Getting insights on bovine mastitis treatment efficacy based on tissular indicators with an integrated udder health management file: Project LAECEA.

Mastitis is the most “antibiotic consuming” pathology in dairy medicine. Though antibiotics and antibiograms are known to vets since the early fifties, our practices did not evolved a lot from empiric antibiotic therapy. Indeed, the need for a treatment, the cost and the delay for an antibiogram are most of the time incoherent with a routine practice. Nevertheless, there is a surge for rational use of antibiotics. Our study was based on 1100 mastitis events from 30 Belgian farms collected between January 2011 and June 2012. We chose to compare tissular cure (TC) based on the threshold of 200.000 somatic cells/ml in milk at milk control at least 60 days after the clinical mastitis event. Regarding the mastitis event, severity (according 3 grades: alteration of milk as grade 1, alteration of quarter as grade 2 and alteration of general state as grade 3), quarter, treatments were recorded. We also assessed a chronicity status based on previous somatic cell count (SCC) of the cow. It was considered a new case a cow which at least 15 days before had an SCC <200.000 cells/ml, other were marked as chronic cases. In our distribution, we see a seasonal rise of incidence between January and May. This period would represent twice as many mastitis as the summer period. Overall TC reaches 46% of all mastitis events, which is quite poor. Rear quarters had significantly lower TC (p<0,05%). Grade 3 mastitis had lower TC, 42,6% (p<0.05%) versus 48,9 % for grade 2 and 44,2% for grade 1. Almost 49% of all mastitis was considered as chronic cases, which TC was 33% on average, whereas new cases reached 55,3% TC. Study of treatment was frustrating given the high number of different combinations of treatments. It was underlined that 4th generation cephalosporins (C4G) were the most used in our cohort, followed by aminopenicillin/methicillin association (PENA/PENM) and 1st generation cephalosporins/aminoglycosids (C1G/AG) association. Of these intramammary treatments, 20% of the cases were submitted to a second intramammary drug, mostly C1G or C1G/AG. One third of the cases were treated parenterally with antimicrobials, mostly macrolids, fluoroquinolones and penethacillin. Finally, 10% of mastitis was treated with anti-inflammatory drugs, mostly tolfenamic acid and flunixin-meglumin. Comparing mastitis without use of a secondary intramammary drug, only PENA and C1G/AG reached more than 60% TC. Considering new cases, then C1G/AG, PENA/PENM and Prednisolone containing specialties were above 60% TC. Use of a parenteral injections increased TC only on new cases (+12%), but not on chronic cases. Refining by severity, TC improved with a parenteral on new cases, mainly in grade 1 (+20%). Regarding associated factors, TC was negatively affected by chronicity, parity and lactation stage. Indeed, TC was lower on cases from more than 4 month in milk, third lactation (OR = 2.8 for no cure) compared with previous, and chronic cases (OR=2,6). Seemingly, chronicity was positively associated with parity and season. The 3rd parity cases had higher chances to be chronic ones (OR = 1,7), as well as cases from April to September (OR = 1,6). This evaluation of cure is rather simple and has a good variability which allows several questions about the real match between antimicrobial treatment for mastitis and the udder inflammation. Based on our epidemiological data, we can modify routine management of mastitis, as some cases might not worth the antimicrobial treatment.LAECE

Multitargeted Imidazoles: Potential Therapeutic Leads for Alzheimer's and Other Neurodegenerative Diseases

Alzheimer’s disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aβ species as well as neuroinflammation. In this context, the development of single multitargeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure−activity relationship studies that led to the identification of multitargeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several examples are brain-penetrant and exhibit balanced multitargeted in vitro activity in the low μM range. As brain-penetrant MT-stabilizing agents have proven effective against tau-mediated neurodegeneration in animal models, and because COX- and 5-LOX-derived eicosanoids are thought to contribute to Aβ plaque deposition, these 1,5-diarylimidazoles provide tools to explore novel multitargeted strategies for AD and other neurodegenerative diseases

Analyse de l'efficience des traitements de mammites de 60 fermes de Wallonie dans la base LAECEA

Le traitement de la mammite bovine est un acte à part dans la routine d’une exploitation bovine. En effet, si les cas les plus graves sont vus presque systématiquement pas le vétérinaire traitant en France ou en Belgique, la plupart des cas peu sévères font l’objet d’une tacite délégation de diagnostic et de traitement, sur base d’une formation préalable et d’une prescription enregistrée. Aujourd’hui, cette pathologie représente le plus important poste de consommation d’antibiotiques en exploitation laitière. Concernant cette problématique, la profession vétérinaire doit disposer de nouveaux outils de diagnostic, de traitement, et surtout d’évaluation de la qualité du traitement. Or, depuis la fin des années 1940, la pratique de l’antibiothérapie est restée, comme en médecine humaine, basée essentiellement sur l’antibiothérapie empirique, plus ou moins régulée par des cultures bactériologiques et des antibiogrammes (Durel et al., 2012). La profession s’est dotée d’outils d’analyse épidémiologique et clinique au cours des décennies, mais les résultats sont mitigés : une diminution globale de la consommation d’antibiotiques, mais le recours accru à des classes de dernières générations. Aujourd’hui le grand enjeu de l’antibiothérapie se corse, avec l’identification de mécanisme de résistance suspects d’être communs avec la médecine humaine(Jaglic et al., 2010). Plusieurs classes de molécules communes avec la médecine humaine sont identifiées, et leur utilisation menace d’être régulée (Bagcigil et al., 2007). Face à ce constat, l’utilisation des antibiotiques destinés au traitement de la mamelle a été étudiée en Belgique, dans soixante fermes laitières wallonnes (Théron et al., 2011).Peer reviewe

Disorganized Attachment in Infancy: A Review of the Phenomenon and Its Implications for Clinicians and Policy-Makers

Disorganized/Disoriented (D) attachment has seen widespread interest from policy makers, practitioners, and clinicians in recent years. However, some of this interest seems to have been based on some false assumptions that (1) attachment measures can be used as definitive assessments of the individual in forensic/child protection settings and that disorganized attachment (2) reliably indicates child maltreatment, (3) is a strong predictor of pathology, and (4) represents a fixed or static trait of the child, impervious to development or help. This paper summarizes the evidence showing that these four assumptions are false and misleading. The paper reviews what is known about disorganized infant attachment and clarifies the implications of the classification for clinical and welfare practice with children. In particular, the difference between disorganized attachment and attachment disorder is examined, and a strong case is made for the value of attachment theory for supportive work with families and for the development and evaluation of evidence-based caregiving interventions

CENPHER five year report 2009-2014: From a research project to a research center

Other than the influence of ionizing radiation and benign thyroid disease, little is known about the risk factors for differentiated thyroid cancer (TC) which is an increasing common cancer worldwide. Consistent evidence shows that body mass is positively associated with TC risk. As excess weight is a state of chronic inflammation, we investigated the relationship between concentrations of leptin, adiponectin, C-reactive protein, interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-α and the risk of TC. A case-control study was nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study and included 475 first primary incident TC cases (399 women and 76 men) and 1,016 matched cancer-free cohort participants. Biomarkers were measured in serum samples using validated and highly sensitive commercially available immunoassays. Odds ratios (ORs) of TC by levels of each biomarker were estimated using conditional logistic regression models, adjusting for BMI and alcohol consumption. Adiponectin was inversely associated with TC risk among women (ORT3vs.T1 = 0.69, 95% CI: 0.49-0.98, Ptrend = 0.04) but not among men (ORT3vs.T1 = 1.36, 95% CI: 0.67-2.76, Ptrend = 0.37). Increasing levels of IL-10 were positively associated with TC risk in both genders and significantly so in women (ORT3vs.T1 = 1.59, 95% CI: 1.13-2.25, Ptrend = 0.01) but not in men (ORT3vs.T1 = 1.78, 95% CI: 0.80-3.98, Ptrend = 0.17). Leptin, CRP, IL-6 and TNF-α were not associated with TC risk in either gender. These results indicate a positive association of TC risk with IL-10 and a negative association with adiponectin that is probably restricted to women. Inflammation may play a role in TC in combination with or independently of excess weight

Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1

Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity, and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.</p

Adipokines and inflammation markers and risk of differentiated thyroid carcinoma: The EPIC study

Other than the influence of ionizing radiation and benign thyroid disease, little is known about the risk factors for differentiated thyroid cancer (TC) which is an increasing common cancer worldwide. Consistent evidence shows that body mass is positively associated with TC risk. As excess weight is a state of chronic inflammation, we investigated the relationship between concentrations of leptin, adiponectin, C-reactive protein, interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-α and the risk of TC. A case-control study was nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study and included 475 first primary incident TC cases (399 women and 76 men) and 1,016 matched cancer-free cohort participants. Biomarkers were measured in serum samples using validated and highly sensitive commercially available immunoassays. Odds ratios (ORs) of TC by levels of each biomarker were estimated using conditional logistic regression models, adjusting for BMI and alcohol consumption. Adiponectin was inversely associated with TC risk among women (ORT3vs.T1 = 0.69, 95% CI: 0.49-0.98, Ptrend = 0.04) but not among men (ORT3vs.T1 = 1.36, 95% CI: 0.67-2.76, Ptrend = 0.37). Increasing levels of IL-10 were positively associated with TC risk in both genders and significantly so in women (ORT3vs.T1 = 1.59, 95% CI: 1.13-2.25, Ptrend = 0.01) but not in men (ORT3vs.T1 = 1.78, 95% CI: 0.80-3.98, Ptrend = 0.17). Leptin, CRP, IL-6 and TNF-α were not associated with TC risk in either gender. These results indicate a positive association of TC risk with IL-10 and a negative association with adiponectin that is probably restricted to women. Inflammation may play a role in TC in combination with or independently of excess weight

De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders

Microtubule-stabilizing 1,2,4-Triazolo[1,5-a]pyrimidines as candidate therapeutics for neurodegenerative disease: Matched molecular pair analyses and computational studies reveal new structure-activity insights

Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer’s disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers (i.e., the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure–activity relationships of MT-active TPDs. These studies led to the identification of novel MT-normalizing TPD candidates that exhibit favorable ADME-PK, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity

A new molecular classification to drive precision treatment strategies in primary Sjögren’s syndrome

There is currently no approved treatment for primary Sjögren's syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren's syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials