Health outcomes of iron supplementation and/or food fortification in iron-replete children aged 4-24 months: Protocol for a systematic review and meta-analysis

© 2019 The Author(s). Background: Direct supplementation or food fortification with iron are two public health initiatives intended to reduce the prevalence of iron deficiency (ID) and iron deficiency anaemia (IDA) in 4-24-month-old infants. In most high-income countries where IDA prevalence is 40%. Emerging concerns about delayed neurological effects of early-life iron overexposure have raised questions as to whether recommended guidelines in high-income countries are unnecessarily excessive. This systematic review will gather evidence from supplementation/fortification trials, comparing health outcomes in studies where iron-replete children did or did not receive additional dietary iron; and determine if replete children at study outset were not receiving additional iron show changes in haematological indices of ID/IDA over the trial duration. Methods: We will perform a systematic review of the literature, including all studies of iron supplementation and/or fortification, including study arms with confirmed iron-replete infants at the commencement of the trial. This includes both dietary iron intervention or placebo/average dietary intakes. One reviewer will conduct searches in electronic databases of published and ongoing trials (Medline, Web of Science, Scopus, CENTRAL, EBSCO [e.g. CINAHL Complete, Food Science and Technology Abstracts], Embase, ClinicalTrials.gov, ClinicalTrialsRegister.eu and who.it/trialsearch), digital theses and dissertations (WorldCat, Networked Digital Library of Theses and Dissertations, DART-Europe E-theses Portal, Australasian Digital Theses Program, Theses Canada Portal and ProQuest). For eligible studies, one reviewer will use a data extraction form, and a second reviewing entered data for accuracy. Both reviewers will independently perform quality assessments before qualitative and, if appropriate, quantitative synthesis as a meta-analysis. We will resolve any discrepancies through discussion or consult a third author to resolve discrepancies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement will be used as the basis for reporting. Discussion: Recommended iron supplementation and food fortification practices in high-income countries have been criticised for being both excessive and based on outdated or underpowered studies. This systematic review will build a case for revisiting iron intake guidelines for infants through the design of new trials where health effects of additional iron intake in iron-replete infants are the primary outcome. Systematic review registration: PROSPERO CRD42018093744

Arachidonic Acid but not Eicosapentaenoic Acid (EPA) and Oleic Acid Activates NF-κB and Elevates ICAM-1 Expression in Caco-2 Cells

In patients with inflammatory bowel disease (IBD), intestinal activation of the transcription factor NF-κB as well as intercellular adhesion molecule (ICAM)-1 expression, which is involved in recruiting leukocytes to the side of inflammation is increased. Moreover, colonic arachidonic acid (ARA) proportions are increased and oleic acid (OA) proportions are decreased. Fish oils are protective in IBD patients however, a side-by-side comparison between effects of fish oils, ARA and OA has not been made. We therefore, compared effects of eicosapentaenoic acid (EPA) versus ARA and OA on ICAM-1 expression in Caco-2 enterocytes. To validate our model we showed that dexamethasone, sulfasalazine and PPARα (GW7647) or PPARγ (troglitazone) agonists significantly lowered ICAM-1 expression. ICAM-1 expression of non-stimulated and cytokine stimulated Caco-2 cells cultured for 22 days with ARA was significant higher as compared to EPA and OA. Furthermore, ARA increased NF-κB activation in a reporter cell-line as compared to EPA. Antibody array analysis of multiple inflammatory proteins particularly showed an increased monocyte chemotactic protein (MCP)-1 and angiogenin production and a decreased interleukin (IL)-6 and IL-10 production by ARA as compared to EPA. Our results showed that ARA but not EPA and OA activates NF-κB and elevates ICAM-1 expression in Caco-2 enterocytes. It suggests that replacement of ARA by EPA or OA in the colon mucosa might have beneficial effects for IBD patients. Finally, we suggest that the pro-inflammatory effects of ARA versus EPA and OA are not related to PPARγ activation and/or eicosanoid formation

Could lymphatic mapping and sentinel node biopsy provide oncological providence for local resectional techniques for colon cancer? A review of the literature

<p>Abstract</p> <p>Background</p> <p>Endoscopic resectional techniques for colon cancer are undermined by their inability to determine lymph node status. This limits their application to only those lesions at the most minimal risk of lymphatic dissemination whereas their technical capacity could allow intraluminal or even transluminal address of larger lesions. Sentinel node biopsy may theoretically address this breach although the variability of its reported results for this disease is worrisome.</p> <p>Methods</p> <p>Medline, EMBASE and Cochrane databases were interrogated back to 1999 to identify all publications concerning lymphatic mapping for colon cancer with reference cross-checking for completeness. All reports were examined from the perspective of in vivo technique accuracy selectively in early stage disease (i.e. lesions potentially within the technical capacity of endoscopic resection).</p> <p>Results</p> <p>Fifty-two studies detailing the experiences of 3390 patients were identified. Considerable variation in patient characteristics as well as in surgical and histological quality assurances were however evident among the studies identified. In addition, considerable contamination of the studies by inclusion of rectal cancer without subgroup separation was frequent. Indeed such is the heterogeneity of the publications to date, formal meta-analysis to pool patient cohorts in order to definitively ascertain technique accuracy in those with T1 and/or T2 cancer is not possible. Although lymphatic mapping in early stage neoplasia alone has rarely been specifically studied, those studies that included examination of false negative rates identified high T3/4 patient proportions and larger tumor size as being important confounders. Under selected circumstances however the technique seems to perform sufficiently reliably to allow it prompt consideration of its use to tailor operative extent.</p> <p>Conclusion</p> <p>The specific question of whether sentinel node biopsy can augment the oncological propriety for endoscopic resective techniques (including Natural Orifice Transluminal Endoscopic Surgery [NOTES]) cannot be definitively answered at present. Study heterogeneity may account for the variability evident in the results from different centers. Enhanced capacity (perhaps to the level necessary to consider selective avoidance of en bloc mesenteric resection) by its confinement to only early stage disease is plausible although not proven. Specific study of the technique in early stage tumors is clearly essential before proffering this approach.</p

AAV ancestral reconstruction library enables selection of broadly infectious viral variants

Adeno-associated virus (AAV) vectors have achieved clinical efficacy in treating several diseases. Enhanced vectors are required to extend these landmark successes to other indications, however, and protein engineering approaches may provide the necessary vector improvements to address such unmet medical needs. To generate new capsid variants with potentially enhanced infectious properties, and to gain insights into AAV’s evolutionary history, we computationally designed and experimentally constructed a putative ancestral AAV library. Combinatorial variations at 32 amino acid sites were introduced to account for uncertainty in their identities. We then analyzed the evolutionary flexibility of these residues, the majority of which have not been previously studied, by subjecting the library to iterative selection on a representative cell line panel. The resulting variants exhibited transduction efficiencies comparable to the most efficient extant serotypes, and in general ancestral libraries were broadly infectious across the cell line panel, indicating that they favored promiscuity over specificity. Interestingly, putative ancestral AAVs were more thermostable than modern serotypes and did not utilize sialic acids, galactose, or heparan sulfate proteoglycans for cellular entry. Finally, variants mediated 19–31 fold higher gene expression in muscle compared to AAV1, a clinically utilized serotype for muscle delivery, highlighting their promise for gene therapy