Overblog Suivre ce blog
Administration Créer mon blog
10 novembre 2012 6 10 /11 /novembre /2012 07:50
http://m.youtube.com/watch?feature=related&v=sM-VI3alvAI
Repost 0
Published by Chronimed - dans Les ondes
commenter cet article
10 novembre 2012 6 10 /11 /novembre /2012 07:42
Knocking on the clinic door Nature Biotechnology 30, 1009 (2012) doi:10.1038/nbt.2428 Published online 08 November 2012 Article tools Download PDF Citation Reprints Rights & permissions High-throughput sequencing for clinical purposes faces technical and quality challenges, but it's worth it. The $3-billion price tag for the first human genome would now buy not one but a million human genome sequences, each completed in just a few weeks. Personal genome sequencing is becoming a reality, and targeted or whole exome sequencing is being explored to facilitate diagnosis and guide treatment, in some conditions and for some patients. The problem is that extracting clinically actionable information from genome data is currently hit or miss, time intensive and dependent on access to knowledgeable specialists. What's more, much of the IT infrastructure and decision support systems necessary to deliver genome information to physicians has yet to be put in place. This issue of Nature Biotechnology summarizes the current status of high-throughput sequencing as applied to life sciences and medical research. The notion of simultaneously accessing all genes associated with all diseases through a patient's genome is both tantalizing and daunting: tantalizing because it could potentially provide a path to patient-centered medicine; daunting because of the sheer scale of data involved and also the numerous changes required to clinical research laboratory practice, accreditation and standards, regulatory oversight, and issues relating to ethics, privacy, consent and legal protections. The requirements for bench sequencing and clinical sequencing differ markedly in at least two respects. First, test results must be delivered rapidly (because patients cannot wait months for results). Second, the data must be distilled to facilitate clinical decision making (physicians already wrestle with information overload). Indeed, one reason why pharmacogenetic testing has been narrowly adopted is that doctors won't order tests when the patient is in front of them waiting for a prescription. To be useful, pharmacogenetic testing must be undertaken a priori, enabling patients' genetically predicted drug responses to guide prescription. Adapting sequencing assays to clinical work will also require higher levels of sensitivity and specificity than research. In most research applications, a 30% false-negative rate (missed variants) and an even higher false-positive rate (erroneous variants called) is the norm. To approach the 99.9% raw base-calling accuracy needed for many medical applications, however, an average sequence depth would have to approach 30× coverage (~10× coverage is acceptable in research), with >95% of all calls made at a depth of ten reads or more. To ensure such quality of sequence coverage, laboratories conducting sequencing services will have to be accredited under the Clinical Laboratory Improvement Amendments (CLIA)—and to equivalent standards outside the United States. This explains the relationship between 23andMe and LabCorp, the acquisition of Navigenics by Life Technologies and in September the acquisition of Complete Genomics by BGI. At the same time, proficiency testing standards, such as those released by the College of American Pathologists in July and those presented on p. 1034, will be essential to assure quality sequencing. But assuring the quality and proficiency of the platforms is not enough. Most of the algorithms for aligning reads, detecting variants and calling genotypes are imperfect. Large copy number deletions and trinucleotide repeats in short read data are fundamentally difficult to detect. Biological variability introduced from samples can also confound analysis and interpretation (e.g., formalin fixation can crosslink cytosines and somatic mosaicism can result in misleading calls). But an even more fundamental problem lies in determining which of the millions of variants in an individual's genome sequence are of clinical validity (that is, give information about the patient) and, more importantly, which are also of clinical utility (that is, aid treatment decisions). According to current estimates, only 10–30% of the variants identified by sequencing have clinical validity, and fewer still are actionable. Identifying variants of clinical significance is very complex technically and far from perfect. ENCODE has revealed to us prolific transcription of noncoding regions. But we struggle to filter even just the thousands of variants revealed by exome sequencing against reference sets, such as common variants identified in the HapMap project, the US National Heart, Lung and Brain Institute exome variant set or the Complete Genomics 69-sample set. This yields hundreds of variants altering protein structure that still need to be screened for likely candidates by painstaking literature research. But the sifting process is imperfect because the reference sets do not truly represent the spectrum of variation in different ethnic groups (1000 Genomes attempts to address this). Even then, the multigenic complexity of many disorders complicates analysis. In short, apart from applications in cancer diagnosis and therapy, the major immediate clinical benefit from sequencing will not arise from personal genomes, but from an increased rate of disease-gene discovery, particularly in undiagnosed patients with putative monogenic disorders. The unserved market today lies in turnkey genome analysis and genome interpretation for the clinic, a niche that companies such as Silicon Valley Biosystems, Knome, Cypher Genomics, Personalis, Genomatix, Omicia, Ingenuity Systems and Station X seek to occupy. In diagnostics, CLIA labs will increasingly use sequencing to test multiple gene panels rapidly and simultaneously—and diagnostic companies will begin to develop multiplexed gene test kits. But the rate of progress will depend on payers' willingness to embrace the technology. Already, a whole-genome sequence costs the same as a handful of single-gene tests. But unlike a gene test, the value of a genome increases with time (as research identifies more causal variants). There are immediate savings for patients who currently confound traditional diagnosis, going from clinical center to center receiving lots of costly and futile treatments. But what insurers really need to see is that one outlay also opens up cost-savings down the line. Truly, a patient's genome is a gift that keeps on giving. Nature Biotechnology
Repost 0
Published by Chronimed - dans Concept
commenter cet article
10 novembre 2012 6 10 /11 /novembre /2012 07:38
Proteomics-directed cloning of circulating antiviral human monoclonal antibodies Shuji Sato, Sean A Beausoleil, Lana Popova, Jason G Beaudet, Ravi K Ramenani, Xiaowu Zhang, James S Wieler, Sandra M Schieferl, Wan Cheung Cheung & Roberto D Polakiewicz AffiliationsCorresponding authors Nature Biotechnology 30, 1039–1043 (2012) doi:10.1038/nbt.2406 Published online 08 November 2012 In the May 2012 issue of your journal, we described an approach that uses proteomics and next-generation sequencing to identify antigen-specific antibodies directly from the serum of immunized animals, and we applied it to clone circulating antibodies to five different antigens from the serum of rabbits and mice1. Many technologies for isolating antibodies have been developed and applied to gain insight into the specific human antibody response to various pathogens, but none have directly addressed the serological response at the proteomic level2, 3, 4, 5. In addition, recent evidence from a study conducted in mice suggests that not all memory B cells contribute directly to the serological response to a pathogen6. Thus, a method capable of interrogating the composition and complexity of the circulating antibody repertoire elicited to specific vaccines or pathogens is necessary. Here, we report the application of our strategy1 to the identification and cloning of high-affinity, antigen-specific human monoclonal antibodies directly from plasma of a donor vaccinated against hepatitis B virus (HBV). We also clone potent neutralizing human monoclonal antibodies against human cytomegalovirus (HCMV) from a healthy, naturally infected individual. A key first step of our approach is the affinity purification of polyclonal material from a serum or plasma sample to enrich for monoclonal antibodies with desired functional properties. Earlier we have enriched for antibodies with high specific activity in various immunoassays such as enzyme-linked immunosorbent assay (ELISA), western blotting, immunofluorescence, flow cytometry and immunohistochemistry1. But the affinity purification can be tailored to select specifically for high-affinity interactions, potent neutralization or activity in other types of assays. Once the desired properties have been enriched, liquid chromatography tandem mass spectrometry (LC-MS/MS) is used to identify the monoclonal components of the purified fraction by matching to a reference database of antibody variable regions (V regions) produced by next-generation sequencing of the B cell immunoglobulin repertoire of the immunized animal. In contrast to work in hyperimmunized laboratory animals, translating our approach to the isolation of circulating human antibodies faces several potential challenges. For instance, in our earlier work1 we isolated B cells from the spleen of sacrificed animals, but in humans, accessing immunological organs that are highly enriched in B cells, such as the spleen, lymph nodes or even bone marrow, may not be feasible. Furthermore, in most cases humans are not hyperimmunized or maintained in a controlled environment, as would be the case for laboratory animals. In some cases, naturally exposed or convalescent donors might be the preferred or only source of polyclonal serum and B cell–derived genetic material, and therefore high-titer or adequate quantity of material could be limiting. In such cases, the immunogen is not known and thus the appropriate antigen for isolating the desired antibodies needs to be characterized before screening. As a proof of principle of our methodology (Supplementary Fig. 1), we first sought to isolate immunogen-specific antibodies from HBV-vaccinated donors. Chronic HBV infection affects >350 million people, a considerable percentage of whom succumb to hepatic failure or have a high risk of developing hepatocellular carcinoma7. HBV small surface antigen (HBsAg) is the main clinical marker indicating acute or chronic HBV infection, and the recombinant version of this protein has been widely used in vaccine formulations since 1986 (ref. 8). To investigate the serological immune response in HBV vaccine recipients, we screened plasma samples from volunteers who were recently immunized during an in-house HBV vaccination program for reactivity to recombinant HBsAg by ELISA. Of the six volunteers who had received their second HBV immunization dose 7 d before blood collection, donor C037 showed the strongest plasma γ immunoglobulin (IgG) reactivity to the antigen (step A in Supplementary Fig. 1, Supplementary Fig. 2). The vaccine-specific response of this donor was confirmed by ELISA using total IgG purified with Sepharose-conjugated protein G, in which the half-maximal effective concentration (EC50) was <10 μg ml−1. Full text : http://www.nature.com/nbt/journal/v30/n11/full/nbt.2406.html Others: http://www.nature.com/nbt/focus/sequencing2012/index.html?WT.ec_id=NBT-201210
Repost 0
Published by Chronimed - dans Concept
commenter cet article
9 novembre 2012 5 09 /11 /novembre /2012 08:01
La composition des peintures évolue. Les peintures à base de solvants sont de plus en plus souvent remplacées par des peintures aqueuses qui contiennent des conservateurs potentiellement allergisants. Une étude menée au Danemark a fait le portrait de la dermatite professionnelle des peintres en analysant les résultats des tests épicutanés pratiqués par le Groupe Danois d’Allergie de Contact entre 2001 et 2010. La profession des patients a pu être identifiée selon un code particulier dans lequel sont regroupés les peintres en bâtiment, les peintres de l’industrie navale et automobile mais aussi les artistes peintres. Chaque peintre a été apparié selon l’âge, le sexe et l’année de test à 5 autres patients témoins n’ayant pas la profession de peintre. Sur les 36 147 sujets testés entre 2001 et 2010, 219 ont été identifiés comme peintres. La dermatite de contact professionnelle s’est avérée plus fréquente chez les peintres que chez les patients témoins (p < 0,0001). La dermatite de contact était le plus souvent localisée sur les mains (58 %) puis sur le visage (16 %) et les jambes (4 %). Seul le visage était plus fréquemment atteint chez les peintres que chez les patients témoins (p < 0,0001). Les patch-tests étaient positifs pour au moins une substance chez 94 peintres (soit 43 %) et chez 409 témoins (soit 37 %). Cette différence n’était pas statistiquement significative (p = 0,12). Les allergènes donnant le plus fréquemment des réactions positives chez les peintres étaient : sulfate de nickel (15 %), méthylchloroisothiazolinone /méthylisothiazolinone (MCI/MI) (10 %), résines époxy (8 %), méthyldibromo glutaronitrile (5 %), et formaldéhyde (5 %). Certaines sensibilisations se sont avérées plus fréquentes chez les peintres que chez les patients témoins : MCI/MI (p < 0,0001), résines époxy (p < 0,0001), formaldéhyde (p = 0,003) et quaternium-15 (p = 0,004) Les peintres étaient par ailleurs fréquemment sensibilisés aux conservateurs non inclus dans la batterie standard : méthylisothiazolinone, octylisothiazolinone et benzisothiazolinone. Aucune allergie aux acrylates ou au isocyanates n’a été décelée. Isothiazolinones et résines époxy sont donc les allergènes les plus souvent incriminables chez les peintres et sont à l’origine de fréquentes dermatites de contact des mains. Dr Geneviève Démonet le 8/11/12 Mose AP et coll. : Occupational contact dermatitis in painters – an analysis of patch testdata from the Danish Contact Dermatitis Group. Contact dermatitis 2012 ; 67: 293-297.
Repost 0
Published by Chronimed - dans Concept
commenter cet article
8 novembre 2012 4 08 /11 /novembre /2012 15:09
Autisme Contexte, Causes, Symptômes L'autisme est un des cinq troubles envahissants du développement (TED), qui sont caractérisées par des anomalies généralisées des interactions sociales et de communication, et des intérêts qui sont strictement réglementés et les comportements très répétitif. L'autisme affecte traitement de l'information dans le cerveau par modification comment les cellules nerveuses et leurs synapses se connectent et s'organisent, comment ces choses viennent - n'est pas bien compris. Les objectifs principaux lors du traitement des enfants autistes sont de réduire les déficits associés et la détresse de la famille, et à améliorer la qualité de la vie et l'indépendance fonctionnelle. Aucun traitement unique est le meilleur et le traitement est généralement adapté aux besoins de l'enfant. Familles et le système éducatif sont les principales ressources pour le traitement. Cellules Souches Fœtales (CSF) dans l'Autisme Thérapie par cellules souches est une approche novatrice et efficace basé sur la capacité unique de cellules souches pour influencer le métabolisme, le système immunitaire et de restaurer les cellules et les tissus endommagés. CSF utilisé dans traitement de l'autisme a une incidence positive sur tout le corps et les organes du système, et, tout d'abord, ce traitement s'adresse le cerveau. Dans l'autisme, les zones du cerveau qui régulent la mémoire, la concentration, l’attention, discours etc sont endommagés. CSF améliorent la circulation sanguine et oxygène au cerveau (la perfusion amélioré), remplacent les neurones endommagés et stimulent la formation des nouvelles artères. Après un certain temps, CSF acquièrent des propriétés des cellules qui les entourent et se multiplient dans ces cellules, et qui font la restauration de la matière blanche et grise et, par conséquent, à de la subsidence des symptômes neurologiques et l'amélioration des capacités intellectuelles. Il a été prouvé que les cellules souches mésenchymateuses améliorent le système immunitaire et arrêtent l'inflammation. Stimulation de CD34 formation des artères nouvelles dans les tissus hypoxiques augmente le flux sanguin dans le lobe temporal et d'autres parties du cerveau. Nous avons traité environ 100 enfants autistes avec des cellules souches méso-etectodermiques récoltés de foetus à partir de 5-10 semaines de gestation, testés et certifiés par l'Etat. Ces cellules sont non-différenciée, et lorsqu'ils sont administrés à un pattient, ils se différencient en types de cellules nécessaires à l'organisme (neurones, les oligodendrocytes, des cellules du sang, etc). Thérapie par cellules souches s'adresse plusieurs aspects de préoccupation: • L'immunité • Le métabolisme • La capacité de communication • La capacité d'apprentissage, la mémoire, la pensée (amélioration grâce à la restauration des connexions neuronales perdues (avec facultés affaiblies) et la formationdes connexions neuronales nouvelles, ce qui accélère les réactions du cerveau grâce à l'amélioration de la transmission synaptique et le développement des connexions neuronales nouvelles) Améliorations attendues chez les enfants autistes: 1. Une meilleure tolérance de différents aliments et une meilleure digestion. Certains enfants commencent à essayer de nouveaux aliments et les aimer. 2. Faciliter le contact avec l'enfant (tout d'abord, contact avec les yeux). Les enfants quin'ont pas été, fixant leur regard sur les objets commencent à les regarder avec intérêt. 3. Un comportement plus adéquat à la maison et à l'extérieur. 4. Moins ou pas peur des bruits forts, des étrangers et des couleurs vives (amélioration progressive). 5. Amélioration des aptitudes verbales (si l'enfant est non-verbale, il / elle est trèssusceptible de commencer à faire des sons, des syllabes, puis prononcer les mots; plusdu vocabulaire chez les enfants verbales) 6. L'amélioration des compétences d'écriture ou de développement. 7. Amélioration des soins auto-administrés compétences. 8. Amélioration de la capacité d'attention et de concentration. Un des objectifs principaux de la thérapie de cellules souches est le déclenchement du développement du cerveau, puis le corps de l'enfant fera son propre travail. Les enfants doivent être heureux, et les parents sont pour les préparer à la vie adulte heureuse en développant les compétences dont ils auront besoin le plus, comme la communication, l'auto-soins, les compétences éducatives et professionnelles. Bien que le degré des améliorations ci-dessus varie, ils ont été signalés dans tous les cas. Afin d'être heureux, personne autiste doit avoir: 1. Le sentiment que sa vie est bien planifié. 2. Bien adaptée système de communication. 3. Compétences d'auto-soins. 4. Capacité de étudier et travailler. 5. Compétences / Capacité de loisirs. 6. Les compétences en communication (et être heureux de communiquer avec les gens). Thérapie par cellules souches est une méthode efficace et sûre de traitement de l'autisme et peut aider de enfants nombreux atteints d'autisme et de troubles du spectre autistique de degré différent. Cependant, la thérapie cellulaire est le dessert, mais pas le plat principal, et le traitement intégré (alimentation, le programme éducatif) est recommandé pour des résultats optimaux. Le plus tôt l'autisme est diagnostiqué et le plus tôt les parents commencent à aider l'enfant, y compris la thérapie de cellules souches, le plus de chance que l'enfant doit être heureux! Témoignages Tous les ci-dessus sont la théorie et les faits, et au-dessous des commentaires des parents de leur expérience et les améliorations qu'ils voient dans leurs enfants, et ces mots sont plus touchante et vraie que n'importe quelle théorie. Patient V.S. de Serbia Patient A.L. des Etats-Unis Patient D.P. de Serbia Patient T. des Émirats Arabes Unis Patient E.D. des Etats-Unis Patient D.S. des États-Unis Patient K.S. de Suède Patient J.G., la Grande-Bretagne Patient K.C. des Etats-Unis Patient G.O. du Canada
Repost 0
Published by Chronimed - dans Concept
commenter cet article
8 novembre 2012 4 08 /11 /novembre /2012 08:22
European Journal of Clinical Nutrition 66, 1234-1241 (November 2012) Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteri NCIMB 30242: a randomized controlled trial M L Jones, C J Martoni and S Prakash Abstract Background/Objectives: The percentage of hypercholesterolemic individuals not reaching their LDL-cholesterol (LDL-C) goal remains high and additional therapeutic strategies should be evaluated. The objective of this study was to evaluate the cholesterol-lowering efficacy and mechanism of action of bile salt hydrolase-active Lactobacillus reuteri NCIMB 30242 capsules in hypercholesterolemic adults. Subjects/Methods: A total of 127 subjects completed a randomized, double-blind, placebo-controlled, parallel-arm, multicenter study. Subjects were randomized to consume L. reuteri NCIMB 30242 capsules or placebo capsules over a 9-week intervention period. The primary outcome was LDL-C relative to placebo at the study end point. Results: L. reuteri NCIMB 30242 capsules reduced LDL-C by 11.64% (P<0.001), total cholesterol by 9.14%, (P<0.001), non-HDL-cholesterol (non-HDL-C) by 11.30% (P<0.001) and apoB-100 by 8.41% (P=0.002) relative to placebo. The ratios of LDL-C/HDL-cholesterol (HDL-C) and apoB-100/apoA-1 were reduced by 13.39% (P=0.006) and 9.00% (P=0.026), respectively, relative to placebo. Triglycerides and HDL-C were unchanged. High-sensitivity C-reactive protein and fibrinogen were reduced by 1.05 mg/l (P=0.005) and 14.25% (P=0.004) relative to placebo, respectively. Mean plasma deconjugated bile acids were increased by 1.00 nmol/l (P=0.025) relative to placebo, whereas plasma campesterol, sitosterol and stigmasterol were decreased by 41.5%, 34.2% and 40.7%, respectively. Conclusions: The present results suggest that the deconjugation of intraluminal bile acids results in reduced absorption of non-cholesterol sterols and indicate that L. reuteri NCIMB 30242 capsules may be useful as an adjunctive therapy for treating hypercholesterolemia.
Repost 0
Published by Chronimed - dans Nutrition
commenter cet article
8 novembre 2012 4 08 /11 /novembre /2012 08:17
European Journal of Clinical Nutrition 66, 1187-1192 (November 2012) | doi:10.1038/ejcn.2012.105 Neural effects of green tea extract on dorsolateral prefrontal cortex S Borgwardt, F Hammann, K Scheffler, M Kreuter, J Drewe and C Beglinger Abstract Background/objectives: Green tea is being recognized as a beverage with potential benefits for human health and cognitive functions. In vivo studies provide preliminary evidence that green tea intake may have a positive role in improving effects on cognitive functions. We aimed to examine the neural effects of green tea extract on brain activation in humans. Subjects/methods: Functional magnetic resonance imaging was recorded while 12 healthy volunteers performed a working memory task following administration of 250 or 500 ml of a milk whey based green tea containing soft drink or milk whey based soft drink without green tea as control in a double-blind, controlled repeated measures within-subject design with counterbalanced order of substance administration. A whole-brain analysis with a cluster-level threshold of P<0.001 (unadjusted) was followed by an a priori-defined region of interest (ROI) analysis of the dorsolateral prefrontal cortex (DLPFC) including a cluster-level threshold of P<0.05 and family-wise error (FWE) adjustment for multiple comparisons. Results: Whole-brain analyses revealed no significant effects after correction for multiple comparisons (FWE P<0.05). Using a ROI approach, green tea extract increased activation in the DLPFC relative to a control condition (FWE P<0.001). This neural effect was related to green tea dosage. Green tea extract was not associated with any significant attenuation in regional activation relative to control condition. Conclusions: These data suggest that green tea extract may modulate brain activity in the DLPFC, a key area that mediates working memory processing in the human brain. Moreover, this is the first neuroimaging study implicating that functional neuroimaging methods provide a means of examining how green tea extract acts on the brain.
Repost 0
Published by Chronimed - dans Nutrition
commenter cet article
8 novembre 2012 4 08 /11 /novembre /2012 08:13
European Journal of Clinical Nutrition (2012) 66, 1182–1186; doi:10.1038/ejcn.2012.135; published online 3 October 2012 Magnesium intake and risk of colorectal cancer: a meta-analysis of prospective studies G-C Chen1, Z Pang2 and Q-F Liu1 1Department of Epidemiology, School of Public Health, Soochow University, Suzhou, China 2Department of Gastroenterology, Suzhou Municipal Hospital (North Campus), Suzhou, China Correspondence: Professor Q-F Liu, Department of Epidemiology, School of Public Health, Soochow University, 199 Renai Road, Dushu Lake Higher Education Town, Suzhou 215123, China. E-mail: lsguorong@126.com Received 25 May 2012; Revised 7 August 2012; Accepted 3 September 2012 Advance online publication 3 October 2012 Top of page Abstract Epidemiologic studies have suggested that magnesium intake may be associated with a decreased risk of colorectal cancer (CRC), but the findings have been inconsistent. We aimed to assess this association by conducting a meta-analysis of prospective studies. We performed a literature search on PubMed database through July 2012 to identify prospective studies of magnesium intake in relation to CRC risk. Reference lists of the retrieved articles were also reviewed. A random-effects model was used to compute the summary risk estimates. Eight prospective studies containing 338 979 participants and 8000 CRC cases met the inclusion criteria. The summary relative risk (RR) for the highest vs lowest category of magnesium intake for CRC was 0.89 (95% CI, 0.79–1.00), with little evidence of heterogeneity. Restricting the analysis to six studies that have adjusted for calcium intake yielded a similar result. For colon and rectal cancer, the pooled RR was 0.81 (95% CI, 0.70–0.93) and 0.94 (95% CI, 0.72–1.24), respectively. In the dose–response analyses, the summary RRs for an increment of magnesium intake of 50 mg/day for colorectal, colon and rectal cancer were, respectively, 0.95 (95% CI, 0.89–1.00), 0.93 (95% CI, 0.88–0.99) and 0.93 (95% CI, 0.83–1.04), and there was some evidence of heterogeneity; omitting one study that substantially contributed to the heterogeneity yielded generally similar results, but with low heterogeneity. We detected no indication of publication bias. On the basis of the findings of this meta-analysis, a higher magnesium intake seems to be associated with a modest reduction in the risk of CRC, in particular, colon cancer. Keywords: prospective studies; colorectal cancer; magnesium; meta-analysis Top of page Introduction Colorectal cancer (CRC) comprises at least 13% of all cancer patients in Europe, and remains the third most common type of cancer in the United States.1, 2 Diet and lifestyle factors have an important role in the etiology of CRC, and a large proportion of CRC incidence might be prevented by a healthy lifestyle.3, 4 However, a limited number of dietary factors were identified to be associated with the risk of CRC. Magnesium is abundant in many foods and is involved in a wide variety of biochemical reactions that modulate key cell functions, such as proliferation, differentiation, migration and apoptosis.5, 6 It also has a crucial role in genetic stability and DNA synthesis.7 In animal experiments, supplemental magnesium has been demonstrated to reduce the incidence of colon cancer, possibly by means of inhibition of c-myc oncogene expression in the colon cancer cells.8, 9, 10, 11 Intake of magnesium has also been reported to reduce the risk of type 2 diabetes,12 a potential risk factor for CRC.13, 14, 15 In addition, a recently published randomized controlled study reported that magnesium treatment significantly decreased fasting C-peptide concentrations.16 Multiple lines of evidence have suggested that high circulating concentrations of C-peptide, a marker for insulin secretion, are associated with an increased risk of CRC in humans.17, 18 This raised the hypothesis that intake of magnesium may decrease the risk of CRC by improving insulin sensitivity and decreasing insulin levels. Evidence from epidemiologic studies has also suggested that intake of magnesium may be associated with a reduction in the risk of CRC, but the findings have been inconsistent.19, 20, 21, 22, 23, 24, 25, 26 The purpose of this study was to examine the relationship between magnesium intake and the risk of CRC by undertaking a meta-analysis of prospective studies. We attempted to plan, conduct and report this meta-analysis in adherence to the guidelines of the ‘Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group'.27 Materials and methods Search strategy We performed a literature search through July 2012 on PubMed database using the following search terms: magnesium; cancer, colorectal cancer, colorectal neoplasms, colon, rectum; and cohort study, prospective study, follow-up study. No language restrictions were imposed. In addition, we also comprehensively reviewed the reference lists of the retrieved articles to identify additional studies. Study selection Studies were included if they met the following criteria: (i) the study design was prospective cohort or case–cohort or nested case-control; (ii) the exposure of interest was intake of dietary magnesium or total magnesium (dietary and supplements combined); (iii) the outcome of interest was colorectal, colon or rectal cancer and (iv) the relative risk (RR) estimates (or odds ratios (OR) in nested case–control studies) with corresponding 95% confidence interval (CI) were provided, or could be calculated using the raw data presented in the studies. First, the titles and abstracts of the relevant studies were reviewed, and then the full papers of potentially eligible studies were obtained. Data extraction and quality assessment The following data were extracted from each included eligible study using a standardized report form: author name, publication year, length of follow-up, study location, the sex of participants, the age range of participants, number of cases and participants (cases and controls or cohort size), the measure of exposure, the range of exposure, exposure assessment method, variables adjusted for in the analysis, the RR or OR of CRC and the corresponding 95% CIs for each category of magnesium intake. We extracted the maximally adjusted RR or OR with the corresponding 95% CI for the highest vs lowest category of magnesium intake for use in the main analyses. We did not assess the study quality using a quality score. Instead, we reported some characteristics of the included studies that are the indicators of study quality,27 such as the numbers of cases and participants, duration of follow-up, assessments of exposure and adjustment for potential confounding factors. Data extraction was conducted independently by two authors (G-CC and ZP), with any disagreements resolved by consensus. Statistical analysis We used a DerSimonian and Laird random-effects model,28 which considers both within- and between-study variation to calculate the summary risk estimate. Because the outcomes were relatively rare, the ORs in a nested case–control study25 were considered to be approximations of RRs. One study21 presented results for both dietary and total magnesium intakes (dietary and supplements combined); we used the results for dietary magnesium in the primary analyses for better comparability between studies. We also attempted to investigate the association of magnesium with CRC risk by colorectal subsites, by sex, anatomical subsites of the colon and also by body mass index (BMI), if possible. We also conducted a dose-response analysis by using the method proposed by Greenland and Longnecker29 and Orsini et al.30 This method requires that the number of cases, person-years (or controls in a nested case–control study) and the risk estimates with their variance estimates for at least three quantitative exposure categories are known. For one study20 that did not present the number of cases and person-years in each exposure category, we used the variance-weighted least square regression model to estimate the slopes. For each study, the median or mean level of magnesium intake for each category was assigned to each corresponding RR estimate. When the median or mean intake per category was not provided, we assigned the midpoint of the upper and lower boundaries in each category as the average intake. If the highest or lowest category was open-ended, we assumed the width of the interval to be the same as in the closest category. We presented the results of linear dose–response for an increment of 50 mg/day. Heterogeneity test was performed by using Q and I2 statistics.31 For the Q statistic, a P-value of <0.1 was considered statistically significant heterogeneity. Potential publication bias was investigated by the use of Begg’s funnel plots and Egger’s regression asymmetry test.32 All statistical analyses were done using STATA software, version 11.0 (STATA, College Station, TX, USA). All P-values are two-sided and the level of significance was <0.05, unless explicitly stated. Top of page Results Study characteristics A flowchart showing the process of study selection is shown in Figure 1. Our literature search identified eight eligible prospective studies (seven cohort studies and one nested case–control study25), which contained a total of 338 979 participants and 8000 CRC cases. Characteristics of the included studies are shown in Table 1. These studies were published between 2005 and 2012. Three of the eight studies were conducted in the United States, four in Europe and one in Japan. Four studies included both men and women, and the other four studies consisted of women only. The follow-up durations of the prospective cohort studies ranged from 7.9 to 28 years. All studies provided multivariable risk estimates for CRC, six studies for both colon and rectal cancer. Figure 1. Flow chart showing the process of study selection. Full figure and legend (57K) Table1 - Characteristics of eight prospective studies on magnesium intake and colorectal cancer. Full table Most studies used a validated food-frequency questionnaire (FFQ) in exposures assessment; one study25 used food diaries. Age and total energy intake were adjusted for in all included studies and most studies additionally adjusted for BMI (N=7), physical activity (N=7), vitamin D or multivitamin use (N=7), calcium use (N=6), smoking status (N=6), alcohol consumption (N=6), dietary fiber intake (N=5) and folate use (N=5). Magnesium intake and CRC The pooled analysis of all studies showed that the summary RR of CRC for the highest vs lowest category of magnesium intake was 0.89 (95% CI, 0.79–1.00). The association was statistically significant (P-trend=0.045), with no heterogeneity (Figure 2). Figure 2. Pooled random-effects RR (95% CI) of colorectal cancer risk comparing the highest with the lowest category of magnesium intake. Full figure and legend (66K) On repeating the analysis by omitting the only nested case–control study,25 which adjusted for the smallest number of confounding factors, the summary was 0.87 (95% CI, 0.77–0.99) and the association was statistically significant (P-trend=0.031), with no heterogeneity (P=0.43, I2=0.0%). One study21 presented results for both dietary and total magnesium intakes. If the results for total magnesium were used in the pooled analysis, the summary RR was 0.89 (95% CI, 0.79–1.00) and the association was statistically significant (P-trend=0.048), with no heterogeneity (P=0.46, I2=0.0%). A high calcium intake has been demonstrated to reduce the absorption of both calcium and magnesium.33 Hence, we further examined the association of magnesium intake with the risk of CRC by removing two studies21, 25 that have not adjusted for calcium intake. After that, the summary RR was 0.87 (95% CI, 0.75–1.00) and the association was statistically significant (P-trend=0.046), with low heterogeneity (P=0.34, I2=12.1%). The summary RR of six19, 20, 21, 22, 23, 26 studies for women was 0.86 (95% CI: 0.75–0.99), with no heterogeneity (P=0.67; I2=0.0%); only two studies22, 23 provided results for men. Six19, 20, 21, 22, 23, 26 of the eight studies also conducted site-specific analyses. For these studies, the pooled RRs for colon and rectal cancer were, respectively, 0.81 (95% CI, 0.70–0.93) and 0.94 (95% CI, 0.72–1.24). Little evidence of heterogeneity was observed in these analyses. Three studies19, 22, 23 also presented results on anatomical subsites of colon cancer. The summary RRs for proximal and distal colon cancer were 0.73 (95% CI, 0.53–1.01) and 0.79 (95% CI, 0.44–1.43), respectively. Three studies22, 23, 26 also presented the risk estimates, stratifying by BMI. For these studies, the pooled RRs were 0.87 (95% CI, 0.54–1.41) for those with a BMI <25 kg/m2 and 1.08 (95% CI, 0.77–1.51) for those with a BMI 25 kg/m2. Dose–response analysis of the primary studies showed that the summary RRs for an increase in magnesium intake of 50 mg/day for colorectal, colon and rectal cancer were, respectively, 0.95 (95%CI, 0.89–1.00; N=8), 0.93 (95%CI, 0.88–0.99; N=6) and 0.93 (95%CI, 0.83–1.04; N=6). There was some evidence of heterogeneity (P=0.05, 0.17 and 0.04, respectively; I2=49.3%, 33.3% and 54.9%, respectively). In the sensitivity analyses, in which one study at a time was removed and the rest pooled, we found that the study by Larsson et al.19 substantially contributed to the heterogeneity among studies. After excluding this study, the summary RRs for colorectal, colon and rectal cancer were 0.96 (95% CI, 0.92–1.00), 0.94 (95% CI, 0.89–0.99) and 0.99 (95% CI, 0.92–1.06), respectively, with little or no evidence of heterogeneity observed (P=0.30, 0.22 and 0.46, respectively; I2=16.0, 28.6 and 0.0%, respectively). Publication bias Begg’s funnel plots suggested the absence of asymmetry, with regard to colorectal, colon or rectal cancer in relation to magnesium intake. This was corroborated by the P-value for Egger regression asymmetry test (all P-values >0.45). Top of page Discussion Findings from this meta-analysis of prospective studies, including more than 8000 CRC cases, indicate that a high magnesium intake may provide a modest protection against CRC risk. The reduction in risk is 11% (95% CI, 0–21%) for the highest vs lowest category of magnesium intake and, on average, 5% (95%CI, 0–11%) for each additional 50 mg/day increase in magnesium intake. The observed beneficial effect of magnesium intake against CRC appeared to be independent of calcium intake and restricted to colon cancer only. One case–control study from France showed that CRC cases had a lower intake of magnesium compared with the controls, but the difference was not significant after adjusting for other nutrients.34 Several subsequent case–control studies have yielded inconsistent results on the relationship between magnesium intake and the risk of CRC, with both inverse35 and null associations suggested.36, 37 Another large case–control found that total magnesium intake was linked to a significant lower risk of colorectal adenoma, particularly in those subjects with a low ratio of calcium:magnesium.38 Studies of a case–control design were subject to biases such as recall and selection, because lifestyles and diet habits in retrospective case–control studies are determined after the diagnosis of cancer. The major strengths of this meta-analysis were that all included studies were of a prospective design, which eliminates the possibility of recall and selection biases. Furthermore, most studies had a long duration of follow-up and a large number of CRC cases. These features of the study enhanced the statistical power to assess the long-term effects of magnesium intake on CRC risk. This meta-analysis also has several limitations. First, as a meta-analysis of epidemiological studies, it is not able to solve the problem of confounding that is universal in the included studies. We cannot entirely rule out the possibility of some confounding factors as a potential explanation for the observed findings. However, most of the included studies have adjusted for major potential confounders. Omitting the only nested case–control study adjusting for the smallest number of confounders or excluding the studies that have not adjusted for calcium intake did not materially alter the summary risk estimate. A second limitation was that most included studies assessed diet with a FFQ, and all but two studies25, 26 assessed magnesium intake only at baseline. This could introduce measurement error and lead to a misclassification of exposure. As an instrument to quantify nutrient intakes, FFQ is relatively rough, even though most FFQs have been validated before application. Another source of misclassification of exposure is that magnesium intake from water, which would be about 1–30 mg/day, as estimated by Larsson et al.,39 has not been taken as a source of magnesium into account. Although misclassification will not create false associations, it would tend to reduce possible real association toward the null. Therefore, the observed reduction in CRC risk is possibly a conservative estimate. Third, we were not able to assess the impact of magnesium from supplement use on CRC risk, because current data of this aspect are scanty. Among the participants in the included studies, supplement magnesium only accounts for a small proportion of total magnesium intake. For instance, magnesium from supplement contributes <8% of total magnesium in the Nurses’ Health Study, 3 and the corresponding figure in the Iowa Women’s Health Study was <5%;20 moreover, in the Netherlands cohort study, only 0.2% individuals used magnesium supplement. Fourth, subgroup analyses to test the possible impact of geographic areas and years of follow-up were not conducted due to the limited numbers of studies. Finally, given that our meta-analysis was based on published studies, publication bias that results from a tendency to publish only positive results also merits consideration. In this meta-analysis, little indication of such bias was detected. In summary, findings from this meta-analysis of prospective studies suggest that a higher or increased intake of magnesium may help to mildly reduce the risk of CRC, in particular colon cancer. Given the observed association of magnesium intake with CRC risk is of borderline significance, the findings are required to be confirmed by more large prospective studies.
Repost 0
Published by Chronimed - dans Nutrition
commenter cet article
8 novembre 2012 4 08 /11 /novembre /2012 08:08
Traitement oral de la fibrose hépatique avec un virus ADN recombinant associé à BMP-7 (animal en Anglais) Molecular Therapy 20, 2043-2051 (November 2012) | doi:10.1038/mt.2012.148 Oral Administration of Recombinant Adeno-associated Virus-mediated Bone Morphogenetic Protein-7 Suppresses CCl4-induced Hepatic Fibrosis in Mice Zhi-Ming Hao, Min Cai, Yi-Fei Lv, Yan-Hua Huang and Hong-Hong Li Fibrogenesis and hepatocyte degeneration are the main pathological processes in chronic liver diseases. Transforming growth factor-β1 (TGF-β1) is the key profibrotic cytokine in hepatic fibrosis. Bone morphogenetic protein-7 (BMP-7) is a potent antagonist of TGF-β1 and an antifibrotic factor. In this study, we generated a recombinant adeno-associated virus carrying BMP-7 (AAV–BMP-7) and tested its ability to suppress carbon tetrachloride (CCl4)-induced hepatic fibrosis when orally administered to mice. Our results show that the ectopic expression of BMP-7 in gastrointestinal (GI) mucosa due to the AAV–BMP-7 administration led to the long-term elevation of serum BMP-7 concentrations and resulted in the drastic amelioration of CCl4-induced hepatic fibrosis in BALB/c mice. Immunostaining for α-smooth muscle actin (α-SMA) and desmin demonstrated that AAV–BMP-7 inhibited the activation of hepatic stellate cells (HSCs) in the fibrotic mouse liver. Moreover, the ectopic expression of BMP-7 promoted hepatocyte proliferation, as confirmed by an increase in the amount of proliferating cell nuclear antigen (PCNA)-positive hepatocytes in the mice that received AAV–BMP-7. Our results clearly indicate that BMP-7 is capable of inhibiting hepatic fibrosis and promoting hepatocyte regeneration. We suggest that oral AAV–BMP-7 could be developed into a safe, simple, and effective therapy for hepatic fibrosis.
Repost 0
Published by Chronimed - dans Concept
commenter cet article
8 novembre 2012 4 08 /11 /novembre /2012 08:00
Molecular Therapy 20, 2010-2011 (November 2012) | doi:10.1038/mt.2012.218 RNAi Joins the “Singles Club” Veronica J. Peschansky, Zicai Liang and Claes Wahlestedt Abstract One of our greatest opportunities in modern medicine is to develop therapies by targeting the body’s very own genetic material. For illnesses characterized by loss-of-function phenotypes, we are tasked with increasing gene expression.
Repost 0
Published by Chronimed - dans Concept
commenter cet article