HAADF imaging of the Al-containing high Al-affinity silica polymer.

<p>Higher resolution high angle annular dark field (HAADF) imaging of the air-dried, 48-h aged, dilute Al(III) and the high Al affinity silica polymer containing-solution (8 µM Al(III), 320 µM Si, pH 7.2) by aberration corrected scanning transmission electron microscopy (SuperSTEM) confirmed the presence of an amorphous gel with ~ 4 nm particulates (A) that are crystalline in nature (B). (C & D) Show false colour elemental maps where the Al (<i>L</i>_2,3-edge) EELS elemental map has been colored green and the Si (<i>L</i>_2,3-edge) has been colored red and the two overlaid. From this it is clear that Al is confined to the particulates and there is little or no Al in the gel. (E) Shows a series of Al and Si <i>L</i>_<i>2,3</i>-edges obtained following a line-scan across a particle (inserted image), confirming little Al in the gel (black line spectra), higher levels in the particle and the presence of Si in the particle (spectra on the particle are colored red). </p

Aluminum binding by human apotransferrin.

<p>(A) UV absorption spectra (220–320 nm) of human apo-transferrin (1.28 mg/mL) in 25 mM sodium bicarbonate and 50 mM MOPS buffer (pH 7.4), titrated with increasing concentrations of Al(III) in the form of Al(NTA)₂. The appearance of a peak (absorbance maxima) at 240 nm was obtained with increasing concentrations of Al(III). A lesser peak between 285–300 nm and a trough between 250–285 nm were also present at the higher Al(III) concentrations. 1.28 mg/mL human apo-transferrin in 25 mM sodium bicarbonate and 50 mM MOPS buffer (pH 7.4) was used as reference. (B) The absorbance maxima at 240 nm was extracted (from A), corrected for variation in baseline/background at 320 nm and plotted against Al(III) concentration. Results are the mean (± SD) of three experiments. Dotted line shows the calculated point of transferrin saturation.</p

Comparison of Al binding affinity of the high-Al affinity silica polymer with commercial Ludox colloids.

<p>(A) Competitive binding of Al(III), from the DMHP-Al complex (8 µM, pH 7.2), by the high Al affinity silica polymer (HSP) and the commercial Ludox silica colloids was assessed at 274 nm by measuring the amount of free DMHP liberated in solution. These results suggest a relationship between Al binding affinity and particle size as SM30 (7 nm) had higher/greater affinity than LS30 (12 nm), which in turn had greater affinity than TM50 (22 nm). (B) To correct for differences in particle size, the Al binding curves for the Ludox silica colloids were re-plotted in terms of total surface area. The red line shows the best fit through the data points. From (A) it was estimated that our polymeric silica was 2.91 times smaller than the smallest Ludox colloid, SM30 (7 nm). This estimate for polymeric silica was confirmed in (C), upon re-plotting the Al binding curve in terms of surface area (squares). The red line shows the best fit line for the Ludox silica colloids (as shown in (B)). Results are the mean (± SD) of two experiments in triplicate.</p

Atomic lattice spacing of the Al-rich silica-containing nanoparticles.

<p>A histogram of lattice plane spacing measured (to the nearest 0.1 Å) from 49 individual crystallites (Al rich silica-containing nanoparticles; ASP) in 12 HAADF-STEM and BF-TEM images. Insert: shows measurement of the lattice spacing in a STEM image (from Figure 5B). Comparison of measured lattice spacing to standard X-ray diffraction data, taken from the International Crystal Diffraction Database (ICDD), produced no clear match to a specific phase (see text). </p

Competition between high-Al affinity silica polymer and human apotransferrin for Al binding.

<p>Competition studies with human apotransferrin. The Al-transferrin complex (40 µM Al(III) and 1.28 mg/mL apo-transferrin) was titrated with the high Al affinity silica polymer (HSP, squares) and monomeric silica (circles) at pH 7.4 (25 mM sodium bicarbonate and 50 mM MOPS buffer). The concentration of Al-transferrin complex in solution was measured at its absorbance maxima at 240 nm and corrected for variation in baseline/background at 320 nm. To determine the amount of Al(III) displaced and bound by HSP or monomeric silica, the concentration of Al-transferrin complex in solution at the different silica concentrations (‘A’) was subtracted from the initial/starting concentration of the Al₂-transferrin complex in solution (A₀). Results are mean ± SD of three experiments. The dotted line indicates the onset of silica polymerization [14].</p

Ferrous Sulfate Supplementation Causes Significant Gastrointestinal Side-Effects in Adults: A Systematic Review and Meta-Analysis

<div><p>Background</p><p>The tolerability of oral iron supplementation for the treatment of iron deficiency anemia is disputed.</p><p>Objective</p><p>Our aim was to quantify the odds of GI side-effects in adults related to current gold standard oral iron therapy, namely ferrous sulfate.</p><p>Methods</p><p>Systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GI side-effects that included ferrous sulfate and a comparator that was either placebo or intravenous (IV) iron. Random effects meta-analysis modelling was undertaken and study heterogeneity was summarised using <i>I²</i> statistics.</p><p>Results</p><p>Forty three trials comprising 6831 adult participants were included. Twenty trials (n = 3168) had a placebo arm and twenty three trials (n = 3663) had an active comparator arm of IV iron. Ferrous sulfate supplementation significantly increased risk of GI side-effects versus placebo with an odds ratio (OR) of 2.32 [95% CI 1.74–3.08, <i>p</i><0.0001, <i>I²</i> = 53.6%] and versus IV iron with an OR of 3.05 [95% CI 2.07-4.48, <i>p</i><0.0001, <i>I²</i> = 41.6%]. Subgroup analysis in IBD patients showed a similar effect versus IV iron (OR = 3.14, 95% CI 1.34-7.36, <i>p</i> = 0.008, <i>I²</i> = 0%). Likewise, subgroup analysis of pooled data from 7 RCTs in pregnant women (n = 1028) showed a statistically significant increased risk of GI side-effects for ferrous sulfate although there was marked heterogeneity in the data (OR = 3.33, 95% CI 1.19-9.28, <i>p</i> = 0.02, <i>I²</i> = 66.1%). Meta-regression did not provide significant evidence of an association between the study OR and the iron dose.</p><p>Conclusions</p><p>Our meta-analysis confirms that ferrous sulfate is associated with a significant increase in gastrointestinal-specific side-effects but does not find a relationship with dose.</p></div

Study flow diagram.

<p>RCT, randomized controlled trial; ICU, intensive care unit. (1) This study was carried out by the co-authors and is currently submitted for publication and under review. A list compiling the 88 references that were not obtained is provided in Table A in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117383#pone.0117383.s002" target="_blank">S1 File</a>.</p

Randomized controlled trials with an intravenous iron comparator arm/group included in the meta-analysis.

<p>Six out of the 23 studies contained a co-intervention in both arms as indicated.</p><p>Abbreviations: M, male; F, female; CKD, chronic kidney disease; IBD, inflammatory bowel disease; NR, not reported or unclear; GISEs, gastrointestinal side effects shown as percentage of patients that experience gastrointestinal side-effects; Hb, hemoglobin;FeSO₄, ferrous sulfate group; IV, intravenous iron group; slow-Fe, modified-release ferrous sulfate.</p><p>⁽¹⁾ Iron dose in the FeSO4 group, unless indicated all trials used standard ferrous sulfate (i.e. not modified-release) and daily posology. Tardyferon® used in studies [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117383#pone.0117383.ref056" target="_blank">56</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117383#pone.0117383.ref057" target="_blank">57</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117383#pone.0117383.ref061" target="_blank">61</a>] and Ferrogradumet-Abbot used in study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117383#pone.0117383.ref058" target="_blank">58</a>].</p><p>⁽²⁾ There was no statistically significant difference in baseline hemoglobin between the ferrous sulfate and the IV iron arms/groups.</p><p>⁽³⁾ Co-intervention: recombinant erythropoietin.</p><p>⁽⁴⁾ Co-intervention: mebendazole and folic acid.</p><p>⁽⁵⁾ Co-intervention: vitamin B12 and folic acid.</p><p>⁽⁶⁾ Co-intervention: folic acid.</p><p>Randomized controlled trials with an intravenous iron comparator arm/group included in the meta-analysis.</p

Meta-regression analysis of the association between daily iron dose and the odds ratio of gastrointestinal side-effects.

<p><b>A,</b> data from 20 placebo-controlled RCTs (n = 3168); <b>B,</b> data from 23 IV iron-controlled RCTs (n = 3663). Individual studies are represented by circles, with the size of the circle being inversely proportional to the variance of the estimated effect (i.e the larger the circle, the more precise the estimated effect). The dotted lines represent the regression line for the analysis. Closed circles, studies with modified release ferrous sulfate; open circles, studies with conventional ferrous sulfate (i.e. not modified-release). All studies used daily posology.</p

Forest plot for the effect of daily ferrous sulfate supplementation on the incidence of gastrointestinal side-effects in placebo-controlled RCTs.

<p>Data for random-effects meta-analysis are shown. For each study the closed diamond represents the mean estimated effect and the horizontal lines the 95% CI. The grey shaded area surrounding each closed diamond represents the weight of each study in the analysis. Weight was assigned based on the (inverse of) the sum of the within-study variance and between study variance. Open diamonds represent the subgroup mean difference and pooled overall mean differences as shown. Test for overall effect: z-score = 7.54 (other), 0.20 (pregnant), 5.79 (overall); <i>p</i>-value <0.0001 (other), = 0.8 (pregnant), <0.0001 (overall). OR, odds ratio; CI, confidence interval. Data shown for 20 RCTs (n = 3168).</p