In the recent literature an inverse relationship between iron status and serum aluminum levels has repeatedly been reported in dialysis patients. To check whether this observation is, at least in part, due to an interference of iron with the protein binding of aluminum, we studied the effect of the latter element on both the number of free binding sites on transferrin (Tf) and on the affinity of the protein for aluminum. For the purpose of this, a recently developed HPLC-ETAAS hybrid method was used, allowing protein-binding studies at clinical relevant metal concentrations and under contamination-free conditions. After we incubated apo-Tf with iron and aluminum which were added in amounts equivalent to the calculated number of metal-binding sites on the protein (i.e., 2 mol metal/mol Tf), we found that Tf can be saturated for 100% with iron. However, for aluminum only a 23% aluminum-Tf saturation was observed. In Tf solutions with iron saturations ranging between 0 and 60% as well as in the serum of 15 subjects with iron-Tf saturations varying between 12 and 48%, a significant (p<0.001) negative correlation between the degree of iron-Tf saturation and the percentage of aluminum (added in amounts equivalent to the number of the remaining binding sites on Tf) bound to Tf was noted (y = -0.26x + 24.5, r = -0.87 in serum). It is concluded that the iron-Tf saturation influences the Tf binding of aluminum not only by occupying binding sites otherwise available for aluminum, but also by lowering the affinity of Tf for aluminum. The effects of iron on serum aluminum levels and bone aluminum deposition are discussed.

BACKGROUND:In addition to antigens, vaccines contain small amounts of preservatives, adjuvants, and residual substances from the manufacturing process. Some parents have concerns about the safety of these ingredients, yet no large epidemiological studies have specifically examined associations between health outcomes and vaccine ingredients, other than thimerosal. This study examined the extent to which the Vaccine Safety Datalink (VSD) could be used to study vaccine ingredient safety in children.

METHODS:Children born 2004-2011 were identified in VSD data. Using immunization records, two cohorts were identified: children who were up-to-date and children who were undervaccinated before age 2 years. A database was also created linking vaccine type and manufacturer with ingredient amounts documented in vaccine package inserts. Thirty-four ingredients in two or more infant vaccines were identified. However, only amounts (in mg) for aluminum were consistently documented and commonly contained in infant vaccines. Analyses compared vaccine aluminum exposure across cohorts and determined the statistical power for studying associations between aluminum exposure and hypothetical vaccine adverse events.

RESULTS:Among 408,608 children, mean cumulative vaccine aluminum exposure increased from 1.11 to 4.00mg between ages 92-730 days. Up-to-date children were exposed to 11-26% more aluminum from vaccines than undervaccinated children. Power analyses demonstrated that safety studies of aluminum could detect relative risks ranging from 1.1 to 5.8 for a range of adverse event incidence.

CONCLUSIONS:The safety of vaccine aluminum exposure can be feasibly studied in the VSD. However, possible biological mechanisms and confounding variables would need to be considered before conducting any studies.

Recent evidence underlines the role of Western diet in the pathogenesis of acne. Acne is absent in populations consuming Palaeolithic diets with low glycaemic load and no consumption of milk or dairy products. Two randomized controlled studies, one of which is presented in this issue of Acta Dermato-Venereologica, have provided evidence for the beneficial therapeutic effects of low glycaemic load diets in acne. Epidemiological evidence confirms that milk consumption has an acne-promoting or acne-aggravating effect. Recent progress in understanding the nutrient-sensitive kinase mammalian target of rapamycin complex 1 (mTORC1) allows a new view of nutrient signalling in acne by both high glycaemic load and increased insulin-, IGF-1-, and leucine signalling due to milk protein consumption. Acne should be regarded as an mTORC1-driven disease of civilization, like obesity, type 2 diabetes and cancer induced by Western diet. Early dietary counselling of teenage acne patients is thus a great opportunity for dermatology, which will not only help to improve acne but may reduce the long-term adverse effects of Western diet on more serious mTORC1-driven diseases of civilization.

OBJECTIVE:This study examined a possible association of dietary exposure to polybrominated biphenyls (PBBs), a brominated flame retardant, and self-reported abnormal Pap test results and cervical dysplasia as a precursor to cervical cancer.

METHODS:Women in Michigan who ingested contaminated poultry, beef, and dairy products in the early 1970s were enrolled in a population-based cohort study in Michigan. Serum PBB and serum polychlorinated biphenyl (PCB) concentrations were measured. Reproductive history and health information, including Pap test results, were self-reported by participants.

RESULTS:Of the women, 23% (223 of 956) reported an abnormal Pap test. In unadjusted analyses, self-reporting an abnormal Pap test was associated with younger age, current smoking (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.19-2.17), and longer duration of lifetime use of oral contraceptives (≥10 years; HR 1.92, 95% CI 1.21-3.06). When adjusting for PCB exposure, age at the interview, and smoking history, there was a slightly elevated risk of self-reporting an abnormal Pap test among the highly exposed women compared to women with nondetectable PBB concentrations (PBB≥13 μg/L, HR1.23, 95% CI 0.74-2.06); however, the CI was imprecise. When breastfeeding duration after the initial PBB measurement was taken into account, there was a reduced risk of self-reporting an abnormal Pap test among the highly exposed women who breastfed for ≥12 months (HR 0.41, 95% CI 0.06-3.03; referent group: women with nondetectable PBB concentrations who did not breastfeed).

CONCLUSIONS:It remains important to evaluate the potential reproductive health consequences of this class of chemicals as well as other potential predictors of abnormal Pap tests.

SCOPE:The main objectives of this study were to estimate dietary fumonisin exposure and nutrient intake in a group of patients diagnosed with celiac disease compared to non-celiac subjects.

METHODS AND RESULTS:The fumonisin level in 118 frequently consumed corn-based products was determined and dietary habits were recorded using a 7-day weighed food record. Data were then compared to those obtained for a control group. The fumonisin intake in the celiac patients was significantly higher than in controls, with mean values (± SE) of 0.395 ± 0.049 and 0.029 ± 0.006 μg/kg body weight per day, respectively. With regard to nutritional habits, celiac patients showed a preference for a high fat diet, coupled with a high intake of sweets and soft drinks and a low intake of vegetables, iron, calcium and folate.

CONCLUSION:These findings may have serious health implications for the celiac population due to the widespread occurrence of fumonisins in most of the widely consumed gluten-free products, leading to continuous exposure to this particular mycotoxin. Moreover, the recorded nutritional quality of the celiac patient's diet raises concerns regarding its long-term adequacy and its potential impact on chronic conditions such as type 2 diabetes and cardiovascular diseases.

BACKGROUND: Evidence from both animal and human studies suggests that abnormal glucose metabolism plays an important role in pancreatic carcinogenesis. We investigated whether diets high in foods that increase postprandial glucose levels are associated with an increased risk of pancreatic cancer.

METHODS: In a cohort of U.S. women (n = 88 802) participating in the Nurses' Health Study, 180 case subjects with pancreatic cancer were diagnosed during 18 years of follow-up. We used frequency of intake of individual foods as reported on a food-frequency questionnaire in 1980 to calculate sucrose, fructose, and carbohydrate intakes; glycemic index (postprandial blood glucose response as compared with a reference food); and glycemic load (glycemic index multiplied by carbohydrate content). Analyses of relative risk (RR) were performed by using multivariable Cox proportional hazards models to adjust for potential confounders. All statistical tests were two-sided.

RESULTS: Carbohydrate and sucrose intake were not associated with overall pancreatic cancer risk in this cohort. A statistically nonsignificant 53% increase in risk of pancreatic cancer (RR = 1.53, 95% confidence interval [CI] = 0.96 to 2.45) was observed among women with a high glycemic load intake, and a similar association was observed for fructose intake (RR = 1.57, 95% CI = 0.95 to 2.57). The associations of glycemic load and fructose intakes with pancreatic cancer risk were most apparent among women with elevated body mass index (>or=25 kg/m(2)) or with low physical activity. Among women who were both overweight and sedentary, a high glycemic load was associated with an RR of 2.67 (95% CI = 1.02 to 6.99; highest versus lowest quartile of intake; P for trend =.03), and high fructose was associated with an RR of 3.17 (95% CI = 1.13 to 8.91; P for trend =.04).

CONCLUSION: Our data support other findings that impaired glucose metabolism may play a role in pancreatic cancer etiology. A diet high in glycemic load may increase the risk of pancreatic cancer in women who already have an underlying degree of insulin resistance.

Background:Premature infants fed formula are more likely to develop necrotizing enterocolitis (NEC) than those who are breastfed, but the mechanisms of intestinal necrosis in NEC and protection by breast milk are unknown. We hypothesized that after lipase digestion, formula, but not fresh breast milk, contains levels of unbound free fatty acids (FFAs) that are cytotoxic to intestinal cells.Methods:We digested multiple term and preterm infant formulas or human milk with pancreatic lipase, proteases (trypsin and chymotrypsin), lipase + proteases, or luminal fluid from a rat small intestine and tested FFA levels and cytotoxicity in vitro on intestinal epithelial cells, endothelial cells, and neutrophils.Results:Lipase digestion of formula, but not milk, caused significant death of neutrophils (ranging from 47 to 99% with formulas vs. 6% with milk) with similar results in endothelial and epithelial cells. FFAs were significantly elevated in digested formula vs. milk and death from formula was significantly decreased with lipase inhibitor pretreatment, or treatments to bind FFAs. Protease digestion significantly increased FFA binding capacity of formula and milk but only enough to decrease cytotoxicity from milk.Conclusion:FFA-induced cytotoxicity may contribute to the pathogenesis of NEC.

Aluminum-based adjuvants (aluminum salts or alum) are widely used in human vaccination, although their mechanisms of action are poorly understood. Here we report that, in mice, alum causes cell death and the subsequent release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we propose that host DNA signaling differentially regulates IgE and IgG1 production after alum-adjuvanted immunization. We suggest that, on the one hand, host DNA induces primary B cell responses, including IgG1 production, through interferon response factor 3 (Irf3)-independent mechanisms. On the other hand, we suggest that host DNA also stimulates 'canonical' T helper type 2 (T(H)2) responses, associated with IgE isotype switching and peripheral effector responses, through Irf3-dependent mechanisms. The finding that host DNA released from dying cells acts as a damage-associated molecular pattern that mediates alum adjuvant activity may increase our understanding of the mechanisms of action of current vaccines and help in the design of new adjuvants.

Acne vulgaris has anecdotally been attributed to diet by individuals affected by this skin condition. In a 2009 systematic literature review of 21 observational studies and 6 clinical trials, the association between acne and diet was evaluated. Observational studies, including 2 large controlled prospective trials, reported that cow's milk intake increased acne prevalence and severity. Furthermore, prospective studies, including randomized controlled trials, demonstrated a positive association between a high-glycemic-load diet, hormonal mediators, and acne risk. Based on these findings, there exists convincing data supporting the role of dairy products and high-glycemic-index foods in influencing hormonal and inflammatory factors, which can increase acne prevalence and severity. Studies have been inconclusive regarding the association between acne and other foods.

OBJECTIVE: Distribution of breast milk substitutes (BMS) after the 2006 Yogyakarta earthquake was uncontrolled and widespread. We assessed the magnitude of BMS distribution after the earthquake, its impact on feeding practices and the association between consumption of infant formula and diarrhoea among infants and young children.

DESIGN: One month after the earthquake, caregivers of 831 children aged 0-23 months were surveyed regarding receipt of unsolicited donations of BMS, and on recent child-feeding practices and diarrhoeal illness.

SETTING: Community-level survey in an earthquake-affected district.

SUBJECTS: Primary caregivers of surveyed children.

RESULTS: In all, 75 % of households with an infant aged 0-5 months and 80 % of all households surveyed received donated infant formula; 76 % of all households received commercial porridge and 49 % received powdered milk. Only 32 % of 0-5-month-old infants had consumed formula before the earthquake, but 43 % had in the 24 h preceding the survey (P<0·001). Consumption of all types of BMS was significantly higher among those who received donated commodities, regardless of age (P<0·01). One-week diarrhoea incidence among those who received donated infant formula (25·4 %) was higher than among those who did not (11·5 %; relative risk = 2·12, 95 % CI = 1·34, 3·35). The rate of diarrhoea among those aged 12-23 months was around five times the pre-earthquake rate.

CONCLUSIONS: There were strong associations between receipt of BMS and changes in feeding practices, and between receipt of infant formula and diarrhoea. Uncontrolled distribution of infant formula exacerbates the risk of diarrhoea among infants and young children in emergencies.

Dramatic improvement of parkinsonian symptoms after gluten-free diet introduction in a patient with silent celiac disease.

Antibody-mediated responses play a critical role in vaccine-mediated immunity. However, for reasons that are poorly understood, these responses are highly variable between individuals. Using a mouse model, we report that antibiotic-driven intestinal dysbiosis, specifically in early life, leads to significantly impaired antibody responses to five different adjuvanted and live vaccines. Restoration of the commensal microbiota following antibiotic exposure rescues these impaired responses. In contrast, antibiotic-treated adult mice do not exhibit impaired antibody responses to vaccination. Interestingly, in contrast to impaired antibody responses, immunized mice exposed to early-life antibiotics display significantly enhanced T cell cytokine recall responses upon ex vivo restimulation with the vaccine antigen. Our results demonstrate that, in mice, antibiotic-driven dysregulation of the gut microbiota in early life can modulate immune responses to vaccines that are routinely administered to infants worldwide.

In order to assess the risk of parenteral aluminium (Al) exposure, we evaluated the effects of intraperitoneal administration of aluminium hydroxide, a compound widely used in medicine. Mice (strain Pzh:SFIS) received intraperitoneally, every two weeks 1 mg Al or 0.1 mg Al for five days a week. Controls received injections of saline. Al concentrations in liver, bone and brain were evaluated by electrothermal atomic absorption spectrometry after exposure to 2 mg, 4 mg, and 6 mg Al. The concentration was the highest in liver and occurred after exposure to only 2 mg Al (265.1 +/- 27.7 mg/kg, 233.5 +/- 28.0 mg/kg). Generally further accumulation was not dose- and treatment-dependent. The only exception was a significant Al increase in the liver after exposure to 6 mg Al, injected 0.1 mg Al five days/week. Development of resorption granulomas was observed in the liver, Al being revealed by Morin fluorescence in constituent macrophages and giant cells. By electron probe X-ray microanalysis, Al was identified predominantly in lysosomes of macrophages and Kupffer cells. In tibia of mice, a dose-dependent Al accumulation was observed. The highest level of Al concentration after the 6 mg treatment was 23.5 +/- 3.82 mg/kg and 25.06 +/- 2.3 mg/kg. The Al concentration in the brain of mice had not changed significantly during Al treatment.

Incubation of human erythroleukaemia K562 cells with Al-transferrin inhibited iron uptake from 59Fe-transferrin by about 80%. The inhibition was greater than that produced by a similar quantity of Fe-transferrin. Preincubation of cells for 6 h with either Al-transferrin or Fe-transferrin diminished the number of surface transferrin receptors by about 40% compared with cells preincubated with apo-transferrin. Al-transferrin did not compete significantly with Fe-transferrin for transferrin receptors and, when cells were preincubated for 15 min instead of 6 h, the inhibitory effect of Al-transferrin on receptor expression was lost. Both forms of transferrin also decreased the level of transferrin receptor mRNA by about 50%, suggesting a common regulatory mechanism. Aluminium citrate had no effect on iron uptake or transferrin-receptor expression. AlCl3 also had no effect on transferrin-receptor expression, but at high concentration it caused an increase in iron uptake by an unknown, possibly non-specific, mechanism. Neither Al-transferrin nor AlCl3 caused a significant change in cell proliferation. It is proposed that aluminium, when bound to transferrin, inhibits iron uptake partly by down-regulating transferrin-receptor expression and partly by interfering with intracellular release of iron from transferrin.

The aim of this study was to assess the effects of an aerobic training program as complementary therapy in patients suffering from moderate depression. 82 female patients weredivided into a group that received traditional pharmacotherapy (Fluoxetine 20 mg) and a group that received pharmacotherapy plus an aerobic training program. This program was carried out for eight consecutive weeks, three days per week, and included gymnastics, dancing, and walking. Depressive symptoms were measured with the Beck Depression Inventory and the ICD-10 Guide for Depression Diagnosis, both administered before and after treatments. The results confirm the effectiveness of the aerobic training program as a complementary therapy to diminish depressive symptoms in patients suffering from moderate depression.

BACKGROUND:Lifestyle modification (i.e., regular physical activity and diet) is effective in preventing the age-related increase in cardiovascular disease risks. Potential therapeutic effects of curcumin (diferuloylmethane) have been confirmed on various diseases, including cancer and Alzheimer's disease, but the effects of curcumin have not been tested on central arterial hemodynamics. The aim of this pilot study was to test the hypothesis that the regular endurance exercise combined with daily curcumin ingestion lowers the age-related increase in left ventricular (LV) afterload to a greater extent than monotherapy with either intervention alone in postmenopausal women using a randomized, double-blind, placebo-controlled, parallel manner.

METHODS:Forty-five women were randomly assigned to four interventions:"placebo ingestion"(n = 11),"curcumin ingestion"(n = 11),"exercise training with placebo ingestion"(n = 11), or"exercise training with curcumin ingestion"(n = 12). Curcumin or placebo pills (150 mg/day) were administered for 8 weeks. Aortic blood pressure (BP) and augmentation index (AIx), an index of LV afterload, were evaluated by pulse wave analysis from tonometrically measured radial arterial pressure waveforms.

RESULTS:There were no significant differences in baseline hemodynamic variables among four groups. After the interventions, brachial systolic BP (SBP) significantly decreased in both exercise-trained groups (P<0.05 for both), whereas aortic SBP significantly decreased only in the combined-treatment (e.g., exercise and curcumin) group (P<0.05). Heart rate (HR) corrected aortic AIx significantly decreases only in the combined-treatment group.

CONCLUSIONS:These findings suggest that regular endurance exercise combined with daily curcumin ingestion may reduce LV afterload to a greater extent than monotherapy with either intervention alone in postmenopausal women.

BACKGROUND AND AIM:In celiac disease (CD) the role of a gluten-free diet (GFD) on gastroesophageal reflux disease-related symptoms (GERD-rs) is unclear. The aim of this study was to establish the recurrence of GERD-rs, in CD patients with nonerosive reflux disease (NERD).

METHODS:From a total of 105 adult CD patients observed, 29 who presented with the NERD form were enrolled in the study. Thirty non-CD patients with NERD were studied as controls. Recurrence of GERD-rs was clinically assessed at 6, 12, 18, and 24 months follow-up (FU) after withdrawal of initial proton-pump inhibitor (PPI) treatment for 8 weeks.

RESULTS:GERD-rs were resolved in 25 (86.2%) CD patients and in 20 (66.7%) controls after 8 weeks of PPI treatment. In the CD group, recurrence of GERD-rs was found in five cases (20%) at 6 months but in none at 12, 18, and 24 months while in the control group recurrence was found in six of 20 controls (30%), in another six (12/20, 60%), in another three (15/20, 75%), and in another two (17/20, 85%) at 6, 12, 18, and 24 months FU respectively.

CONCLUSIONS:The present study is the first to have evaluated the effect of a GFD in the nonerosive form of GERD in CD patients, by means of clinical long-term follow-up, suggesting that GFD could be a useful approach in reducing GERD symptoms and in the prevention of recurrence.

Parenteral feedings containing more than 4 to 5 μg/kg/d of aluminum have been shown to result in neurodevelopmental delay in preterm infants.1 However, an infant at the 2-month checkup receives multiple aluminum-containing vaccines that in combination may have as high as 1225 μg of intramuscular aluminum; this is a much higher intramuscular aluminum dose than the safely recommended intravenous aluminum dose.2 Our first objective was to measure prevaccine and postvaccine levels of aluminum in preterm infants, a population at higher risk of aluminum neurotoxic effects. Our second objective was to measure prevaccine and postvaccine levels of essential elements (EE). Inflammation from trauma can cause declines in serum levels of specific EE such as zinc and selenium3-5; there may be similar EE perturbations secondary to vaccination-induced inflammation.