Association between environmental exposure to perchlorate, nitrate, and thiocyanate and serum α-Klotho levels among adults from the National Health and nutrition examination survey (2007-2014).

BACKGROUND & AIMS: Aging is a pathophysiological process driven by a diverse set of complex biological processes, and environmental pollution plays an important role in this process. This study aimed to explore the association between serum α-Klotho levels and urinary perchlorate, nitrate, and thiocyanate levels. METHODS: This secondary dataset analysis included 4875 participants (mean age, 57.69 year; male, 49.58%; non-Hispanic White, 47.67%) from the US National Health and Nutrition Examination Survey (2007-2014). Enzyme-linked immunosorbent assay was used to quantify α-Klotho levels, and ion chromatography coupled with electrospray tandem mass spectrometry was used to quantify thiocyanate, nitrate, and perchlorate levels. Multivariate linear regression models were applied to estimate the association between perchlorate, nitrate, and thiocyanate levels and serum α-Klotho levels. RESULTS: Urinary thiocyanate levels were negatively associated with α-Klotho levels (ß = - 0.006; 95% confidence interval, - 0.010 to - 0.003; P = 0.0004) after adjusting for age, sex, body mass index, race, alcohol consumption, estimated glomerular filtration rate, underlying disease, physical activity, smoking status, usual energy intake, and urinary creatinine and serum cotinine levels and mutual adjustment of urinary perchlorate, urinary nitrate, and urinary thiocyanate levels. The α-Klotho level in participants in the highest quartile was higher by 50.567 ng/mL (ß = 50.567; 95% confidence interval, 14.407 to 86.726; P = 0.009) than that in participants in the lowest quartile of urinary perchlorate. A linear relationship was observed between urinary thiocyanate and α-Klotho levels. CONCLUSIONS: Urinary thiocyanate levels were negatively associated with serum α-Klotho levels. Urinary thiocyanate should be further investigated as a potential mediator of aging and age-related diseases.

Sex-Dependent Effects of Nephron Ift88 Disruption on BP, Renal Function, and Cystogenesis.

BACKGROUND: Primary cilia regulation of renal function and BP in health and disease is incompletely understood. This study investigated the effect of nephron ciliary loss on renal physiology, BP, and ensuing cystogenesis. METHODS: Mice underwent doxycycline (DOX)-inducible nephron-specific knockout (KO) of the Ift88 gene at 2 months of age using a Cre-LoxP strategy. BP, kidney function, and renal pathology were studied 2 and 9 months after DOX (Ift88 KO) or vehicle (control). RESULTS: At 2 months post-DOX, male, but not female, Ift88 KO, compared with sex-matched control, mice had reduced BP, enhanced salt-induced natriuresis, increased urinary nitrite and nitrate (NOx) excretion, and increased kidney NOS3 levels, which localized to the outer medulla; the reductions in BP in male mice were prevented by L-NAME. At 9 months post-DOX, male, but not female, Ift88 KO mice had polycystic kidneys, elevated BP, and reduced urinary NOx excretion. No differences were observed in plasma renin concentration, plasma aldosterone, urine vasopressin, or urine PGE2 between Ift88 KO and control mice at 2 or 9 months post-DOX. CONCLUSIONS: Nephron cilia disruption in male, but not female, mice (1) reduces BP prior to cyst formation, (2) increases NOx production that may account for the lower BP prior to cyst formation, and (3) induces polycystic kidneys that are associated with hypertension and reduced renal NO production.

Urinary nitrate concentration as a marker for kidney transplant rejection.

BACKGROUND: Early identification and treatment of kidney transplant rejection episodes is vital to limit loss of function and prolong the life of the transplanted kidney and recipient. Current practice depends on detecting a creatinine rise. A biomarker to diagnose transplant rejection at an earlier time point than current practice, or to inform earlier decision making to biopsy, could be transformative. It has previously been shown that urinary nitrate concentration is elevated in renal transplant rejection. Nitrate is a nitric oxide (NO) oxidation product. Transplant rejection upregulates NO synthesis via inducible nitric oxide synthase leading to elevations in urinary nitrate concentration. We have recently validated a urinary nitrate concentration assay which could provide results in a clinically relevant timeframe. Our aim was to determine whether urinary nitrate concentration is a useful tool to predict renal transplant rejection in the context of contemporary clinical practice. METHODS: We conducted a prospective observational study, recruiting renal transplant participants over an 18-month period. We made no alterations to the patients' clinical care including medications, immunosuppression, diet and frequency of visits. We collected urine samples from every clinical attendance. We assessed the urinary nitrate to creatinine ratio (uNCR) between patient groups: routine attendances, biopsy proven rejection, biopsy proven no rejection and other call backs. uNCR was examined over time for those with biopsy proven transplant rejection. These four groups were compared using an ANOVA test. RESULTS: A total of 2656 samples were collected. uNCR during biopsy proven rejection, n = 15 (median 49 µmol/mmol, IQR 23-61) was not significantly different from that of routine samples, n = 164 (median 55 µmol/mmol, IQR 37-82) (p = 0.55), or biopsy proven no rejection, n = 12 (median 39 µmol/mmol, IQR 21-89) (P = 0.77). Overall uNCR was highly variable with no diagnostic threshold for kidney transplant rejection. Furthermore, within-patient uNCR was highly variable over time, and thus it was not possible to produce individualised patient thresholds to identify rejection. The total taking Tacrolimus was 204 patients, with no statistical difference between the uNCR of all those on Tacrolimus, against those not, p = 0.18. CONCLUSION: The urinary nitrate to creatinine ratio is not a useful biomarker for renal transplant rejection.

Renomedullary Interstitial Cell Endothelin A Receptors Regulate BP and Renal Function.

BACKGROUND: The physiologic role of renomedullary interstitial cells, which are uniquely and abundantly found in the renal inner medulla, is largely unknown. Endothelin A receptors regulate multiple aspects of renomedullary interstitial cell function in vitro. METHODS: To assess the effect of targeting renomedullary interstitial cell endothelin A receptors in vivo, we generated a mouse knockout model with inducible disruption of renomedullary interstitial cell endothelin A receptors at 3 months of age. RESULTS: BP and renal function were similar between endothelin A receptor knockout and control mice during normal and reduced sodium or water intake. In contrast, on a high-salt diet, compared with control mice, the knockout mice had reduced BP; increased urinary sodium, potassium, water, and endothelin-1 excretion; increased urinary nitrite/nitrate excretion associated with increased noncollecting duct nitric oxide synthase-1 expression; increased PGE2 excretion associated with increased collecting duct cyclooxygenase-1 expression; and reduced inner medullary epithelial sodium channel expression. Water-loaded endothelin A receptor knockout mice, compared with control mice, had markedly enhanced urine volume and reduced urine osmolality associated with increased urinary endothelin-1 and PGE2 excretion, increased cyclooxygenase-2 protein expression, and decreased inner medullary aquaporin-2 protein content. No evidence of endothelin-1-induced renomedullary interstitial cell contraction was observed. CONCLUSIONS: Disruption of renomedullary interstitial cell endothelin A receptors reduces BP and increases salt and water excretion associated with enhanced production of intrinsic renal natriuretic and diuretic factors. These studies indicate that renomedullary interstitial cells can modulate BP and renal function under physiologic conditions.

Renal nitrate clearance in chronic kidney disease.

BACKGROUND: Nitric oxide (NO) is rapidly oxidised in humans to nitrite and nitrate, with nitrate being present in much greater abundance. These oxidation products can be recycled back into nitric oxide via a complex entero-salivary pathway, thus preserving NO activity. Approximately 65% of circulating nitrate is excreted in the urine in 48 h, with the excretory pathway of the remainder unknown. The effect of declining renal function on nitrate clearance is unknown METHODS: Forty five subjects, 21 M, 24F, median age 69 (range 27-75 years) with renal function assessed by CKD-EPI eGFR between 9 and 89 ml/min/1.73 m2 completed the study. Following a 24 h low nitrate diet a microplate spectrophotometric method was employed to measure plasma nitrate concentration and 24 h urinary nitrate excretion were measured to determine renal nitrate clearance. RESULTS: There was a strong positive correlation between urinary nitrate clearance and eGFR, (Spearman R = 0.7665, p < 0.0001) with a moderate negative correlation between plasma nitrate concentration and CKD-EPI eGFR, (Spearman's R = -0.37, p = 0.012). There was a trend between fractional excretion of nitrate and CKD-EPI eGFR (ml/min/1.73 m2) Spearman's R 0.27, p = 0.07 though this did not reach statistical significance. Plasma nitrate concentration and serum creatinine concentration were positively correlated, Spearman's R = 0.39, p = 0.008. CONCLUSIONS: We have observed a strong positive association between renal nitrate clearance and renal function such that plasma nitrate rises as renal function falls. Fractional excretion of nitrate appears to decline as renal function falls. As such, urinary nitrate excretion is unlikely to be a reliable marker of endogenous NO synthesis in settings where renal function is altered.

Consumption of Nitrate-Rich Beetroot Juice with or without Vitamin C Supplementation Increases the Excretion of Urinary Nitrate, Nitrite, and N-nitroso Compounds in Humans.

Consumption of nitrate-rich beetroot juice (BRJ) by athletes induces a number of beneficial physiological health effects, which are linked to the formation of nitric oxide (NO) from nitrate. However, following a secondary pathway, NO may also lead to the formation of N-nitroso compounds (NOCs), which are known to be carcinogenic in 39 animal species. The extent of the formation of NOCs is modulated by various other dietary factors, such as vitamin C. The present study investigates the endogenous formation of NOCs after BRJ intake and the impact of vitamin C on urinary NOC excretion. In a randomized, controlled trial, 29 healthy recreationally active volunteers ingested BRJ with or without additional vitamin C supplements for one week. A significant increase of urinary apparent total N-nitroso Compounds (ATNC) was found after one dose (5 to 47 nmol/mmol: p < 0.0001) and a further increase was found after seven consecutive doses of BRJ (104 nmol/mmol: p < 0.0001). Vitamin C supplementation inhibited ATNC increase after one dose (16 compared to 72 nmol/mmol, p < 0.01), but not after seven daily doses. This is the first study that shows that BRJ supplementation leads to an increase in formation of potentially carcinogenic NOCs. In order to protect athlete's health, it is therefore important to be cautious with chronic use of BRJ to enhance sports performances.

Curcumin prevents potassium dichromate (K2Cr2O7)-induced renal hypoxia.

Curcumin exhibits several therapeutic properties. Potassium dichromate (K2Cr2O7)-induced nephropathy is associated with oxidative stress. Reactive oxygen species production affects renal oxygenation that may participate in the progression of renal damage. The aim of the present work was to elucidate whether K2Cr2O7-induced nephropathy is associated to partial O2 pressure (pO2) impairment and if curcumin is able to prevent it. Four groups of rats were studied: control group; K2Cr2O7 group (12.5 mg/kg, s.c.); curcumin + K2Cr2O7 group, in which animals were treated with curcumin (400 mg/kg/day, p.o.) for 10 days before K2Cr2O7 injection; and curcumin group. All animals were sacrificed 48 h after the end of the treatments. K2Cr2O7 administration increased renal function markers and decreased glomerular filtration rate, pO2 and renal perfusion. Concerning hemodynamic parameters, K2Cr2O7 increased mean arterial pressure and renal vascular resistance and reduced renal blood flow. The hemodynamic changes were attributed to decreased availability of nitric oxide and increased 3-nitrotyrosine levels. Moreover, increased superoxide anion production and vascular endothelial growth factor levels were observed after K2Cr2O7 administration. Curcumin attenuated all the above-described alterations. Our results suggest that the protective effects of curcumin in K2Cr2O7-induced nephropathy are associated with its ability to prevent O2 supply reduction.

Disparity of nitrate and nitrite in vivo in cancer villages as compared to other areas in Huai River Basin, China.

Saliva and Urine samples were collected for the study on how nitrate and nitrite concentration in human body may be related to the corresponding health risk in a high cancer incidence area. The study area includes three known cancer villages in Huai River basin, China. The results of analyzing collected sample show that there are higher levels of nitrate and nitrite concentration in human saliva and urine sample collected in the study area as compared to those collected in other areas. In addition, levels of nitrate and nitrite concentration in saliva and urine sample change significantly with the ages of sampled population. NO3-concentrations in saliva and urine sample are the most outstanding among the middle-aged and elderly populations. It means that the middle-aged and elderly populations have relatively high vivo nitrate reductive transformation rates and they also have higher N-nitroso compounds synthesis risks in the studied cancer villages.

Exposure to perchlorate, nitrate and thiocyanate, and prevalence of diabetes mellitus.

Background: It is known that perchlorate, nitrate and thiocyanate have the property of inhibiting sodium iodide symporter. Animal studies have suggested that these compounds, especially perchlorate, might also interfere with insulin secretion. However, the association between their exposure and diabetes risk is largely unknown in humans. Methods: Among 11 443 participants (mean age 42.3 years) from the National Health and Nutritional Examination Survey 2001-14, urinary perchlorate, nitrate and thiocyanate were measured by using ion chromatography coupled with electrospray tandem mass spectrometry. Diabetes was defined as self-reported doctor diagnosis, use of oral hypoglycaemic medication or insulin, fasting plasma glucose ≥ 126 mg/dl or glycated haemoglobin A1c (HbA1c) ≥ 6.5%. Results: The median (interquartile range) levels of urinary perchlorate, nitrate and thiocyanate were 3.32 (1.84, 5.70) µg/l, 46.4 (27.9, 72.0) mg/l and 1.23 (0.59, 2.78) mg/l, respectively. Higher levels of urinary perchlorate were associated with elevated levels of fasting glucose, HbA1c, insulin and homeostatic model assessment of insulin resistance (all Ptrend < 0.001). After multivariate adjustment including urinary creatinine, smoking status and body mass index (BMI), higher urinary perchlorate, but not nitrate or thiocyanate, was associated with an increased prevalence of diabetes mellitus. Comparing extreme quintiles, the odds ratio (95% confidence interval) of diabetes was 1.53 (1.21, 1.93; Ptrend < 0.001) for perchlorate, 1.01 (0.77, 1.32; Ptrend = 0.44) for nitrate and 0.98 (0.73, 1.31; Ptrend = 0.64) for thiocyanate. When urinary perchlorate, nitrate and thiocyanate were further mutually adjusted, the results did not materially change. Similar results were observed when analyses were stratified by smoking status, as well as by age, gender, kidney function and BMI. Conclusions: Higher urinary perchlorate levels are associated with an increased prevalence of diabetes mellitus, independent of traditional risk factors. Future prospective studies are needed to confirm these findings.

Relationship Between Urinary Nitrate Excretion and Blood Pressure in the InChianti Cohort.

BACKGROUND: Inorganic nitrate from the oxidation of endogenously synthesized nitric oxide (NO) or consumed in the diet can be reduced to NO via a complex enterosalivary circulation pathway. The relationship between total nitrate exposure by measured urinary nitrate excretion and blood pressure in a large population sample has not been assessed previously. METHODS: For this cross-sectional study, 24-hour urinary nitrate excretion was measured by spectrophotometry in the 919 participants from the InChianti cohort at baseline and blood pressure measured with a mercury sphygmomanometer. RESULTS: After adjusting for age and sex only, diastolic blood pressure was 1.9 mm Hg lower in subjects with ≥2 mmol urinary nitrate excretion compared with those excreting <1 mmol nitrate in 24 hours: systolic blood pressure was 3.4 mm Hg (95% confidence interval (CI): -3.5 to -0.4) lower in subjects for the same comparison. Effect sizes in fully adjusted models (for age, sex, potassium intake, use of antihypertensive medications, diabetes, HS-CRP, or current smoking status) were marginally larger: systolic blood pressure in the ≥2 mmol urinary nitrate excretion group was 3.9 (CI: -7.1 to -0.7) mm Hg lower than in the comparison <1 mmol excretion group. CONCLUSIONS: Modest differences in total nitrate exposure are associated with lower blood pressure. These differences are at least equivalent to those seen from substantial (100 mmol) reductions in sodium intake.

Thyroid antagonists and thyroid indicators in U.S. pregnant women in the Vanguard Study of the National Children's Study.

The sodium iodide-symporter (NIS) mediates uptake of iodide into thyroid follicular cells. This key step in thyroid hormone synthesis is inhibited by perchlorate, thiocyanate (SCN) and nitrate (NO3) anions. When these exposures occur during pregnancy the resulting decreases in thyroid hormones may adversely affect neurodevelopment of the human fetus. Our objectives were to describe and examine the relationship of these anions to the serum thyroid indicators, thyroid stimulating hormone (TSH) and free thyroxine (FT4), in third trimester women from the initial Vanguard Study of the National Children's Study (NCS); and to compare urine perchlorate results with those in pregnant women from the National Health and Nutritional Examination Survey (NHANES). Urinary perchlorate, SCN, NO3, and iodine, serum TSH, FT4, and cotinine were measured and a food frequency questionnaire (FFQ) was administered to pregnant women enrolled in the initial Vanguard Study. We used multiple regression models of FT4 and TSH that included perchlorate equivalent concentration (PEC, which estimates combined inhibitory effects of the anions perchlorate, SCN, and NO3 on the NIS). We used multiple regression to model predictors of each urinary anion, using FFQ results, drinking water source, season of year, smoking status, and demographic characteristics. Descriptive statistics were calculated for pregnant women in NHANES 2001-2012. The geometric mean (GM) for urinary perchlorate was 4.04µg/L, for TSH 1.46mIU/L, and the arithmetic mean for FT4 1.11ng/dL in 359 NCS women. In 330 women with completed FFQs, consumption of leafy greens, winter season, and Hispanic ethnicity were significant predictors of higher urinary perchlorate, which differed significantly by study site and primary drinking water source, and bottled water was associated with higher urinary perchlorate compared to filtered tap water. Leafy greens consumption was associated with higher urinary NO3 and higher urinary SCN. There was no association between urinary perchlorate or PEC and TSH or FT4, even for women with urinary iodine <100µg/L. GM urinary perchlorate concentrations in the full sample (n=494) of third trimester NCS women (4.03µg/L) were similar to pregnant women in NHANES (3.58µg/L).

Trends and variability in the levels of urinary thiocyanate, perchlorate, and nitrate by age, gender, race/ethnicity, smoking status, and exposure to environmental tobacco smoke over 2005-2012.

Data from National Health and Nutrition Examination Survey for 2005-2012 were used to study the trends and variability in the levels of urinary thiocyanate (u-SCN), perchlorate (u-P8), and nitrate (u-NO3) by gender, race/ethnicity, active smoking, and exposure to environmental tobacco smoke (ETS) at home for those aged 12-19 and ≥20years old. For those aged ≥20years, adjusted levels of u-SCN, u-P8, and u-NO3 (i) were lower for males than females (p<0.01), and (ii) were higher for non-Hispanic white (NHW) than non-Hispanic black (NHB) (p<0.01). Also, for those aged ≥20years NHB had higher adjusted levels than Mexican American (MA) for u-SCN (p<0.01) but NHB had lower adjusted levels than MA for u-P8 (p<0.01) and u-NO3 (p<0.01). For those aged 12-19years, adjusted levels of u-SCN, u-P8, and u-NO3 did not vary by gender (p>0.05), and adjusted levels of u-P8 and u-NO3 for NHB were lower than for NHW (p<0.01) as well as higher for NHB than MA for u-SCN (p<0.01) and lower for NHB than MA (p<0.01) for u-P8 and u-NO3. Among those aged ≥20years, active smoking was associated with higher adjusted levels of u-SCN (p<0.01) in a dose-response manner and active smoking was associated with lower adjusted levels of u-P8 (p<0.01) in a dose-response manner. Exposure to ETS was associated with higher adjusted levels of u-SCN (p=0.02) and lower adjusted levels of u-P8 (p<0.01) among ≥20years old. Adjusted levels of u-P8 decreased over 2005-2012 among both 12-19 (p<0.01) and ≥20years old (p=0.04). There was borderline increase in the adjusted levels of u-NO3 for those aged ≥20years (p=0.05) over 2005-2012.

Plutonium-DTPA Model Application with USTUR Case 0269.

A plutonium-DTPA (Pu-DTPA) biokinetic model was introduced that had originated from the study of a plutonium-contaminated wound. This work evaluated the extension of the Pu-DTPA model to United States Transuranium and Uranium Registry (USTUR) Case 0269 involving an acute inhalation of a plutonium nitrate aerosol. Chelation was administered intermittently for the first 7 mo as Ca-EDTA, mostly through intravenous injection, with Ca-DTPA treatments administered approximately 2.5 y post intake. Urine and fecal bioassays were collected following intake for several years. Tissues were collected and analyzed for plutonium content approximately 38 y post intake. This work employed the Pu-DTPA model for predicting the urine and fecal bioassay and final tissue quantity at autopsy. The Pu-DTPA model was integrated with two separate plutonium systemic models (i.e., ICRP Publication 67 and its proposed modification). This work illustrated that the Pu-DTPA model was useful for predicting urine and fecal bioassay, including final tissue quantity, 38 y post intake.

Thyroid Antagonists (Perchlorate, Thiocyanate, and Nitrate) and Childhood Growth in a Longitudinal Study of U.S. Girls.

BACKGROUND: Perchlorate, thiocyanate, and nitrate are sodium/iodide symporter (NIS) inhibitors that block iodide uptake into the thyroid, thus affecting thyroid function. Thyroid dysfunction can adversely affect somatic growth and development in children. To our knowledge, no studies have examined effects of NIS inhibitors on body size measures. OBJECTIVE: We investigated associations between NIS inhibitors and childhood growth in 940 girls from the Puberty Study of the Breast Cancer and Environment Research Program. METHODS: Urine samples collected from girls 6-8 years of age at enrollment (2004-2007) from New York City, greater Cincinnati, Ohio, and the Bay Area in California were analyzed for NIS inhibitors and creatinine (C). The longitudinal association between NIS inhibitors and anthropometric measures [height, waist circumference, and body mass index (BMI)] during at least three visits was examined using mixed effects linear models, adjusted for race and site. RESULTS: Compared with girls in the low-exposure group (3.6, 626, and 500 mg/gC, median perchlorate, thiocyanate, and nitrate, respectively) girls with the highest NIS inhibitor exposure (9.6, 2,343, and 955 mg/gC, median perchlorate, thiocyanate, and nitrate, respectively) had slower growth in waist circumference and BMI but not height. Significant differences in the predicted mean waist circumference and BMI between the low- and high-exposure groups were observed beginning at 11 years of age. CONCLUSIONS: Higher NIS inhibitor exposure biomarkers were associated with reductions in waist circumference and BMI. These findings underscore the need to assess exposure to NIS inhibitors with respect to their influence on childhood growth. CITATION: Mervish NA, Pajak A, Teitelbaum SL, Pinney SM, Windham GC, Kushi LH, Biro FM, Valentin-Blasini L, Blount BC, Wolff MS, for the Breast Cancer and Environment Research Project (BCERP). 2016. Thyroid antagonists (perchlorate, thiocyanate, and nitrate) and childhood growth in a longitudinal study of U.S. girls. Environ Health Perspect 124:542-549; http://dx.doi.org/10.1289/ehp.1409309.

Association between anaerobic components of the maximal accumulated oxygen deficit and 30-second Wingate test

The purpose of this study was to analyze the relationship between the anaerobic components of the maximal accumulated oxygen deficit (MAOD) and of the 30-second Wingate anaerobic test (30-WAnT). Nine male physical education students performed: a) a maximal incremental exercise test; b) a supramaximal constant workload test to determine the anaerobic components of the MAOD; and c) a 30-WAnT to measure the peak power (PP) and mean power (MP). The fast component of the excess post-exercise oxygen consumption and blood lactate accumulation were measured after the supramaximal constant workload test in order to determine the contributions made by alactic (ALMET) and lactic (LAMET) metabolism. Significant correlations were found between PP and ALMET (r=0.71; P=0.033) and between MP and LAMET (r=0.72; P=0.030). The study results suggested that the anaerobic components of the MAOD and of the 30-WAnT are similarly applicable in the assessment of ALMET and LAMET during high-intensity exercise.

Urinary levels of N-nitroso compounds in relation to risk of gastric cancer: findings from the shanghai cohort study.

BACKGROUND: N-Nitroso compounds are thought to play a significant role in the development of gastric cancer. Epidemiological data, however, are sparse in examining the associations between biomarkers of exposure to N-nitroso compounds and the risk of gastric cancer. METHODS: A nested case-control study within a prospective cohort of 18,244 middle-aged and older men in Shanghai, China, was conducted to examine the association between urinary level of N-nitroso compounds and risk of gastric cancer. Information on demographics, usual dietary intake, and use of alcohol and tobacco was collected through in-person interviews at enrollment. Urinary levels of nitrate, nitrite, N-nitroso-2-methylthiazolidine-4-carboxylic acid (NMTCA), N-nitrosoproline (NPRO), N-nitrososarcosine (NSAR), N-nitrosothiazolidine-4-carboxylic acid (NTCA), as well as serum H. pylori antibodies were quantified in 191 gastric cancer cases and 569 individually matched controls. Logistic regression method was used to assess the association between urinary levels of N-nitroso compounds and risk of gastric cancer. RESULTS: Compared with controls, gastric cancer patients had overall comparable levels of urinary nitrate, nitrite, and N-nitroso compounds. Among individuals seronegative for antibodies to H. pylori, elevated levels of urinary nitrate were associated with increased risk of gastric cancer. The multivariate-adjusted odds ratios for the second and third tertiles of nitrate were 3.27 (95% confidence interval = 0.76-14.04) and 4.82 (95% confidence interval = 1.05-22.17), respectively, compared with the lowest tertile (P for trend = 0.042). There was no statistically significant association between urinary levels of nitrite or N-nitroso compounds and risk of gastric cancer. Urinary NMTCA level was significantly associated with consumption of alcohol and preserved meat and fish food items. CONCLUSION: The present study demonstrates that exposure to nitrate, a precursor of N-nitroso compounds, may increase the risk of gastric cancer among individuals without a history of H. pylori infection.

Improved oxidative status in major abdominal surgery patients after N-acetyl cystein supplementation.

BACKGROUND: Increased levels of reactive oxygen species during and after surgery may affect inflammatory response, post-operative adhesion molecule formation, and hemodynamic stability. The glutathione redox cycle is an important regulator in oxidative stress and its reduced forms scavenge free radicals. N-acetyl cysteine, a precursor of reduced glutathione, is considered as a potentially therapeutic wide spectrum agent in clinical practice. We therefore examined whether N-acetyl cysteine improves some biochemical parameters in cancer patients undergoing major abdominal surgery. METHODS: Thirty-three patients diagnosed with pancreas, stomach, rectum, colon malignancies, and undergoing major abdominal surgery at Ankara Numune Training and Research Hospital were randomly divided into two groups; control (CON) and N-acetyl cysteine (NAC). The NAC group had 1,200 mg N-acetyl cysteine starting two days before the operation day, in addition to isonitrogenous and isocaloric total parenteral nutrition of 1.2 g/kg protein, 25 kcal/kg, and 60:40 carbohydrate/fat ratio. Blood and urine samples were drawn two days before the operation, on operation day, and on the first, third, and fifth days post-operation. RESULTS: Plasma malondialdehyde was significantly lower in the NAC group (P < 0.001). N-acetyl cysteine treatment did not affect plasma levels of vitamin A, C or E. The NAC group exhibited a higher ratio of reduced glutathione to oxidised glutathione (P = 0.019). Urinary nitrate level was also significantly lower in the NAC group (P = 0.016). CONCLUSION: The study demonstrated the clinical importance of N-acetyl cysteine supplementation on antioxidant parameters in abdominal surgery patients. In these patients N-acetyl cysteine and vitamin administration can be considered as an effective method for improvement of oxidative status.

Urinary thiocyanate concentrations are associated with adult cancer and lung problems: US NHANES, 2009-2012.

Links between environmental chemicals and human health have emerged but the effects from perchlorate, nitrate and thiocyanate were unclear. Therefore, it was aimed to study the relationships of urinary perchlorate, nitrate and thiocyanate concentrations and adult health conditions in a national and population-based study. Data was retrieved from US National Health and Nutrition Examination Surveys, 2009-2012, including demographics, blood pressure readings, self-reported health conditions and urinary perchlorate, nitrate and thiocyanate concentrations. Analyses included chi-square test, t test survey-weighted logistic regression models and population attributable risk estimation. There were no clear associations between urinary perchlorate concentrations and adult health conditions, although people with hearing loss and diabetes could be at the borderline risk. Urinary thiocyanate concentrations were significantly associated with emphysema (odds ratio (OR) 2.70 95% confidence intervals (CI) 1.91-3.82, P < 0.001), cancer (OR 1.21 95%CI 1.06-1.39, P = 0.008), chronic bronchitis (OR 1.23 95%CI 1.10-1.52, P = 0.003), wheezing (OR 1.24 95%CI 1.05-1.46, P = 0.011), coughing (OR 1.19 95%CI 1.03-1.37, P = 0.018) and sleep complaints (OR 1.14 95%CI 1.02-1.26, P = 0.019). The population attributable risks accounted for 3.3% (1.8-5.3%), 1.9% (0.6-3.5%), 1.2% (0.5-2.6%), 2.2% (0.5-4.1%), 1.8% (0.3-6.2%) and 1.3% (0.2-2.4%) for emphysema, cancer, chronic bronchitis, wheezing, coughing and sleep complaints, respectively. In addition, there was an inverse association observed between urinary nitrate level and heart failure. This is for the first time observing significant risk effects of urinary thiocyanate concentrations on adult cancer and lung problems, although the causality cannot be established. Elimination of such environmental chemical in humans should be included in future health policy and intervention programs.

The flavonoid quercetin induces acute vasodilator effects in healthy volunteers: correlation with beta-glucuronidase activity.

UNLABELLED: Quercetin exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end-organ damage in hypertensive humans and animal models. We hypothesized that oral quercetin might induce vasodilator effects in humans and that they might be related to the deconjugation of quercetin-3-O-glucuronide (Q3GA). DESIGN: double blind, randomized, placebo-controlled trial. Fifteen healthy volunteers (26±5 years, 6 female) were given a capsule containing placebo, 200 or 400mg of quercetin in random order in three consecutive weeks. At 2h a dose-dependent increase in Q3GA was observed in plasma (∼0.4 and 1µM for 200 and 400mg, respectively) with minor levels of quercetin and isorhamnetin. No changes were observed in blood pressure. At 5h quercetin induced and increase in brachial arterial diameter that correlated with the product of the levels of Q3GA by the plasma glucuronidase activity. There was an increase in urinary levels of glutathione but there was no increase in nitrites plus nitrates. Quercetin and isorhamnetin also relaxed human umbilical arteries in vitro while Q3GA was without effect. In conclusions, quercetin exerts acute vasodilator effects in vivo in normotensive, normocholesterolemic human subjects. These results are consistent with the effects being due to the deconjugation of the metabolite Q3GA.

[Production of nitric oxide metabolites during transplanted tumors growth with different metastatic potential].

The endogenous formation of metabolites of NO - nitrite (NI), nitrates (NA) and volatile nitrosamines in the body, tumor tissue and by abdominal cavity by macrophages for dynamics was investigated in mice F1(C57BlxCBA), Balb/c and BDF with subcutaneous transplanted tumors (Erlich carcinoma - EC and metastatic Lewis lung carcinoma - LLC). It was shown that growth of EC was accompanied by a statistically significant increase in the concentrations of NI and NA in tumor tissue to (7.3±4.67)'10-6 - (7.8±2.57)'10-5 (mol/kg) for the first three weeks and a sharp increase in urinary excretion of NI and NA. The maximum total concentration of NI and NA - (3.,6±0.46)'10-5 in tissue LLC was registered during the early stage of the tumor growth (7 days); it later declined, negatively correlating with the mass of the tumor. NI secretion by abdominal cavity macrophages demonstrated statistically significantly decrease at the stage of intensive growth LLC (14, 21 days). The tissue of EC contained varied concentration of cancerogenic N-nitrosodimethylamine and N-nitrosodiethylamine at all investigated time points. Thus, the ability of different gistogenesis tumor tissue to synthesize metabolites NO depended on time parameters and was more pronounced for EC, than LLC.