Genetic Background of Patients from a University Medical Center in Manhattan: Implications for Personalized Medicine

Background: The rapid progress currently being made in genomic science has created interest in potential clinical applications; however, formal translational research has been limited thus far. Studies of population genetics have demonstrated substantial variation in allele frequencies and haplotype structure at loci of medical relevance and the genetic background of patient cohorts may often be complex. Methods and Findings: To describe the heterogeneity in an unselected clinical sample we used the Affymetrix 6.0 gene array chip to genotype self-identified European Americans (N = 326), African Americans (N = 324) and Hispanics (N = 327) from the medical practice of Mount Sinai Medical Center in Manhattan, NY. Additional data from US minority groups and Brazil were used for external comparison. Substantial variation in ancestral origin was observed for both African Americans and Hispanics; data from the latter group overlapped with both Mexican Americans and Brazilians in the external data sets. A pooled analysis of the African Americans and Hispanics from NY demonstrated a broad continuum of ancestral origin making classification by race/ethnicity uninformative. Selected loci harboring variants associated with medical traits and drug response confirmed substantial within-and between-group heterogeneity. Conclusion: As a consequence of these complementary levels of heterogeneity group labels offered no guidance at the individual level. These findings demonstrate the complexity involved in clinical translation of the results from genome-wide association studies and suggest that in the genomic era conventional racial/ethnic labels are of little value.National Heart Lung and Blood Institute (NHLBI/NIH)[RO1 HL53353]Andrea and Charles Bronfman Philantropie

Minimal to no transfer of certolizumab pegol into breast milk: Results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study

Background Women with chronic inflammatory diseases face uncertainty regarding the safety of biologics during breast feeding. CRADLE was the first industry-sponsored study to evaluate certolizumab pegol (CZP) concentrations in human breast milk and estimate average daily infant dose (ADID) of maternal CZP. Methods CRADLE (NCT02154425) was a pharmacokinetic study of lactating mothers receiving CZP. After ≥3 CZP doses, breast milk samples were collected across one dosing period (14 days for 200 mg every 2 weeks [Q2W]; 28 days for 400 mg every 4 weeks [Q4W]). Optimal analytical methods were developed to determine CZP and polyethylene glycol (PEG) levels in breast milk. ADID and relative infant dose (RID) were estimated. Safety events in mothers and infants were assessed. Results 19 CZP-Treated mothers were screened; 17 entered the sampling period: 16 on 200 mg Q2W, 1 on 400 mg Q4W. 77/137 (56%) breast milk samples had no measurable CZP. For 4/17 mothers, all samples were below the lower limit of quantification (LLOQ). Estimated ADID was 0-0.0104 mg/kg/day; median RID: 0.15%. PEG was undetectable in 134/137 samples (results could not be determined in three samples). Infants of CZP-exposed mothers had a safety profile consistent with that of unexposed similar-Age infants. Conclusion When quantifiable, CZP concentrations were <3× LLOQ (<1% plasma concentration observed with therapeutic dose), indicating no/minimal CZP transfer from plasma to breast milk. RID was 0.15% of maternal dose; <10% is considered unlikely to be of clinical concern. No PEG transfer was observed. CZP absorption by infants via breast milk is unlikely due to its low oral bioavailability and Fc-Â-free molecular structure. These findings are reassuring and support continuation of CZP treatment during breast feeding. Trial registration number NCT02154425; Results

On Cheese, microbes and humans

International audienc

On Cheeses, microbes and humans - Teaser

Microbe populations in milk have been in constant decline. Even if they work with raw milk, cheese makers are obliged to inoculate the milk with cultures so as to restore the cheese flora, which transforms the milk into cheese. What happens? The documentary “On cheese, microbes and humans” presents a detailed analysis of the cheese-making evolution that took place in a variety of countries when Louis Pasteur and his collaborators highlighted the essential role microbes play in infectious diseases, and also in milk fermentation. Pierre Dornic who gave his name to an acidity measurement, wrote in 1896: « Without microbes, no cheese, no delicate and aromatic butter with a good hazelnut taste as is found in our best brands in Isigny. We should stop cursing microbes and here like everywhere, learn to distinguish between the good and the bad ones, the beneficial and harmful ones. »Are microbes dangerous pathogens or vital cheese-making component? Faced with the increasing pressure of sanitary norms as well as the modernization of dairy farms, which are accused of depleting milk of its precious microbes, cheese-makers are resisting: microbes are, for a good many small producers, a vital resource for their quest for quality, and thus contribute to the profitability of their farming activities. They criticize excessive cleanliness and hygiene practices. They are bringing back traditional materials previously considered too risky and banned from production. They are also turning to flora culturing, which in their opinion, best expresses the terroir quality of cheese. A close monitoring of risk management is being elaborated. A new way of producing is emerging, where milk is no longer just a simple raw material. Cheese makers and researchers are avid to go further and to continue to develop this unique partnership between cheese makers and microbes, at the heart of a new way of thinking about cheese quality. In doing so they are also inventing an alternative to the precautionary principle in health matters, which requires a greater level of discernment towards microbes

Des fromages, des microbes et des hommes - Film - INRA

Il y a de moins en moins de microbes dans le lait. Même lorsqu’ils travaillent avec du lait cru, les fromagers sont obligés d’ensemencer le lait avec des ferments pour restaurer une flore fromagère à même de transformer le lait en fromage. Que se passe-t-il ? « Des fromages, des microbes et des hommes » propose une analyse de l’évolution de la fabrication fromagère dans différents pays, depuis que Louis Pasteur et ses collaborateurs ont mis en évidence le rôle des microbes dans les maladies infectieuses, mais aussi dans la fermentation du lait. Pierre Dornic qui a laissé son nom à une mesure de l’acidité du lait, écrit en 1896 : « Sans microbes point de fromages, point de beurre fin et aromatique, à bon goût de noisette, comme nos meilleures marques d’Isigny. Sachons donc qu’il ne faut pas toujours maudire les microbes et qu’il faut, là comme en toute chose, savoir distinguer les bons et les mauvais, les bienfaisants et les malfaisants. »Les microbes sont-ils de dangereux agents pathogènes ou d’indispensables auxiliaires de fabrication ? Face à la pression des normes sanitaires, accusées, avec la modernisation des exploitations, d’induire un appauvrissement des laits, la résistance s’organise : les microbes sont pour nombre de petits producteurs, une ressource essentielle pour la recherche de qualité, grâce à laquelle ils assurent la rentabilité de leurs exploitations. Ils montrent du doigt les pratiques de nettoyage et d’hygiène excessives. Les matériaux traditionnels jugés trop risqués et bannis des productions réapparaissent, de même que la culture des microbes fromagers dont ils soulignent l’importance pour la qualité de terroir des fromages. Un encadrement plus étroit de la gestion des risques s’élabore. Une nouvelle façon de produire se met doucement en place, dans laquelle le lait n’est plus une simple matière première, et qui pousse les fromagers et les chercheurs à aller plus loin, en continuant de développer ce partenariat particulier entre les microbes et les fromagers, au cœur de la réflexion nouvelle sur la qualité des fromages. Ce faisant, ils inventent aussi une alternative au principe de précaution sanitaire qui exige un plus grand discernement dans les interactions avec les microbes

On Cheeses, microbes and humans - Film - INRA

Microbe populations in milk have been in constant decline. Even if they work with raw milk, cheese makers are obliged to inoculate the milk with cultures so as to restore the cheese flora, which transforms the milk into cheese. What happens? The documentary “On cheese, microbes and humans” presents a detailed analysis of the cheese-making evolution that took place in a variety of countries when Louis Pasteur and his collaborators highlighted the essential role microbes play in infectious diseases, and also in milk fermentation. Pierre Dornic who gave his name to an acidity measurement, wrote in 1896: « Without microbes, no cheese, no delicate and aromatic butter with a good hazelnut taste as is found in our best brands in Isigny. We should stop cursing microbes and here like everywhere, learn to distinguish between the good and the bad ones, the beneficial and harmful ones. »Are microbes dangerous pathogens or vital cheese-making component? Faced with the increasing pressure of sanitary norms as well as the modernization of dairy farms, which are accused of depleting milk of its precious microbes, cheese-makers are resisting: microbes are, for a good many small producers, a vital resource for their quest for quality, and thus contribute to the profitability of their farming activities. They criticize excessive cleanliness and hygiene practices. They are bringing back traditional materials previously considered too risky and banned from production. They are also turning to flora culturing, which in their opinion, best expresses the terroir quality of cheese. A close monitoring of risk management is being elaborated. A new way of producing is emerging, where milk is no longer just a simple raw material. Cheese makers and researchers are avid to go further and to continue to develop this unique partnership between cheese makers and microbes, at the heart of a new way of thinking about cheese quality. In doing so they are also inventing an alternative to the precautionary principle in health matters, which requires a greater level of discernment towards microbes

Des fromages, des microbes et des hommes - Bande Annonce

Il y a de moins en moins de microbes dans le lait. Même lorsqu’ils travaillent avec du lait cru, les fromagers sont obligés d’ensemencer le lait avec des ferments pour restaurer une flore fromagère à même de transformer le lait en fromage. Que se passe-t-il ? « Des fromages, des microbes et des hommes » propose une analyse de l’évolution de la fabrication fromagère dans différents pays, depuis que Louis Pasteur et ses collaborateurs ont mis en évidence le rôle des microbes dans les maladies infectieuses, mais aussi dans la fermentation du lait. Pierre Dornic qui a laissé son nom à une mesure de l’acidité du lait, écrit en 1896 : « Sans microbes point de fromages, point de beurre fin et aromatique, à bon goût de noisette, comme nos meilleures marques d’Isigny. Sachons donc qu’il ne faut pas toujours maudire les microbes et qu’il faut, là comme en toute chose, savoir distinguer les bons et les mauvais, les bienfaisants et les malfaisants. »Les microbes sont-ils de dangereux agents pathogènes ou d’indispensables auxiliaires de fabrication ? Face à la pression des normes sanitaires, accusées, avec la modernisation des exploitations, d’induire un appauvrissement des laits, la résistance s’organise : les microbes sont pour nombre de petits producteurs, une ressource essentielle pour la recherche de qualité, grâce à laquelle ils assurent la rentabilité de leurs exploitations. Ils montrent du doigt les pratiques de nettoyage et d’hygiène excessives. Les matériaux traditionnels jugés trop risqués et bannis des productions réapparaissent, de même que la culture des microbes fromagers dont ils soulignent l’importance pour la qualité de terroir des fromages. Un encadrement plus étroit de la gestion des risques s’élabore. Une nouvelle façon de produire se met doucement en place, dans laquelle le lait n’est plus une simple matière première, et qui pousse les fromagers et les chercheurs à aller plus loin, en continuant de développer ce partenariat particulier entre les microbes et les fromagers, au cœur de la réflexion nouvelle sur la qualité des fromages. Ce faisant, ils inventent aussi une alternative au principe de précaution sanitaire qui exige un plus grand discernement dans les interactions avec les microbes

Qualité et origines

communication faite à la session 2 :Qualifications, territoires et savoirs locaux : apports et regards croisés des disciplinesQualité et origines. Séminaire du département SAD : Indications géographiques, territoire et développement durabl

Autophagy in Synucleinopathy: The Overwhelmed and Defective Machinery

International audienceAlpha-synuclein positive-intracytoplasmic inclusions are the common denominators of the synucleinopathies present as Lewy bodies in Parkinson's disease, dementia with Lewy bodies, or glial cytoplasmic inclusions in multiple system atrophy. These neurodegenerative diseases also exhibit cellular dyshomeostasis, such as autophagy impairment. Several decades of research have questioned the potential link between the autophagy machinery and alpha-synuclein protein toxicity in synucleinopathy and neurodegenerative processes. Here, we aimed to discuss the active participation of autophagy impairment in alpha-synuclein accumulation and propagation, as well as alpha-synuclein-independent neurodegenerative processes in the field of synucleinopathy. Therapeutic approaches targeting the restoration of autophagy have started to emerge as relevant strategies to reverse pathological features in synucleinopathies

A New Rise of Non-Human Primate Models of Synucleinopathies

International audienceSynucleinopathies are neurodegenerative diseases characterized by the presence of α-synuclein-positive intracytoplasmic inclusions in the central nervous system. Multiple experimental models have been extensively used to understand better the mechanisms involved in the pathogenesis of synucleinopathy. Non-human primate (NHP) models are of interest in neurodegenerative diseases as they constitute the highest relevant preclinical model in translational research. They also contribute to bringing new insights into synucleinopathy’s pathogenicity and help in the quest and validation of therapeutical strategies. Here, we reviewed the different NHP models that have recapitulated key characteristics of synucleinopathy, and we aimed to highlight the contribution of NHP in mechanistic and translational approaches for synucleinopathies