Urinary Concentrations Research Articles

Beyond Nutritional Treatment: Effects of Fitwalking on Physical Capacity and Intestinal Barrier Integrity in BMI-Stratified IBS Patients

Background: Irritable bowel syndrome (IBS) and obesity are associated with intestinal barrier alterations that result in low-grade inflammation. Zonulin and intestinal fatty acid-binding protein (I-FABP) assess gut barrier health, while urinary indican concentrations reflect dysbiosis in the small intestine. Physical activity, such as Fitwalking, aids weight management and improves intestinal permeability. This study assesses the impact of a 12-week Fitwalking program on intestinal barrier health in IBS patients categorized by body mass index (BMI). Methods: Fifty-seven mild IBS patients were categorized as obese (OB = 18), overweight (OW = 24), or normal weight (NW = 15) and assigned to a walking group. Participants walked thrice weekly at moderate intensity for 60 min per session, using the specific Fitwalking technique, supervised by staff. Results: No significant changes in biochemical or anthropometric variables were observed. However, Fitwalking improved the Global Physical Capacity Score (GPCS) by 46%, 48%, and 24% in the NW, OW, and OB groups. Post-intervention, serum zonulin levels notably decreased in OB individuals, suggesting reduced inflammation. OW patients unexpectedly showed increased fecal zonulin levels. OB participants experienced decreased urinary indican levels. Zonulin levels positively correlated with BMI and inversely with GPCS. Conclusions: Regular exercise benefits the intestinal barrier, especially in obese IBS patients. Monitoring zonulin and I-FABP may offer insights into gut barrier integrity and GI injury severity. Future studies should explore longer intervention durations, larger populations, and advanced diagnostic tools to validate findings and investigate the mechanisms behind exercise-induced changes in intestinal permeability and gut health markers.

Urinary biomarkers in neonates born to mothers with preeclampsia: A case-control study

BackgroundEffects of preeclampsia (PE) on fetal renal development are unknown. We hypothesized that the circulating factors causing endothelial dysfunction and impaired renal function in mothers with PE adversely affect fetal kidneys. ObjectiveTo compare urinary biomarkers in infants born to mothers with and without PE. MethodsSixty-eight mothers and their newborns with gestational age ≥ 32 weeks were enrolled. We collected bag urine samples from infants during the first 48 h of life. Urine samples were centrifuged at 1500 rpm for 10 min. Supernatant after excluding the bottom 1 mL of urine was stored at −70 °C until assayed. Urinary creatinine, protein, cystatin C, nephrin, kidney injury molecule – 1, and klotho were measured. ResultsSixteen mothers in the PE group had severe features of PE. The PE group infants had lower body length compared to the control group (46.4 ± 3.4 vs 48.6 ± 3.4 cm; p = 0.007). Urine protein and creatinine were significantly higher in the PE group infants [protein 37.1 (14.4, 53.5) vs 20.3 (7.5, 30.0) mg/dl, p = 0.04; creatinine 63.4 (25.2, 96.6) vs 24.8 (19.8, 44.2) mg/dl, p = 0.008]. There were no statistically significant differences in the urinary concentrations of the remaining four biomarkers. The urinary protein, creatinine and nephrin concentrations had significant negative correlation with gestational age (p values 0.07, 0.0003 and 0.0008 respectively). ConclusionsThe findings of higher urinary protein and the observed trends in the levels of urinary nephrin and klotho are suggestive of glomerular immaturity and/or impaired function in infants born to mothers with PE.

Effects of benzoic acid in pig diets on nitrogen utilization, urinary pH, slurry pH, and odorous compounds.

The objective was to investigate the effects of dietary benzoic acid (BA) on nitrogen (N) balance, urinary pH, slurry pH, and odorous compounds in feces and slurry of pigs. Twelve barrows with an initial body weight of 56.2±2.6 kg were individually housed in metabolism crates. The animals were allocated to a replicated 6×4 incomplete Latin square design with 12 animals, 6 experimental diets, and 4 periods, resulting in 8 observations per treatment. The basal diet consisted mainly of corn, soybean meal, and rapeseed meal. Benzoic acid was supplemented to the basal diet at 0.5%, 1.0%, 1.5%, 2.0%, or 2.5% at the expense of corn starch. Each period consisted of a 4-day adaptation period and a 24-h collection period for slurry, followed by a 4-day collection period for feces and urine. On day 5, feces and urine were collected for 24 h and mixed to obtain slurry samples. The daily digested N linearly increased (p<0.05) with increasing BA supplementation. Supplemental BA lowered urinary pH (p<0.001) and slurry pH (p<0.05) in a linear and quadratic manner. In the fecal samples, the concentrations of acetate, propionate, butyrate, and skatole linearly decreased (p<0.05) with supplemental BA. In the slurry samples, the concentrations of butyrate, isovalerate, and skatole linearly decreased (p<0.05) by supplemental BA. In conclusion, supplemental benzoic acid has the potential to improve nitrogen digestion in a dose-dependent manner for pigs. Additionally, dietary benzoic acid lowers urinary pH, slurry pH, and concentrations of odorous compounds in pig feces and slurry.

Relationship Between Urinary Uranium and Cardiac Geometry and Left Ventricular Function: The Strong Heart Study

BackgroundUranium is a potentially cardiotoxic, nonessential element commonly found in drinking water throughout the United States. ObjectivesThe purpose of this study was to evaluate if urinary uranium concentrations were associated with measures of cardiac geometry and function among American Indian young adults from the Strong Heart Family Study. MethodsUrinary uranium was measured among 1,332 participants free of diabetes, cardiovascular disease, and <50 years of age at baseline (2001-2003). Transthoracic echocardiography and blood pressure were assessed at baseline and at a follow-up visit (2006-2009). We estimated adjusted mean differences in cardiac geometry and function measures at baseline and follow-up using linear mixed-effect models with a random intercept and slope over time. ResultsMedian (interquartile range) uranium was 0.029 (0.045) μg/g creatinine. In fully adjusted cross-sectional models, a log-doubling of urinary uranium was positively associated with left ventricular (LV) mass index (mean difference: 0.49 g/m2, 95% CI: 0.07-0.92 g/m2), left atrial systolic diameter (0.01 cm/m2, 0.01-0.02 cm/m2), and stroke volume (0.66 mL, 0.25-1.08 mL) at baseline. Prospectively, uranium was associated with increases in left atrial diameter (0.01 cm/m2, 0.01-0.02 cm/m2), pulse pressure (0.28 mm Hg, 0.05-0.52 mm Hg), and incident LV hypertrophy (odds ratio: 1.25, 95% confidence interval: 1.06, 1.48). ConclusionsUrinary uranium levels were adversely associated with measures of cardiac geometry and LV function among American Indian adults, including increases in pulse pressure and LV hypertrophy. These findings support the need to determine the potential long-term subclinical and clinical cardiovascular effects of chronic uranium exposure, and the need for future strategies to reduce exposure.

Impact of Short-Term Diesel Exhaust Exposure on Prothrombotic Markers in Chronic Obstructive Pulmonary Disease: A Randomized, Double-Blind, Crossover Study.

Rationale: Growing evidence suggests that air pollution exposure is a major risk factor in chronic obstructive pulmonary disease (COPD) that is associated with an increased prothrombotic state and adverse cardiovascular outcomes. However, much of this work is based on observational data or human exposure studies involving younger participants. The biological causality and mechanism of air pollution-induced prothrombotic response in patients with COPD remain to be explored. Objectives: The main aim of this work was to investigate the impact of short-term diesel exhaust (DE) exposure on circulating prothrombotic markers-fibrinogen and plasminogen activator inhibitor-1 (PAI-1)-and urinary eicosanoids in patients with COPD. Methods: Twenty-nine research participants were recruited in this randomized, double-blind, crossover, controlled human exposure study to DE. Participants included former smokers with and without mild or moderate COPD (ex-smokers [ES] and COPD group) and healthy never-smokers without COPD (nonsmoker [NS] group). Each participant was exposed to DE (300 μg/m3 of particulate matter with an aerodynamic diameter ≤2.5 μm) and filtered air for 2 hours on different occasions, in randomized order, separated by a 4-week washout. Blood and urine samples were collected before and 24 hours after each exposure. Plasma fibrinogen and serum PAI-1 concentrations were quantified using enzyme-linked immunosorbent assays. Urinary eicosanoid concentrations were quantified using ultraperformance liquid chromatography coupled to tandem mass spectrometry. Linear mixed-effects models were used for statistical comparisons. Results: Participants with COPD showed an increase in plasma fibrinogen (effect estimate, 1.27 [1.06-1.53]; P = 0.01) after DE relative to filtered air, but no significant DE-associated change in serum PAI-1 (0.95 [0.87-1.04]; P = 0.26). In never-smokers and ex-smokers without COPD, fibrinogen (NS group, 1.10 [0.99-1.23]; P = 0.08; ES group, 0.86 [0.68-1.09]; P = 0.08] and PAI-1 (NS group, 1.12 [0.96-1.32]; P = 0.15; ES group, 0.90 [0.79-1.03]; P = 0.13) were not changed after DE exposure. Participants with COPD showed a DE-attributable increase in urinary thromboxane B2 (TXB2) metabolite concentrations as follows: 11-dehydro-TXB2 (1.45 [1.02-2.08]; P = 0.04) and 2,3-dinor-TXB2 (1.45 [1.05-2.00]; P = 0.03). Conclusions: Participants with COPD had increased plasma fibrinogen and urinary TXB2 metabolites after short-term DE exposure, suggesting they may be more susceptible to a pollution-attributable prothrombotic response than healthy control subjects or ex-smokers without COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02236039).

Sunscreen use associated with elevated prevalence of anti-nuclear antibodies in U.S. adults.

Antinuclear antibody (ANA) prevalence in the U.S. population increased from 1988 to 2012, especially in white and more educated individuals. In adults ages 20-39 years from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 and 2011-2012, ANA prevalence was previously associated with urinary concentrations of a common sunscreen ingredient, benzophenone 3, measured in winter. Spot urines may not capture relevant chronic exposures, thus we examined whether ANA was related to sunscreen use. In a cross-sectional study of adults ages 20-59 (N=416 ANA positive, 2656 ANA negative, by Hep-2 immunofluorescence, 1:80 dilution), we examined associations of ANA with reported sunscreen use when in the sun for 1h or more. Logistic regression was used to calculate covariate-adjusted prevalence odds ratios (POR) and 95% Confidence Intervals (CI), overall and stratified by demographic factors, season, and vitamin D. We explored associations and joint effects with other sun protective behaviors and sunburn in the past 12 months. The association of ANA with sunscreen differed by age (interaction p=0.004): for ages 20-39, we saw an exposure response (POR 2.61, 95% CI 1.50, 4.24 for using sunscreen always or most of the time, and POR 1.85; 1.12, 3.05 for less frequent versus never-use; trend p<0.001). These associations were more apparent in females (interaction p=0.082), non-Hispanic white and black participants (vs. other race/ethnicity, interaction p=0.023), and those with sufficient serum vitamin D (≥50 vs. <50nmol/L, interaction p=0.001). ANA was not associated with other protective behaviors and not confounded or modified by these behaviors or recent sunburn. These cross-sectional findings showed frequent sunscreen was associated with ANA in younger adults, supporting the need for replication, and longitudinal studies with detailed exposure histories.

Pyrethroid exposure biomarker 3-phenoxybenzoic acid (3-PBA) binds to transthyretin and is positively associated with free T3 in pregnant women

Pyrethroids constitute a large group of insecticides widely used in agriculture, indoor environments, and in vector control. Structurally, pyrethroids resemble thyroid hormones, and have been suggested to be thyroid hormone disruptors based on experimental studies. During pregnancy, even minor disturbances in maternal levels can affect fetal brain development. Therefore, we aimed to investigate whether three commonly used pyrethroids and their common metabolite, 3-PBA, were able to trigger thyroid disrupting effects on thyroid hormone production and transport, activation or deactivation of thyroid hormones, recycling of iodine, or on iodide uptake into the thyroid. Furthermore, we investigated associations between urinary 3-PBA concentrations (as biomarker of pyrethroid exposure) and serum concentrations of thyroid hormones in early pregnancy in the large prospective Odense Child Cohort (OCC).We found that the generic metabolite, 3-PBA, was capable of binding to transthyretin (TTR) at low concentrations, comparable to those reported in human cord blood. Among pregnant women in OCC, we found urinary 3-PBA concentrations to be positively associated with free triiodothyronine (fT3) serum levels. Displacement of thyroid hormones from TTR by pyrethroid exposure in early pregnancy may disturb the transplacental transport of thyroid hormones to the fetus during a very vulnerable window of development, including neural maturation. We did not find any evidence for thyroid disrupting effects in vitro for the three pyrethroids: Deltamethrin, α-cypermethrin, and etofenprox.

Exploratory Study on Reference Intervals of Calprotectin and Pentraxin 3.

The aim of our study was to determine reference intervals for serum pentraxin 3 and calprotectin, as well as for urine calprotectin according to the CLSI EP28-A3C guidelines for defining, establishing, and verifying reference intervals in the clinical laboratory. A total of 120 serum and urine samples from either healthy volunteers or outpatients were used for reference interval establishment. The participants had CRP levels, leukocyte counts, serum urea levels, creatinine levels, and estimated glomerular filtration rates (CKD-EPI eGFRs) within the reference range and no medical history of acute/chronic inflammatory diseases/conditions or cancer. Calprotectin was measured via a commercially available turbidimetric method - the Bühhlmann fCAL® Turbo Reagent Kit - while pentraxin 3 was measured using the Human Pentraxin 3 ELISA Kit from the BioVendor Group. The serum calprotectin reference range was ≤ 3.6 mg/L, the 90% CI for the upper reference range was 3.1-4.1 mg/L, while the serum pentraxin 3 reference concentration was ≤ 3.0 µg/L, and the 90% CI for the upper reference range being 2.7-3.2 µg/L. Additionally, the urinary calprotectin concentration was ≤ 1.4 mg/L, with a 90% CI for the upper reference range of 1.0-1.7 mg/L. This study reports sample and method-specific reference intervals for the detection of various inflammatory conditions.

The Impact of Maternal Gestational Diabetes Mellitus on Minipuberty in Boys

Background/Objectives: Minipuberty is thought to play an important role in the sexual maturation of infants. Maternal disorders during pregnancy were found to have an impact on the activity of the reproductive axis in the first year of life. This prospective, matched, cohort study was aimed at investigating whether the course of minipuberty in boys is affected by maternal gestational diabetes mellitus (GDM). Methods: The study population consisted of three matched groups of boys: infants born to women with poorly controlled GDM, sons of women with adequately controlled GDM, and infants of healthy women with normal carbohydrate tolerance during pregnancy (control group). Salivary levels of testosterone, androstenedione, DHEA-S and estradiol, and urinary concentrations of FSH and LH were repeatedly measured over the first 12 months of life. Hormone levels were correlated with the size of genital organs (testicular volume and penile length), which were measured at each visit. Results: Compared with the remaining groups, the male offspring of women with poorly controlled GDM were characterized by higher concentrations of both gonadotropins, higher salivary testosterone levels, lower salivary DHEA-S concentrations, and longer periods of detection for LH and testosterone. Levels of gonadotropin, testosterone and DHEA-S in sons of mothers with poorly controlled GDM correlated with mean levels of glycated hemoglobin during pregnancy. Moreover, the infant boys assigned to this group were characterized by larger sizes of the testes and penis. Over the entire study period, there were no differences in hormone levels, testicular volume and penile length between sons of adequately treated women with GDM and sons of healthy women. Conclusions: The obtained results indicate that GDM, if poorly controlled, may affect the activity of the reproductive axis and postnatal growth of male genital organs in the offspring.

Adult Dietary Patterns and Their Association With Iodine Nutrition Levels and Thyroid Function: A Cross-Sectional Study.

To understand the dietary patterns of adults and explore their association with iodine nutritional levels and thyroid function in adults. We randomly collected 5 ml of adult urine samples and measured urinary iodine concentration by cerium arsenate-catalyzed spectrophotometry. A serum sample of 5 ml was collected for the determination of free triiodothyronine (FT3), free thyroxine (FT4) and thyrotropin (TSH), and diet-related information was collected through a food frequency questionnaire. Dietary patterns were extracted by principal component analysis and the relationship between dietary patterns and iodine nutrition levels and thyroid function was explored. A cross-sectional study involving adults in Xinjiang, China was conducted. A total of 435 adults were enrolled in the study. The overall median urinary iodine of the 435 respondents was 219.73 μg/L.The dietary patterns were PCA1 (staple food pattern), PCA2 (fruit, vegetable, and meat pattern), PCA3 (fish, shrimp, and legume pattern), and PCA4 (Dairy-based protein pattern). The correlation analyses showed that PCA1 and PCA3 were positively correlated with the urinary iodine concentration (UIC). The results of the multivariable analysis showed that PCA1, Q1, Q2, and Q3 were associated with an increased risk of iodine deficiency compared with Q4 [ (OR): 260.41 (95%CI: 20.16, 663.70)], 59.89 (5.64, 335.81), and 2.01 (0.15, 26.16), respectively]. In PCA2, Q3 was associated with an increased risk of iodine deficiency compared with Q4 [OR: 0.16 (0.05, 0.53)]. In PCA3, Q3 was associated with an increased risk of iodine deficiency compared with Q4 [OR: 0.23 (0.06, 0.90)]. In PCA4, Q1 was associated with an increased risk of iodine deficiency compared with Q4 [OR: 31.30 (4.88, 200.64)]. This study demonstrated that of the four dietary patterns, the least dependent staple food pattern (Q1) had a higher risk of iodine deficiency compared to the most dependent staple food pattern (Q4). However, the current evidence on the effect of dietary patterns on thyroid function needs to be validated by further longitudinal studies that include long-term follow-up, larger sample sizes, and repeated measures.

Anti-urolithiatic Effect of Psiadia Punctulata Leaves Ethanolic Extracts Against Sodium Oxalate-Induced Urolithiasis in Rats

Kidney stones are rigid mineral and acidic salt deposits that accumulate in concentrated urine, leading to urolithiasis, the third most common urinary tract disorder. Current treatments for urolithiasis have limitations and frequent recurrences. This study aimed to investigate the anti-urolithiatic effects of ethanolic extracts from Psiadia Punctulata leaves on sodium oxalate-induced urolithiasis in rats. Rats were administered orally Psiadia Punctulata leaves ethanolic extract (PPEE) at 200 and 400 mg/kg doses for 14 days to assess its effectiveness against urolithiasis induced by sodium oxalate. Cystone (500 mg/kg) was used as a positive control. The effects of PPEE on body and kidney weights, urinary output and pH levels, urine and serum parameters, renal oxidative and antioxidative markers, and histopathological evaluations were examined. Oral administration of PPEE at 200 and 400 mg/kg doses showed a significant dose-dependent (P&lt;0.01) antiurolithiatic effect, reversing sodium oxalate-induced ion excretion and urinary calcium oxalate concentration. These findings support the traditional use of PPEE for renal calculi management, possibly due to its antioxidant properties identified through phytochemical screening. However, further research is needed to understand the exact mechanism of action

Comparison of urinary exposure profiles to phthalates and bisphenol analogues in kindergartens in Korea: Impact of environmental choices on children’s health

Phthalates and bisphenols (BPs) are well-known endocrine disrupting chemicals (EDCs) that are widely used in diverse consumer and personal care products. Despite their vulnerability, children are frequently exposed to phthalates and BPs in their surrounding environments. Although pre-school children spend most of their time in kindergarten, no comprehensive assessment of children’ exposure to EDCs has been conducted according to the type of kindergarten. In this study, the urinary concentrations of phthalate metabolites and BPs were determined in Korean children attending conventional and eco-friendly kindergartens. The exposure levels and contaminant profiles were investigated according to kindergarten type and their association with oxidative stress was assessed. Di-(2-ethylhexyl) phthalate (DEHP) metabolites, such as mono-(2-ethyl-5-carboxypentyl) phthalate (median: 47.1 ng/mL) and mono-[(2-carboxymethyl)hexyl] phthalate (8.45 ng/mL) had the highest levels, indicating that they were the primary contaminants to which the children were exposed. Urinary concentrations of phthalate metabolites and bisphenol A (BPA) were higher in children from conventional kindergarten than an eco-friendly kindergarten. Conversely, bisphenol S (BPS) concentrations were significantly higher in children from the eco-friendly kindergarten than in those from conventional kindergartens, implying that eco-friendly plastic products might contain BPS as a replacement for BPA. The estimated daily intakes of BPA for all children exceeded the new tolerable daily intake proposed by the European Food Safety Authority. Malondialdehyde levels were significantly associated with the urinary concentrations of certain phthalate metabolites, indicating potential adverse health outcomes from phthalate exposure in children. The study highlights the need for targeted interventions to reduce EDC exposure in children, especially in settings where alternative chemicals may still pose health risks.

Measurement of acrolein concentrations in postmortem specimens as an indicator for stroke diagnosis.

Acrolein, a polyamine produced from spermine during brain infarction, has recently been used in clinical settings for brain infarction risk assessment. However, few studies have investigated the diagnostic usefulness of acrolein measurement in postmortem specimens. In this study, we measured the acrolein concentration in postmortem specimens to assess its potential as a marker for stroke diagnosis. Acrolein concentrations in the serum and urine were measured using an enzyme-linked immunosorbent assay in 25, 19, 21, and 93 brain infarction, subarachnoid hemorrhage, cerebral hemorrhage, and control cases, respectively. No correlations or significant differences were observed between the acrolein concentrations in blood or urine, age, time since death, or sex. However, the serum acrolein concentrations increased significantly in cases of brain infarction, subarachnoid hemorrhage, and cerebral hemorrhage compared with non-stroke cases, with diagnostic cutoff values of 117.1, 119.9, and 130.3nmol/mL, respectively. Conversely, the urinary acrolein concentrations decreased in specimens from subarachnoid hemorrhage and cerebral hemorrhage cases, suggesting dilution due to higher urine volumes. In conclusion, our findings suggest that serum acrolein concentration remains unaffected by the time elapsed after death. Moreover, the measurement of serum acrolein in postmortem specimens is effective in diagnosing stroke.

Association between urinary heavy metal/trace element concentrations and kidney function: a prospective study

Abstract Background Chronic kidney disease (CKD) is an important public health problem. Although cross-sectional studies have identified many heavy metals/trace elements associated with reduced kidney function, prospective studies are needed to determine the pathogenic role of these elements in the development and progression of CKD. Methods To explore the association between baseline urinary heavy metal/trace element concentrations and long-term impaired kidney function (IKF)/CKD, as well as the incidence of rapid decline in kidney function in a population-based exploratory prospective study, we mean age 51.9 years at baseline) whose urinary trace elements concentrations have been determined by inductively coupled plasma mass spectrometry (ICP-MS). IKF was defined by a reduced estimated glomerular filtration rate (eGFR) between 60-90 mL/min/1.73 m2, and CKD was defined as an eGFR&amp;lt;60 mL/min/1.73 m2. Rapid eGFR decline was defined as a decrease≥3 mL/min/1.73 m2 /year. Results Over a mean follow-up of 12.5 years, 123 participants (2.6%) experienced rapid decline in kidney function, and 1455 (31.7%) developed IKF or CKD. After adjusting for covariates including baseline eGFR, we found that urinary vanadium (HR=1.07, 1.03-1.12), cobalt (HR=1.69, 1.21-2.37), nickel (HR=1.19, 1.08-1.3), copper (HR=1.03, 1.01-1.06), selenium (HR=1.33, 1.02-1.73), molybdenum (HR=1.48, 1.2-1.82) and iodine (HR=1.1, 1.02-1.2) were associated with an increased risk of new incident IKF or CKD cases during the follow-up. Also, urinary copper (OR=1.12, 1.04-1.21), silver (OR=1.83, 1-3.35), molybdenum (OR=1.02, 1.01-1.04) and cadmium (OR=1.05, 1.01-1.09) were associated with an increased risk of rapid eGFR decline. Conclusion In the general population, several urinary heavy metals/trace elements are associated with a rapid decline in kidney function or new cases of IKF/CKD.

Disruption of mitochondrial electron transport impairs urinary concentration via AMPK-dependent suppression of aquaporin 2.

Urinary concentration is an energy-dependent process that minimizes body water loss by increasing aquaporin 2 (AQP2) expression in collecting duct (CD) principal cells. To investigate the role of mitochondrial (mt) ATP production in renal water clearance, we disrupted mt electron transport in CD cells by targeting ubiquinone (Q) binding protein QPC (UQCRQ), a subunit of mt complex III essential for oxidative phosphorylation. QPC-deficient mice produced less concentrated urine than controls, both at baseline and after type 2 vasopressin receptor stimulation with desmopressin. Impaired urinary concentration in QPC-deficient mice was associated with reduced total AQP2 protein levels in CD tubules, while AQP2 phosphorylation and membrane trafficking remained unaffected. In cultured inner medullary CD cells treated with mt complex III inhibitor antimycin A, the reduction in AQP2 abundance was associated with activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and was reversed by treatment with AMPK inhibitor SBI-0206965. In summary, our studies demonstrated that the physiological regulation of AQP2 abundance in principal CD cells was dependent on mt electron transport. Furthermore, our data suggested that oxidative phosphorylation in CD cells was dispensable for maintaining water homeostasis under baseline conditions, but necessary for maximal stimulation of AQP2 expression and urinary concentration.

A comprehensive library of lifetime physiological equations for PBK models: Enhancing dietary exposure modeling with mercury as a case study

Dietary risk assessment of food contaminants requires a well-established understanding of the exposure in a heterogeneous population. There are many methods for estimating human exposure to food contaminants, such as intake calculations and internal biomarkers of exposure measured in individuals. However, those methods are expensive, partly invasive, and often provide a momentary exposure snapshot. Physiologically Based Kinetic (PBK) modelling is increasingly used to overcome those challenges that traditional human exposure methods encounter. Still, PBK models are often restricted to certain life stages (e.g., children, adolescents, adults). This study outlines a strategy for implementing nonlinear organ growths in age-specific PBK models to enhance dietary risk assessment from lifetime exposure. To this end, lifetime physiological equations calculating organ growth for both sexes were inventoried from literature and a library was established for 24 organs. We then assessed total lifelong mercury exposure via foodstuff by combining two existing age-specific PBK models for methylmercury (MeHg) and inorganic mercury (iHg) that simulated internal exposure to total mercury, the speciation typically measured in hair and urine. We implemented a set of physiological equations in the PBK model that fitted best the total mercury measured in individuals' organs, hair, and urine from heterogeneous populations. For refined dietary risk assessment, we ultimately estimated total mercury concentration in hair and urine based on i) maximum limits defined by the regulation for MeHg in seafood, ii) the health-based guidance values for MeHg and iHg, and iii) realistic intakes considering French demographic parameters and food consumption data. These exposure scenarios demonstrated that total mercury concentrations in hair and urine estimated from realistic intakes are below critical effect level measures at all ages. The result of this study is the creation of easily accessible tools in Excel and R that facilitate the implementation of physiological equations in Next Generation PBK models.

Exploring the impact of 3,3’-diindolylmethane on the urinary estrogen profile of premenopausal women

Background3,3’-diindolylmethane (DIM) is a phytonutrient derived from cruciferous vegetables that is an often-used supplement in the complementary and alternative medicine space. The most common goal for providers when recommending DIM to their patients is to alter estrogen metabolism, yet research into DIM’s effect on the estrogen profile is lacking in the published literature. The objective of this study was to comprehensively evaluate DIM’s effect on the urinary estrogen profile.MethodsIn this retrospective cohort study, we analyzed data from a clinical laboratory, including urinary estrogen and estrogen metabolite concentrations. Analyte concentrations were determined from dried urine samples using a gas chromatography-tandem mass spectrometry assay. Individuals were separated into two groups, either reporting taking DIM (N = 909) or reporting not taking DIM (N = 18,385). Comparisons between individuals in these two groups were made using the Wilcoxon rank sum test. Additionally, we were also able to explore a subset of women who had laboratory results in the database before and after initiating DIM treatment (N = 53). In this subset, differences were assessed with Wilcoxon signed rank tests.ResultsIn the larger group that was separated into women reporting either DIM use or no use, significant differences were observed in the concentrations of almost every urinary estrogen and estrogen metabolite (with the only exception being 2-methoxyestrone) in the urinary estrogen profiles of those taking DIM compared to those not taking DIM (all P values < 0.001). In the smaller subset of individuals with results before and after initiating DIM use, differences were only seen in 4 of the urinary estrogens and estrogen metabolites (P < 0.001 for estrone, estradiol, estriol, and 16-hydroxyestrone). Differences in total estrogens were significant in both the larger group and the smaller subset (both with P < 0.001). Additionally, observed differences in the ratios of metabolites followed a similar trend with more significant differences observed in the larger group. Notably, the 2-hydroxyestrone:16-hydroxyestrone ratio increased significantly in both the larger group and the smaller subset with results before and after DIM use.ConclusionsThe results of this study provide the most comprehensive evaluation to date of DIM’s effect on the urinary estrogen profile. Additionally, the results demonstrate that the dried urine collection and accompanying assay used capture changes that are similar in direction, but not necessarily magnitude, to previous reports in the literature. Considered together, these two things highlight the clinical validity and utility of this approach to the evaluation of DIM supplementation and suggest the need for additional studies using this approach to fully understand the potential clinical utility of DIM.

Efficacy and safety of switching therapy from chenodeoxycholic acid to cholic acid in Japanese patients with bile acid synthesis disorders

ObjectivesThis study aimed to assess the safety and efficacy of cholic acid (CA) treatment over 74 weeks in Japanese patients with inherited enzymatic bile acid synthesis disorders (BASD). MethodsThis phase 3, open-label, single-arm study enrolled four Japanese patients diagnosed with BASD, including two with 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (HSD3B7) deficiency and two with Δ4–3-oxosteroid 5β-reductase (SRD5B1) deficiency. The patients had received chenodeoxycholic acid (CDCA) treatment but were switched to CA treatment. Treatment efficacy was evaluated by measuring serum and urinary bile acid levels and liver-related biomarkers, and adverse events were evaluated to monitor safety. ResultsThe daily CA doses ranged from 3.8 to 13.7 mg/kg/day. Laboratory values of liver-related biomarkers were maintained within normal ranges or improved. Bile acid analysis revealed CDCA replacement with CA in serum within the initial few weeks of CA treatment. Urinary concentrations of toxic bile acid metabolites associated with liver damage were higher than serum. Adverse effects from CA treatment were mild to moderate, and no treatment discontinuations were due to adverse events. ConclusionsCA treatment over 74 weeks resulted in favorable efficacy and safety outcomes in Japanese patients with BASD, consistent with previous studies. These results support the utility of CA as a therapeutic option for Japanese patients with BASD.

Health risk modeling and risk factors of fluorosis in the fluoride endemic village of Maharashtra: A cross-sectional study.

Fluorosis, a debilitating disease, causes dental mottling and bone deformities among other adverse health effects. The current epidemiological study focused on the prevalence and risk factors of fluorosis in the fluoride endemic village, Dongargaon, Maharashtra, India. The clinical diagnosis of subjects showed 96.49% prevalence of dental fluorosis, and 63.16% prevalence of skeletal fluorosis. Duration of exposure, age of subjects and physiological symptoms like chronic joint pain were found to be significantly correlated with skeletal fluorosis (p < 0.05). Fluoride in drinking water showed seasonal variation with highest level in winter (6.54 mg/L) and lowest level in monsoon (0.54 mg/L). Consequently, the mean urinary fluoride concentration was also highest in winter (9.37 mg/L) and lowest in monsoon (3.88 mg/L). Multilogit regression analysis demonstrated that subjects excreting urinary fluoride above 4 mg/L had 7.25 times higher odds of developing skeletal fluorosis (p < 0.05). Health risk assessment showed a high value of hazard quotient, indicating a high probability of adverse health effects. The estimated daily ingestion of 8.80 mg F and a predicted bone uptake of 0.19 mg/kg/day raised significant health concerns for the studied population. Exposure and bone F uptake modeling suggested that the predicted mean fluoride concentrations of 4018.77 ± 1762.45 mg/kg bone ash in asymptomatic, and 5535.12 ± 1526.30 mg/kg bone ash in symptomatic subjects were significantly different (p < 0.05). The comprehensive risk evaluation in the study clearly brings out the high risk of fluoride exposure and adverse effects in Dongargaon village for the first time. Further, urinary fluoride was shown to have significant association with the risk of skeletal fluorosis. The study warrants implementation of immediate control measures at the study site.

A Cross Sectional Study of Cytokines in Women with Refractory Detrusor Overactivity versus Controls.

Previous work has suggested that refractory detrusor overactivity (DO) was commonly associated with urinary tract infection (UTI), which can lead to inflammatory changes in the bladder. This study aimed to investigate the concentrations of urinary cytokines in a large sample of women with refractory detrusor overactivity (DO) and age matched controls. The urinary concentration of 27 cytokines in 140 women (95 with refractory DO and 45 age matched controls (women without urge incontinence)) was determined using the Human Cytokine 27-plex Assay. Cytokine concentrations were correlated with a "UTI score", the presence or absence of bacteriuria or pyuria on the day of sample collection and a previous history of UTI. Pro-inflammatory cytokines were increased in refractory DO women compared to the controls. In women with refractory DO, the UTI score significantly correlated with urinary cytokine concentrations in 15 of the 22 cytokines detected. A previous history of UTI did not affect urinary cytokine concentrations in refractory DO women with no current UTI. Increasing pyuria was associated with increasing concentrations of urinary cytokines. Careful comparison of cytokine concentrations in women with refractory DO versus age matched controls has shown that changes in pro-inflammatory cytokines are related to the UTI disease burden, suggesting that an underlying inflammatory response, together with UTI, may be an aetiological contributor to the development of refractory DO.