VGF function in depression and antidepressant efficacy.

Brain-derived neurotrophic factor (BDNF) is a critical effector of depression-like behaviors and antidepressant responses. Here, we show that VGF (non-acronymic), which is robustly regulated by BDNF/TrkB signaling, is downregulated in hippocampus (male/female) and upregulated in nucleus accumbens (NAc) (male) in depressed human subjects and in mice subjected to chronic social defeat stress (CSDS). Adeno-associated virus (AAV)-Cre-mediated Vgf ablation in floxed VGF mice, in dorsal hippocampus (dHc) or NAc, led to pro-depressant or antidepressant behaviors, respectively, while dHc- or NAc-AAV-VGF overexpression induced opposite outcomes. Mice with reduced VGF levels in the germ line (Vgf+/-) or in dHc (AAV-Cre-injected floxed mice) showed increased susceptibility to CSDS and impaired responses to ketamine treatment in the forced swim test. Floxed mice with conditional pan-neuronal (Synapsin-Cre) but not those with forebrain (αCaMKII-Cre) Vgf ablation displayed increased susceptibility to subthreshold social defeat stress, suggesting that neuronal VGF, expressed in part in inhibitory interneurons, regulates depression-like behavior. Acute antibody-mediated sequestration of VGF-derived C-terminal peptides AQEE-30 and TLQP-62 in dHc induced pro-depressant effects. Conversely, dHc TLQP-62 infusion had rapid antidepressant efficacy, which was reduced in BDNF floxed mice injected in dHc with AAV-Cre, and in NBQX- and rapamycin-pretreated wild-type mice, these compounds blocking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling, respectively. VGF is therefore a critical modulator of depression-like behaviors in dHc and NAc. In hippocampus, the antidepressant response to ketamine is associated with rapid VGF translation, is impaired by reduced VGF expression, and as previously reported, requires coincident, rapid BDNF translation and release.

Factors associated with acquisition of glycopeptide-resistant enterococci during a single-strain outbreak.

The aim of our study was to describe and to investigate the factors associated with glycopeptide-resistant enterococci (GRE) acquisition during a single-strain outbreak which occurred in several wards of hospital from September 2013 to January 2014. We designed a case-control study. Analyses were performed using Bayesian methods. Univariate logistic regressions with informative priors from published studies were conducted. A multivariate model was build including variables with a probability of odd-ratio exceeding one (Pr) >85% or <15%. Thirteen cases and 52 controls were recruited. The description of this outbreak highlighted the importance to quickly detect patients at risk of GRE carriage in order to implement the isolation measures and to transfer to dedicated department if they are effectively carriers. Following multivariate analysis, antibiotics during hospitalisation (Pr = 0.968), number of hospitalisation days in the year (Pr = 0.964), antacids intake (Pr = 0.878) (with a risk increase), immunosuppression (Pr = 0.026) and isolation measures (Pr = 0.003) (both with protective effect) were associated with GRE acquisition. The use of Bayesian statistics was useful because of our study's small population size and prior information availability.

Adipose mesenchymal stromal cells: Definition, immunomodulatory properties, mechanical isolation and interest for plastic surgery.

Ever since their discovery in 2001, adipose mesenchymal stromal cells (ASC) have profoundly modified clinical indications and our practice of plastic surgery, thereby placing our discipline at the forefront of regenerative medicine. These cells act through paracrine signaling by synthesizing immunosuppressive and pro-angiogenic factors. They are of key importance with regard to the regenerative properties of autologously grafted adipose tissue (AT). Taken together, they make up the stromal vascular fraction (SVF) comprising all AT cells except for adipocytes. As our knowledge evolves, we are moving from fat grafting towards SVF grafting, of which the essential sought-after effect is tissue regeneration. The objective of the present review is to synthesize present-day information on ASCs and their immunomodulatory properties and, from a practical standpoint, to indicate present-day and future steps towards establishment of clinical routine, particularly through application of techniques favoring mechanical digestion of adipose tissue.

Procarbazine, lomustine and vincristine toxicity in low-grade gliomas.

BACKGROUND: Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice. METHODS: We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l'Université de Montréal between 1 January 2005 and 27 July 2016. RESULTS: Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia (p = 0.040) and thrombocytopenia (p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment (p = 0.042). CONCLUSION: Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti-Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity.

[Adipose-derived stromal cells: history, isolation, immunomodulatory properties and clinical perspectives]. / Les cellules stromales mésenchymateuses du tissu adipeux : historique, isolement, propriétés immunomodulatrices et perspectives cliniques.

Over the last decade, the clinical use of adipose-derived stromal/stem cells (ASC) in regenerative medicine is rapidly increasing. ASC belong to the mesenchymal stromal cells initially obtained from the bone marrow. Their limited differentiation capacity in vivo into functional mature cells has led to a reassessment of their mechanisms of action. One of the major clinical interests appears related to paracrine effects through a temporary production of trophic and immunomodulatory factors. Our purpose is to provide a review on the latest knowledge in the field of ASC, mechanisms of action, mainly immunomodulatory/immunosuppressive properties, methods of obtention, with a focus on clinical perspectives particularly in the field of cellular therapy and fat grafting technique in plastic surgery.

Non-Intrusive Real Time Eye Tracking Using Facial Alignment for Assistive Technologies.

Most affordable eye tracking systems use either intrusive setup such as head-mounted cameras or use fixed cameras with infrared corneal reflections via illuminators. In the case of assistive technologies, using intrusive eye tracking systems can be a burden to wear for extended periods of time and infrared based solutions generally do not work in all environments, especially outside or inside if the sunlight reaches the space. Therefore, we propose an eye-tracking solution using state-of-the-art convolutional neural network face alignment algorithms that is both accurate and lightweight for assistive tasks such as selecting an object for use with assistive robotics arms. This solution uses a simple webcam for gaze and face position and pose estimation. We achieve a much faster computation time than the current state-of-the-art while maintaining comparable accuracy. This paves the way for accurate appearance-based gaze estimation even on mobile devices, giving an average error of around 4.5°on the MPIIGaze dataset [1] and state-of-the-art average errors of 3.9°and 3.3°on the UTMultiview [2] and GazeCapture [3], [4] datasets respectively, while achieving a decrease in computation time of up to 91%.

Plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response.

BACKGROUND: High plasma osteopontin (OPN) has been linked to tumour hypoxia, metastasis, and poor prognosis. This study aims to assess whether plasma osteopontin was a biomarker of increasing progression within prostate cancer (PCa) prognostic groups and whether it reflected treatment response to local and systemic therapies. METHODS: Baseline OPN was determined in men with localised (n=199), locally recurrent (n=9) and castrate-resistant, metastatic PCa (CRPC-MET; n=37). Receiver-operating curves (ROC) were generated to describe the accuracy of OPN for distinguishing between localised risk groups or localised vs metastatic disease. We also measured OPN pre- and posttreatment, following radical prostatectomy, external beam radiotherapy (EBRT), androgen deprivation (AD) or taxane-based chemotherapy. RESULTS: The CRPC-MET patients had increased baseline values (mean 219; 56-513 ng ml(-1); P<0.0001) compared with the localised, non-metastatic group (mean 72; 12-438 ng ml(-1)). The area under the ROC to differentiate localised vs metastatic disease was improved when OPN was added to prostate-specific antigen (PSA) (0.943-0.969). Osteopontin neither distinguished high-risk PCa from other localised PCa nor correlated with serum PSA at baseline. Osteopontin levels reduced in low-risk patients after radical prostatectomy (P=0.005) and in CRPC-MET patients after chemotherapy (P=0.027), but not after EBRT or AD. CONCLUSION: Plasma OPN is as good as PSA at predicting treatment response in CRPC-MET patients after chemotherapy. Our data do not support the use of plasma OPN as a biomarker of increasing tumour burden within localised PCa.

The French OQALI survey on dairy products: comparison of nutrient contents and other nutrition information on labels among types of brands.

BACKGROUND: Depending on their spending power, consumers may choose foodstuffs from more or less expensive types of brands (national, retailer, economy-line retailer or discount brands). The present study, on dairy products, assesses the nutritional composition and the frequencies of labelled nutrition parameters, according to types of brands. METHODS: The 1646 most consumed dairy products were collected. Nutrient contents and other labelled nutrition parameters provided on the packaging (i.e. nutrition and health claims, nutrition guidelines such as guideline daily amounts, consumption advice and information on added vitamins and minerals) were captured in the French branded product composition database (OQALI). RESULTS: Significant differences between brands were found for energy, protein, fat, saturates, carbohydrate, sugars, dietary fibre, calcium and sodium, in four of six dairy groups studied, but not systematically. National brands and retailer brands provided more detailed nutrition labelling and more frequent nutrition claims than cheaper brands. More retailer brand products provided nutrition guidelines and consumption advice than the other branded products. National brand products more frequently contained added vitamins and minerals and more frequently bore health claims. CONCLUSIONS: Nutrient contents of the cheaper brands of dairy products did not vary systematically from more expensive ones. However, national brands and retailer brands products provided more nutrition information on labels than the cheaper ones. There should be more detailed studies comparing different types of brands regarding labelling practices for nutrient contents and other nutrition information about foodstuffs to help prepare public health recommendations, adapted to all consumers, regardless of their income.

Focal HDR brachytherapy boost to stereotactic radiotherapy (fBTsRT) for prostate cancer: a phase II randomized controlled trial.

BACKGROUND: For patients with a higher burden of localized prostate cancer, radiation dose escalation with brachytherapy boosts have improved cancer control outcomes at the cost of urinary toxicity. We hypothesize that a focal approach to brachytherapy boosts targeting only grossly visualized tumor volumes (GTV) combined with stereotactic radiotherapy will improve quality of life (QoL) outcomes without compromising cancer control. METHODS: 150 patients with intermediate or high-risk prostate cancer will be enrolled and randomized 1:1 in a cohort multiple randomized clinical trial phase 2 design. Patients are eligible if planned for standard-of-care (SOC) high dose rate (HDR) brachytherapy boost to radiotherapy (RT) with GTVs encompassing < 50% of the prostate gland. Those randomly selected will be offered the experimental treatment, consisting of focal HDR brachytherapy boost (fBT) of 13-15 Gy in 1 fraction followed by stereotactic radiotherapy (sRT) 36.25-40 Gy in 5 fractions to the prostate (+/- 25 Gy to the elective pelvis) delivered every other day. The primary endpoint is to determine if fBTsRT is superior to SOC by having fewer patients experience a minimally important decline (MID) in urinary function as measured by EPIC-26 at 1 and 2 years. Secondary endpoints include rates of toxicity measured by Common Terminology Criteria for Adverse Events (CTCAE), and failure-free survival outcomes. DISCUSSION: This study will determine whether a novel approach for the treatment of localized prostate cancer, fBTsRT, improves QoL and merits further evaluation. Trial registration This trial was prospectively registered in ClinicalTrials.gov as NCT04100174 as a companion to registry NCT03378856 on September 24, 2019.

Human neutrophils produce high levels of the interleukin 1 receptor antagonist in response to granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha.

Neutrophils, an abundant cell type at sites of inflammation, have the ability to produce a number of cytokines, including interleukin 1 (IL-1), IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-alpha). In this study, we have examined the ability of human neutrophils to produce the IL-1 receptor antagonist (IL-1Ra), a 17-23-kD protein recently isolated and cloned from macrophages. Since IL-1Ra has been shown to inhibit both the in vitro and in vivo effects of IL-1, its production by large numbers of tissue-invading neutrophils might provide a mechanism by which the effects of IL-1 are regulated in inflammation. Using antibodies that are specific for IL-1Ra and a cDNA probe encoding for this protein, we were able to show that neutrophils constitutively produce IL-1Ra. However, after activation by GM-CSF and TNF-alpha, IL-1Ra was secreted into the extracellular milieu where it constituted the major de novo synthesized product of activated neutrophils. None of a large array of other potent neutrophil agonists were found to affect the production of IL-1Ra by neutrophils. Quantitative measurements by enzyme-linked immunosorbent assay revealed that intracellular IL-1Ra is in eightfold excess of the amount secreted in supernatants when studying nonactivated neutrophils. However, in GM-CSF- and TNF-alpha-activated cells, this difference was reduced to values between four- and fivefold, as virtually all of the de novo synthesized IL-1Ra was secreted. In activated cells, the intracellular content of IL-1Ra was found to be in the 2-2.5-ng/ml range per 10(6) neutrophils, whereas levels reached the 0.5-ng/ml range in supernatants. This would imply that IL-1Ra is produced in excess of IL-1 by a factor of at least 100, an observation that is in agreement with the reported amounts of IL-1Ra needed to inhibit the proinflammatory effects of IL-1. Neutrophils isolated from an inflammatory milieu, the synovial fluid of patients with rheumatoid arthritis, were found to respond to GM-CSF and TNF-alpha in terms of IL-1Ra synthesis, indicating that the in vitro observations made in this study are likely to occur in an inflammatory setting in vivo.

Clinical outcomes of adult patients with primary intracranial germinomas treated with low-dose craniospinal radiotherapy and local boost.

The authors document the long term follow up of adult patients with histologically proven primary intracranial germinoma treated with radiotherapy alone using a craniospinal with local boost technique. A retrospective review was conducted on adults diagnosed with intracranial germinoma who received radiotherapy at the Princess Margaret Hospital, Toronto from 1990 to 2007. The study group consisted of 10 males with a median age of 24.1 years. All patients received radiotherapy alone using craniospinal radiotherapy and local boost. There were 10 patients (all male) with a median follow up of 10.9 years (range 2.2-18.9 years). At date of last follow up all patients were still alive, none with relapsed disease. Seven of ten patients (70%) had panhypopituitarianism prior to commencing radiotherapy and hormonal function was not affected in those with an intact pituitary axis. There was no reported cognitive decline in the treated cohort. For adult intracranial germinomas, with long term follow up, low-dose craniospinal radiotherapy with in field boost is highly effective with minimal morbidity.

A ribonucleotide reductase homolog of cytomegalovirus and endothelial cell tropism.

Human cytomegalovirus infects vascular tissues and has been associated with atherogenesis and coronary restenosis. Although established laboratory strains of human cytomegalovirus have lost the ability to grow on vascular endothelial cells, laboratory strains of murine cytomegalovirus retain this ability. With the use of a forward-genetic procedure involving random transposon mutagenesis and rapid phenotypic screening, we identified a murine cytomegalovirus gene governing endothelial cell tropism. This gene, M45, shares sequence homology to ribonucleotide reductase genes. Endothelial cells infected with M45-mutant viruses rapidly undergo apoptosis, suggesting that a viral strategy to evade destruction by cellular apoptosis is indispensable for viral growth in endothelial cells.

Rapid identification of essential and nonessential herpesvirus genes by direct transposon mutagenesis.

Herpesviruses are important pathogens in animals and humans. The large DNA genomes of several herpesviruses have been sequenced, but the function of the majority of putative genes is elusive. Determining which genes are essential for their replication is important for identifying potential chemotherapy targets, designing herpesvirus vectors, and generating attenuated vaccines. For this purpose, we recently reported that herpesvirus genomes can be maintained as infectious bacterial artificial chromosomes (BAC) in Escherichia coli. Here we describe a one-step procedure for random-insertion mutagenesis of a herpesvirus BAC using a Tn1721-based transposon system. Transposon insertion sites were determined by direct sequencing, and infectious virus was recovered by transfecting cultured cells with the mutant genomes. Lethal mutations were rescued by cotransfecting cells containing noninfectious genomes with the corresponding wild-type subgenomic fragments. We also constructed revertant genomes by allelic exchange in bacteria. These methods, which are generally applicable to any cloned herpesvirus genome, will facilitate analysis of gene function for this virus family.

Clinical use of magnetic resonance imaging across the prostate brachytherapy workflow.

MRI produces better soft tissue contrast than does ultrasonography or computed tomography for visualizing male pelvic anatomy and prostate cancer. Better visualization of the tumor and organs at risk could allow better conformation of the dose to the target volumes while at the same time minimizing the dose to critical structures and the associated toxicity. Although the use of MRI for prostate brachytherapy would theoretically result in an improved therapeutic ratio, its implementation been slow, mostly because of technical challenges. In this review, we describe the potential role of MRI at different steps in the treatment workflow for prostate brachytherapy: for patient selection, treatment planning, in the operating room, or for postimplant assessment. We further present the current clinical experience with MRI-guided prostate brachytherapy, both for permanent seed implantation and high-dose-rate brachytherapy.

The utilization of magnetic resonance imaging in the operating room.

Online image guidance in the operating room using ultrasound imaging led to the resurgence of prostate brachytherapy in the 1980s. Here we describe the evolution of integrating MRI technology in the brachytherapy suite or operating room. Given the complexity, cost, and inherent safety issues associated with MRI system integration, first steps focused on the computational integration of images rather than systems. This approach has broad appeal given minimal infrastructure costs and efficiencies comparable with standard care workflows. However, many concerns remain regarding accuracy of registration through the course of a brachytherapy procedure. In selected academic institutions, MRI systems have been integrated in or near the brachytherapy suite in varied configurations to improve the precision and quality of treatments. Navigation toolsets specifically adapted to prostate brachytherapy are in development and are reviewed.

Use of magnetic resonance imaging in low-dose-rate and high-dose-rate prostate brachytherapy from diagnosis to treatment assessment: Defining the knowledge gaps, technical challenges, and barriers to implementation.

MRI is rapidly evolving as an imaging tool in both low-dose-rate and high-dose-rate brachytherapy for prostate cancer. The ability of MRI to identify intraprostatic tumors and reduce uncertainties in the workflow process should enable a more accurate and precise radiation delivery approach while simultaneously improving the quality assurance process. The ability to identify functional anatomic structures adjacent to the prostate cancer could reduce or eliminate some of the more common side effects of the treatment. However, MRI is complex, and collaborative efforts and future research are required to address the current knowledge gaps, technical challenges, and barriers to widespread the implementation of MRI-assisted and MRI-guided prostate brachytherapy.

Honeybee locomotion is impaired by Am-CaV3 low voltage-activated Ca2+ channel antagonist.

Voltage-gated Ca2+ channels are key transducers of cellular excitability and participate in several crucial physiological responses. In vertebrates, 10 Ca2+ channel genes, grouped in 3 families (CaV1, CaV2 and CaV3), have been described and characterized. Insects possess only one member of each family. These genes have been isolated in a limited number of species and very few have been characterized although, in addition to their crucial role, they may represent a collateral target for neurotoxic insecticides. We have isolated the 3 genes coding for the 3 Ca2+ channels expressed in Apis mellifera. This work provides the first detailed characterization of the honeybee T-type CaV3 Ca2+ channel and demonstrates the low toxicity of inhibiting this channel. Comparing Ca2+ currents recorded in bee neurons and myocytes with Ca2+ currents recorded in Xenopus oocytes expressing the honeybee CaV3 gene suggests native expression in bee muscle cells only. High-voltage activated Ca2+ channels could be recorded in the somata of different cultured bee neurons. These functional data were confirmed by in situ hybridization, immunolocalization and in vivo analysis of the effects of a CaV3 inhibitor. The biophysical and pharmacological characterization and the tissue distribution of CaV3 suggest a role in honeybee muscle function.

Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells.

Cardiomyocyte regeneration is limited in adult life. Thus, the identification of a putative source of cardiomyocyte progenitors is of great interest to provide a usable model in vitro and new perspective in regenerative therapy. As adipose tissues were recently demonstrated to contain pluripotent stem cells, the emergence of cardiomyocyte phenotype from adipose-derived cells was investigated. We demonstrated that rare beating cells with cardiomyocyte features could be identified after culture of adipose stroma cells without addition of 5-azacytidine. The cardiomyocyte phenotype was first identified by morphological observation, confirmed with expression of specific cardiac markers, immunocytochemistry staining, and ultrastructural analysis, revealing the presence of ventricle- and atrial-like cells. Electrophysiological studies performed on early culture revealed a pacemaker activity of the cells. Finally, functional studies showed that adrenergic agonist stimulated the beating rate whereas cholinergic agonist decreased it. Taken together, this study demonstrated that functional cardiomyocyte-like cells could be directly obtained from adipose tissue. According to the large amount of this tissue in adult mammal, it could represent a useful source of cardiomyocyte progenitors.

HPAI surveillance programme in Cambodia: results and perspectives.

Cambodia has faced 15 confirmed highly pathogenic avian influenza (H5N1) outbreaks in different sectors of the poultry industry since January 2004. The country has very limited human and financial resources and, when the outbreak first began, the veterinary services were not equipped with the basic tools to collect accurate epidemiological information or to fight the disease. Therefore, different agencies, under the umbrella of the Food and Agriculture Organisation, are providing support to the Government to strengthen its capacity to diagnose, survey and control the avian influenza (AI) virus. Different surveillance tools are being tested, such as market monitoring and a sentinel villages' network, to offset the weakness of the national passive surveillance network. Several constraints were identified during the implementation of this programme, such as a lack of motivation among provincial staff, the limited capacity of the central team to compile and analyse the data generated, the reluctance of farmers to have their animals sampled, and weak diagnostic capacities. The sustainability of such a surveillance system once international support ends remains to be seen. Participatory epidemiology (PE) may be an appropriate complementary tool to track diseases. PE works on the principle that livestock keepers often possess detailed knowledge of animal diseases and can provide valuable diagnostics that could help in identifying AI outbreaks, particularly in remote areas.