Aysel Ozpinar

Perchlorate, nitrate, thiocyanate, and iodide levels in chicken feed, water, and eggs from three farms.

Perchlorate is an inhibitor of iodide uptake that is found widely in the environment. Given the potential for perchlorate accumulation during egg formation and the widespread consumption of eggs, it is important to examine eggs as a source of exposure to perchlorate and other potential inhibitors of iodide uptake (nitrate and thiocyanate). This study was conducted to determine potential human exposure to perchlorate from eggs produced by chicken flocks consuming differing amounts of perchlorate. The mean concentrations of perchlorate (7.16 ( 1.99 microg/kg of dry weight), nitrate (2820 ( 2100 microg/kg of dry weight), thiocyanate (574 +/- 433 microg/kg of dry weight), and iodide (2980 ( 1490 microg/kg of dry weight) in eggs (n = 180) from 15 chicken houses on 3 U.S. farms were determined. Chickens secreted into eggs an average of 23% of the perchlorate ingested from feed and water. Perchlorate levels in eggs were positively correlated with perchlorate intake (p < 0.001). Increased intake of perchlorate, nitrate, and thiocyanate was associated with decreased iodide levels in eggs, possibly indicating a competitive transport mechanism, such as sodium-iodide symporter. It was estimated that egg consumption contributes minimal perchlorate (approximately 0.040 microg) compared to the average total intake of approximately 10.5 microg for U.S. adults. Additionally, it was found that egg consumption was not associated with increased perchlorate exposure in 2820 individuals from the National Health and Nutrition Examination Survey (p value for the difference of least-squares means, pDiff = 0.225). From these findings it was concluded that, although chickens secrete perchlorate in eggs, eggs do not appear to be a significant source of perchlorate exposure for adults in the United States.

Iodine status in Turkish populations and exposure to iodide uptake inhibitors.

Perchlorate, nitrate, and thiocyanate are competitive inhibitors of the sodium iodide symporter of the thyroid membrane. These inhibitors can decrease iodine uptake by the symporter into the thyroid gland and may disrupt thyroid function. This study assesses iodine status and exposure to iodide uptake inhibitors of non-pregnant and non-lactating adult women living in three different cities in Turkey (Istanbul, Isparta and Kayseri). We measured iodine and iodide uptake inhibitors in 24-hr urines collected from study participants (N = 255). All three study populations were mildly iodine deficient, with median urinary iodine (UI) levels of 77.5 µg/L in Istanbul, 58.8 µg/L in Isparta, and 69.8 µg/L in Kayseri. Perchlorate doses were higher in the study population (median 0.13 µg/kg/day), compared with a reference population (median 0.059 µg/kg/day), but lower than the U.S. EPA reference dose (0.7 µg/kg/day). Urinary thiocyanate levels increased with increasing exposure to tobacco smoke, with non-smokers (268 µg/L) significantly lower than light smokers (1110 µg/L), who were significantly lower than heavy smokers (2410 µg/L). This pilot study provides novel data indicating that study participants were moderately iodine deficient and had higher intakes of the iodide uptake inhibitor perchlorate compared with a reference population. Further investigation is needed to characterize the thyroid impact resulting from iodine deficiency coupled with exposure to iodide uptake inhibitors such as perchlorate, thiocyanate and nitrate.

Association of vitamin D receptor polymorphisms and type 1 diabetes susceptibility in children: a meta-analysis

Background There have been studies focused on FokI, BsmI, ApaI and TaqI polymorphisms of the vitamin D receptor (VDR) gene and susceptibility to type 1 diabetes mellitus with controversial results. Methods This present study is a meta-analysis investigating the association between FokI, ApaI, TaqI and BsmI polymorphisms of VDR gene and type 1 DM in children. A literature search was performed using Medline, EMBASE, Cochrane and PubMed. Any study was considered eligible for inclusion if at least one of FokI, ApaI, TaqI and BsmI polymorphisms was determined, and outcome was type 1 DM at pediatric age. Results A total of 9 studies comprising 1053 patients and 1017 controls met the study inclusion criteria. The pooled odds ratios (ORs) of the FokI, ApaI, TaqI and BsmI polymorphisms were combined and calculated. Forest plots and funnel plots of the OR value distributions were drawn. Our meta-analysis has demonstrated statistically significant associations between DM1 and VDR genotypes, BsmIBB (P < 0.05), BsmIBb, (P < 0.05), BsmIbb (P < 0.05), TaqITT (P < 0.05) and TaqItt (P < 0.05) in children. Conclusion The results indicated that BsmIBB, BsmIBb and TaqItt polymorphisms were associated with an increased risk of type 1 DM, whereas BsmIbb and TaqITT had protective effect for type 1 DM in children.

Clinical applications of MALDI imaging technologies in cancer and neurodegenerative diseases

Matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) enables localization of analytes of interest along with histology. More specifically, MALDI-IMS identifies the distributions of proteins, peptides, small molecules, lipids, and drugs and their metabolites in tissues, with high spatial resolution. This unique capacity to directly analyze tissue samples without the need for lengthy sample preparation reduces technical variability and renders MALDI-IMS ideal for the identification of potential diagnostic and prognostic biomarkers and disease gradation. MALDI-IMS has evolved rapidly over the last decade and has been successfully used in both medical and basic research by scientists worldwide. In this review, we explore the clinical applications of MALDI-IMS, focusing on the major cancer types and neurodegenerative diseases. In particular, we re-emphasize the diagnostic potential of IMS and the challenges that must be confronted when conducting MALDI-IMS in clinical settings. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.

Post‐translational modifications of transthyretin affect the triiodonine‐binding potential

Transthyretin (TTR) is a visceral protein, which facilitates the transport of thyroid hormones in blood and cerebrospinal fluid. The homotetrameric structure of TTR enables the simultaneous binding of two thyroid hormones per molecule. Each TTR subunit provides a single cysteine residue (Cys10), which is frequently affected by oxidative post‐translational modifications. As Cys10 is part of the thyroid hormone‐binding channel within the TTR molecule, PTM of Cys10 may influence the binding of thyroid hormones. Therefore, we analysed the effects of Cys10 modification with sulphonic acid, cysteine, cysteinylglycine and glutathione on binding of triiodothyronine (T3) by molecular modelling. Furthermore, we determined the PTM pattern of TTR in serum of patients with thyroid disease by immunoprecipitation and mass spectrometry to evaluate this association in vivo. The in silico assays demonstrated that oxidative PTM of TTR resulted in substantial reorganization of the intramolecular interactions and also affected the binding of T3 in a chemotype‐ and site‐specific manner with S‐glutathionylation as the most potent modulator of T3 binding. These findings were supported by the in vivo results, which indicated thyroid function‐specific patterns of TTR with a substantial decrease in S‐sulphonated, S‐cysteinylglycinated and S‐glutathionylated TTR in hypothyroid patients. In conclusion, this study provides evidence that oxidative modifications of Cys10 seem to affect binding of T3 to TTR probably because of the introduction of a sterical hindrance and induction of conformational changes. As oxidative modifications can be dynamically regulated, this may represent a sensitive mechanism to adjust thyroid hormone availability.

Analysis of Changes in Parathyroid Hormone and 25 (OH) Vitamin D Levels with Respect to Age, Gender and Season: A Data Mining Study

Summary Background: 25 (OH) vitamin D3 (25(OH)D) and parathyroid hormone (PTH) are important regulators of calcium homeostasis. The aim of this study was to retrospectively determine the cut–off for sufficient 25(OH)D in a four-season region and the influence of age, seasons, and gender on serum 25(OH)D and PTH levels. Methods: Laboratory results of 9890 female and 2723 male individuals aged 38.8±22.1 years who had simultaneous measurements of 25(OH)D and PTH were retrospectively analyzed by statistical softwares. Serum 25(OH)D and PTH levels were measured by a mass spectrometry method and by an electrochemiluminescence immunoassay, respectively. Results: Mean serum 25(OH)D levels showed a sinusoidal fluctuation throughout the year and were significantly (p<0.01) higher in summer and autumn. On the other hand, PTH levels were significantly higher (p<0.01) in women and showed an opposite response to seasonal effects relative to 25(OH)D. Lowest levels of 25(OH)D were detected in people aged between 20 and 40 years whereas PTH hormone levels were gradually increasing in response to aging. The significant exponential inverse relationship that was found between PTH and 25(OH)D (PTH=exp(4.12–0.064*sqrt(25(OH)D)) (r=−0.325, R–squared=0.105, p<0.001)) suggested that the cut–off for sufficient 25(OH)D should be 75 nmol/L. Conclusions: Our retrospective study based on large data set supports the suitability of the currently accepted clinical cut–off of 75 nmol/L for sufficient 25(OH)D. However, the issue of assessing Vitamin D deficiency remains difficult due to seasonal variations in serum 25(OH)D. Therefore, PTH measurements should complement 25(OH)D results for diagnosing Vitamin D deficiency. It is imperative that seasonally different criteria should be considered in future.

Hemoglobins, Hemorphins, and 11p15.5 Chromosomal Region in Cancer Biology and İmmunity with Special Emphasis for Brain Tumors.

In systemic cancers, increased hemolysis leads to extracellular hemoglobin (HB), and experimental studies have shown its provoking role on tumor growth and metastasis. However, investigations have shown that HB chains presented by tumor vascular pericytes or serum protein complexes of HB could also induce antitumor immunity, which may be harnessed to treat refractory cancers and brain tumors. Mounting recent evidence shows that expression of HBs is not restricted to erythrocytes and that HBs exist in the cells of lung and kidney, in macrophages, and in neurons and glia of the central nervous system (CNS). HBs mediate coping with hypoxia and free radical stress in normal and tumor cells, and they are increased in certain tumors including breast, lung, colon, and squamous cell cancers. Recent studies showed HBs in meningioma, in the cyst fluid of craniopharyngioma, in the cerebrospinal fluid (CSF) of pediatric patients with posterior fossa tumors, and in glioblastoma cell lines. Hemorphins, abundant brain peptides formed via HB-chain cleavage, exert opioid activity and antiproliferative and immunomodifier effects. Hence mutations in HBs may modify brain tumorigenesis via influencing hemorphins and perturbing regulations of immune surveillance and cell growth in the neuroectodermal tissues. The β-globin gene cluster resides in the chromosome region 11p15.5, harboring important immunity genes and IGF2, H19, PHLDA2/TSSC3, TRIM3, and SLC22A18 genes associated with cancers and gliomas. 11p15.5 is a prominent region subject to epigenetic regulation. Thus the β-globin loci may exert haplotypal interactions with these. Some clues support this theory. It is well established that iron load induces liver cancer in thalassemia major; however iron load-independent associations also exist. Enhanced rates of hematologic malignancies are associated with HB Lepore, association of hemoglobin E with cholangiocarcinoma, and enhanced gastric cancer rates in the thalassemia trait. In the African Herero population, a mutant form of δ-globin is very prevalent, and this population has higher rates of pediatric brain tumors. Globins are also expressed in healthy endothelia and in tumoral vessels, indicating potential involvement in angiogenesis. Studies on HBs and their cleavage peptides in cancers and brain tumors may lead to innovative treatment strategies.

Thyroid status of female rhesus monkeys and preliminary information on impact of perchlorate administration

Thyroid status was assessed in adult female rhesus monkey breeders at the California National Primate Research Center at the beginning of the breeding season. The 95% confidence intervals for thyrotropin (TSH), thyroxine (T4) and triiodothyronine (T3) (n = 66–80) were similar to those previously reported in smaller samples of macaque monkeys. Based on human criteria, 10 of 80 monkeys (12%) were hypothyroid (TSH > 2.0 µIU/mL). Because hypothyroxinaemia can be a risk factor in pregnancy, T4 status was compared with past breeding history, breeding outcome for that season and general health records in a subset of 42 breeders. Age, weight and parity did not differ between monkeys in the lowest T4 quartile as compared with those in the upper three quartiles. However, T4 concentrations were significantly associated with the number of missed menstrual cycles during the previous breeding season. In additional work, three healthy lactating rhesus monkeys were given three different doses of environmental contaminant and thyroid iodine uptake inhibitor, ammonium perchlorate (0.006, 0.34, 12.8 mg/kg/day, respectively) in food for two weeks. Thyroid status variables (TSH, T4, T3, thyroid radioactive iodine uptake) were then measured. In the monkey receiving the highest perchlorate dose, iodine uptake was suppressed relative to baseline. The study shows the availability of tools to study thyroid status in rhesus monkeys, the variability of thyroid status in the breeder colony and the potential ability of environmental factors to influence thyroid status.

Vinorelbine’s anti-tumor actions may depend on the mitotic apoptosis, autophagy and inflammation: hypotheses with implications for chemo-immunotherapy of advanced cancers and pediatric gliomas

Vinorelbine is a very potent chemotherapeutic agent which is used to treat a number of cancers including breast and non-small cell lung tumors. Vinorelbine mainly acts via blocking microtubules and induces a specific type of cell death called ‘mitotic catastrophe/apoptosis’ subsequent to mitotic slippage, which is the failure of cells to stay in a mitotic arrested state and replicating their DNA without cytokinesis. Glial tumor cells are especially sensitive to mitotic slippage. In recent years, vinorelbine demonstrated potency in pediatric optic and pontine gliomas. In this manuscript, we propose that vinorelbine’s anti-tumor actions involve mitotic apoptosis, autophagy and inflammation. Intravenous infusion of vinorelbine induces a peculiar severe pain in the tumor site and patients with highly vascularized, oedematous and necrotic tumors are particularly vulnerable to this pain. Severe pain is a sign of robust inflammation and anti-inflammatory agents are used in treatment of this side effect. However, no one has questioned whether inflammation contributes to anti-tumor effects of vinorelbine, despite the existing data that vinorelbine induces Toll-Like Receptor-4 (TLR4), cytokines and cell death in endothelial cells especially under hypoxia. Robust inflammation may contribute to tumor necrosis such as seen during immunotherapy with lipopolysaccharides (LPS). Evidence also emerges that enhanced cyclooxygenase activity may increase cancer cell death in certain contexts. There are data indicating that non-steroidal anti-inflammatory drugs (NSAIDs) could block anti-tumor efficacy of taxanes, which also work mainly via anti-microtubule actions. Further, combining vinorelbine with immunostimulant cytokines provided encouraging results in far advanced melanoma and renal cell carcinoma, which are highly antigenic tumors. Vinorelbine also showed potential in treatment of inflammatory breast cancer. Finally, pontine gliomas – where partial activity of vinorelbine is shown by some studies – are also tumors which partially respond to immune stimulation. Animal experiments shall be conducted whether TLR4-activating molecules or immune-checkpoint inhibitors could augment anti-tumor actions of vinorelbine. Noteworthy, TLR4-activation seems as the most promising way of cancer immunotherapy, as a high percentage of molecules which demonstrated clinical benefits in cancer treatment are activators of TLR4, including BCG vaccine, monophosphoryl lipid A and picibanil (OKT-432). The provided data would be meaningful for the oncological practice.

Thyroidal radioactive iodide uptake in the lactating rhesus monkey.

Although radioactive iodide uptake (RAIU) is one of the reliable diagnostic methods for thyroid function in adult humans, especially in the diagnosis of thyrotoxicosis, there are limited data for RAIU during pregnancy and lactation in humans and animals. Therefore, we proposed to validate RAIU for the lactating rhesus monkey to further human model studies in thyroid disease. RAIU was performed at 6 and 24 h using 100 µCi of 123I orally in four lactating monkeys. The thyroid and thigh were counted using a scintillation probe and multichannel analyser. A dose/standard ratio of counts/minute was calculated to compensate for background, utilizing differences in the activity between the dose administered and a standard. Thyroidal RAIU varied significantly among monkeys: 6.71 ± 2.40% for the 6 h uptake and 15.44 ± 7.71% for the 24 h uptake. These data showed that the RAIU test may allow a rational clinical approach to thyroid function testing for lactating rhesus monkeys. Additional studies are needed for assessing thyroid function in rhesus monkeys of varying ages and gender with clinical abnormalities.