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Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide, CAP) is an important ingredient in spicy foods consumed throughout the world. Vinblastine (VBL) is a naturally occurring alkaloid prescribed to cancer patients. Many cancer patients treated with VBL were taking CAP at the same time. This study attempted to investigate the effect of CAP on the pharmacokinetics of VBL, which is the substrate of CYP3A, P-gp, and Mrp2. CAP, cyclosporine (CsA) or olive oil was given to rats for seven consecutive days, and on the seventh day, VBL (1.3 mg/kg) was administered intravenously. CsA was used as a CYP3A1/2 and transporter inhibitor, and olive oil was used as a vehicle. The results showed that pretreatment of rats with CAP (3.0 mg/kg) for seven consecutive days resulted in an increase in the AUC0-t of VBL of about 29.8% (P < 0.05) compared with the control group. Moreover, CAP decreased the CL of VBL to 75.5% (P < 0.05). At this time, CYP3A1/2 and Mrp2/Abcc2 in the liver was decreased at the mRNA and protein levels. These results demonstrate that chronic ingestion of CAP will increase systemic exposure and reduce clearance of VBL in rats. The food-drug interaction between CAP and VBL appears to be due to modulation of CYP3A1/2 and Mpr2 expression by CAP.

The widespread occurrence of microplastics (MPLs) and nanoplastics (NPLs), collectively abbreviated as M/NPLs, has markedly affected the ecosystem and has become a global threat to human health. Multiple investigations have shown that the chronic ingestion of M/NPLs negatively affects gut barrier function but the mechanism remains unclear. Herein, this research has investigated the toxic effects of pristine polystyrene (PS) M/NPLs, negatively charged carboxylated polystyrene M/NPLs (PS-COOH) and positively charged aminated polystyrene M/NPLs (PS-NH2) of two sizes (70 nm and 5 μm in diameter) in mice. Gavage of these PS M/NPLs for 28 days caused obvious injuries to the gut tract, leading to the decreased expression of tight junction proteins. The toxicity of the M/NPLs was ranked as PS-NH2 > PS-COOH > pristine PS. Oral administration of these M/NPLs resulted in marked gut microbiota dysbiosis. The M/NPLs-enriched genera generally contained opportunistic pathogens which are accompanied by a deteriorated intestinal barrier function, while most M/NPLs-decreased bacteria were beneficial microbes with known tight junction-promoting functions, implicating an important indirect toxic effect of gut microbiota dysbiosis in M/NPLs-induced gut barrier dysfunction. In conclusion, this research highlights the importance of gut microbiota in the toxicity of M/NPLs exposure on gut barrier function, providing novel insights into the adverse effects of M/NPLs exposure on human health.

Objective: The aim of this study was to determine sucralose and acesulfame-potassium (ace-K) pharmacokinetics in breast milk following maternal ingestion of a diet soda. Methods: Thirty-four exclusively breast-feeding women (14 normal-weight, 20 obese) consumed 12 ounces of Diet Rite Cola, sweetened with 68-mg sucralose and 41-mg ace-K, before a standardized breakfast meal. Habitual non-nutritional sweeteners intake was assessed via a diet questionnaire. Breast milk was collected from the same breast before beverage ingestion and hourly for 6 hours. Results: Owing to one mother having extremely high concentrations, peak sucralose and acesulfame-potassium concentrations following ingestion of diet soda ranged from 4.0 to 7387.9 ng/mL (median peak 8.1 ng/mL) and 299.0 to 4764.2 ng/mL (median peak 945.3 ng/mL), respectively. Conclusions: Ace-K and sucralose transfer into breast milk following ingestion of a diet soda. Future research should measure concentrations after repeated exposure and determine whether chronic ingestion of sucralose and acesulfame-potassium via the breast milk has clinically relevant health consequences.

Chronic ingestion of licorice is known to cause numerous metabolic and electrolyte disturbances. Severe hyponatremia, hypertension, and hypokalemia as well as metabolic alkalosis are amongst the most common consequences of chronic ingestion resulting in an apparent mineralocorticoid excess (AME). Treatment predominantly consists of cessation of licorice ingestion, potassium replenishment and aldosterone antagonists. Given the potentially lethal effects of chronic licorice ingestion, clinicians should be made aware of the presentation of AME and the proper management. We present the rare case of a 62-year-old male with licorice-induced apparent mineralocorticoid excess secondary to excessive licorice tea intake. Initial presentation included severe hypokalemia of 2.2mmol/L and hypertension of 180/110mmHg, while eunatremic (Na, 144meq/L).

In combat sports, anaerobic power and anaerobic capacity determine sport performance and the dominant metabolic pathways. The decline in performance during exercise that is attributed to the cumulative effects of fatigue, including excessive accumulation of metabolites, depletion of energy substrates, and water and electrolyte disturbances, seems to be of greatest significance. In our experiment, we evaluated the effectiveness of three weeks of bicarbonate-rich water ingestion on anaerobic performance in a state of hydration and dehydration in elite judo athletes. Eight male, elite judo athletes participated in two single-blind, repeated-measures trials. They were assigned to two hydration protocols, ingesting low mineralized table water and bicarbonate-rich water. Anaerobic performance was evaluated by two 30 s Wingate tests for lower and upper limbs, respectively, under conditions of hydration as well as exercise-induced dehydration. Resting, post-ingestion, and post-exercise concentrations of bicarbonate (HCO3), urine osmolality (UOSM), urine specific gravity (UGRAV), and lactate (La) were measured. The current investigation assessed two related factors that impair anaerobic performance—hypohydration and buffering capacity. High-bicarbonate water ingestion improved buffering capacity, and we demonstrated the potential role of this mechanism and its phenomenon in masking the adverse effects of dehydration in the context of repeated high-intensity anaerobic exercise (HIAE).

The presence of 137Cesium (137Cs) in the environment after nuclear accidents at Chernobyl and more recently Fukushima Daiichi raises many health issues for the surrounding populations chronically exposed through the food chain. To mimic different exposure situations, we set up a male rat model of exposure by chronic ingestion of a 137Cs concentration likely to be ingested daily by residents of contaminated areas (6500 Bq.l−1) and tested contaminations lasting 9 months for adult, neonatal and fetal rats. We tested plasma and serum biochemistry to identify disturbances in general indicators (lipids, proteins, carbohydrates and electrolytes) and in biomarkers of thyroid, heart, brain, bone, kidney, liver and testis functions. Analysis of the general indicators showed increased levels of cholesterol (+26%), HDL cholesterol (+31%), phospholipids B (+15%) and phosphorus (+100%) in the postnatal group only. Thyroid, heart, brain, bone and kidney functions showed no blood changes in any model. The liver function evaluation showed changes in total bilirubin (+67%) and alkaline phosphatase (–11%) levels, but only for the rats exposed to 137Cs intake in adulthood. Large changes in 17β-estradiol (–69%) and corticosterone (+36%) levels affected steroidogenesis, but only in the adult model. This study showed that response profiles differed according to age at exposure: lipid metabolism was most radiosensitive in the postnatal model, and steroid hormone metabolism was most radiosensitive in rats exposed in adulthood. There was no evidence of deleterious effects suggesting a potential impact on fertility or procreation.

For the first time, the levels of benzo(a)anthracene (BaA), chrysene (CHR), benzo(b)fluoranthene (BbF) and benzo(a)pyrene (BaP) and their sum (PAH4) were investigated in a total of 180 samples of fish, shellfish and meat products produced in Croatia. In addition, dietary polycyclic aromatic hydrocarbons (PAHs) intake of adult Croatian consumers was estimated for both acute and chronic ingestion circumstances. None of the food samples exceeded the currently legal PAHs levels according to the European legislation. The mean PAH4 level was 1.47 µg/kg for meat and 1.48 µg/kg for shellfish products. The acute daily ingestion of BaP and PAH4 through meat and shellfish products was 2? to 7? fold higher in comparison to chronic intake, with meat products being the major contributors. Consequently, the evaluation of consumption patterns that used the margin-of-exposure approach indicated a negligible risk to human health. © 2018 Elsevier Inc.

Introduction: Bisphenol A (BPA) is a chemical used in synthesis of plastic. BPA seeps into food from the plastic containers used to store food items. Exposure to BPA is implicated as a causative factor for detrimental effects on fetal development and various body systems like endocrine, reproductive and immune. Few studies report that BPA ingestion impair small intestinal contractility in-vitro. Government organisations of many countries have probed into the matter and imposed regulations on marketing of BPA. To meet the terms with regulations on BPA, manufacturers are increasingly replacing BPA with Bisphenol S (BPS). BPS has been advertised as a safer substitute to BPA. The various ill effects on BPS are being explored but the effect on gut motility is less clear. Aim: To examine the effect of chronic ingestion of BPA and BPS on rat gut contractions in-vitro. Materials and Methods: Healthy male adult albino rats (175- 225 g) were fed BPA (50 mg/kg/day) or BPS (50 mg/kg/day) or vehicle (Dimethyl sulphoxide) for four weeks by oral gavage. The animals were gently restrained so that the head is immobilised by retaining the animal in an upright position. Gavage needle was passed along the side of the mouth and moved into the esophagus and towards the stomach. After four weeks, they were sacrificed and isometric contractions of gut muscle strips were recorded in an organ bath (maintained at 37±0.5°C) using force transducer, computerised polygraph (power lab 4ST) and chart-5 for Windows, ADI, Sydney, Australia. Results: Acetylcholine (Ach) (0.1-100 µM) evoked gut contractions in-vitro and the basal tone and maximum contractile tension increased in a concentration-dependent manner. However, in both the treated groups, the Ach induced contractions were significantly (p

Inorganic arsenic (InAs) is ubiquitous in the environment and has greater toxicity than do organic arsenic species. It is a proven fact based on epidemiologic studies in groundwater-contaminated regions that chronic ingestion of InAs can lead to adverse health effects. This chapter deals with InAs intake, as well as its health risk from diet in Asia. Dietary intake of InAs in contaminated regions is at least an order of magnitude higher than that in non-contaminated regions. In the contaminated region, daily intake of InAs increased not only by drinking contaminated water but also by the consumption of crops grown with contaminated water and/or by consumption of foods cooked with contaminated water. Consumption of rice is a dominant source of InAs intake in the non-contaminated regions. The mean dietary InAs intake ranges 36–1200 and 3.8–53 μg/day in contaminated and non-contaminated regions, respectively. On the basis of these data and the benchmark dose reported by the EFSA for InAs, the margin of exposure was estimated to be less than 200. Therefore, Asian people are exposed to the levels of InAs that could not be free from cancer and non-cancer risk in the contaminated and non-contaminated regions.

The article describes the clinical case of a patient with multi-organ failure and ischemic colitis secondary to magnesium poisoning, due to the chronic intake of a parapharmacy product, used for the treatment of chronic constipation. The clinical case is described and a review of the literature is made.

A miniature dachshund male with severe azotemia of unknown cause was referred. Serum biochemistry revealed severe azotemia and hypercalcemia, but serum intact parathormone and parathormone-related protein were normal. Although the owner reported that the dog had never ingested any drugs or supplements, it was revealed that the owner's son used antipsoriatic ointment, maxacalcitol, which contained an active vitamin D3 analogue, daily and the dog often ate the son's dander and licked his skin, especially after he applied the maxacalcitol ointment. After the dog was insulated from the maxacalcitol ointment and the son as much as possible, the hypercalcemia and azotemia improved gradually and had mostly resolved at 3 mo. The dog has been generally free of clinical signs without any treatment for over 2 yr.

Energy drinks are emerging as a major component of the beverage market with sales projected to top $60 billion globally in the next five years. Energy drinks contain a variety of ingredients, but many of the top-selling brands include high doses of caffeine and the amino acid taurine. Energy drink consumption by children has raised concerns, due to potential caffeine toxicity. An additional risk has been noted among college-aged consumers of energy drinks who appear at higher risk of over-consumption of alcohol when the two drinks are consumed together. The differential and combinatorial effects of caffeine and taurine on the developing brain are reviewed here with an emphasis on the adolescent brain, which is still maturing. Key data from animal studies are summarized to highlight both reported benefits and adverse effects reported following acute and chronic exposures. The data suggest that age is an important factor in both caffeine and taurine toxicity. Although the aged or diseased brain might benefit from taurine or caffeine supplementation, it appears that adolescents are not likely to benefit from supplementation and may, in fact, suffer ill effects from chronic ingestion of high doses. Additional work is needed though to address gaps in our understanding of how taurine affects females, since the majority of animal studies focused exclusively on male subjects.

To assess the dosimetry of Ra-226 in a two-year chronic ingestion study in laboratory maintained fathead minnow fed environmentally relevant levels of the isotope known to occur in gut contents of fish from a uranium mining area.Fish were established on reconstituted commercial fish food containing 10 mBq-10 Bq Ra-226.g(- 1) dry food. The fish were sampled at 1, 6, 18 and 24 months and the Ra-226 levels in the whole fish were directly determined using measurement performed using inorganic mass spectrometry. Pilot experiments using higher doses were also done during development of a liquid scintillation detection system which support some data.The data show that after 1 month the levels of accumulation in the fish were below detection. At 6 months there was an activity dependent accumulation which was relatively higher in the low activity groups. By 18 and 24 months the radium was very low in all groups - well below 6 month levels suggesting considerable loss of radium from the fish. These data were confirmed in a small and shorter study using higher dietary activities. The highest dose calculated for any measurement point was 16 μGy.h(- 1) in the 6-month-old fish fed the diet containing 10 Bq.g(- 1).We conclude that environmentally relevant levels of Ra-226 have a maximum impact at early time-points when the fish are still growing. After that they appear to depurate accumulated radium. In terms of environmental impact, the maximum accumulation peaks at the age where fish could be spawning but is extremely low leading to μGy.year(- 1) doses even after exposure to the high activity diets.

This study examined effects of 4 weeks of caffeine supplementation on endurance performance. Eighteen low-habitual caffeine consumers ( 0.05). Before supplementation, all participants completed one VO2peak test, one practice trial and 2 experimental trials (acute 3 mg · kg−1 caffeine [precaf] and placebo [testpla]). During the supplementation period a second VO2peak test was completed on day 21 before a final, acute 3 mg · kg−1 caffeine trial (postcaf) on day 29. Trials consisted of 60 min cycle exercise at 60% VO2peak followed by a 30 min performance task. All participants produced more external work during the precaf trial than testpla, with increases in the caffeine (383.3 ± 75 kJ vs. 344.9 ± 80.3 kJ; Cohen’s d effect size [ES] = 0.49; P = 0.001) and placebo (354.5 ± 55.2 kJ vs. 333.1 ± 56.4 kJ; ES = 0.38; P = 0.004...

International audience; The knowledge of the absorbed radiation dose is essential in order to interpret the results of animal experiments with chronic ingestion of radionuclides by rodents. In order to evaluate this absorbed dose, we applied the dose conversion factors proposed by ICRP publication 108 to mouse chronic ingestion experiments with 20 kBq.L-1 137Cs- or 90Sr-contaminated water. The results indicated that whole-body absorbed doses were 9 mGy and 10 mGy by the end of 20 weeks of 137Cs or 90Sr ingestion, respectively. These results of dose calculations were compared with results obtained with a more refined method using published organ-specific absorbed fractions of energy. There was good agreement between the two methods, indicating that, despite the simple hypotheses used to apply the ICRP 108 dose conversion factors to our mouse model, this method allows one to calculate in a simple and reliable way the absorbed radiation dose received by the rodents during long-term experiments on chronic ingestion of radionuclides. © 2012 EDP Sciences.

International audience; Uranium is naturally found in the environment, and its extensive use results in an increased risk of human exposure. Kidney cells have mainly been used as in vitro models to study effects of uranium exposure, and very little about the effects on other cell types is known. The aim of this study was to assess the impact of depleted uranium exposure at the cellular level in human kidney (HEK-293), liver (HepG2), and neuronal (IMR-32) cell lines. Cytotoxicity studies showed that these cell lines reacted in a roughly similar manner to depleted uranium exposure, responding at a cytotoxicity threshold of 300-500 μM. Uranium was localized in cells with secondary ion mass spectrometry technology. Results showed that uranium precipitates at subtoxic concentrations (>100 μM). With this approach, we were able for the first time to observe the soluble form of uranium in the cell at low concentrations (10-100 μM). Moreover, this technique allows us to localize it mainly in the nucleus. These innovative results raise the question of how uranium penetrates into cells and open new perspectives for studying the mechanisms of uranium chemical toxicity.

Recently, arsenic-toxicity has become the major focus of strenuous assessment and dynamic research from the academy and regulatory agency. To elucidate the cause and the mechanism underlying the serious adverse health effects from chronic ingestion of arsenic-contaminated drinking water, numerous studies have been directed on the investigation of arsenic-toxicity using various in vitro as well as in vivo systems. Neverthless, some questions for arsenic effects remain unexplained, reflecting the contribution of unknown factors to the manifestation of arsenic-toxicity. Interestingly, very recent studies on arsenic metabolites have discovered that trivalent methylated arsenicals show stronger cytotoxic and genotoxic potentials than inorganic arsenic or pentavalent metabolites, arguing that these metabolites could play a key role in arsenic-associated disorders. In this review, recent progress and literatures are summarized on the metabolism of trivalent methylated metabolites and their toxicity on body systems including cardiovascular system in an effort to provide an insight into the future research on arsenic-associated disorders.

Human bone/Plutonium/Uranium/Semipalatinsk nuclear test site/Internal dose. To evaluate the present levels of 239,240 Pu and U in residents living near the Semipalatinsk nuclear test site, more than 70 bone samples were obtained at autopsy. The subjects ranged in age from 30 to 86 years (mean 59.3±12.9). Most of the samples consisted of victims who died of various diseases. Plutonium and U were radiochemically separated and determined by α-ray spectrometry. The mean concentrations of 239,240 Pu and 238 U observed were 0.050±0.041 mBq/g-ash (vertebrae 71, long-bones 18) and 0.28±0.13 mBq/g-ash (22.8±10.6 µg U/kg-ash) (vertebrae 58, long bones 16), respectively. The present 239,240 Pu levels were within the range found for human bone samples from other countries due solely to global fallout in the early 1980s. The average U concentration was close to the estimate (mean 22.5 µg U/kg-ash) for the UK, and about 10 times higher than those estimated for residents in New York City and Japan. By assuming that the average concentration of 239,240 Pu in bone samples is the value at 45 years after instantaneous inhalation in 1955, the initial total intake and the effective dose for 45 years were estimated as 10 Bq and 0.2 mSv, respectively. The annual intake of total U ( 234,235,238 U) and its effective dose for 60 years were estimated as 30 Bq for adult and 0.1 mSv, respectively, for chronic ingestion.

Introduction: Methylsulfonylmethane (MSM) is a commonly used dietary supplement for the alleviation of joint and muscle pain. It is known primarily for its anti-inflammatory and antioxidant properties. While it is believed to have excellent bioavailability, little is known about its serum concentrations following chronic ingestion. Methods: 20 healthy men were supplemented with 3 grams of MSM daily for four weeks. Blood was collected at baseline and after two and four weeks of supplementation. Serum was analyzed for MSM concentration using Nuclear Magnetic Resonance (NMR) spectroscopy. Results: All baseline samples but one (0.028 mM) was below the limit of quantification for the NMR assay (0.002 mM). Serum MSM values increased across time (p 0.05). A total of 13 of the 20 men demonstrated higher serum MSM values at week 4 as compared to week 2. and eight of these men demonstrated an increase at week 4 of at least 25% above what was observed at week 2. Conclusions: Serum MSM concentrations increase following oral MSM supplementation, in somewhat of a timedependent manner in selected subjects. The pattern of increase varies somewhat from subject to subject, although all individuals experience an increase of approximately 1-3 mM after 2-4 weeks of supplementation.

International audience; Deoxynivalenol (DON), nivalenol (NIV) and zearalenone (ZEA) are mycotoxins commonly produced by Fusarium species. The purpose of the present study was to investigate the effects of DON alone and in combination with NIV and ZEA on several parameters including weight gain and histological aspects of pigs submitted to chronic intoxication. Twenty, 5-week-old piglets received for 28 days one of the following diets: a control diet, a diet mono- contaminated with DON (1.5 mg/kg), a diet multi-contaminated with DON (2 mg/kg) + NIV (1.3 mg/kg) + ZEA (1.5 mg/kg) or a diet contaminated with DON (3 mg/kg) + NIV (1.3 mg/kg) + ZEA (1.5 mg/kg). Animals fed the multi-contaminated diets presented a significant decrease in weight gain over the total period. The chronic ingestion of the contaminated diets induced a significant increase on histological changes on the intestine, liver and lymphoid organs. In addition, a significant increase on lymphocyte apoptosis was observed in lymph nodes and spleen in the animals receiving the contaminated diets. These data provide a better understanding of the possible effects of Fusarium toxins, alone or in combinations on the morphology of the intestine and lymphoid organs, which would contribute to the risk assessment of these toxins.

Dental fluorosis is a defect of enamel formation caused by chronic ingestion of fluoride from different sources during tooth development, which results in interference in proper mineralization. Clinically the tooth enamel may present as white striae along the lines of enamel, opaque white spot and in more severe cases as brown spots. Diagnosis is based on clinical characteristics associated with a history of exposure to fluoride. The aim of this report is to present a treatment in a child with severe aesthetic compromising in anterior maxillary permanent teeth caused by fluorosis. The treatment was based on a combination of three techniques in order to be minimally invasive, enhance aesthetics and preserving the dental structure.

Chronic hypervitaminosis A can occur in many species after excessive dietary intake of Vitamin A (retinol). The most common presentation of chronic hypervitaminosis A is a polyarthropathy with hyperostosis and ankylosis of various joints. This case report describes a probable case of naturally occurring hypervitaminosis A-induced polyarthropathy in a rabbit after chronic ingestion of a diet made up almost exclusively of carrots. Carrots do not contain retinol, but are rich in provitamin A (or beta-carotene). Rabbits are unique in that they can convert 100% of dietary beta-carotene into retinol. A syndrome of naturally occurring hypervitaminosis A-induced polyarthropathy has not been described in a rabbit before.

The authors conducted a survey by mail of Wisconsin families who had their well water tested for nitrate to (a) assess their awareness and compliance with the state's health advisories for nitrate, (b) evaluate their reaction(s) to their test results, and (c) compare demographic differences between exposure levels. Owners of contaminated wells (i.e., > 12.9 mg/l nitrate-nitrogen) were more likely to have lived on a farm, had lower annual incomes, and had older and shallower wells than families whose wells were low in nitrate (i.e., < 2.0 mg/l nitrate-nitrogen). Most respondents were aware of the advisories for pregnant women and infants and, in accordance with these advisories, the majority of families with nitrate-contaminated drinking water took no remedial action. Given that many rural families consume nitrate-contaminated water daily, scientists should conduct additional research to determine whether chronic ingestion of nitrate-contaminated water poses a significant health threat to these families.

Enterostatin (Ent), the activation pentapeptide from procolipase, inhibits the intake of dietary fat. The selectivity of the response to fat suggests that the rat must recognize a permissive signal related to dietary fat for the Ent biological response. To investigate the nature of this signal, we studied the effects of Ent in rats that were adapted to either a high-fat (HF) or high-carbohydrate/low-fat (HC) diet and then naively exposed to either HF or HC diets. Ent (1 nmol) was injected into the lateral ventricle of overnight-fasted rats, and food intake was measured. Rats adapted to HF diet and tested with HC diet responded to Ent, but rats adapted to HC diet and tested with HF did not respond to Ent. The groups were maintained on their new test diets for up to 21 days and tested again for their response to Ent at 3, 7, 14, and 21 days. Ent response did not appear in HC-adapted rats switched to HF diet before 21 days. Conversely, the HF-adapted rats, which responded to Ent when tested with HC diet for the first time, did not respond at any subsequent testing time. The data suggest that chronic ingestion of dietary fat is required for Ent action and that chronic consumption of fat initiates a postingestion metabolic, endocrine, or neurochemical change that is required for the biological response to Ent.

Purpose: To estimate the nitrate levels in private wells located in different parts of Enugu and discuss the future health implications following chronic ingestion of well water. Materials and Methods : The map of Enugu was used to divide the city into many 25 units, using grid lines 1 cm apart. Cluster sampling method was used to collect samples. These samples were sent to two laboratories for estimation of nitrate levels. The people drawing water from the different wells were interviewed to determine what they used the water for. Result: The subjects who were interviewed said they ingested the water. The nitrate levels found in these wells (median value of 31 mg/L) were significantly higher than the internationally accepted levels of nitrate in water for ingestion, (P < 0.0001). Conclusion: High nitrate levels drinking water is dangerous to health and can cause methemoglobinemia in children. It may also increase cancer risk in adults because nitrate is endogenously reduced to nitrite and subsequent nitrosation reactions give rise to N‑nitroso compounds (NOCs), which are highly carcinogenic and can act systemically. Key words : Cancer, contamination, nitrates, private wells

WOS:000322997205226; International audience; no abstract

OBJECTIVE To assess the effect of dietary flavonoids on cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes on established statin and hypoglycemic therapy. RESEARCH DESIGN AND METHODS Despite being medicated, patients with type 2 diabetes have elevated CVD risk, particularly postmenopausal women. Although dietary flavonoids have been shown to reduce CVD risk factors in healthy participants, no long-term trials have examined the additional benefits of flavonoids to CVD risk in medicated postmenopausal women with type 2 diabetes. We conducted a parallel-design, placebo-controlled trial with type 2 diabetic patients randomized to consume 27 g/day (split dose) flavonoid-enriched chocolate (containing 850 mg flavan-3-ols [90 mg epicatechin] and 100 mg isoflavones [aglycone equivalents)]/day) or matched placebo for 1 year. RESULTS Ninety-three patients completed the trial, and adherence was high (flavonoid 91.3%; placebo 91.6%). Compared with the placebo group, the combined flavonoid intervention resulted in a significant reduction in estimated peripheral insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] −0.3 ± 0.2; P = 0.004) and improvement in insulin sensitivity (quantitative insulin sensitivity index [QUICKI] 0.003 ± 0.00; P = 0.04) as a result of a significant decrease in insulin levels (−0.8 ± 0.5 mU/L; P = 0.02). Significant reductions in total cholesterol:HDL-cholesterol (HDL-C) ratio (−0.2 ± 0.1; P = 0.01) and LDL-cholesterol (LDL-C) (−0.1 ± 0.1 mmol/L; P = 0.04) were also observed. Estimated 10-year total coronary heart disease risk (derived from UK Prospective Diabetes Study algorithm) was attenuated after flavonoid intervention (flavonoid +0.1 ± 0.3 vs. placebo 1.1 ± 0.3; P = 0.02). No effect on blood pressure, HbA1c, or glucose was observed. CONCLUSIONS One-year intervention with flavan-3-ols and isoflavones improved biomarkers of CVD risk, highlighting the additional benefit of flavonoids to standard drug therapy in managing CVD risk in postmenopausal type 2 diabetic patients.

Epidemiological studies have shown that high intake of carotenoid-rich vegetables and fruits and high blood levels of β-carotene are associated with decreased risk of cancer. In western countries, carrot is the most important source of dietary β-carotene. In the present study, the serum response to chronic ingestion of β-carotene from raw carrots, carrot juice and capsules containing purified β-carotene was studied. The subjects were 38 healthy, non-smoking female volunteers, aged 20–53 years. They were instructed to consume low-carotenoid diets for 10 days before starting the supplementation and throughout the study. According to food frequency questionnaires, the average habitual intake of β-carotene was 4.5 mg/day, whereas the low-carotenoid diet provided only 0.4 mg/day. After the 10-day depletion period, the average serum β-carotene concentration fell to 53% of the habitual level. The participants were assigned into three groups with similar mean serum β-carotene concentrations. Each group was supplemented for 6 weeks with approximately 12 mg of β-carotene/day, either as raw carrots (120 g/day), carrot juice (1 dl/day) or β-carotene capsules (2 capsules/day). The increase in serum β-carotene level was determined after 3 and 6 weeks of supplementation. The mean serum β-carotene concentration increased significantly in all test groups, the response being greatest in the group receiving β-carotene capsules. No difference in the serum response between carrot and carrot juice was detected. However, there was a wide variation in the individual response of serum β-carotene to supplementation, regardless of the source. Variation was especially large — ranging from a lack of response to over 8-fold increase in the serum β-carotene concentration — in the group receiving β-carotene capsules. These data indicate that 1) serum response is lower after ingestion of natural β-carotene than after ingestion of purified β-carotene from capsules, and 2) equal intake of β-carotene, whether from carrot, carrot juice or capsules, elicits very different serum responses in different individuals.

The element fluorine has long been recognised to have benefits for dental health: low-fluoride intake has been linked to development of dental caries and the use of fluoride toothpastes and mouthwashes is widely advocated in mitigating dental health problems. Fluoridation of water supplies to augment naturally low fluoride concentrations is also undertaken in some countries. However, despite the benefits , optimal doses of fluoride appear to fall within a narrow range. The detrimental effects of ingestion of excessive doses of fluoride are also well documented. Chronic ingestion of high doses has been linked to the development of dental fluorosis, and in extreme cases, skeletal fluorosis. High doses have also been linked to cancer (Marshall 1990), although the association is not well-established (Hamilton 1992).

Chronic intake of alcohol increases the risk of gastrointestinal and hepatic carcinogenesis. The present study was focused to investigate the incidence and mechanism of pathogenesis of hepatocellular carcinoma (HCC) during chronic ingestion of alcohol without any additional hepatic injury.Ethanol was administered to Institute for Cancer Research male mice through drinking water for 70 weeks at concentrations of 5 % (first week), 10 % (next 8 weeks), and 15 % thereafter. The animals were killed at 60 and 70 weeks, the livers were examined for hepatic tumors, and evaluated for foci of cellular alteration (FCA). Immunohistochemical staining was performed in the liver sections for cytochrome P4502E1 (CYP2E1), 4-hydroxy-nonenal (4-HNE), and proto-oncogene, c-Myc.At the 60th week, 40 % of the mice in the ethanol group had visible white nodules (5-10 mm) in the liver, but not in the control mice. At the 70th week, several larger nodules (5-22 mm) were present in the livers of 50 % mice in the ethanol group. In the control group, one mouse developed a single nodule. All nodules were histologically trabecular HCC composed of eosinophilic and vacuolated cells. In the livers of both control and ethanol group, several foci with cellular alteration were present, which were significantly higher in ethanol group. Staining for CYP2E1, 4-HNE and c-Myc depicted marked upregulation of all these molecules in the FCA.Our data demonstrated that upregulation of CYP2E1 and subsequent production of reactive oxygen species along with the persistent expression of c-Myc play a significant role in the pathogenesis of HCC during chronic ingestion of ethanol.

Chronic ingestion of saturated fatty acids (SFAs) was previously shown to compromise blood-brain barrier integrity, leading to brain parenchymal extravasation of apolipoprotein B (apo B) lipoproteins enriched in amyloid beta. In contrast, diets enriched in mono- or polyunsaturated (PUFA) oils had no detrimental effect. Rather, n3 and n6 oils generally confer protection via suppression of inflammation. This study investigated in wild-type mice if a PUFA diet enriched in docosahexanoic acid (DHA) restored blood-brain barrier integrity and attenuated parenchymal apo B abundance induced by chronic ingestion of SFA. Cerebrovascular leakage of apo B was quantitated utilising immunofluorescent staining. The plasma concentration of brain-derived S100 𝛽 was measured as a marker of cerebrovascular inflammation. In mice fed SFA for 3 months, provision thereafter of a DHA-enriched diet exacerbated parenchymal apo B retention, concomitant with a significant increase in plasma cholesterol. In contrast, provision of a low-fat diet following chronic SFA feeding had no effect on SFA-induced parenchymal apo B. The findings suggest that in a heightened state of cerebrovascular inflammation, the provision of unsaturated fatty acids may be detrimental, possibly as a consequence of a greater susceptibility for oxidation.

International audience; Reports have described apparent biological effects of Cs-137 (the most persistent dispersed radionuclide) irradiation in people living in Chernobyl-contaminated territory. The sensitive analytical technology described here should now help assess the relation of this contamination to the observed effects. A rat model chronically exposed to Cs-137 through drinking water was developed to identify biomarkers of radiation-induced metabolic disorders, and the biological impact was evaluated by a metabolomic approach that allowed us to detect several hundred metabolites in biofluids and assess their association with disease states. After collection of plasma and urine from contaminated and non-contaminated rats at the end of the 9-months contamination period, analysis with a LC-MS system detected 742 features in urine and 1309 in plasma. Biostatistical discriminant analysis extracted a subset of 26 metabolite signals (2 urinary, 4 plasma non-polar, and 19 plasma polar metabolites) that in combination were able to predict from 68 up to 94% of the contaminated rats, depending on the prediction method used, with a misclassification rate as low as 5.3%. The difference in this metabolic score between the contaminated and non-contaminated rats was highly significant (P = 0.019 after ANOVA cross-validation). In conclusion, our proof-of-principle study demonstrated for the first time the usefulness of a metabolomic approach for addressing biological effects of chronic low-dose contamination. We can conclude that a metabolomic signature discriminated Cs-137-contaminated from control animals in our model. Further validation is nevertheless required together with full annotation of the metabolic indicators.

The stochastic aspects of alpha-particle traversals through nuclei of bone-lining cells from nonuniform radioactive labels are worked out. Both the residence time of the target and the hit rate are considered random variables. It is shown that with any type of bone remodeling the fraction of cells not hit increases with increasing nonuniformity of the label concentration. Thus, a completely uniform concentration represents the most dangerous situation. A possible negative correlation between residence times and hit rates, observed in some experiments, tends to decrease the probability of alpha-particle hits. As a practical application, the theory is applied to the International Commission on Radiological Protection model of the distribution of 239Pu in the human body. In the case of 50 years of chronic ingestion of 1 annual limit of intake (ALI) per year for class W and chronic inhalation of 1 ALI/year for class Y compounds, more than 19.4 and 8.5% of the nuclei of bone-lining cells are traversed by at least one alpha-particle, respectively.

These studies were conducted to determine whether the bioavailability of pyridoxine-β-D-glucoside (PN-glucoside) as a source of vitamin B6 is related to a possible induction of intestinal β-glucosidase activity by chronic ingestion of PH-glucoside. Diets that were deficient (no added vitamin B6) or marginally adequate [1 mg/kg pyridoxine (PN) as PN-HCl] in vitamin B6 and containing graded levels of PN-glucoside (0, 5, 10 and 15 nmol/g) were fed to rats for a period of four weeks. β-glucosidase activity was measured on the 20,000 x g supernatant fraction of scraped mucosa using [ 3 H]PN-glucoside and 4-methylumbelliferyl glucoside (MUG) as substrates. After four weeks of dietary treatment, plasma pyridoxal-5'-phosphate (PLP) levels in rats fed the deficient diets were found to increase with increasing levels of dietary PN-glucoside, indicating that PN-glucoside was partially utilized. However, the specific activity of the β-glucosidase as monitored with either substrate was not correlated with the level of dietary PN-glucoside that was fed, regardless of the vitamin B6 status of the animals. These results indicate that the conversion of PN-glucoside to pyridoxine by the intestinal β-glucosidase is not an inducible activity with respect to dietary PN-glucoside. The results are consistent with previous findings that the relative bioavailability of PN-glucoside in the rat, albeit incomplete, is relatively constant regardless of its dietary concentration.

The aim of this study was to determine the level of toxicity of nitrosamine on some biochemical and hematological parameters and the curative effect of olive oil and ephedra extract on domestic 24 male rabbits divided into four groups, each with different doses which were applied for 33 days. In the present study, olive oil and ephedra administration with nitrosamine reduced its induced harm in a significant way. These finding suggest that olive oil, effectively, reduces nitrosamine-induced toxicity more than ephedra, and generally, their use concomitantly with nitrosamine have an extremely beneficial role in overcoming the adverse effects occurring due to chronic ingestion of nitrosamines.

PURPOSE. To investigate how supplementation of the monkey's diet with high doses of lutein (L), zeaxanthin (Z), or a combination of the two affects the plasma levels and ocular tissue deposition of these carotenoids and their metabolites over time and to determine whether these high doses can cause ocular toxicity. METHODS. Eighteen female rhesus monkeys were divided into groups of control (n = 3 control), L-treated (n = 5, 9.34 mg lutein/kg and 0.66 mg zeaxanthin/kg), Z-treated (n = 5, 10 mg zeaxanthin/kg), and L/Z-treated (n = 5, lutein and zeaxanthin, each 0.5 mg/kg). After 12 months of daily supplementation, one control animal, two L-treated animals, two Z-treated animals, and all the L/Z-treated animals were killed. The rest of the monkeys were killed after an additional six months without supplementation. Plasma and ocular tissue carotenoid analyses, fundus photography, and retina histopathology were performed on the animals. RESULTS. Supplementation of monkeys with L and/or Z increased the mean plasma and ocular tissue concentrations of these carotenoids and their metabolites. The mean levels of L and Z in the retinas of the L- and Z-treated animals after 1 year increased significantly over baseline. High dose supplementation of monkeys with L or Z did not cause ocular toxicity and had no effect on biomarkers associated with kidney toxicity. CONCLUSIONS. The mean levels of L and Z in plasma and ocular tissues of the rhesus monkeys increase with supplementation and in most cases correlate with the levels of their metabolites. Supplementation of monkeys with L or Z at high doses, or their combination does not cause ocular toxicity.

Eucalyptus leaf-eating marsupials such as the brushtail possum (Trichosurus vulpecula) ingest large amounts of terpenes, especially 1,8-cineole (cineole)--the major component of many eucalyptus oils. Brushtail possums were acclimated to a non-Eucalyptus diet with increasing concentrations of cineole (0.5-4.0% wet weight) added over 18 d. We measured food and cineole consumption and urinary metabolites of cineole. Food intake decreased with cineole content, indicating that it was constrained by the maximum tolerable intake of cineole that was 3.8 +/- 0.2 g kg(-1) or 5.2 +/- 0.3 g kg(-0.75) (mean +/- SE, N = 6). The pattern of metabolites was similar at all cineole intakes (56% hydroxycineolic acids, 27% cineolic acids, 13% hydroxycineoles, and 4% dihydroxycineoles). In another experiment, possums maintained on artificial diet were abruptly presented with 4% cineole for 5 d. Food intake fell by 45 +/- 6% (mean +/- SE, N = 6) and mean cineole intake was 2.9 +/- 0.3 g kg(-1). There was evidence of induction of secondary oxidative pathways, as hydroxycineoles were the major metabolites (48% total) on the first day, but rapidly dropped to 15% on subsequent days as the acid metabolites increased. These findings indicate that ingestion of cineole is not constrained by selective saturation of individual enzymes involved in its multiple pathways of oxidation, but rather the total detoxification capacity appears to limit feeding on a cineole diet.

The aim of this study was to determine the tissue distribution of 17 PCDD/Fs following the chronic ingestion of contaminated milk in rats and to assess the "target tissue/milk" BioConcentration Factors (BCFs) of these molecules. Contaminated milk, collected in a polluted area, has been incorporated into the diet of male rats at a low dose (31 pg I-TEQ/day/rat). For this exposure, the accumulation of PCDD/Fs in target tissues (liver and adipose tissue) was limited, the tissue concentrations stabilising between 90 and 120 days of daily intake to levels close to 3 pg/g of tissue (all tissues and molecules combined). The tissue distribution seemed to be governed by the congeners properties and by the tissue characteristics. An increase in the chlorination degree of dioxins caused a decrease in their incorporation in the adipose tissue, and consequently of the BCF values. Moreover, the distribution of dioxins between hepatocytes and adipocytes differed: unlike the liver, the quantities of dioxins in the adipose tissue were significantly (P

Brain serotonin synthesis depends on the uptake of its precursor, tryptophan (Trp), and is correlated to the plasma ratio of Trp to large neutral amino acids (LNAA) which compete for the same transporter system in the brain. As the plasma Trp/LNAA ratio decreases when the dietary protein content exceeds 5%, we tested whether a diet containing 17% of a Trp-rich protein, namely alpha-lactalbumin (LAC), might increase the plasma Trp/LNAA ratio over a long period. Blood samples were obtained at different days (-1, 3, 6 and 9) from rats receiving either a LAC or casein (CAS) diet, and plasma amino acids and insulin concentrations were determined. The increase in plasma Trp concentration was much higher during the LAC diet (49 vs 26%; P0.001), while the plasma LNAA concentration remained fairly constant. Consequently, the plasma Trp/LNAA ratio increased by 40% during the LAC diet while it decreased by 15% during the CAS diet (P0.001). The above results were not related to plasma insulin concentration differences during these diets. These data suggest that a balanced diet containing a natural Trp rich-protein increases the plasma Trp/LNAA ratio over a long period, leading to a probable increase in brain serotonin activity.

A 43-year-old woman with a history of hyperthyroidism presented to the hospital with recurrent heart burn, muscular pain, difficulty in walking, giddiness and numbness in all four limbs. She had a history of hyperthyroidism and had been on carbimazole 20mg twice daily for 6 months and ingested beads of silica gel provided as a desiccant in bottles with carbimazole tablets. She was treated with rabeprazole 20mg daily and carbimazole 10mg daily while she was being investigated. After completion of investigations, she was reassured and carbimazole was continued. She was followed up at six months, twelve months and two years. She was symptom free. We believe this is the first reported case of chronic ingestion of silica gel. DOI: http://dx.doi.org/10.4038/jccp.v44i1-2.7690 Journal of the Ceylon College of Physicians, 2013, 44, 38-39

Several traditional medicines contain potentially toxic heavy metals. Heavy metal poisoning is not an uncommon cause of renal damage, although the diagnosis can be easily missed. We report a case of chronic ingestion of an ayurvedic medicine containing mercury in a 2-year-old girl, resulting in anuric renal failure due to acute interstitial nephritis.

The aim of this study was to assess regional haemodynamic changes in conscious Brattleboro rats during chronic ingestion of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Animals were instrumented with renal, mesenteric and hindquarters pulsed Doppler flow probes and an intra-arterial catheter, and haemodynamic measurements were made before, during and after 14 days' exposure to L-NAME (0.01 mg ml-1 in the drinking water). Within 6 h after addition of L-NAME to the drinking water, mean arterial blood pressure was increased (maximum, 33 +/- 6 mm Hg), and remained so until L-NAME was withdrawn, whereupon blood pressure returned to normal levels within 24 h. The hypertension was accompanied by a transient reduction in mesenteric blood flow, and a more persistent reduction in hindquarters blood flow. Mesenteric and, particularly, hindquarters vascular conductance showed a sustained reduction. However, during ingestion of L-NAME, renal blood flow was not diminished and, over the final 4 days of exposure to L-NAME there was no significant renal vasoconstriction. All regional haemodynamic effects of L-NAME were lost within 24 h of its withdrawal. Hence, as with shorter periods of exposure to the less potent NO synthase inhibitor, NG-monomethyl-L-arginine, the hypertension caused by L-NAME is dependent on its continued administration, and is associated with a particularly marked hindquarters vasoconstriction.

Chronic ingestion of alcohol (ethanol) is clearly implicated in the pathogenesis of chronic pancreatitis. The effects of ethanol on pancreatic secretion are complex and vary with the circumstances. These effects have been investigated most fully in man and in the dog, with studies covering three different circumstances: first, bolus administration of ethanol in normal subjects; second, the modifications of the response to physiological stimuli after chronic administration; and third, the alterations to the response to a bolus following chronic administration.