Zinc supplementation induces CD4<Superscript>+</Superscript>CD25<Superscript>+</Superscript>Foxp3<Superscript>+</Superscript> antigen-specific regulatory T cells and suppresses IFN-γ production by upregulation of Foxp3 and KLF-10 and downregulation of IRF-1

Purpose

The essential trace element zinc plays a fundamental role in immune function and regulation since its deficiency is associated with autoimmunity, allergies, and transplant rejection. Thus, we investigated the influence of zinc supplementation on the Th1-driven alloreaction in mixed lymphocyte cultures (MLC), on generation of antigen-specific T cells, and analyzed underlying molecular mechanisms.

Methods

Cell proliferation and pro-inflammatory cytokine production were monitored by [³H]-thymidine proliferation assay and ELISA, respectively. Analysis of surface and intracellular T cell marker was performed by flow cytometry. Western blotting and mRNA analysis were used for Foxp3, KLF-10, and IRF-1 expression.

Results

Zinc supplementation on antigen-specific T cells in physiological doses (50 µM) provokes a significant amelioration of cell proliferation and pro-inflammatory cytokine production after reactivation compared to untreated controls. Zinc administration on MLC results in an increased induction and stabilization of CD4⁺CD25⁺Foxp3⁺ and CD4⁺CD25⁺CTLA-4⁺ T cells (p < 0.05). The effect is based on zinc-induced upregulation of Foxp3 and KLF-10 and downregulation of IRF-1. However, in resting lymphocytes zinc increases IRF-1.

Conclusion

In summary, zinc is capable of ameliorating the allogeneic immune reaction by enhancement of antigen-specific iTreg cells due to modulation of essential molecular targets: Foxp3, KLF-10, and IRF-1. Thus, zinc can be seen as an auspicious tool for inducing tolerance in adverse immune reactions.

     

Association of Heart Rate Variability of the Elderly with Personal Exposure to PM<Subscript>1</Subscript>, PM<Subscript>1–2.5</Subscript>, and PM<Subscript>2.5–10</Subscript>

Environmental epidemiologic studies have shown that elderly people are susceptible to particulate air pollution. The decreases in heart rate variability are important indices of health effect caused by particulate matter. The objective of this study was to investigate the effects of submicron particle (PM₁), PM_1–2.5, and coarse particle (PM_2.5–10) on heart rate variability parameters in the elderly. Results of our study indicated that short-term and medium-term PM exposures were associated with the reduction of heart rate variability in the elderly, with stronger effects found for coarse particles in comparison with particles of other size ranges.     

Soy isoflavones reduce electronegative low-density lipoprotein (LDL<Superscript>−</Superscript>) and anti-LDL<Superscript>−</Superscript> autoantibodies in experimental atherosclerosis

Background Isoflavones present in soybean may contribute to soy atheroprotectective effects. Aim of the study To investigate the effect of soy isoflavones supplementation on the formation of electronegative LDL (LDL⁻) and its autoantibodies in blood plasma and aortic atheromas of rabbits fed an atherogenic casein-based diet enriched with isoflavones. Methods New Zealand male rabbits (n = 15) were fed an atherogenic diet (27% casein) supplemented with isoflavones (0.73 or 7.3 mg of isoflavones/kg/day, Low and High Iso groups, respectively) for 180 days. Monthly, blood samples were collected after 12–15 h fasting and at 180 days of treatment all animals were sacrificed. Isoflavones were analyzed in plasma and urine samples by HPLC. LDL⁻ in plasma and atheromas was detected by ELISA and immunohistochemistry, respectively, with a monoclonal antibody reactive to LDL⁻. Autoantibodies reactive to LDL⁻ were analyzed in plasma and aorta by ELISA. Results Low and High Iso groups had decreased LDL-cholesterol, increased HDL-cholesterol and lower levels of LDL⁻ in blood plasma and aortic atherosclerotic lesions than the non-supplemented Control group. IgG autoantibodies reactive to LDL⁻ were higher in plasma of the Control group in comparison with the High and Low Iso groups. In contrast, the aortas from animals that consumed isoflavones showed higher levels of IgG reactive to LDL⁻ than the Control group. Conclusion Soy isoflavones showed hypolipidemic effects and decreased the pro-inflammatory LDL⁻ subfraction in blood plasma and aorta of hypercholesterolemic rabbits.     

How does a 10-fold pulse increase of aircraft-related NO<Subscript><Emphasis Type="Italic">x</Emphasis></Subscript> impact the global burdens of O<Subscript>3</Subscript> and secondary organic aerosol (SOA)?

Aircraft emissions are an important and growing global source of nitrogen oxides (NO _x ). At cruising altitude, the atmosphere is particularly NO _x -sensitive and aircraft emissions contribute to ozone (O₃) production and oxidation of volatile organic pollutants that ultimately produce secondary organic aerosol (SOA). Rapid growth of the global fleet of aircraft and the number of flights require a careful investigation on the atmospheric impact of potential increases in total aircraft-emitted NO _x . In this study, we simulated atmospheric composition before, during and after two 10× pulses of total aircraft NO _x emissions, one in winter and one in summer of 2007. Results showed that the initial NO _x enhancement (up to 3.25% averaged over the globe) was removed after the first 2 months and the change in O₃ burden increases for 5 months (up to 3.1 and 2.7% averaged over the globe, respectively, for winter and summer perturbations). The NO _x and O₃ enhancements follow previously observed temporal patterns, but SOA showed strong season-specific results. During the summer, the NO _x pulse decreased total secondary organic gases (SOGs) and SOA burdens, suggesting an inverse relationship with enhanced oxidation. During the winter, the NO _x pulse increased the SOG and SOA burdens with SOA lagging SOG. The SOG enhancement has a spatio-temporal pattern similar to NO _x . The highest changes in SOA and SOG burdens of different regions during the summer and winter pulse increases were below 1.6%. However, O₃ pollution with burden increases as high as 8% in the winter months and 6% in the summer months of the northern hemisphere may even represent an air quality concern.     

Urinary α<Subscript>1</Subscript>-microglobulin excretion as biomarker of renal toxicity in trichloroethylene-exposed persons

Objectives Concern on human renal toxicity and carcinogenicity of trichloroethylene is based on findings of increased incidences of renal cell cancers in persons with long-lasting and high occupational exposures to this solvent. The full tumour development is likely to require promotional stimuli, by repetitive episodes of high peak exposures to trichloroethylene, leading to nephrotoxicity. This process is visualised by the excretion of tubular marker proteins in the urine of exposed persons. For this purpose, surveillance of ₁-microglobulin excretion is being suggested by the Deutsche Forschungsgemeinschaft.Methods The present study assessed the applicability of ₁-microglobulin as a biomarker of proximal tubule damage in the prevention of nephrotoxicity by trichloroethylene exposures. For this purpose, ₁-microglobulin excretions were assessed in trichloroethylene-exposed and non-exposed subgroups of both cases (diseased with renal cancer) and controls (not diseased with renal cancer) of a recent case–control study.Results The median of ₁-microglobulin excretions in non-exposed persons was below the detection limit, but it was clearly elevated in exposed persons. The Wilcoxon rank sum test showed a significant difference (P=0.0090). Consistent with the underlying concept, renal cell cancer cases who had been exposed to trichloroethylene had higher ₁-microglobulin excretions than non-exposed cases (P=0.0005) and also had higher ₁-microglobulin excretions than exposed controls (P=0.0004). Of 20 trichloroethylene-exposed renal cell cancer cases only three (15%) displayed a normal ₁-microglobulin excretion of <5 mg/l. By contrast, 41 (52%) out of 79 non-exposed renal cancer cases showed normal excretions of the biomarker.Conclusion The present data are in agreement with the concept of pathogenesis of renal cell cancers developing under high (suggested: >500 ppm peak exposures) and long-term (several years) exposure to trichloroethylene. They also visualise the potential value of ₁-microglobulin excretion as a routine biomarker of renal toxicity that may be used in the medical surveillance of trichloroethylene-exposed persons.     

A defect in Δ<Superscript>6</Superscript> and Δ<Superscript>5</Superscript> desaturases may be a factor in the initiation and progression of insulin resistance,the metabolic syndrome and ischemic heart disease in South Asians

The high incidence of insulin resistance and the metabolic syndrome in South Asians remains unexplained. I propose that a defect in the activity of Δ⁶ and Δ⁵ desaturases and consequent low plasma and tissue concentrations of polyunsaturated fatty acids such as γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and formation of their anti-inflammatory products prostaglandin E₁ (PGE₁), prostacyclin (PGI₂), PGI₃, lipoxins, resolvins, protectins, maresins and nitrolipids could be responsible for the high incidence of insulin resistance, the metabolic syndrome and ischemic heart disease (IHD) in South Asians. This proposal is supported by the observation that South Asian Indians have lower plasma and tissue concentrations of GLA, DGLA, AA, EPA and DHA, the precursors of PGE₁, PGI₂, PGI₃, lipoxins, resolvins, protectins, and nitrolipids, the endogenous molecules that prevent platelet aggregation, vasoconstriction, thrombus formation, leukocyte activation and possess anti-inflammatory action and thus, are capable of preventing the development of insulin resistance, atherosclerosis, hypertension, type 2 diabetes mellitus and premature ischemic heart disease. Genetic predisposition, high carbohydrate intake, lack of exercise, tobacco use and low birth weight due to maternal malnutrition suppress the activity of Δ⁶ and Δ⁵ desaturases that leads to low plasma and tissue concentrations of polyunsaturated fatty acids and their products. This implies that adequate provision of polyunsaturated fatty acids and co-factors needed for their metabolism, and efforts to enhance the formation of their beneficial metabolites PGE₁, PGI₂, PGI₃, lipoxins, resolvins, protectins, maresins and nitrolipids could form a novel approach in the prevention and management of these diseases in this high-risk population.     

Validity of environmental audits using GigaPan<Superscript>®</Superscript> and Google Earth Technology

Background

Health behaviors are shaped by the context in which people live. However, documenting environmental context has remained a challenge. More specifically, direct observation techniques require large investments in time and resources and auditing the environment through web-based platforms has limited stability in spatio-temporal imagery. This study examined the validity of a new methodology, using GigaPan^® imagery, where we took photos locally and, stitched them together using GigaPan^® technology, and quantified environmental attributes from the resulting panoramic photo. For comparison, we examined validity using Google Earth imagery.

Methods

A total of 464 street segments were assessed using three methods: GigaPan^® audits, Google Earth audits, and direct observation audits. Thirty-seven different attributes were captured representing three broad constructs: land use, traffic and safety, and amenities. Sensitivity (i.e. the proportion of true positives) and specificity (i.e. the proportion of true negatives) were used to estimate the validity of GigaPan^® and Google Earth audits using direct observation audits as the gold standard.

Results

Using GigaPan^®, sensitivity was 80% or higher for 6 of 37 items and specificity was 80% or higher for 31 of 37 items. Using Google Earth, sensitivity was 80% or higher for 8 of 37 items and specificity was 80% or higher for 30 of 37 items. The validity of GigaPan^® and Google Earth was similar, with significant differences in sensitivity and specificity for 7 items and 2 items, respectively.

Conclusion

GigaPan^® performed well, especially when identifying features absent from the environment. A major strength of the GigaPan^® technology is its ability to be implemented quickly in the field relative to direct observation. GigaPan^® is a method to consider as an alternative to direct observation when temporality is prioritized or Google Earth imagery is unavailable.

     

One Key Question<Superscript>®</Superscript>: First Things First in Reproductive Health

Objectives Preconceptional health care is increasingly recognized as important to promotion of healthy birth outcomes. Preconceptional care offers an opportunity to influence pregnancy timing and intent and mother’s health status prior to conception, all predictors of individual outcomes and of inequality in birth outcomes based on race, ethnicity and class. Methods One Key Question, a promising practice developed in Oregon which is now attracting national interest, provides an entry point into preconceptional care by calling on providers to screen for pregnancy intent in well woman and chronic disease care for women of reproductive age. For women who choose not to become pregnant or are not definitive in their pregnancy intent, One Key Question provides an opportunity for provision of or referral to counseling and contraceptive care. Results Adoption of One Key Question and preconceptional care as standard practices will require important shifts in medical practice challenging the longstanding schism between well woman care generally and reproductive care in particular. Adoption will also require shifts in cultural norms which define the onset of pregnancy as the appropriate starting point for attention to infant health. Conclusions for Practice This commentary reviews the case for preconceptional care, presents the rationale for One Key Question as a strategy for linking primary care to preconceptional and/or contraceptive care for women, outlines what is entailed in implementation of One Key Question in a health care setting, and suggests ways to build community support for preconceptional health.     

Linkage between the PROMIS<Superscript>®</Superscript> pediatric and adult emotional distress measures

Purpose

Research studies that measure health-related quality of life (HRQOL) in both children and adults and longitudinal studies that follow children into adulthood need measures that can be compared across these age groups. This study links the PROMIS pediatric and adult emotional distress measures using data from participants with diverse health conditions and disabilities.

Methods

Analyses were conducted and compared in two separate samples to confirm the stability of results. One sample (n = 874) included individuals aged 14–20 years with special health care needs and who require health services. The other sample (n = 641) included individuals aged 14–25 years who have a physical or cognitive disability. Participants completed both PROMIS pediatric and adult measures. Item response theory-based scores were linked using the linear approximation to calibrated projection.

Results

The estimated latent-variable correlation between pediatric and adult PROMIS measures ranged from 0.87 to 0.94. Regression coefficients β ₀ (intercept) and β ₁ (slope), and mean squared error are provided to transform scores from the pediatric to the adult measures, and vice versa.

Conclusions

This study used a relatively new linking method, calibrated projection, to link PROMIS pediatric and adult measure scores, thus expanding the use of PROMIS measures to research that includes both populations.

     

Measuring the health status burden in hemodialysis patients using the SF-36<Superscript>®</Superscript> health survey

Purpose  

The SF-36, a generic measure of 8 domains of health-related quality of life (HRQOL), has been widely used to examine HRQOL of end-stage renal disease (ESRD) patients undergoing hemodialysis (HD). The current study synthesizes existing literature to examine which SF-36 domains capture the largest burden in this patient population.     

Implementing Intervention Research into Public Policy—the “I<Superscript>3</Superscript>-Approach”

Evidence-based intervention programs have become highly important in recent years, especially in educational contexts. However, transferring these programs into practice and into the wider field of public policy often fails. As a consequence, the field of implementation research has emerged, several implementation frameworks have been developed, and implementation studies conducted. However, intervention research and implementation research have not yet been connected systematically and different traditions and research groups are involved. Implementation researchers are mostly given mandates by politicians to take on the implementation of already existing interventions. This might be one of the key reasons why there are still many problems in translating programs into widespread community practice. In this paper, we argue for a systematic integration of intervention and implementation research (“I³-Approach”) and recommend a six-step procedure (PASCIT). This requires researchers to design and develop intervention programs using a field-oriented and participative approach. In particular, the perspective of policymakers has to be included as well as an analysis of which factors support or hinder evidence-based policy in contrast to opinion-based policy. How this systematic connection between intervention and implementation research can be realized, is illustrated by means of the development and implementation of the ViSC school program, which intends to reduce aggressive behavior and bullying and to foster social and intercultural competencies.     

Does the biomarker <Superscript>15</Superscript>N-lactose ureide allow to estimate the site of fermentation of resistant starch?

We evaluated the effect of resistant starch (RS) and resistant starch with wheat bran (RS+WB) on the colonic ammonia metabolism in healthy volunteers using the biomarker (15)N-lactose ureide ((15)N-LU). Particularly, it was investigated whether this biomarker allowed to estimate differences in the site of fermentation. Ten volunteers were included in a placebo-controlled crossover study. They consumed in random order 2 x 15 g RS/day for 2 weeks and placebo for 2 weeks separated by 2 weeks wash-out. At baseline, on the first day of each intake period and after each intake period, they consumed a (15)N-labelled test meal and collected all urine in different fractions for 48 h. In ten other volunteers, the effect of 2 x 15 g RS/day and of 2 x 15 g RS + 2 x 6 g WB was compared. These volunteers collected urine and feces for 72 h. (15)N-content of urine and feces was measured using combustion-isotope ratio mass spectrometry. RS exerted a significant decrease in cumulative urinary (15)N-excretion which was different from placebo. The effect was most pronounced in the 6-24 h urine fraction which suggest fermentation in the proximal colon. The effect of RS+WB on cumulative urinary (15)N-excretion was not significantly different from the effect of RS. A less pronounced decrease in the 6-24 h fraction was observed suggesting less fermentation in the proximal colon whereas no indications for more distal fermentation were observed. Since about 80% of the cumulative urinary (15)N was recovered within 24 h, it was concluded that the biomarker (15)N-LU was useful to monitor processes in the proximal colon rather than in the distal colon.     

Fruitflow<Superscript>®</Superscript>: the first European Food Safety Authority-approved natural cardio-protective functional ingredient

Hyperactive platelets, in addition to their roles in thrombosis, are also important mediators of atherogenesis. Antiplatelet drugs are not suitable for use where risk of a cardiovascular event is relatively low. It is therefore important to find alternative safe antiplatelet inhibitors for the vulnerable population who has hyperactive platelets in order to reduce the risk of cardiovascular disease. Potent antiplatelet factors were identified in water-soluble tomato extract (Fruitflow^®), which significantly inhibited platelet aggregation. Human volunteer studies demonstrated the potency and bioavailability of active compounds in Fruitflow^®. Fruitflow^® became the first product in Europe to obtain an approved, proprietary health claim under Article 13(5) of the European Health Claims Regulation 1924/2006 on nutrition and health claims made on foods. Fruitflow^® is now commercially available in different countries worldwide. In addition to its reduction in platelet reactivity, Fruitflow^® contains anti-angiotensin-converting enzyme and anti-inflammatory factors, making it an effective and natural cardio-protective functional food.     

PROMIS<Superscript>®</Superscript>-29 v2.0 profile physical and mental health summary scores

Purpose

The PROMIS-29 v2.0 profile assesses pain intensity using a single 0–10 numeric rating item and seven health domains (physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance) using four items per domain. This paper describes the development of physical and mental health summary scores for the PROMIS-29 v2.0.

Method

We conducted factor analyses of PROMIS-29 scales on data collected from two internet panels (n?=?3000 and 2000).

Results

Confirmatory factor analyses provided support for a physical health factor defined by physical function, pain (interference and intensity), and ability to participate in social roles and activities, and a mental health factor defined primarily by emotional distress (anxiety and depressive symptoms). Reliabilities for these two summary scores were 0.98 (physical health) and 0.97 (mental health). Correlations of the PROMIS-29 v2.0 physical and mental health summary scores with chronic conditions and other health-related quality of life measures were consistent with a priori hypotheses.

Conclusions

This study develops and provides preliminary evidence supporting the reliability and validity of PROMIS-29 v2.0 physical and mental health summary scores that can be used in future studies to assess impacts of health care interventions and track changes in health over time. Further evaluation of these and alternative summary measures is recommended.

     

Establishing clinical severity for PROMIS<Superscript>®</Superscript> measures in adult patients with rheumatic diseases

Purpose

Different patient-reported outcome (PRO) measures are used for rheumatic diseases (RD). The aims of this study are—(1) Identify PROMIS^® domains most relevant to care of patients with RD, (2) Collect T-Score metrics in patients with RD, and (3) Identify clinically meaningful cut-points for these domains.

Methods

A convenience sample of RD patients was recruited consecutively during clinic visits, and asked to complete computer-adaptive tests on thirteen Patient-Reported Outcomes Measurement Information System (PROMIS^®) instruments. Based on discussion with clinical providers, four measures were chosen to be relevant and actionable (from rheumatologists’ perspective) in RD patients. Data from RD patients were used to develop clinical vignettes across a range of symptom severity. Vignettes were created based on most likely item responses at different levels on the T-score metric (mean?=?50; SD?=?10) and anchored at 5-point intervals (0.5 SDs). Patients with RD (N?=?9) and clinical providers (N?=?10) participated as expert panelists in separate one-day meetings using a modified educational standard setting method.

Results

Four domains (physical function, pain interferences, sleep disturbance, depression) that are actionable at the point-of-care were selected. For all domains, patients endorsed cut-points at lower levels of impairment than providers by 0.5 to 1 SD (e.g., severe impairment in physical function was defined as a T-score of 35 by patients and 25 by providers).

Conclusions

We used a modified educational method to estimate clinically relevant cut-points to classify severity for PROMIS measures This allows for meaningful interpretation of PROMIS^® measures in a clinical setting of RD population.

     

Determination of Aflatoxin M<Subscript>1</Subscript> in Breast Milk Samples in Tabriz–Iran

The aim of this study was to examine the exposure of lactating mothers to aflatoxins using aflatoxin M₁ in breast milk as a biomarker for exposure and to detect its determining factors and possible effects on child growth. A 9% sample of 2022 lactating women who exclusively breastfed their infants, including 91 lactating women of urban areas of Tabriz city and 91 lactating women of its rural areas were recruited by a geographical clustered sampling method. Breast milk samples and information on food intake were collected from subjects using structured food-frequency questionnaire. Extraction of AFM₁ was performed with the ELISA test procedure. Aflatoxin M₁ was detected in breast milk of 20 out of 91 mothers (22%) in concentrations of 6.96 ± 0.94 (pg/ml) in rural areas. Aflatoxin M₁ contamination was not present in samples of urban areas. The presence of aflatoxin M₁ was significantly associated with consumption of local milk (β = 0.71, P < 0.001) and stunted growth in children (β = −0.31, P < 0.015). These findings emphasize the need for developing strategies to reduce exposure to aflatoxin, possibly involving interventions targeted at reducing contamination of foods.