Normative values for ureteral diameter in children.

BACKGROUND: Assessment of the ureter is a fundamental part of the radiologic evaluation of the urinary tract. Abnormal ureteral dilation warrants further investigation to assess the etiology, which includes obstruction and/or reflux. Despite this fundamental need, there are no established normative values in children based on imaging. OBJECTIVE: To provide normative values for ureteral diameter in pediatric patients with age-related ranges. MATERIALS AND METHODS: We retrospectively reviewed all magnetic resonance (MR) urography studies and chose only normal ureters for assessment. The images were analyzed on commercially available software to assess maximum internal diameter. Manual measurements were done in cases where the images were below the resolution for automated assessment. Maximum intraluminal ureteral diameters were measured in upper, mid and lower thirds and the average of the three maximum ureteral diameters was used to obtain the average widest internal ureteral diameter. Multivariable linear regression was performed to test the association between the calculated diameter and gender. Differences in sizes between the left and right ureter were assessed using paired Wilcoxon signed rank test. RESULTS: One hundred twenty-one MR urography studies were selected, which included 160 ureter units. The diameter increases progressively with age, ranging from 3.2 mm during infancy to 5.0 mm in patients older than 16 years of age. After 9 years of age, the average widest internal ureteral diameter is slightly larger in males compared to females (odds ratio [OR]=1.91, 95% confidence interval [CI] [1.63, 2.25], P<0.0001). The right ureter was slightly larger than the left (3.9 mm vs. 3.7 mm, P=0.004) among 39 patients in whom both right and left ureter units were included. The average mid ureteral diameter is widest, followed by the distal third then proximal third. CONCLUSION: We present the normative values for the average widest internal ureteral diameter based on laterality and different segments. In the pediatric population, 3.8 mm should be considered the average widest internal ureteral diameter.

Retrospective Distortion and Motion Correction for Free-Breathing DW-MRI of the Kidneys Using Dual-Echo EPI and Slice-to-Volume Registration.

BACKGROUND: Diffusion-weighted MRI (DW-MRI) of the kidneys is a technique that provides information about the microstructure of renal tissue without requiring exogenous contrasts such as gadolinium, and it can be used for diagnosis in cases of renal disease and assessing response-to-therapy. However, physiological motion and large geometric distortions due to main B0 field inhomogeneities degrade the image quality, reduce the accuracy of quantitative imaging markers, and impede their subsequent clinical applicability. PURPOSE: To retrospectively correct for geometric distortion for free-breathing DW-MRI of the kidneys at 3T, in the presence of a nonstatic distortion field due to breathing and bulk motion. STUDY TYPE: Prospective. SUBJECTS: Ten healthy volunteers (ages 29-38, four females). FIELD STRENGTH/SEQUENCE: 3T; DW-MR dual-echo echo-planar imaging (EPI) sequence (10 b-values and 17 directions) and a T2 volume. ASSESSMENT: The distortion correction was evaluated subjectively (Likert scale 0-5) and numerically with cross-correlation between the DW images at b = 0 s/mm2 and a T2 volume. The intravoxel incoherent motion (IVIM) and diffusion tensor (DTI) model-fitting performance was evaluated using the root-mean-squared error (nRMSE) and the coefficient of variation (CV%) of their parameters. STATISTICAL TESTS: Statistical comparisons were done using Wilcoxon tests. RESULTS: The proposed method improved the Likert scores by 1.1 ± 0.8 (P < 0.05), the cross-correlation with the T2 reference image by 0.13 ± 0.05 (P < 0.05), and reduced the nRMSE by 0.13 ± 0.03 (P < 0.05) and 0.23 ± 0.06 (P < 0.05) for IVIM and DTI, respectively. The CV% of the IVIM parameters (slow and fast diffusion, and diffusion fraction for IVIM and mean diffusivity, and fractional anisotropy for DTI) was reduced by 2.26 ± 3.98% (P = 6.971 × 10-2 ), 11.24 ± 26.26% (P = 6.971 × 10-2 ), 4.12 ± 12.91% (P = 0.101), 3.22 ± 0.55% (P < 0.05), and 2.42 ± 1.15% (P < 0.05). DATA CONCLUSION: The results indicate that the proposed Di + MoCo method can effectively correct for time-varying geometric distortions and for misalignments due to breathing motion. Consequently, the image quality and precision of the DW-MRI model parameters improved. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Zinner syndrome in pediatric age group: An underdiagnosed entity.

INTRODUCTION: Zinner Syndrome (ZS), a rare congenital malformation of the mesonephric duct, combines seminal vesicle cyst (SVC) with ipsilateral upper urinary tract abnormalities. Typically asymptomatic in childhood, ZS manifests between 2nd to 4th decades with bladder symptoms, perineal pain and infertility. Diagnostic confirmation with additional imaging is needed when either renal or seminal abnormalities are identified. MATERIALS AND METHODS: A retrospective study spanning 22 years identified 20 pediatric ZS cases through clinical analytics. Demographic, clinical, and radiological data were analyzed, including presenting complaints, imaging modalities (ultrasound, CT, MRI), and surgical findings. The study was HIPAA-compliant and IRB-approved. RESULTS: Among 20 cases (mean age: 7.3 years), clinical presentations included asymptomatic cases, urinary symptoms, and abdominal pain. Imaging revealed renal anomalies (agenesis, multicystic dysplastic kidney) and seminal vesicle abnormalities. Surgical interventions (n = 12) addressed symptomatic cases, often involving robotic or laparoscopic procedures. DISCUSSION: ZS, though rare, presents with varied clinical features, necessitating a multidisciplinary approach. Early diagnosis is facilitated by prenatal identification of renal abnormalities. Surgical intervention is reserved for symptomatic cases, with techniques such as vesiculectomy and resection of remnant structures employed. CONCLUSION: This study highlights ZS's diverse clinical and radiological spectrum, emphasizing the need for vigilance in detecting overlapping entities. Timely identification, utilizing advanced imaging techniques, is crucial for accurate diagnosis and appropriate management of Zinner Syndrome in the pediatric population.

Concentration- and stage-specific effects of nitrite on colon cancer cell lines.

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Nitrite in cured meats is thought to contribute to increased incidence of colon cancer. We sought to determine the effect of nitrite on human colon cancer cell lines at different stages. Our results indicate nitrite has no effect on proliferation of stage 1 SW116 colon cancer cells, while nitrite inhibits proliferation of stage 2 SW480 at 10 nM-100 µM and inhibits stage 3 HCT15 proliferation at 100 nM-1 µM, but promotes a significant increase in proliferation on stage 4 COLO205 cells at 100 µM. Furthermore, nitrite inhibited invasion into Matrigel® of stage 3 SW480 colon cancer cells in a concentration-dependent manner. However, it significantly promotes the invasion of stage 4 cells at 100 µM. Our FACS data demonstrated that nitrite decreased cell cycle progression in SW480 and HCT15 with arrested G2/M transition and delayed G1 phase entry in a concentration-dependent manner. However, 100 µM nitrite promoted cell cycle progression in COLO205 cells with increased S-phase entry. Taken together, our data indicate nitrite inhibits cancer cell progression at low concentrations and early stage but promotes cancer cell progression at higher concentrations in cells representing stage 4 colon carcinomas.

Urinary nitrate might be an early biomarker for pediatric acute kidney injury in the emergency department.

NO is involved in normal kidney function and perturbed in acute kidney injury (AKI). We hypothesized that urinary concentration of NO metabolites, nitrite, and nitrate would be lower in children with early AKI presenting to the emergency department (ED), when serum creatinine (SCr) was uninformative. Patients up to 19 y were recruited if they had a urinalysis and SCr obtained for routine care. Primary outcome, AKI, was defined by pediatric Risk, Injury, Failure, Loss of function, End-stage renal disease (pRIFLE) criteria. Urinary nitrite and nitrate were determined by HPLC. A total of 252 patients were enrolled, the majority (93%) of whom were without AKI. Although 18 (7%) had AKI by pRIFLE, 50% may not have had it identified by the SCr value alone at the time of visit. Median urinary nitrate was lower for injury versus risk (p = 0.03); this difference remained significant when the injury group was compared against the combined risk and no AKI groups (p = 0.01). Urinary nitrite was not significantly different between groups. Thus, low urinary nitrate is associated with AKI in the pediatric ED even when SCr is normal. Predictive potential of this putative urinary biomarker for AKI needs further evaluation in sicker patients.

Nutritional epidemiology in the context of nitric oxide biology: a risk-benefit evaluation for dietary nitrite and nitrate.

The discovery of the nitric oxide (NO) pathway in the 1980s represented a critical advance in understanding cardiovascular disease, and today a number of human diseases are characterized by NO insufficiency. In the interim, recent biomedical research has demonstrated that NO can be modulated by the diet independent of its enzymatic synthesis from l-arginine, e.g., the consumption of nitrite- and nitrate-rich foods such as fruits, leafy vegetables, and cured meats along with antioxidants. Regular intake of nitrate-containing food such as green leafy vegetables may ensure that blood and tissue levels of nitrite and NO pools are maintained at a level sufficient to compensate for any disturbances in endogenous NO synthesis. However, some in the public perceive that dietary sources of nitrite and nitrate are harmful, and some epidemiological studies reveal a weak association between foods that contain nitrite and nitrate, namely cured and processed meats, and cancer. This paradigm needs revisiting in the face of undisputed health benefits of nitrite- and nitrate-enriched diets. This review will address and interpret the epidemiological data and discuss the risk-benefit evaluation of dietary nitrite and nitrate in the context of nitric oxide biology. The weak and inconclusive data on the cancer risk of nitrite, nitrate and processed meats are far outweighed by the health benefits of restoring NO homeostasis via dietary nitrite and nitrate. This risk/benefit balance should be a strong consideration before there are any suggestions for new regulatory or public health guidelines for dietary nitrite and nitrate exposures.

Dietary sources of nitrite as a modulator of ischemia/reperfusion injury.

The nitrite anion is an endogenous product of nitric oxide (NO) metabolism, a key intermediate in the nitrogen cycle in plants and bacteria, and a constituent of many foods. Research over the past 6 years has revealed a surprising biological and cytoprotective activity of this anion. Its ability to restore NO homeostasis throughout the physiological oxygen gradient in vivo has transformed this once-thought to be inert anion into a critical molecule in health and disease. Ischemia-reperfusion (I/R) injury is a major clinical problem worldwide. NO has been shown to be one of the most important molecules for the prevention of injury from I/R. Paradoxically, however, enzymatic NO formation from NO synthase (NOS) is inactive during conditions of inadequate oxygen and substrate delivery, such as in ischemia. Nitrite has emerged as a viable alternative source of NO under ischemic conditions. As nitrite is known to be derived not only from the oxidation of NO but also through diet, understanding nitrite metabolism and mechanisms of cytoprotection may offer novel and natural means to prevent disease or at least limit injury from an I/R event. Here, we review the current body of knowledge regarding dietary sources of nitrite and its modulation of cytoprotection in an I/R injury.

A survey of nitrate and nitrite concentrations in conventional and organic-labeled raw vegetables at retail.

A national survey of the nitrate ( NO3(-)) and nitrite ( NO2(-)) concentrations in raw and highly consumed vegetables available at retail in the United States was conducted. A total of 194 samples of fresh broccoli, cabbage, celery, lettuce, and spinach categorized as conventional or organic by label were collected from 5 major cities in different geographic regions of the United States and analyzed to determine NO3(-) and NO2(-) concentrations. There were no differences in the mean NO2(-) values of conventional compared with organic vegetables taken from the 5 metropolitan areas. However, significant differences in mean pairwise comparisons between some conventional and organic vegetables for NO3(-) content were observed. The mean NO2(-) concentration of both conventional and organic vegetables ranged between 0.1 and 1.2 mg/kg of fresh weight (FW) with the exception of conventional spinach that contained 8.0 mg/kg FW. Mean NO3(-) contents of conventional broccoli, cabbage, celery, lettuce, and spinach were 394, 418, 1496, 851, and 2797 mg/kg FW, respectively, while their organic-labeled counterparts averaged 204, 552, 912, 844, and 1318 mg/kg FW. In most cases, organic vegetables were numerically lower in NO3(-) content than their conventional counterparts. Based on survey results, the finding that low NO3(-) levels were observed in some organic vegetables in different cities may warrant further study to determine if true differences exist, due to production practices, seasonal differences, and the magnitudes of those differences. Furthermore, the geographic differences in NO3(-) content of vegetables may flaw estimates of daily NO2(-) and NO3(-) exposure.

Dietary nitrite improves insulin signaling through GLUT4 translocation.

Diabetes mellitus type 2 is a syndrome of disordered metabolism with inappropriate hyperglycemia owing to a reduction in the biological effectiveness of insulin. Type 2 diabetes is associated with an impaired nitric oxide (NO) pathway that probably serves as the key link between metabolic disorders and cardiovascular disease. Insulin-mediated translocation of GLUT4 involves the PI3K/Akt kinase signal cascade that results in activation of endothelial NO synthase (eNOS). eNOS is dysfunctional during diabetes. We hypothesize that loss of eNOS-derived NO terminates the signaling cascade and therefore cannot activate GLUT4 translocation and that dietary nitrite may repair this pathway. In this study, we administered 50mg/L sodium nitrite to db/db diabetic mice for 4 weeks. After 4 weeks treatment, the db/db mice experienced less weight gain, improved fasting glucose levels, and reduced insulin levels. Cell culture experiments using CHO-HIRc-myc-GLUT4eGFP cell lines stably expressing insulin receptor and myc-GLUT4eGFP protein, as well as L6 skeletal muscle cells stably expressing rat GLUT4 with a Myc epitope (L6-GLUT4myc), showed that NO, nitrite, and GSNO stimulate GLUT4 translocation independent of insulin, which is inhibited by NEM. Collectively our data suggest that nitrite improves insulin signaling through restoration of NO-dependent nitrosation of GLUT4 signaling translocation. These data suggest that NO-mediated nitrosation of GLUT4 by nitrite or other nitrosating agents is necessary and sufficient for GLUT4 translocation in target tissue. Description of this pathway may justify a high-nitrate/nitrite diet along with the glycemic index to provide a safe and nutritional regimen for the management and treatment of diabetes.

Nitric oxide metabolites as biomarkers for influenza-like acute respiratory infections presenting to the emergency room.

AIMS: Nitric oxide (NO) is increased in the respiratory tract in pulmonary infections. The aim was to determine whether nasal wash NO metabolites could serve as biomarkers of viral pathogen and disease severity in children with influenza-like illness (ILI) presenting to the emergency department (ED) during the 2009 influenza A H1N1 pandemic. METHODS: Children ≤18 years old presenting to the ED with ILI were eligible. Nasal wash specimens were tested for NO metabolites, nitrate and nitrite, by HPLC and for respiratory viruses by real-time PCR. RESULTS: Eighty-nine patients with ILI were prospectively enrolled during Oct-Dec, 2009. In the entire cohort, nasal wash nitrite was low to undetectable (interquartile range [IQR], 0 - 2 µM), while median nitrate was 3.4 µM (IQR 0-8.6). Rhinovirus (23%), respiratory syncytial virus (RSV) (20%), novel H1N1 (19%), and adenovirus (11%) were the most common viruses found. Children with RSV subtype B-associated ILI had higher nitrate compared to all other viruses combined (P=0.002). CONCLUSION: Concentration of NO-derived nitrate in nasal secretions in children in the ED is suggestive of viral pathogen causative for ILI, and thus might be of clinical utility. Predictive potential of this putative biomarker for ILI needs further evaluation in sicker patients in a prospective manner.

Survey of residual nitrite and nitrate in conventional and organic/natural/uncured/indirectly cured meats available at retail in the United States.

A survey of residual nitrite (NO(2)(-)) and nitrate (NO(3)(-)) in cured meats available at retail was conducted to verify concentrations in conventional (C) products and establish a baseline for organic/natural/uncured/indirectly cured (ONC) products. In this study, 470 cured meat products representing six major categories were taken from retail outlets in five major metropolitan cities across the United States. Random samples representing both C and ONC type products were analyzed for NO(2)(-) and NO(3)(-) content (ppm) using an ENO-20 high-performance liquid chromatography system equipped with a reverse phase column. Generally, there were no differences in NO(2)(-) concentrations between C and ONC meat categories, but a few ONC products surveyed in certain cities were lower in NO(3)(-) content. Pairwise comparisons between cities indicated that NO(2)(-) and NO(3)(-) contents of all C type products were not appreciably different, and the same was true for most ONC products. Numerical NO(2)(-) values were less variable than NO(3)(-) concentrations within each meat product category. NO(2)(-) concentrations were similar to those previously reported by Cassens ( Cassens , R. G. Residual nitrite in cured meat . Food Technol. 1997a , 51 , 53 - 55 ) in 1997. Residual NO(2)(-) and NO(3)(-) values in this study were numerically lower than those reported by NAS ( National Academy of Sciences . The Health Effects of Nitrate, Nitrite, and N-Nitroso Compounds ; National Academy Press : Washington, DC , 1981 ) in 1981. Data from this survey provide a benchmark of NO(2)(-) and NO(3)(-) concentrations for ONC products available at retail.

All-natural nitrite and nitrate containing dietary supplement promotes nitric oxide production and reduces triglycerides in humans.

There is an emerging paradigm that certain foods promote nitric oxide (NO) production from the stepwise reduction of nitrate to nitrite to NO, providing an endothelium independent source of bioactive NO. We hypothesize that a unique formulation containing nitrate-rich beetroot along with Hawthorn berry shown to have a robust nitrite reductase activity would improve NO status in humans and modify cardiovascular risk factors. The trial was conducted at the Houston Institute for Clinical Research in Houston, Texas. Inclusion criteria for this double-blinded, placebo-controlled study were patients older than 40 years with 3 or more of the following cardiovascular risk factors: hypertension, obesity, hyperlipidemia, smoking, sedentary, family history of cardiovascular disease, and diabetes. Subjects were instructed to take either the NO dietary supplement called Neo40 Daily® or placebo twice daily on an empty stomach for 30 days. Patients taking the NO dietary supplement twice a day for 30 days led to a significant increase in both plasma nitrite (P < .01) and nitrate (P < .0001), indicating an increase in systemic NO availability. There was a statistically significant reduction in 72% of patients with elevated triglycerides (>150 mg/dL) after 30 days compared with their starting levels before taking the NO dietary supplement (168 ± 17 mg/dL vs 232 ± 19 mg/dL, P = .02). The strategy of formulating a combination of natural products and botanicals chosen specifically for their NO activity shows promise in restoring NO homeostasis in human subjects at risk for cardiovascular disease for use as a dietary supplement.

Nitrate and nitrite content of human, formula, bovine, and soy milks: implications for dietary nitrite and nitrate recommendations.

BACKGROUND: Estimation of nitrate and nitrite concentrations of milk sources may provide insight into potential health risks and benefits of these food sources for infants, children, and adults. The World Health Organization and American Academy of Pediatrics recommends exclusive consumption of human milk for the first 6 months of life. Human milk is known to confer significant nutritional and immunological benefits for the infant. Consumption of formula, cow's, and soy milk may be used as alternatives to human milk for infants. METHODS: We sought to estimate potential exposure to nitrate and nitrite in human, formula, bovine, and soy milk to inform total dietary exposure estimates and recommendations. Using sensitive quantitative methodologies, nitrite and nitrate were analyzed in different samples of milk. RESULTS: Human milk concentrations of colostrum (expressed days 1-3 postpartum; n=12), transition milk (expressed days 3-7 postpartum; n=17), and mature milk (expressed >7 days postpartum; n=50) were 0.08 mg/100 mL nitrite and 0.19 mg/100 mL nitrate, 0.001 mg/100 mL nitrite and 0.52 mg/100 mL nitrate, and 0.001 mg/100 mL nitrite and 0.3 mg/100 mL nitrate, respectively, revealing that the absolute amounts of these anions change as the composition of milk changes. When expressed as a percentage of the World Health Organization's Acceptable Daily Intake limits, Silk® Soy Vanilla (WhiteWave Foods, Broomfield, CO) intake could result in high nitrate intakes (104% of this standard), while intake of Bright Beginnings Soy Pediatric® formula (PBM Nutritionals, Georgia, VT) could result in the highest nitrite intakes (383% of this standard). CONCLUSIONS: The temporal relationship between the provision of nitrite in human milk and the development of commensal microbiota capable of reducing dietary nitrate to nitrite supports a hypothesis that humans are adapted to provide nitrite to the gastrointestinal tract from birth. These data support the hypothesis that the high concentrations of breastmilk nitrite and nitrate are evidence for a physiologic requirement to support gastrointestinal and immune homeostasis in the neonate.

Requirement of argininosuccinate lyase for systemic nitric oxide production.

Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases.

Nitric oxide bioactivity of traditional Chinese medicines used for cardiovascular indications.

Traditional Chinese medicine (TCM) has been used for centuries to treat and prevent certain ailments and diseases. Although TCM has served as mainstream medical care throughout Asia for many generations, it is considered an alternative medical system in much of the Western world. Because many TCMs are used primarily for cardiovascular indications characterized by a nitric oxide (NO) insufficiency, we hypothesized that some, if not all, of these TCMs have a robust NO bioactivity that may act to restore NO homeostasis. We tested a group of convenience samples of TCMs obtained in the United States for endogenous nitrite, nitrate, nitroso, and nitrite reductase activity as well as their ability to relax isolated aortic rings. The results from this study reveal that all of the TCMs tested reveal NO bioactivity through their inherent nitrite and nitrate content and their ability to reduce nitrite to NO. Many of the TCM extracts contain a nitrite reductase activity greater by 1000 times that of biological tissues. Repletion of biological nitrite and nitrate by these extracts and providing a natural system for NO generation in both endothelium-dependent and -independent mechanisms may account for some of the therapeutic effects of TCMs.

Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction.

The nitrite anion is an endogenous product of mammalian nitric oxide (NO) metabolism, a key intermediate in the nitrogen cycle in plants, and a constituent of many foods. Research over the past 6 years has revealed surprising biological and cytoprotective activity of this anion. Hypercholesterolemia causes a proinflammatory phenotype in the microcirculation. This phenotype appears to result from a decline in NO bioavailability that results from a reduction in NO biosynthesis, inactivation of NO by superoxide, or both. Since nitrite has been shown to be potently cytoprotective and restore NO biochemical homeostasis, we investigated if supplemental nitrite could attenuate microvascular inflammation caused by a high cholesterol diet. C57Bl/6J mice were fed either a normal diet or a high cholesterol diet for 3 wk to induce microvascular inflammation. Mice on the high cholesterol diet received either nitrite-free drinking water or supplemental nitrite at 33 or 99 mg/l ad libitum in their drinking water. The results from this investigation reveal that mice fed a cholesterol-enriched diet exhibited significantly elevated leukocyte adhesion to and emigration through the venular endothelium as well as impaired endothelium-dependent relaxation in arterioles. Administration of nitrite in the drinking water inhibited the leukocyte adhesion and emigration and prevented the arteriolar dysfunction. This was associated with sparing of reduced tetrahydrobiopterin and decreased levels of C-reactive protein. These data reveal novel anti-inflammatory properties of nitrite and implicate the use of nitrite as a new natural therapy for microvascular inflammation and endothelial dysfunction associated with hypercholesterolemia.