulations confirm the detrimental influence of the preformed plasma on the bulk target heating.

Hot electrons transverse refluxing in ultraintense laser-solid interactions.

We have analyzed the coupling of ultraintense lasers (at ∼2×10{19} W/cm{2}) with solid foils of limited transverse extent (∼10 s of µm) by monitoring the electrons and ions emitted from the target. We observe that reducing the target surface area allows electrons at the target surface to be reflected from the target edges during or shortly after the laser pulse. This transverse refluxing can maintain a hotter, denser and more homogeneous electron sheath around the target for a longer time. Consequently, when transverse refluxing takes places within the acceleration time of associated ions, we observe increased maximum proton energies (up to threefold), increased laser-to-ion conversion efficiency (up to a factor 30), and reduced divergence which bodes well for a number of applications.

GreenPhylDB: a database for plant comparative genomics.

GreenPhylDB (http://greenphyl.cirad.fr) is a comprehensive platform designed to facilitate comparative functional genomics in Oryza sativa and Arabidopsis thaliana genomes. The main functions of GreenPhylDB are to assign O. sativa and A. thaliana sequences to gene families using a semi-automatic clustering procedure and to create 'orthologous' groups using a phylogenomic approach. To date, GreenPhylDB comprises the most complete list of plant gene families, which have been manually curated (6421 families). GreenPhylDB also contains all of the phylogenomic relationships computed for 4375 families. A total of 492 TAIR, 1903 InterPro and 981 KEGG families and subfamilies were manually curated using the clusters created with the TribeMCL software. GreenPhylDB integrates information from several other databases including UniProt, KEGG, InterPro, TAIR and TIGR. Several entry points can be used to display phylogenomic relationships for A. thaliana or O. sativa sequences, using TAIR, TIGR gene ID, family name, InterPro, gene alias, UniProt or protein/nucleic sequence. Finally, a powerful phylogenomics tool, GreenPhyl Ortholog Search Tool (GOST), was incorporated into GreenPhylDB to predict orthologous relationships between O. sativa/A. thaliana protein(s) and sequences from other plant species.

[How to manage bone metastasis in prostate cancer. A case report]. / Prise en charge des métastases osseuses du cancer de la prostate. A propos d'un cas.

Androgen deprivation therapy with LHRH agonists is the gold standard in the treatment of metastatic prostate cancer. This treatment leads to decrease the bone mass, thus bone mineral density evaluation is recommended after one year of hormonal treatment to measure bone loss. Bisphosphonate is recommended when metastasis occurred during hormonal resistance phase to reduce bone events. The necessity of preventive treatment and the appropriate schedule is not well established. Long term fracture risk should be ideally evaluated with a CT scan and an MRI. Fragmented and focal radiotherapy is considered as the treatment of choice to decrease localized pain. Metastasis surgery has functional results and should be performed before major neurologic symptoms occur. Metabolic radiotherapy is an option for multifocal bone metastases.

USPIO-enhanced magnetic resonance imaging of the knee in asymptomatic volunteers.

The aim of this study was to compare signal characteristics of the synovium in knees of asymptomatic volunteers before and after intravenous administration of ultrasmall superparamagnetic iron oxide particles (USPIO). Ten knees of 10 asymptomatic volunteers were examined before and 36 h after intravenous administration of USPIO on a 1.5-T MR system using T1-weighted spin-echo, T2-weighted fast spin-echo, T2*-weighted gradient-echo (GRE), and short inversion time inversion-recovery sequences. In addition, synovial perfusion was measured using Gd-enhanced GRE imaging during the first imaging session. Images were analyzed qualitatively for any visual changes before and after USPIO administration. Signal-to-noise ratios (SNR) of the synovium were determined on unenhanced and USPIO-enhanced sequences. All MR images were reviewed for presence of any degenerative changes. Qualitative image analysis revealed no visually detectable changes of any knee joint before and after USPIO administration. The SNR values of the synovium on T1w, T2w, and T2*w images before and after USPIO administration showed no significant difference (T1, P = 0.86; T2, P = 0.95; T2*, P = 0.86). None of the volunteers showed any relevant degenerative changes of the knee and synovial perfusion was within normal limits. In knees of asymptomatic volunteers without any relevant degenerative changes and normal synovial perfusion neither visual changes nor changes of SNR values of the synovium can be depicted after USPIO administration. This means that USPIO-enhanced MRI may be used for assessment of knee disorders with increased macrophage activity.

Enhanced hot-electron localization and heating in high-contrast ultraintense laser irradiation of microcone targets.

We report experiments demonstrating enhanced coupling efficiencies of high-contrast laser irradiation to nanofabricated conical targets. Peak temperatures near 200 eV are observed with modest laser energy (10 J), revealing similar hot-electron localization and material heating to reduced mass targets (RMTs), despite having a significantly larger mass. Collisional particle-in-cell simulations attribute the enhancement to self-generated resistive (approximately 10 MG) magnetic fields forming within the curvature of the cone wall, which confine energetic electrons to heat a reduced volume at the tip. This represents a different electron confinement mechanism (magnetic, as opposed to electrostatic sheath confinement in RMTs) controllable by target shape.