The effects of oral ferrous bisglycinate supplementation on hemoglobin and ferritin concentrations in adults and children: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: Iron deficiency and anemia have serious consequences, especially for children and pregnant women. Iron salts are commonly provided as oral supplements to prevent and treat iron deficiency, despite poor bioavailability and frequently reported adverse side effects. Ferrous bisglycinate is a novel amino acid iron chelate that is thought to be more bioavailable and associated with fewer gastrointestinal (GI) adverse events as compared with iron salts. OBJECTIVE: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the effects of ferrous bisglycinate supplementation compared with other iron supplements on hemoglobin and ferritin concentrations and GI adverse events. DATA SOURCES: A systematic search of electronic databases and grey literature was performed up to July 17, 2020, yielding 17 RCTs that reported hemoglobin or ferritin concentrations following at least 4 weeks' supplementation of ferrous bisglycinate compared with other iron supplements in any dose or frequency. DATA EXTRACTION: Random-effects meta-analyses were conducted among trials of pregnant women (n = 9) and children (n = 4); pooled estimates were expressed as standardized mean differences (SMDs). Incidence rate ratios (IRRs) were estimated for GI adverse events, using Poisson generalized linear mixed-effects models. The remaining trials in other populations (n = 4; men and nonpregnant women) were qualitatively evaluated. DATA ANALYSIS: Compared with other iron supplements, supplementation with ferrous bisglycinate for 4-20 weeks resulted in higher hemoglobin concentrations in pregnant women (SMD, 0.54 g/dL; 95% confidence interval [CI], 0.15-0.94; P < 0.01) and fewer reported GI adverse events (IRR, 0.36; 95%CI, 0.17-0.76; P < 0.01). We observed a non-significant trend for higher ferritin concentrations in pregnant women supplemented with ferrous bisglycinate. No significant differences in hemoglobin or ferritin concentrations were detected among children. CONCLUSION: Ferrous bisglycinate shows some benefit over other iron supplements in increasing hemoglobin concentration and reducing GI adverse events among pregnant women. More trials are needed to assess the efficacy of ferrous bisglycinate against other iron supplements in other populations. PROSPERO REGISTRATION NO: CRD42020196984.

Long-term efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta-analysis including 13,146 patients.

WHAT IS KNOWN AND OBJECTIVE: Previous studies based on small-sample clinical data proved that short-term use of hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors increased haemoglobin levels in anaemic patients with chronic kidney disease (CKD). However, these studies reached conflicting conclusions on iron parameters and adverse event profiles. Our meta-analysis aimed to evaluate the long-term efficacy and safety of HIF-PHD inhibitors in renal anaemia. METHODS: Randomized controlled trials comparing treatment with HIF-PHD inhibitors versus placebo or erythropoiesis-stimulating agents (ESAs) were thoroughly searched in the PubMed, Embase, Cochrane Library and international clinical trial registries. Meta-analysis was performed on main outcomes with random effects models. RESULTS AND DISCUSSION: A total of 30 studies comprising 13,146 patients were included. The HIF-PHD inhibitors used included roxadustat, daprodustat, vadadustat, molidustat, desidustat and enarodustat. HIF-PHD inhibitors significantly increased haemoglobin levels in comparison with placebo [weighted mean difference (WMD) 1.53, 95% confidence interval (CI) 1.39 to 1.67] or ESAs (WMD 0.13, 95% CI 0.03 to 0.22). Hepcidin, ferritin and serum iron levels were decreased, while total iron binding capacity and transferrin levels were increased in the HIF-PHD inhibitor group versus those in placebo or ESAs group. Additionally, HIF-PHD inhibitors medication was associated with cholesterol-lowering effects. As for safety, the risk of serious adverse events in the HIF-PHD inhibitor group was increased in comparison with placebo group [risk ratio (RR) 1.07, 95% CI 1.01 to 1.13], but comparable to the ESAs group (RR 1.02, 95% CI 0.94 to 1.10). Compared with placebo, the agents increased the risk of diarrhoea (1.21, 1.00 to 1.47), nausea (1.46, 1.09 to 1.97), oedema peripheral (1.32, 1.01 to 1.59), hyperkalemia (1.27, 1.05 to 1.54) and hypertension (1.34, 1.02 to 1.76). Compared with ESAs, the drugs increased the risk of vomiting (1.30, 1.02 to 1.65), headache (1.27, 1.05 to 1.53) and thrombosis events (1.31, 1.05 to 1.63). WHAT IS NEW AND CONCLUSION: HIF-PHD inhibitors treatment effectively increased haemoglobin levels and promoted iron utilization in anaemic patients with CKD, and they were well tolerated for long-term use. In order to avoid unfavourable effects of excessive iron consumption, it was appropriate to administer HIF-PHD inhibitors in combination with iron supplements for long-term treatment.

Exercise Training and Vitamin C Supplementation Affects Ferritin mRNA in Leukocytes without Affecting Prooxidative/Antioxidative Balance in Elderly Women.

Physical training and antioxidant supplementation may influence iron metabolism through reduced oxidative stress and subsequent lowering of mRNA levels of genes that are easily induced by this stress, including those responsible for iron homeostasis. Fifteen elderly women participated in our 12-week experiment, involving six weeks of training without supplementation and six weeks of training supported by oral supplementation of 1000 mg of vitamin C daily. The participants were divided into two groups (n = 7 in group 1 and n = 8 in group 2). In group 1, we applied vitamin C supplementation in the first six weeks of training, while in group 2 during the remaining six weeks of training. In both phases, the health-related training occurred three times per week. Training accompanied by vitamin C supplementation did not affect prooxidative/antioxidative balance but significantly decreased ferritin heavy chain (FTH) and ferritin light chain (FTL) mRNA in leukocytes (for FTH mRNA from 2^64.24 to 2^11.06, p = 0.03 in group 1 and from 2^60.54 to 2^16.03, p = 0.01 in group 2, for FTL mRNA from 2^20.22 to 2^4.53, p = 0.01 in group 2). We concluded that vitamin C supplementation might have caused a decrease in gene expression of two important antioxidative genes (FTH, FTL) and had no effect on plasma prooxidative/antioxidative balance.

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis.

The current chemotherapeutical treatment against alveolar echinococcosis relies exclusively on benzimidazoles, which are not parasiticidal and can induce severe toxicity. There are no alternative treatment options. To identify novel drugs with activity against Echinococcus multilocularis metacestodes, researchers have studied potentially interesting drug targets (e.g. the parasite's energy metabolism), and/or adopted drug repurposing approaches by undertaking whole organism screenings. We here focus on drug screening approaches, which utilize an in vitro screening cascade that includes assessment of the drug-induced physical damage of metacestodes, the impact on metacestode viability and the viability of isolated parasite stem cells, structure-activity relationship (SAR) analysis of compound derivatives, and the mode of action. Finally, once in vitro data are indicative for a therapeutic window, the efficacy of selected compounds is assessed in experimentally infected mice. Using this screening cascade, we found that the anti-malarial mefloquine was active against E. multilocularis metacestodes in vitro and in vivo. To shed more light into the mode of action of mefloquine, SAR analysis on mefloquine analogues was performed. E. multilocularis ferritin was identified as a mefloquine-binding protein, but its precise role as a drug target remains to be elucidated. In mice that were infected either intraperitoneally with metacestodes or orally with eggs, oral treatment with mefloquine led to a significant reduction of parasite growth compared to the standard treatment with albendazole. However, mefloquine was not acting parasiticidally. Assessment of mefloquine plasma concentrations in treated mice showed that levels were reached which are close to serum concentrations that are achieved in humans during long-term malaria prophylaxis. Mefloquine might be applied in human AE patients as a salvage treatment. Future studies should focus on other repurposed anti-infective compounds (MMV665807, niclosamide, atovaquone), which showed stronger in vitro activity against E. multilocularis than mefloquine.

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

The effect of vitamin D supplementation on hemoglobin concentration: a systematic review and meta-analysis.

AIMS: The purpose of this review was to investigate the effect of vitamin D supplements on hemoglobin concentration in subjects aged 17.5-68 years old; using randomized controlled trials (RCTs). METHODS: Relevant RCT studies were identified from January 2000 to January 2019 by using MeSH terms in PubMed, Embase, Cochrane Library, Clinical trials, Scopus databases and gray literature. The studies were reviewed systematically, and quality assessments were evaluated by the guidelines of the Cochrane risk of bias. The effect of vitamin D supplements (n = 14) on hemoglobin concentration was considered as primary outcome, while its effects on the levels of ferritin, transferrin saturation and iron status were derived as secondary outcomes. In total, 1385 subjects with age range of 17.5 to 68 years old were examined for 3 h to 6 months; Mean (standard deviation) or median interquartile changes in the hemoglobin concentration in each treatment group was recorded for meta-analysis. RESULTS: Fourteen RCTs met the inclusion criteria. Current study findings propose that vitamin D supplementation leads to a non-significant reduction in hemoglobin levels in subjects (17.5-68 years old) [std. mean difference (SMD): 0.01; 95% CI: - 0.28, 0.29; P = 0.95], also it has no significant effect on ferritin concentrations [std. mean difference (SMD): -0.01; 95% CI: [- 0.20, 0.18; P = 0.91]. However, vitamin D supplementation demonstrated positive effects on transferrin saturation [mean difference (MD): 1.54; 95% CI: 0.31, 2.76; P = 0.01] and iron status [std. mean difference (SMD): 0.24; 95% CI: - 0.09, 0.39; P = 0.002]. CONCLUSION: Current review concluded that supplementation with vitamin D had no significant effect on hemoglobin and ferritin levels while positive effects on transferrin saturation and iron status were observed. Further clinical studies are required to determine the actual effect of this intervention on hemoglobin levels.

Effects of Coenzyme Q10 Supplementation on Serum Values of Gamma-glutamyl transferase, Pseudocholinesterase, Bilirubin, Ferritin, and High-Sensitivity C-Reactive Protein in Women with Type 2 Diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a disease associated with increased oxidative stress which results from mitochondrial dysfunction. Coenzyme Q10 (CoQ10) is an essential antioxidant for energy production in mitochondria. The purpose of this randomized double-blind clinical trial study was to evaluate the effects of CoQ10 supplementation on serum values of gamma-glutamyl transferase (GGT), pseudocholinesterase (PchE), bilirubin, ferritin, and high-sensitivity c-reactive protein (hs-CRP) and metabolic syndrome biomarkers in women with T2DM. MATERIAL & METHODS: Eighty women with T2DM enrolled in this study. Thirty six of them were randomized in the drug group (receiving 100 mg/day of CoQ10) and 44 women were randomized in placebo group. Intervention was continued for 12 weeks. In both groups 35 subjects finished the study and were included in the analysis. Serum levels of the variables were measured before and after supplementation. RESULTS: Serum values of FBS (P=0.039), HOMA-IR (P=0.01), ferritin (P<0.001), total cholesterol (TC) (P=0.006), LDL-C (P=0.007) decreased and HDL-C (P=0.02) increased significantly in the drug group after intervention. Serum levels of triglyceride (P=0.09) decreased marginally in CoQ10 group. CONCLUSIONS: The results of the current study had shown that after supplementation with 100 mg/day of CoQ10 for 12 weeks, serum values of FBS, HOMA-IR, TC, LDL-C and ferritin were decreased and values of HDL-C were increased in women with T2DM.

Iron Supplementation, Response in Iron-Deficiency Anemia: Analysis of Five Trials.

BACKGROUND: Oral iron-replacement therapy is the mainstay of treatment for iron-deficiency anemia, but it is often poorly tolerated or ineffective. Hemoglobin response at day 14 of oral iron may be useful in assessing whether and when to transition patients from oral to intravenous (IV) iron. METHODS: Pooled data from 5 randomized trials were analyzed to compare oral and IV iron-replacement therapy for iron-deficiency anemia. Treatment criteria and assignment to oral versus IV iron were defined per protocol; this analysis included only subjects receiving oral iron. Responders were subjects with ≥1.0-g/dL increases in hemoglobin at day 14, and nonresponders were those with smaller increases. Demographic and clinical characteristics were evaluated for association with hemoglobin response at multiple timepoints. RESULTS: Most subjects (72.8%) were classified as responders. The proportion of subjects with hemoglobin increases ≥1.0, ≥2.0, and ≥3.0 g/dL was greatest among those with postpartum anemia, intermediate among those with heavy uterine bleeding or gastrointestinal-related causes of anemia, and lowest among those with other causes; this proportion was also significantly greater among responders than nonresponders. A ≥1.0-g/dL increase in hemoglobin on day 14 most accurately predicted satisfactory overall hemoglobin response to oral iron on day 42/56 (sensitivity 90.1%; specificity 79.3%; positive and negative predictive values of 92.9% and 72.7%, respectively). Iron-replacement therapy improved quality of life and reduced fatigue. CONCLUSION: Hemoglobin responses <1.0 g/dL at day 14 of oral iron identify subjects with iron-deficiency anemia who should be transitioned to IV iron supplementation.

Effects of cranberry (Vaccinum macrocarpon) supplementation on iron status and inflammatory markers in rowers.

BACKGROUND: The aim of this study was to analyze the effect of supplementation with cranberry (Vaccinum macrocarpon) on the levels of pro-inflammatory cytokines, hepcidin and selected markers of iron metabolism in rowers subjected to exhaustive exercise. METHODS: This double-blind study included 16 members of the Polish Rowing Team. The subjects were randomly assigned to the supplemented group (n = 9), receiving 1200 mg of cranberry extract for 6 weeks, or to the placebo group (n = 7). The participants performed a 2000-m test on a rowing ergometer at the beginning and at the end of the preparatory camp. Blood samples were obtained from the antecubital vein prior to each exercise test, one minute after completing the test, and after a 24-h recovery period. The levels of hepcidin, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), ferritin, iron, soluble transferrin receptor (sTfR) and myoglobin were determined, along with total iron-binding capacity (TIBC), unbound iron-binding capacity (UIBC) and total antioxidant capacity (TAC). RESULTS: Both prior and after the supplementation, a significant post-exercise increase in the concentration of IL-6 was observed in both groups. At the end of the study period, cranberry-supplemented athletes presented with significantly higher resting, post-exercise and post-recovery levels of TAC than the controls. However, a significant exercise-induced increase in the concentrations of TNF-alpha, myoglobin and hepcidin was observed solely in the control group. CONCLUSION: Supplementation with cranberry extract contributed to a significant strengthening of antioxidant potential in individuals exposed to strenuous physical exercise. However, supplementation did not exert direct effects on other analyzed parameters: inflammatory markers and indices of iron metabolism (TNF-alpha, hepcidin and myoglobin).

Effect of vitamin B-12 and n-3 polyunsaturated fatty acids on plasma homocysteine, ferritin, C-reaction protein, and other cardiovascular risk factors: a randomized controlled trial.

OBJECTIVES: Vitamin B-12 and n-3 polyunsaturated fatty acids (PUFA) decrease blood homocysteine (Hcy) concentrations. However, the combined effect of these nutrients on Hcy and ferritin, and C-reactive protein is limited and inconclusive. The objective was to examine the synergistic effect of vitamin B-12 in combination of n-3 PUFA on plasma Hcy, ferritin, and other biochemical markers. METHODS: In a randomized controlled trial, thirty eligible subjects were randomly divided into three groups, and assigned to receive 1000 µg of vitamin B-12, 2 g fish oil, or 1000 µg vitamin B-12 and 2 g fish oil, respectively, for 8 weeks. Plasma phospholipids (PL) fatty acids and biochemical markers were determined. This study was registered under ClinicalTrials.gov Identifier: NCT01762072. RESULTS: Plasma PL 20:5n-3, 22:6n-3 and n-3 PUFA was increased after 4 and 8 week supplementation of fish oil, and vitamin B-12+fish oil. Plasma concentrations of triacylglycerol, uric acid, C-reactive protein, and ferritin were significantly decreased after 4 and 8 week supplementation of fish oil, and vitamin B-12+fish oil. In all groups, significant changes in plasma Hcy were observed during the study period. Vitamin B-12, fish oil, and vitamin B-12+fish oil supplementation lowered plasma Hcy concentrations by 22%, 19%, and 39%, respectively. CONCLUSIONS: The combination of vitamin B-12 and fish oil has a synergistic effect on lowering plasma concentrations of Hcy.

Glial cell activity is maintained during prolonged inflammatory challenge in rats

We evaluated the expression of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), ionized calcium binding adaptor protein-1 (Iba-1), and ferritin in rats after single or repeated lipopolysaccharide (LPS) treatment, which is known to induce endotoxin tolerance and glial activation. Male Wistar rats (200-250 g) received ip injections of LPS (100 µg/kg) or saline for 6 days: 6 saline (N = 5), 5 saline + 1 LPS (N = 6) and 6 LPS (N = 6). After the sixth injection, the rats were perfused and the brains were collected for immunohistochemistry. After a single LPS dose, the number of GFAP-positive cells increased in the hypothalamic arcuate nucleus (ARC; 1 LPS: 35.6 ± 1.4 vs control: 23.1 ± 2.5) and hippocampus (1 LPS: 165.0 ± 3.0 vs control: 137.5 ± 2.5), and interestingly, 6 LPS injections further increased GFAP expression in these regions (ARC = 52.5 ± 4.3; hippocampus = 182.2 ± 4.1). We found a higher GS expression only in the hippocampus of the 6 LPS injections group (56.6 ± 0.8 vs 46.7 ± 1.9). Ferritin-positive cells increased similarly in the hippocampus of rats treated with a single (49.2 ± 1.7 vs 28.1 ± 1.9) or repeated (47.6 ± 1.1 vs 28.1 ± 1.9) LPS dose. Single LPS enhanced Iba-1 in the paraventricular nucleus (PVN: 92.8 ± 4.1 vs 65.2 ± 2.2) and hippocampus (99.4 ± 4.4 vs 73.8 ± 2.1), but had no effect in the retrochiasmatic nucleus (RCA) and ARC. Interestingly, 6 LPS increased the Iba-1 expression in these hypothalamic and hippocampal regions (RCA: 57.8 ± 4.6 vs 36.6 ± 2.2; ARC: 62.4 ± 6.0 vs 37.0 ± 2.2; PVN: 100.7 ± 4.4 vs 65.2 ± 2.2; hippocampus: 123.0 ± 3.8 vs 73.8 ± 2.1). The results suggest that repeated LPS treatment stimulates the expression of glial activation markers, protecting neuronal activity during prolonged inflammatory challenges.

Glial cell activity is maintained during prolonged inflammatory challenge in rats.

We evaluated the expression of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), ionized calcium binding adaptor protein-1 (Iba-1), and ferritin in rats after single or repeated lipopolysaccharide (LPS) treatment, which is known to induce endotoxin tolerance and glial activation. Male Wistar rats (200-250 g) received ip injections of LPS (100 µg/kg) or saline for 6 days: 6 saline (N = 5), 5 saline + 1 LPS (N = 6) and 6 LPS (N = 6). After the sixth injection, the rats were perfused and the brains were collected for immunohistochemistry. After a single LPS dose, the number of GFAP-positive cells increased in the hypothalamic arcuate nucleus (ARC; 1 LPS: 35.6 ± 1.4 vs control: 23.1 ± 2.5) and hippocampus (1 LPS: 165.0 ± 3.0 vs control: 137.5 ± 2.5), and interestingly, 6 LPS injections further increased GFAP expression in these regions (ARC = 52.5 ± 4.3; hippocampus = 182.2 ± 4.1). We found a higher GS expression only in the hippocampus of the 6 LPS injections group (56.6 ± 0.8 vs 46.7 ± 1.9). Ferritin-positive cells increased similarly in the hippocampus of rats treated with a single (49.2 ± 1.7 vs 28.1 ± 1.9) or repeated (47.6 ± 1.1 vs 28.1 ± 1.9) LPS dose. Single LPS enhanced Iba-1 in the paraventricular nucleus (PVN: 92.8 ± 4.1 vs 65.2 ± 2.2) and hippocampus (99.4 ± 4.4 vs 73.8 ± 2.1), but had no effect in the retrochiasmatic nucleus (RCA) and ARC. Interestingly, 6 LPS increased the Iba-1 expression in these hypothalamic and hippocampal regions (RCA: 57.8 ± 4.6 vs 36.6 ± 2.2; ARC: 62.4 ± 6.0 vs 37.0 ± 2.2; PVN: 100.7 ± 4.4 vs 65.2 ± 2.2; hippocampus: 123.0 ± 3.8 vs 73.8 ± 2.1). The results suggest that repeated LPS treatment stimulates the expression of glial activation markers, protecting neuronal activity during prolonged inflammatory challenges.

Oral ferrous sulfate does not increase preoperative hemoglobin in patients scheduled for hip or knee arthroplasty.

BACKGROUND: Low hemoglobin (Hb) concentrations before lower limb joint replacement are associated with the need for blood transfusions and increased mortality. To optimize preoperative Hb, blood conservation protocols often recommend oral iron supplements, even in nonanemic patients. OBJECTIVE: To investigate the impact of ferrous sulfate on the change in Hb prior to hip or knee arthroplasty and evaluate the effect of oral iron on hematocrit, mean corpuscular volume (MCV), ferritin, and transferrin saturation, as well as its tolerability and treatment adherence. METHODS: We conducted a prospective, observational cohort study of adults with Hb concentrations between 10 and 15 g/dL who received iron supplementation prior to hip or knee arthroplasty. Systemic inflammatory diseases, vitamin B(12) or folate deficiency, and current use of iron supplements, intravenous iron, or erythropoietin were exclusion criteria. All participants were prescribed ferrous sulfate 300 mg 3 times daily for a minimum of 3 weeks. Complete blood cell counts and iron studies were performed before therapy and surgery. RESULTS: Eighty-seven patients with a mean (SD) Hb of 13.47 (0.84) g/dL were included in the study. Preoperative Hb decreased after treatment with iron (-0.14 [0.53] g/dL, p = 0.015). Hematocrit also declined (-0.6% [1.8%], p = 0.002), whereas ferritin increased (25.8 [38.6] ng/mL, p < 0.001). No significant change was seen in MCV and transferrin saturation. The most common adverse effects were constipation (33.3%), heartburn (13.8%), and abdominal pain (12.6%). The adherence rate was 67.1%. CONCLUSIONS: Oral ferrous sulfate supplementation is not an effective method to increase preoperative Hb in patients scheduled for hip or knee arthroplasty, and its use is associated with adverse effects.

A combination of iron and retinol supplementation benefits iron status, IL-2 level and lymphocyte proliferation in anemic pregnant women.

BACKGROUND: Iron and vitamin A deficiencies impact anemia and the immune system. OBJECTIVE: to investigate the effect of iron combined with retinol supplementation on iron status, IL-2 level and lymphocyte proliferation. METHODS: a double-blind randomized trial conducted over 2 months. We randomly allocated 186 anemic pregnant women with 80 ≤ Hb 0 < 110 g/L into four groups. Group I (n=47) was supplemented daily with 60 mg iron as ferrous sulfate, IF (n=46) with 60 mg iron and 0.4 mg folic acid, IR (n=46) with 60 mg iron, 2.0 mg retinol and 0.4 mg folic acid and C (n=47) was the placebo group,. RESULTS: after the 2 months trial, there were considerable increases of iron status in Hb, plasma iron and ferritin in the I, IF and IR groups compared with Group C. Increases in plasma iron and ferritin in the IR group were also significantly greater than in Groups I and IF. Compared with group C, increases of IL-2 levels were 119, 184 and 206 ng/L; and lymphocyte proliferation increased by 0.095, 0.112 and 0.219 in Groups I, IF and IR, respectively. Increases of IL-2 were 65.3 ng/L and 87.5 ng/L in Groups IF and IR, greater than in Group I (both p values <0.01); and lymphocyte proliferation in Group IR were 0.124 and 0.107, also greater than in Groups I and IF, respectively. CONCLUSION: iron combined retinol supplementation was more beneficial to improving iron status and lymphocyte proliferation during pregnancy than iron alone.

Supplemental dietary inulin influences expression of iron and inflammation related genes in young pigs.

We have previously shown improved hemoglobin (Hb) repletion efficiency by supplementing a 50:50 mixture of short (P95) and long-chain (HP) inulin (Synergy 1, BENEO-Orafti) into a corn-soybean meal-basal diet (BD) for young pigs. In this study, weanling pigs (5 or 6 wk old) were fed the BD or the BD + 4% of P95, HP, or Synergy 1 (50:50 mixtures of HP and P95) for 5-7 wk. Blood Hb concentrations of pigs were measured weekly and digesta samples were collected at the end of the trial. In a replicate experiment, total RNA was isolated from the liver and mucosa of duodenum, ileum, cecum, and colon of all pigs at the end of the trial. Relative mRNA expression of 27 genes, including iron and inflammation-related genes, was quantified using real-time quantitative-PCR. Although all 3 types of inulin resulted in similar improvements (P < 0.05) in blood Hb concentration and liver ferritin protein amount, neither type of inulin was detectable in the digesta of cecum or colon. Supplemental inulin enhanced the expression of iron-storing protein genes but decreased that of inflammation-related genes. Such effects were more pronounced (P < 0.05) in the mucosa of the lower than the upper gut and were seen on 7 genes in liver. In conclusion, all 3 types of inulin shared similar efficacy and possibly similar modes of action in improving dietary iron utilization by young pigs. Suppressing inflammation-induced genes that can negatively influence iron metabolism might help explain the benefit of inulin.

Combined therapy of silymarin and desferrioxamine in patients with beta-thalassemia major: a randomized double-blind clinical trial.

Silymarin, a flavonolignan complex isolated from Silybum marianum, has a strong antioxidant, hepatoprotective, and iron chelating activities. The present study was designed to investigate the therapeutic activity of orally administered silymarin in patients with thalassemia major under conventional iron chelation therapy. A 3-month randomized, double-blind, clinical trial was conducted in 59 beta-thalassemia major patients in two well-matched groups. Patients were randomized to receive a silymarin tablet (140 mg) three times a day plus conventional desferrioxamine therapy. The second group received the same therapy but a placebo tablet instead of silymarin. Clinical laboratory tests were assessed at the beginning and the end of the trial, except for serum ferritin level that was assessed at the middle of the trial as well. Results of this study revealed that the combined therapy was well tolerated and more effective than desferrioxamine in reducing serum ferritin level. Significant improvement in liver alkaline phosphatase and glutathione levels of red blood cells was also observed in silymarin-treated beta-thalassemia patients. However, no significant difference in serum ferritin levels was detected between silymarin and placebo groups after 1.5 and 3 months treatment, probably because of insufficient sample size to detect subtle changes in ferritin levels between groups. This is the first report showing the beneficial effects of silymarin in thalassemia patients and suggests that silymarin in combination with desferrioxamine can be safely and effectively used in the treatment of iron-loaded patients.

Intravenous iron versus erythropoiesis-stimulating agents: friends or foes in treating chronic kidney disease anemia?

Patients with chronic kidney disease (CKD), especially those requiring maintenance hemodialysis treatments, may lose up to 3 g of iron each year because of frequent blood losses. Higher doses of erythropoiesis-stimulating agents (ESAs) may worsen iron depletion and lead to an increased platelet count (thrombocytosis), ESA hyporesponsiveness, and hemoglobin variability. Hence, ESA therapy requires concurrent iron supplementation. Traditional iron markers such as serum ferritin and transferrin saturation ratio (TSAT) (ie, serum iron divided by total iron-binding capacity [TIBC]), may be confounded by non-iron-related conditions. Whereas serum ferritin <200 ng/mL suggests iron deficiency in CKD patients, ferritin levels between 200 and 1,200 ng/mL may be related to inflammation, latent infections, malignancies, or liver disease. Protein-energy wasting may lower TIBC, leading to a TSAT within the normal range, even when iron deficiency is present. Iron and anemia indices have different mortality predictabilities, in that high serum ferritin but low iron, TIBC, and TSAT levels are associated with increased mortality, whereas hemoglobin exhibits a U-shaped risk for death. The increased mortality associated with targeting hemoglobin above 13 g/dL may result from iron depletion-associated thrombocytosis. Intravenous (IV) iron administration may not only decrease hemoglobin variability and ESA hyporesponsiveness, it may also reduce the greater mortality associated with the much higher ESA doses that have been used in some patients when targeting higher hemoglobin levels.

Intravenous iron in chronic kidney disease: haemoglobin change shortly after treatment of patients neither on dialysis nor on erythropoietin.

Anaemia is a common in chronic kidney disease. Although erythropoietin and iron supplementation are established treatments, knowledge on the use of IV iron alone in patients not on dialysis or erythropoietin is incomplete. The responses of 82 patients referred to the renal anaemia service with haemoglobin of 11.5 g/dl or less were assessed 1 week after completing four once weekly doses of 200 mg of venofer. No patients were on dialysis or erythropoietin. The haemoglobin rise 1 week after treatment was 0.53 g/dl. Ferritin levels improved from 110.8 to 410.2 ng/l and transferrin saturation from 17.7 to 27.3%. Ferritin levels remained below our target range (200-500 ng/l) in 7.7% while 25.6% had levels above this. Ferritin levels remained less than 800 ng/l in nearly all patients. Intravenous iron is cost effective and should be considered for use in patients with renal anaemia. Patients with CKD stage 5 appeared to respond less well.

Silybin treatment is associated with reduction in serum ferritin in patients with chronic hepatitis C.

GOALS: The goal of this study was to examine the effect of a standardized silybin and soy phosphatidylcholine complex (IdB 1016) on serum markers of iron status. BACKGROUND: Milk thistle and its components are widely used as an alternative therapy for liver disease because of purported antioxidant, anti-inflammatory, and iron chelating properties. STUDY: Thirty-seven patients with chronic hepatitis C and Batts-Ludwig fibrosis stage II, III, or IV were randomized to 1 of 3 doses of IdB 1016 for 12 weeks. Serum ferritin, serum iron, total iron binding capacity, and transferrin-iron saturation were measured at baseline, during treatment, and 4 weeks thereafter. Wilcoxon signed rank tests were used to compare baseline and posttreatment values. RESULTS: There was a significant decrease in serum ferritin from baseline to end of treatment (mean, 244 vs. 215 mug/L; median, 178 vs. 148 mug/L; P=0.0005); 78% of subjects had a decrease in serum ferritin level. There was no significant change in serum iron or transferrin-iron saturation. Multivariate logistic regression analysis in a model that included dose, age, sex, HFE genotype, history of alcohol use, and elevated baseline ferritin levels demonstrated that stage III or IV fibrosis was independently associated with decreased posttreatment serum ferritin level. CONCLUSIONS: Treatment with IdB 1016 is associated with reduced body iron stores, especially among patients with advanced fibrosis stage.

Fullerene C60 exposure elicits an oxidative stress response in embryonic zebrafish.

Due to its unique physicochemical and optical properties, C60 has raised interest in commercialization for a variety of products. While several reports have determined this nanomaterial to act as a powerful antioxidant, many other studies have demonstrated a strong oxidative potential through photoactivation. To directly address the oxidative potential of C60, the effects of light and chemical supplementation and depletion of glutathione (GSH) on C60-induced toxicity were evaluated. Embryonic zebrafish were used as a model organism to examine the potential of C60 to elicit oxidative stress responses. Reduced light during C60 exposure significantly decreased mortality and the incidence of fin malformations and pericardial edema at 200 and 300 ppb C60. Embryos co-exposed to the glutathione precursor, N-acetylcysteine (NAC), also showed reduced mortality and pericardial edema; however, fin malformations were not reduced. Conversely, co-exposure to the GSH synthesis inhibitors, buthionine sulfoximine (BSO) and diethyl maleate (DEM), increased the sensitivity of zebrafish to C60 exposure. Co-exposure of C60 or its hydroxylated derivative, C60(OH)(24), with H2O2 resulted in increased mortality along the concentration gradient of H2O2 for both materials. Microarrays were used to examine the effects of C60 on the global gene expression at two time points, 36 and 48 h post fertilization (hpf). At both life stages there were alterations in the expression of several key stress response genes including glutathione-S-transferase, glutamate cysteine ligase, ferritin, alpha-tocopherol transport protein and heat shock protein 70. These results support the hypothesis that C60 induces oxidative stress in this model system.