Search

High sodium intake is strongly associated with hypertension and obesity. This study aims to investigate the relationship between 24-h urinary sodium (a surrogate measure of sodium intake), ambulatory blood pressure parameters, left atrial function, and left atrioventricular coupling. Further, we intend to examine whether blood pressure and BMI might be mediators of the relationship between 24-h urinary sodium and subclinical cardiac function.Our study had 398 participants, all of whom were subjected to 24-h urine collection, 24-h ambulatory blood pressure measurement, and cardiac magnetic resonance imaging.The average age of the participants was 55.70 ± 11.30 years old. The mean urinary sodium of the participants was 172.01 ± 80.24 mmol/24 h. After adjusting for age, sex, history of diabetes, smoking status, alcohol consumption, and use of diuretics, 24-h urinary sodium was correlated with multiple ambulatory blood pressure parameters, BMI, left atrial function, and the left atrioventricular coupling index (LACI) (P 0.05). Mediation analysis showed that BMI explained 16% of the indirect effect of 24-h urinary sodium and left atrial function and 30% of the indirect effect of LACI. Independent of the mediator, 24-h urinary sodium had a significant direct effect on left atrial function and left atrioventricular coupling.Higher 24-h urinary sodium was associated with a greater BMI as well as poor left atrial function and left atrioventricular coupling, and the BMI mediated the relationship between 24-h urinary sodium and subclinical left cardiac function. Furthermore, and more importantly, 24-h urinary sodium may have directly affected the left atrial function and left atrioventricular coupling independent of intermediary factors.

BACKGROUND & AIMS: Dietary sodium restriction is recommended by current guidelines to reduce blood pressure and decrease the risk of cardiovascular disease. Current methods to assess sodium intake such as dietary questionnaires and 24-h urine collection are cumbersome, and the results are not readily available to patients. In this analysis, we evaluated using chloride and creatinine dipsticks as a convenient method to monitor sodium intake, in addition to patients’ ability to practice this method independently. METHODS: This is a post-hoc analysis of a previously published trial, LowSalt4Life, that measured change in sodium consumption over 8 weeks to evaluate the effect of a just-in-time adaptive mobile application intervention. Participants were instructed on how to complete and interpret Quantab(®) chloride and Multistix(®) PRO 10 LS creatinine dipstick measurements at home and upload a picture of their results. A pharmacy student interpreted the chloride dipsticks, and intraclass correlation coefficients (ICC) were calculated to assess interrater reliability between the participant and pharmacy student. Predicted 24-h sodium values were calculated by the Kawasaki and Mann methods and compared to actual 24-h sodium excretion. RESULTS: There was a strong interobserver correlation between interpretations of the chloride dipsticks, with the ICC values 0.90, 0.97, 0.99, and 0.98 at weeks 2, 4, 6, and 8, respectively. There was a moderate correlation between the dipstick predicted 24-h sodium excretion and actual 24-h sodium excretion at baseline (r = 0.506; P < 0.001), and a weak correlation at week 8 (r = 0.187; P = 0.217). When corrected creatinine values were used, the dipstick predicted 24-h sodium excretion correlated with the actual 24-h sodium excretion at baseline and week 8 (r = 0.512; P < 0.001 and r = 0.451; P = 0.002). CONCLUSIONS: Our analysis suggests that chloride and creatinine dipsticks have the potential to predict total daily excretion of sodium. This method provides patients with an easy, convenient, and accurate method to assess sodium excretion at home. Further research is needed to identify the optimal timing of performing the dipstick analysis as well as ways to improve the creatinine measurement of the urine samples. TRIAL REGISTRATION: ClinicalTrials.gov NCT03099343; https://clinicaltrials.gov/ct2/show/NCT03099343.

Spot urine specimens have been used to estimate 24 h urinary sodium (Na) excretion (24UNaV) and potassium (K) excretion (24UKV). However, the validity is limited for 24UNaV and unknown for 24UKV in stroke patients, using the existing formulas. Herein, we developed and validated a new formula for 24UNaV and 24UKV by spot urine specimens in stroke patients. Spot and 24 h urine samples were collected from 970 stroke patients. The models of 24UNaV and 24UKV were developed using stepwise multivariate linear regression in 689 patients. The performance of different formulas was internally validated in 281 patients at the population and individual levels. The obtained new formulas were: (1) estimated 24UNaV (mmol/day): −0.191 × Age + 4.349 × BMI + 0.229 × SpotNa + 1.744 × SpotNa/Spot creatinine (Cr) + 41.492 (for male); −1.030 × Age + 2.011 × BMI + 0.143 × SpotNa + 1.035 × SpotNa/SpotCr + 147.159 (for female); and (2) estimated 24UKV (mmol/day): −0.052 × Age + 0.410 × BMI + 0.031 × SpotK + 33.280 × Ln (spotK/spot Cr) − 5.789 × Ln (spotNa/spot Cr) − 1.035 (for male); −0.235 × Age + 0.530 × BMI + 0.040 × SpotK + 30.990 × Ln (spot K/spot Cr) − 7.837 × Ln (spotNa/spotCr) + 4.318 (for female). The new formula obtained the lowest mean bias (5.17 mmol/day for 24UNaV and 0.85 mmol/day for 24UKV) and highest proportion at the cutoff under the ±30% level for the estimation of 24UNaV (59.43%) and 24UKV (70.11%). The new formula provides a meaningful exploration to estimate 24UNaV and 24UKV in stroke patients by using spot urine specimens.

The relationship between sodium intake and cardiovascular (CV) events remains unconfirmed. Therefore, we carried out a systematic review and dose-response meta-analysis for evaluating the potential impact of 24-hour sodium excretion on CV risk. Besides, 24-hour sodium excretion was used to replace daily sodium diet intake.We searched ISI Web of Science, Embase, PubMed, and the Cochrane Library. Our study included cohort studies reporting hazard ratio (A total of 9 studies involving 645,006 participants were included in this study. A significant non-linear relationship was observed between sodium excretion and CV events (In a linear dose-response manner, every 1 g increase in sodium intake was associated with an increased risk of CV events up to 4%. Further studies are required to validate our conclusions further.

The unique feature of nuclear accidents with neutron exposure is the induced radioactivity in body tissues. For dosimetry purposes, the most important stable isotopes occurring in human body, which can be activated by neutrons, are 23 Na and 32 S. The respective activation reactions are as follows:23Na(n,γ)24Na and32S(n,p)32P. While sodium occurs in human blood, sulfur is present in human hair. In order to verify the practical feasibility of this dosimetry technique in conditions of our laboratory, samples of human blood and hair were irradiated in a channel of a training reactor VR-1.24Na activity was measured by gamma-ray spectrometry.32P activity in hair was measured by means of a proportional counter. Based on neutron-spectrum calculation, relationships between neutron dose and induced activity were derived for both blood and hair.

Background Due to the known contribution of excess sodium intake on elevations in blood pressure, salt reduction regulations are being introduced in countries all over the world. To study the contribution of sodium intake on cardiovascular disease development, we determined whether left ventricular mass associates with sodium excretion in young adults free from overt cardiovascular disease and those with masked hypertension. Methods We included 681 participants (41% men and 50% black) in a cross-sectional analysis from the African-PREDICT study with complete 24-hour urine collections and successful ambulatory blood pressure monitoring (>70% valid readings). The participants were categorized as normotensive (n = 534) or masked hypertensive (n = 147). In addition, we determined left ventricular mass index (LVMI) along with traditional risk factors. Results Masked hypertensive individuals had higher sodium excretion (149 vs. 128 mmol/L/day) and LVMI (78.1 vs. 69.6 g/m2) than normotensives. In single, partial and multiple regression analyses, LVMI independently associated with higher sodium excretion in the total group of young adults (β = 0.089; p = 0.011). This result was also evident among masked hypertensives (β = 0.215; p = 0.008), but not in normotensives (β = 0.054; p = 0.134). Conclusion Our results indicated that higher sodium excretion (reflecting a higher salt intake) may contribute to increased left ventricular mass, potentially driven by the early development of masked or undetected hypertension.

Positron emission tomography (PET) with 18F-sodium fluoride (18F-NaF) has emerged as a promising non-invasive imaging modality to identify high-risk and ruptured atherosclerotic plaques. By visualizing microcalcification, 18F-NaF PET holds clinical promise in refining how we evaluate coronary artery disease, shifting our focus from assessing disease burden to atherosclerosis activity. In this review, we provide an overview of studies that have utilized 18F-NaF PET for imaging atherosclerosis. We discuss the associations between traditional coronary artery disease measures (risk factors) and 18F-NaF plaque activity. We also present the data on the histological validation as well as show how 18F-NaF uptake is associated with plaque morphology on intravascular and CT imaging. Finally, we discuss the technical challenges associated with 18F-NaF coronary PET highlighting recent advances in this area.

Little is known about the effect of sodium intake on health-related quality of life (HR-QOL). In this study, we investigated the association between estimated 24-h urine sodium and HR-QOL in Korean adults.In this cross-sectional study, we analyzed 10,672 participants from Korea National Health and Nutrition Examination Survey (KNHANES) 2010~2011. To assess sodium intake, 24-h urine sodium excretion was estimated from random urine sodium and creatinine using the Kawasaki formula. HR-QOL was assessed using EQ-5D (EuroQol five-dimension) index calculated from Korean version of the EQ-5D questionnaire. Low HR-QOL was defined as the lowest quartile of the EQ-5D index. Participants were divided into three groups according to their estimated 24-h urine sodium level (low,2.0 g/day; moderate, 2.0~3.9 g/day; high,4.0 g/day).Adjusted means of EQ-5D index were 0.975, 0.995, and 0.991 in the low, moderate, and high estimated 24-h urine sodium group, respectively (P = 0.003 for low vs. moderate, P = 0.078 for high vs. moderate). In a multiple logistic analysis, the odds ratio (OR) for low EQ-5D index in the low estimated 24-h urine sodium group compared to the moderate group was 1.87 (95% confidence interval (CI), 1.33-2.64; P 0.001). The OR in the high estimated 24-h urine sodium group compared to the moderate group was 1.09 (95% CI, 0.95-1.24; P = 0.218).Low estimated 24-h urine sodium rather than high estimated 24-h urine sodium was associated with low HR-QOL in representative Korean adults. Further studies are warranted to verify the effect of sodium intake on HR-QOL and the adequate-level sodium restriction in terms of HR-QOL.

The action of free radicals is believed responsible for much or most biological injury resulting from exposure to ionizing radiation. These molecules in solution possess short lifetimes on the order of nanoseconds to microseconds. As a result, the dose-which measures the energy dissipated in tissue due to radiolysis-should not be considered a reliable indicator of the free radical concentration, nor of the chemical effects that follow from it. Rather, the chemical state of affected tissue is properly represented only by the dissipated power, which describes the distribution of energy with time. The present report demonstrates the validity of this assertion using data contained in a report describing a benchtop experiment published in 1972. The experiment used the visible rupture of a model phospholipid membrane as a means to quantify the degree of chemical insult caused by ionizing radiation. The experiment found that beta doses in the range from 1-10 rad were equivalent to x-ray rupture doses of 3,500 rad. This report demonstrates that the experimental results are convincingly explained by reference to the properly calculated time-averaged dissipated power due to beta decay. The theoretical explanation is derived by analogy to a well-understood result from electronic systems known as shot noise. If the result described in this report is demonstrated to extrapolate from the benchtop to living systems, then it is likely that exposure to beta radiation via internal incorporation is far more hazardous than commonly believed. The finding could be revolutionary in the field of health physics.

Purpose To investigate the clinical feasibility of a quantitative sodium 23 ((23)Na) magnetic resonance (MR) imaging protocol developed for breast tumor assessment and to compare it with 7-T diffusion-weighted imaging (DWI). Materials and Methods Written informed consent in this institutional review board-approved study was obtained from eight healthy volunteers and 17 patients with 20 breast tumors (five benign, 15 malignant). To achieve the best image quality and reproducibility, the (23)Na sequence was optimized and tested on phantoms and healthy volunteers. For in vivo quantification of absolute tissue sodium concentration (TSC), an external phantom was used. Static magnetic field, or B0, and combined transmit and receive radiofrequency field, or B1, maps were acquired, and image quality, measurement reproducibility, and accuracy testing were performed. Bilateral (23)Na and DWI sequences were performed before contrast material-enhanced MR imaging in patients with breast tumors. TSC and apparent diffusion coefficient (ADC) were calculated and correlated for healthy glandular tissue and benign and malignant lesions. Results The (23)Na MR imaging protocol is feasible, with 1.5-mm in-plane resolution and 16-minute imaging time. Good image quality was achieved, with high reproducibility (mean TSC values ± standard deviation for the test, 36 mmol per kilogram of wet weight ± 2 [range, 34-37 mmol/kg]; for the retest, 37 mmol/kg ± 1 [range, 35-39 mmol/kg]; P = .610) and accuracy (r = 0.998, P < .001). TSC values in normal glandular and adipose breast tissue were 35 mmol/kg ± 3 and 18 mmol/kg ± 3, respectively. In malignant lesions (mean size, 31 mm ± 24; range, 6-92 mm), the TSC of 69 mmol/kg ± 10 was, on average, 49% higher than that in benign lesions (mean size, 14 mm ± 12; range, 6-35 mm), with a TSC of 47 mmol/kg ± 8 (P = .002). There were similar ADC differences between benign ([1.78 ± 0.23] × 10(-3) mm(2)/sec) and malignant ([1.03 ± 0.23] × 10(-3) mm(2)/sec) tumors (P = .002). ADC and TSC were inversely correlated (r = -0.881, P < .001). Conclusion Quantitative (23)Na MR imaging is clinically feasible, may provide good differentiation between malignant and benign breast lesions, and demonstrates an inverse correlation with ADC. (©) RSNA, 2016 Online supplemental material is available for this article.

Sodium MRI (23Na-MRI) has been used to non-invasively quantify tissue sodium but has been limited by low spatial resolution. Here we demonstrate for the first time that high resolution 23Na-MRI reveals the spatial heterogeneity of sodium concentration within a multiple sclerosis (MS) lesion. A patient with treatment-naïve relapsing-remitting MS and a ring-enhancing lesion was imaged using 23Na-MRI. The periphery of the lesion demonstrated an elevated total sodium content compared to the normal appearing white and grey matter (p

Textbook theory holds that extracellular fluids readily equilibrate, electrolyte concentrations in the extracellular fluid compartments are constant, and the kidney is solely responsible for controlling the body sodium content.Investigation of salt and water balance traditionally relies on short-term studies of bodily responses to extremes in salt intake. Ultra-long-term sodium balance studies instead studied the kidney's response to constant salt intake. The studies suggest that steady-state sodium balance in humans is characterized by storage and release of sodium from the body. The absence of accompanying changes in the body fluid matrix indicates the presence of metabolically relevant sodium reservoir sites in the body. In rats and mice, sodium is stored in skeletal muscle and skin. Homeostatic immune cells control reservoir electrolyte metabolism via the lymphatics. Failure of this extrarenal clearance process results in skin electrolyte accumulation and arterial hypertension. Noninvasive detection of sodium reservoir metabolism in patients by NaMRi methodology allows rapid transfer into the clinical arena.Body sodium content in humans and animals is not constant, does not always readily equilibrate with water, and is not exclusively controlled by the kidneys. This different view provides with new research avenues for basic and clinical investigators.

In proton therapy, imaging of proton-induced positrons is a useful method to monitor the proton beam distribution after therapy. Usually, a positron emission tomography (PET) system installed in or near the proton beam treatment room is used for this purpose. However, a PET system is sometimes too large and expensive for this purpose. We developed a small field-of-view (FOV) gamma camera for high-energy gamma photons and used it for monitoring the proton-induced positron distribution. The gamma camera used 0.85 mm × 0.85 mm × 10 mm Ce:Gd3Al2Ga3O12 (GAGG) pixels arranged in 20 × 20 matrix to form a scintillator block, which was optically coupled to a 1-inch-square position-sensitive photomultiplier tube (PSPMT). The GAGG detector was encased in a 20-mm thick container and a pinhole collimator was mounted on its front. The gamma camera was set 1.2 m from the 35 cm × 35 cm × 5 cm plastic phantom in the proton therapy treatment room, and proton beams were irradiated to the phantom with two proton energies. The gamma camera had spatial resolution of ~6.7 cm and sensitivity of 3.2 × 10−7 at 1 m from the collimator surface. For both proton energies, positron distribution in the phantom could be imaged by the gamma camera with 10-min acquisition. The lengths of the range of protons measured from the images were almost identical to the simulation results. These results indicate that the developed high-energy gamma camera is useful for imaging positron distributions in proton therapy.

Sodium MRI (23Na-MRI) has been used to non-invasively quantify tissue sodium but has been limited by low spatial resolution. Here we demonstrate for the first time that high resolution 23Na-MRI reveals the spatial heterogeneity of sodium concentration within a multiple sclerosis (MS) lesion. A patient with treatment-naïve relapsing-remitting MS and a ring-enhancing lesion was imaged using 23Na-MRI. The periphery of the lesion demonstrated an elevated total sodium content compared to the normal appearing white and grey matter (p, Graphical abstract Images and analysis showing the heterogeneous distribution of sodium in an active Multiple Sclerosis lesion. A & B show total and intracellular weighted sodium concentration maps of the MS brain, respectively. C shows regional differences in sodium distribution relative to normal appearing brain and D reveals a spatially dependent distribution of sodium in an active MS lesion.Unlabelled Image, Highlights • High spatial resolution 23Na MRI acquired in a clinically feasible time at 3 T. • Quantification of the intracellular sodium concentration in an active MS lesion for the first time • Characterization of a sodium gradient in an active MS lesion

In this article, we induced acute changes in extracellular volume fraction in skeletal muscle tissue and compared the sensitivity of a standard 1H T2 imaging method with different 23Na‐NMR spectroscopy parameters within acquisition times compatible with clinical investigations. First, we analyzed the effect of a short ischemia on the sodium distribution in the skeletal muscle. Then, the lower leg of 21 healthy volunteers was scanned under different vascular filling conditions (vascular draining, filling, and normal condition) expected to modify exclusively the extracellular volume. The first experiment showed no change in the total sodium content during a 15 min ischemia, but the intracellular weighted 23Na signal slowly decreased. For the second part, significant variations of total sodium content, sodium distribution, and T1 and T2∗ of 23Na signal were observed between different vascular filling conditions. The measured sodium distribution correlates significantly with sodium T1 and with the short and long T2∗ fractions. In contrast, significant changes in the proton T2w signal were observed only in three muscles. Altogether, the mean T2w signal intensity of all muscles as well as their mean T2 did not vary significantly with the extracellular volume changes. In conclusion, at the expense of giving up spatial resolution, the proposed 23Na spectroscopic method proved to be more sensitive than standard 1H T2 approach to monitor acute extracellular compartment changes within muscle tissue.

Na(+)/H(+) exchanger (NHE) 1 is a member of the solute carrier superfamily, which regulates intracellular ionic homeostasis. NHE1 is known to require cellular ATP for its activity, despite there being no requirement for energy input from ATP hydrolysis. In this study, we investigated whether NHE1 is an ATP-binding protein. We designed a baculovirus vector carrying both epitope-tagged NHE1 and its cytosolic subunit CHP1, and expressed the functional NHE1-CHP1 complex on the surface of Sf9 insect cells. Using the purified complex protein consisting of NHE1 and CHP1 from Sf9 cells, we examined a photoaffinity labeling reaction with 8-azido-ATP-biotin. UV irradiation promoted the incorporation of 8-azido-ATP into NHE1, but not into CHP1, with an apparent Kd of 29.1 µM in the presence of Mg(2+). The nonlabeled nucleotides ATP, GTP, TTP and CTP all inhibited this crosslinking. However, ATP had the strongest inhibitory effect, with an apparent inhibition constant (IC50) for ATP of 2.2 mM, close to the ATP concentration giving the half-maximal activation of NHE1 activity. Importantly, crosslinking was more strongly inhibited by ATP than by ADP, suggesting that ATP is dissociated from NHE1 upon ATP hydrolysis. Limited proteolysis with thrombin and deletion mutant analysis revealed that the 8-azido-ATP-binding site is within the C-terminal cytoplasmic domain of NHE1. Equilibrium dialysis with NHE1-derived peptides provided evidence that ATP directly binds to the proximal cytoplasmic region (Gly542-Pro598), which is critical for ATP-dependent regulation of NHE1. These findings suggest that NHE1 is an ATP-binding transporter. Thus, ATP may serve as a direct activator of NHE1.

New experimental data for production of 7 Be and 22,24 Na in deuteron irradiation of nat Mg and Al up to 50 MeV are presented. The induced activity, measured with HPGe spectroscopy, allows us to determine excitation functions of nat Mg(d,x) and 27 Al(d,x) reactions involved in the activation process with reference to nat Ti(d,x) 48 V monitor cross sections. A comparison with experimental literature values and results from updated theoretical codes is discussed. Thick target yields were derived from fits to our cross-sections and integrated personnel dose was calculated for different irradiation cycles and exposure scenarios around high power deuteron accelerator facilities.

Renal denervation (RDN) has been considered a promising therapy option for patients suffering from therapy-resistant hypertension. Besides, in blood-pressure regularization, the kidneys play a fundamental role in sodium ((23)Na) homeostasis. This study assesses the effect of RDN on renal (23)Na concentration using (23)Na magnetic resonance imaging (MRI).Two patients with therapy-resistant hypertension underwent RDN. (23)Na-MRI, (1)H-MRI, including diffusion weighted imaging (DWI), as well as endothelial dysfunction assessment, were performed 1 day prior, as well as 1, 30 and 90 days after RDN.The renal corticomedullary (23)Na gradient did not change after RDN for all time points. Additionally, functional imaging and retinal vessel parameters were not influenced by RDN. Results regarding blood pressure changes and arterial stiffness, as well as patients' clinical outcome, were heterogeneous.RDN does not seem to alter renal (23)Na concentration gradients, as measured by MRI.

In this study, the short component of the 23Na T2 (T2f) and the 23Na and 2H quadrupolar interactions (νQ) were measured in bone-cartilage samples of osteoarthritic (OA) and osteoporotic (OP) patients. 23Na νQ was found to increase in osteoarthritic articular cartilage relative to controls. Similar results were found in bovine cartilage following proteoglycan (PG) depletion, a condition that prevails in osteoarthritis. 23Na νQ and 1/T2f for articular cartilage obtained from osteoporotic patients were significantly larger than for control and osteoarthritic cartilage. Decalcification of both human and bovine articular cartilage resulted in an increase of 23Na νQ and 1/T2f, showing the same trend as the osteoporotic samples. Differences in the ratio of the intensity of the large 2H splitting to that of the small one in the calcified zone were also observed. In osteoporosis, this ratio was twice as large as that obtained for both control and osteoarthritic samples. The 2H and 23Na results can be interpreted as due to sodium ions and water molecules filling the void created by the calcium depletion and to calcium ions being located in close association with the collagen fibers. To the best of our knowledge, this is the first study reporting differences of NMR parameters in cartilage of osteoporotic patients. Magn Reson Med, 2010. © 2010 Wiley-Liss, Inc.

The interest in positron emission tomography (PET) and particularly in hybrid integrated PET/CT systems has significantly increased in the last few years due to the improved quality of the obtained images. Nevertheless, one of the most important limits of the PET imaging technique is still its poor spatial resolution due to several physical factors originating both at the emission (e.g. positron range, photon non-collinearity) and at detection levels (e.g. scatter inside the scintillating crystals, finite dimensions of the crystals and depth of interaction). To improve the spatial resolution of the images, a possible way consists of measuring the point spread function (PSF) of the system and then accounting for it inside the reconstruction algorithm. In this work, the system response of the GE Discovery STE operating in 3D mode has been characterized by acquiring 22Na point sources in different positions of the scanner field of view. An image-based model of the PSF was then obtained by fitting asymmetric two-dimensional Gaussians on the 22Na images reconstructed with small pixel sizes. The PSF was then incorporated, at the image level, in a three-dimensional ordered subset maximum likelihood expectation maximization (OS-MLEM) reconstruction algorithm. A qualitative and quantitative validation of the algorithm accounting for the PSF has been performed on phantom and clinical data, showing improved spatial resolution, higher contrast and lower noise compared with the corresponding images obtained using the standard OS-MLEM algorithm. © 2010 Institute of Physics and Engineering in Medicine.

The reduction of molecular oxygen to water is the final step of oxidative phosphorylation that couples adenosine triphosphate production to the reoxidation of reducing equivalents formed during the oxidation of glucose to carbon dioxide. This coupling makes the cerebral metabolic rate of oxygen consumption (CMRO(2)) an excellent reflection of the metabolic health of the brain. A multi-nuclear magnetic resonance (MR) imaging based method for CMRO(2) mapping is proposed. Oxygen consumption is determined by applying a new three-phase metabolic model for water generation and clearance to the changing 17-oxygen ((17)O) labeled water MR signal measured using quantitative (17)O MR imaging during inhalation of (17)O-enriched oxygen gas. These CMRO(2) data are corrected for the regional brain tissue mass computed from quantitative 23-sodium MR imaging of endogenous tissue sodium ions to derive quantitative results of oxygen consumption in micromoles O(2)/g tissue/minute that agree with literature results reported from positron emission tomography. The proposed technique is demonstrated in the human brain using a 9.4 T MR scanner optimized for human brain imaging.

Rationale and Objectives Sodium magnetic resonance imaging (MRI) of the kidneys has been used to spatially map areas of sodium-concentrating activity and to quantify the corticomedullary sodium gradient in various physiologic and pathophysiologic conditions. In this case study, sodium MRI of a clinically well-functioning transplanted kidney was performed to determine whether its sodium gradient could be detected and quantified using this method. Materials and Methods Sodium MRI was performed on a 3T scanner with a commercial rectangular sodium surface coil placed on the lower abdomen over the palpable transplanted kidney. A three-dimensional gradient echo sequence, modified for multinuclear imaging, was applied to acquire 23 Na images. Results Five main renal pyramids within the medulla were detected, and the corticomedullary sodium gradient was quantified in each renal pyramid by both region of interest–based and pixel-by-pixel analyses, resulting in a mean medulla/cortex signal-to-noise ratio of 1.8 ± 0.1 ( n = 5) and a mean linear increase slope of 1.1 ± 0.1 relative arbitrary units per mm ( n = 5). Conclusions The feasibility and usability of 23 Na MRI of a human renal allograft was demonstrated. Further studies are required to determine the clinical significance of this technique in the follow-up of patients after renal transplantation.

Non-nutrient-dependent salt absorption across the brush-border membrane of intestinal epithelial cells is primarily mediated by coupled apical Na+/H+(aNHE) and anion exchange transport, with the latter suspected of being mediated by DRA (downregulated in adenoma; SLC26A3) that is defective in congenital chloridorrhea. To investigate DRA in greater detail and determine whether DRA and NHE activities can be coupled, we measured22Na+and36Cl−uptake in Caco2BBE colon cells infected with the tet-off-inducible DRA transgene. Under basal conditions, DRA activity was low in normal and infected Caco2BBE cells in the presence of tetracycline, whereas NHE activities could be easily detected. When apical NHE activity was increased by transfection or serum-induced expression of the aNHE isoforms NHE2 and NHE3, increased36Cl−uptake was observed. Inhibition of DRA activity by niflumic acid was greater than that by DIDS as well as by the NHE inhibitor dimethylamiloride and the carbonic anhydrase inhibitor methazolamide. DRA activity was largely aNHE-dependent, whereas a component of DRA-independent aNHE uptake continued to be observed. Coupled aNHE and DRA activities were inhibited by increased cellular cAMP and calcium and were associated with synaptotagmin I-dependent, clathrin-mediated endocytosis. In summary, these data support the role of DRA in electroneutral NaCl absorption involving functional coupling of Cl−/base exchange and apical NHE.

Members of the SLC20 family or type III Na+-coupled Picotransporters (PiT-1, PiT-2) are ubiquitously expressed in mammalian tissue and are thought to perform a housekeeping function for intracellular Pihomeostasis. Previous studies have shown that PiT-1 and PiT-2 mediate electrogenic Picotransport when expressed in Xenopus oocytes, but only limited kinetic characterizations were made. To address this shortcoming, we performed a detailed analysis of SLC20 transport function. Three SLC20 clones ( Xenopus PiT-1, human PiT-1, and human PiT-2) were expressed in Xenopus oocytes. Each clone gave robust Na+-dependent32Piuptake, but only Xenopus PiT-1 showed sufficient activity for complete kinetic characterization by using two-electrode voltage clamp and radionuclide uptake. Transport activity was also documented with Li+substituted for Na+. The dependence of the Pi-induced current on Piconcentration was Michaelian, and the dependence on Na+concentration indicated weak cooperativity. The dependence on external pH was unique: the apparent Piaffinity constant showed a minimum in the pH range 6.2–6.8 of ∼0.05 mM and increased to ∼0.2 mM at pH 5.0 and pH 8.0. Xenopus PiT-1 stoichiometry was determined by dual22Na-32Piuptake and suggested a 2:1 Na+:Pistoichiometry. A correlation of32Piuptake and net charge movement indicated one charge translocation per Pi. Changes in oocyte surface pH were consistent with transport of monovalent Pi. On the basis of the kinetics of substrate interdependence, we propose an ordered binding scheme of Na+:H2PO4−:Na+. Significantly, in contrast to type II Na+-Picotransporters, the transport inhibitor phosphonoformic acid did not inhibit PiT-1 or PiT-2 activity.

The low energy model of the GEANT4 Monte Carlo toolkit was used to simulate the energy response of a T.P.A. Mk-II ionization chamber under a variety of different conditions. The sample position resulting in the maximum response along the axial direction of the chamber was obtained. The parameters of the simulation were chosen to account for the maximum effect of the particle backscattering and the setting of most suitable values for the production thresholds and the energy cuts in the GEANT4 Monte Carlo code. The chamber response for different compositions of detector elements was also studied. The simulated radioactive source was a glass ampoule containing 3.6 ml of the radionuclide in an aqueous solution. The energy response of the chamber at the maximum response was obtained for simulations for (60)Co, (22)Na and (59)Fe nuclides. Verification of the simulated response was obtained using experimental measurements with radioactive sources. The simulated results were in good agreement with the experimentally measured data to within 0.04-2.0%. In the energy range below 200 keV the response curve was complex due to the increase of photoelectric cross sections of the chamber materials. Effects due to backscattering occur at boundaries between chamber elements and also become significant at sites of lead shielding at photon energies above 700 keV. The chamber response for different compositions of detector elements was also studied. The response of the chamber depended highly on the energies of emitting particles, source position and materials used in electrodes and thimble wall.

The use of neutrons for cargo interrogation has the potential to drastically improve threat detection. Previous research has focussed on the production of 24Na, based on the isotopes produced in pharmaceuticals and medical devices. For both the total activity and the ingestion dose we show that a variety of isotopes contribute and that 24Na is only dominant under certain conditions. The composition of the foods has a strong influence on the resulting activity and ingestion dose suggesting that the pharmaceuticals and medical devices considered initially are not a viable analogue for foodstuffs.There is an energy dependence to the isotopes produced due to the cross-sections of different reactions varying with neutron energy. We show that this results in different isotopes dominating the ingestion dose at different energies, which has not been considered in the previous literature.

The general phosphate need in mammalian cells is accommodated by members of the Pitransport (PiT) family ( SLC20), which use either Na+or H+to mediate inorganic phosphate (Pi) symport. The mammalian PiT paralogs PiT1 and PiT2 are Na+-dependent Pi(NaPi) transporters and are exploited by a group of retroviruses for cell entry. Human PiT1 and PiT2 were characterized by expression in Xenopus laevis oocytes with32Pias a traceable Pisource. For PiT1, the Michaelis-Menten constant for Piwas determined as 322.5 ± 124.5 μM. PiT2 was analyzed for the first time and showed positive cooperativity in Piuptake with a half-maximal activity constant for Piof 163.5 ± 39.8 μM. PiT1- and PiT2-mediated Na+-dependent Piuptake functions were not significantly affected by acidic and alkaline pH and displayed similar Na+dependency patterns. However, only PiT2 was capable of Na+-independent Pitransport at acidic pH. Study of the impact of divalent cations Ca2+and Mg2+revealed that Ca2+was important, but not critical, for NaPitransport function of PiT proteins. To gain insight into the NaPicotransport function, we analyzed PiT2 and a PiT2 Pitransport knockout mutant using22Na+as a traceable Na+source. Na+was transported by PiT2 even without Piin the uptake medium and also when Pitransport function was knocked out. This is the first time decoupling of Pifrom Na+transport has been demonstrated for a PiT family member. Moreover, the results imply that putative transmembrane amino acids E55and E575are responsible for linking Piimport to Na+transport in PiT2.

Background Established imaging methods are still not confident in the determination of stroke onset. Sodium imaging in animal models and lately in humans implicates that the sodium signal intensity within the ischemic lesion increases in a time-dependent fashion. Sodium imaging usually requires a time-consuming change of resonators or magnetic resonance imaging systems. To avoid this, we used a double-tuned 1H/23Na birdcage head coil in combination with a protocol minimizing T1- and T2*-weighting effects for measurement of sodium intensity in acute stroke patients. Methods Multinuclear 1H/23Na data sets were obtained from 16 stroke patients [75 ± 9.9 (standard deviation) years old] 4-130 h after symptom onset. The protocol was acquired on a clinical 3T magnetic resonance imaging site using a double-tuned 1H/23Na birdcage head coil. Sodium signal intensity within the lesion and homologous contralateral side was measured and compared. Results With an acquisition time of the complete magnetic resonance imaging protocol of 22 min, a nonlinear sodium signal intensity increase within the lesion over time after stroke onset was acknowledged. Onset time within six-hours showed an increase of only 8% or less, whereas onset time beyond 8.5 h demonstrated increases of 36% or more reaching a maximum of 170% > 120 h. In addition, some patients showed a difference in sodium signal intensity compared with diffusion weighted imaging lesion. Conclusions The use of a double-tuned 1H/23Na birdcage head coil in a clinical setting ‘allowed sodium intensity measurements’ in a justifiable time also for acute stroke patients, and heterogenous sodium signal intensity in the diffusion weighted imaging lesion might represent differences in tissue damage or repair.

Over the last decade, wireless capsule endoscope has been the tool of choice for noninvasive inspection of the gastrointestinal tract, especially in the small intestine. However, the latest clinical products have not been equipped with a sufficiently accurate localization system which makes it difficult to determine the location of intestinal abnormalities, and to apply follow-up interventions such as biopsy or drug delivery. In this paper, the authors present a novel localization method based on tracking three positron emission markers embedded inside an endoscopic capsule.Three spherical(22)Na markers with diameters of less than 1 mm are embedded in the cover of the capsule. Gamma ray detectors are arranged around a patient body to detect coincidence gamma rays emitted from the three markers. The position of each marker can then be estimated using the collected data by the authors' tracking algorithm which consists of four consecutive steps: a method to remove corrupted data, an initialization method, a clustering method based on the Fuzzy C-means clustering algorithm, and a failure prediction method.The tracking algorithm has been implemented inMATLAB utilizing simulation data generated from the Geant4 Application for Emission Tomography toolkit. The results show that this localization method can achieve real-time tracking with an average position error of less than 0.4 mm and an average orientation error of less than 2°.The authors conclude that this study has proven the feasibility and potential of the proposed technique in effectively determining the position and orientation of a robotic endoscopic capsule.

Diagnosis of new bone growth in patients with compound tibia fractures or deformities treated using a Taylor spatial frame is difficult with conventional radiography because the frame obstructs the images and creates artifacts. The use of Na(18)F PET studies may help to eliminate this difficulty.Patients were positioned on the pallet of a clinical PET/CT scanner and made as comfortable as possible with their legs immobilized. One bed position covering the site of the fracture, including the Taylor spatial frame, was chosen for the study. A topogram was performed, as well as diagnostic and attenuation correction CT. The patients were given 2 MBq of Na(18)F per kilogram of body weight. A 45-min list-mode acquisition was performed starting at the time of injection, followed by a 5-min static acquisition 60 min after injection. The patients were examined 6 wk after the Taylor spatial frame had been applied and again at 3 mo to assess new bone growth.A list-mode reconstruction sequence of 1 × 1,800 and 1 × 2,700 s, as well as the 5-min static scan, allowed visualization of regional bone turnover.With Na(18)F PET/CT, it was possible to confirm regional bone turnover as a means of visualizing bone remodeling without the interference of artifacts from the Taylor spatial frame. Furthermore, dynamic list-mode acquisition allowed different sequences to be performed, enabling, for example, visualization of tracer transport from blood to the fracture site.

24Na in the human body, activated by neutrons emitted at the JCO criticality accident, was observed for 62 subjects, where 148 subjects were measured by the whole body counter of JNC Tokai Works. The 148 subjects, including JCO employees and the contractors, residents neighboring the site and emergency service officers, were measured by the whole-body counter. The neutron-energy spectrum around the facility was calculated using neutron transport codes (ANISN and MCNP), and the relation between an amount of activated sodium in human body and neutron dose was evaluated from the calculated neutron energy spectrum and theoretical neutron capture probability by the human body. The maximum 24Na activity in the body was 7.7 kBq (83 Bq(24Na)/g(23Na)) and the relevant effective dose equivalent was 47 mSv.

The doses for the overexposed patients were estimated by the measurement result of specific activity of 24Na in blood. The present method is almost based on documents of the International Atomic Energy Agency (IAEA) and the Oak Ridge National Laboratory. The neutron energy spectrum obtained using the ANISN code (Multigroup One-Dimensional Discrete Ordinates Transport Code System with Anisotropic Scattering) was assumed. The values in ICRP Publication 74 were applied for the doses in each organ per unit neutron fluence. Gamma-ray dose was indirectly estimated based on (a) the result of environmental monitoring around the accident site and (b) a graph in IAEA manual, which gives the kerma ratio of neutrons and gamma-rays as a function of the critical volume or the atomic ratio of hydrogen to 235U. The estimated neutron doses were 5.4 Gy for patient A. 2.9 Gy for patient B and 0.81 Gy for patient C. The estimated gamma-ray doses were 8.5 or 13 Gy for patient A, 4.5 or 6.9 Gy for patient B, and 1.3 or 2.0 Gy for patient C.

Background & Aims: HCO 3 − supply to the enterocyte is rate limiting for duodenal HCO 3 − secretion (J HCO3− ). This study defines the molecular nature of the major HCO 3 − uptake pathways in rabbit duodenocytes and investigates their physiologic significance and regulation during basal and stimulated J HCO3− . Methods & Results: pH gradient–driven 22 Na + uptake into duodenal basolateral membrane vesicles was partly HCO 3 − dependent, stilbene sensitive, and therefore mediated by Na + HCO 3 − cotransport, and partly HCO 3 − independent, Hoechst 642 sensitive, and therefore mediated by the Na + /H + exchanger isoform NHE1. Semiquantitative polymerase chain reaction (PCR) revealed high duodenal expression levels for the NBC1 isoform of the Na + HCO 3 − cotransporter gene family and NHE1. Cloning and comparison of full-length rabbit with human gastrointestinal and kidney NBC1 subtype revealed a conserved protein kinase A consensus sequence in the cytoplasmic N-terminus of the gastrointestinal NBC1. Inhibition of either Na + HCO 3 − cotransport or carbonic anhydrase reduced ouabain-sensitive J HCO3− in in vitro rabbit duodenal mucosae by approximately 50%, but did not affect 8-Br-cAMP–induced ΔJ HCO3− , suggesting cAMP-mediated up-regulation of the alternative pathway. However, inhibition of both Na + HCO 3 − cotransport and either carbonic anhydrase or NHE1 strongly reduced ΔJ HCO3− . Conclusions: NBC1 and NHE1 are the major base importers in rabbit duodenocytes. Na + HCO 3 − cotransport and CO 2 hydration/Na + /H + exchange are equally important pathways for duodenal HCO 3 − supply and are up-regulated during cAMP-mediated stimulation. GASTROENTEROLOGY 2000;119:406-419

Unilateral nephrectomy results in a rapid and specific stimulation of growth and function of the remaining kidney (Ogden, 1967; Fine, 1986). In experimental animals, the bulk of such renal growth is accounted for by hypertrophy of the proximal tubule, which is detectable within 24-48 h and is preceded by an increase in proximal tubule sodium reabsorption via activated apical sodium-hydrogen exchange (NHE) (Fine, 1986; Pollock & Field, 1993). Although the existence of a kidney-specific humoral growth factor, which incites and/or regulates compensatory renal growth, has been long established by parabiotic experiments (Van Vroonhoven, Soler-Montesinos & Malt, 1972; Austin, Goldin & Preuss, 1981; Malt, 1983), serum injections in live animals (Lowenstein & Stern, 1963; Austin et al. 1981; Malt, 1983; Pollock, Nobes, Gyory, Heng & Field, 1996) and in vitro assays (Austin et al. 1981; Malt, 1983; Yamada, Kanetake, Saito, Kondo & Yamamoto, 1983; Yamamoto, Kanetake & Yamada, 1983; Yun, Areas, Yamamoto & Preuss, 1988; Esbrit, Garcia Ocana, Garcia Canero, Manzano & Jiminez Clavero, 1991; Garcia Ocana & Esbrit, 1994; Nobe, Pollock, Heng & Field, 1995), its precise identity remains elusive. Attempts at characterization have so far suggested that this factor is species specific (Yamamoto et al. 1983; Fine, 1986; Yun et al. 1988), unaffected by dialysis or heating (Fine, 1986), and possibly synthesized by the liver and activated by the remnant kidney in a time-dependent fashion following nephrectomy (Dicker, Morris & Shipolini, 1977; Fine, 1986; Garcia Ocana & Esbrit, 1992). Insulin-like growth factor-I (IGF-I), a 7.5 kDa peptide produced in the liver and kidney, exerts renotropic effects in proximal tubule cells (PTCs) and enhances Na+ reabsorption in in vitro and in vivo studies (Zumkeller & Schofield, 1992; Hammerman & Miller, 1993; Nobes et al. 1995; Feld & Hirschberg, 1996; Johnson et al. 1997b). A humoral role in the development of renal hypertrophy has been postulated since binding of IGF-I to PTCs is enhanced following reductions in renal mass (Polychronakos, Guyda & Posner, 1985; Hise, Lahn, Shao, Mantzouris & Fontana, 1993), endogenous renal cortical IGF-I accumulation precedes compensatory renal growth (Stiles, Sosenko, D'Ercole & Smith, 1985; Fagin & Melmed, 1987; Flyvbjerg, Thorlacius Ussing, Naeraa, Ingerslev & Orskov, 1988; Lajara et al. 1989; Zumkeller & Schofield, 1992; Feld & Hirschberg, 1996; Gronboek, Nielsen, Flyvbjerg & Orskov, 1997) and administration of a somatostatin analogue prevents compensatory renal growth and increased renal IGF-I content (Flyvbjerg, Frystyk, Thoracius Ussing & Orskov, 1989; Hammerman & Miller, 1993). Although serum IGF-I levels are reported to be either unchanged (Stiles et al. 1985; Fagin & Melmed, 1987; Lajara et al. 1989; Hammerman & Miller, 1993; Gronboek et al. 1997) or decreased (Flyvbjerg et al. 1988) and renal IGF-I mRNA levels are either unchanged (Lajara et al. 1989) or increased (Fagin & Melmed, 1987) following reductions in renal mass, the accumulation and enhanced action of IGF-I at the proximal tubule following uninephrectomy might be explained by alterations in circulating levels of IGF binding proteins (IGFBPs), which tightly regulate the delivery of serum IGF-I to tissues (Jones & Clemmons, 1995; Feld & Hirschberg, 1996). Circulating IGF-I may then be trapped in the proximal tubule by post-nephrectomy increases in IGF receptor number/affinity or in cell-associated IGFBPs, which potentiate IGF-I action on PTCs (Johnson et al. 1997c). However, the circulating levels of IGFBPs following unilateral nephrectomy and their effects on IGF-I binding to PTCs have not been studied to date. Therefore, the aim of the present study was to determine whether alterations in the IGF-I/IGFBP axis and its direct interaction with human PTCs account for the renotropic effect of serum following a reduction of renal mass.

Radiotherapy with nuclear reactor fission neutrons was applied in 49 cases of pretreated patients with superficial metastases or relapses from primary carcinoma. Measurements of the decay rates of the radiation-induced radioactivity of 49Ca, 38Cl and 24Na in the irradiated tissue resulted in values for the simultaneous local kinetics of chlorine and sodium, and in approximate data on the electrolyte masses. The electrolytes were present in non-exchangeable and exchangeable compartments of soft tissue. Exchange times of the intravascular to extravascular turnover and the frequencies of the exchange fractions were determined for a series of irradiations. The results have been interpreted in terms of the mean electrolyte exchange rates, of a standardized functional blood flow, and of the supply capacity of the vascular system. In the average of all cases, the regional perfusion was reduced by about 30% by irradiation up to 14 Gy (equivalent photon dose = 45 Gy) connected with an increase in the non-exchangeable fractions. After fractionated doses higher than 14 Gy, functional blood flow and supply capacity increased to 120%, and fixed electrolytes were removed from the irradiated tissue. Data on electrolyte kinetics and vascularity are compared with the literature.

After the transfer of the thick copper target plate irradiated with 3 meV protons from a medical cyclotron, the gamma dose rate in the target cave was monitored every minute for 25 hours using wall-mounted gamma area monitors. The dose rate decay curve was fitted with four exponential functions. By analysing the slope of the exponentials the traces of radioactive 28 Al, 56 Mn 24 Na and 59 Fe were identified. The results were used to minimize personnel radiation exposure during maintenance work on the cyclotron.

Multi-modal MR-PET-EEG data acquisition in simultaneous mode confers a number of advantages at 3 T and 9.4 T. The three modalities complement each other well; structural-functional imaging being the domain of MRI, molecular imaging with specific tracers is the strength of PET, and EEG provides a temporal dimension where the other two modalities are weak. The utility of hybrid MR-PET at 3 T in a clinical setting is presented and critically discussed. The potential problems and the putative gains to be accrued from hybrid imaging at 9.4 T, with examples from the human brain, are outlined. Steps on the road to 9.4 T multi-modal MR-PET-EEG are also illustrated. From an MR perspective, the potential for ultra-high resolution structural imaging is discussed and example images of the cerebellum with an isotropic resolution of 320 μm are presented, setting the stage for hybrid imaging at ultra-high field. Further, metabolic imaging is discussed and high-resolution images of the sodium distribution are presented. Examples of tumour imaging on a 3 T MR-PET system are presented and discussed. Finally, the perspectives for multi-modal imaging are discussed based on two on-going studies, the first comparing MR and PET methods for the measurement of perfusion and the second which looks at tumour delineation based on MRI contrasts but the knowledge of tumour extent is based on simultaneously acquired PET data.

To develop quantitative dual-tuned (DT) (1) H/(23) Na MRI of human knee cartilage in vivo at 7 Tesla (T).A sensitive (23) Na transceiver array RF coil was developed at 7T. B1 fields generated by the transceiver array coil were characterized and corrected in the (23) Na images. Point spread function (PSF) of the (23) Na images was measured, and the signal decrease due to partial-volume-effect was compensated in [(23) Na] quantification of knee cartilage. SNR and [(23) Na] in anterior femoral cartilage were measured from seven healthy subjects.SNR of (23) Na image with the transceiver array coil was higher than that of birdcage coil. SNR in the cartilage at 2-mm isotropic resolution was 26.80 ± 3.69 (n = 7). B1 transmission and reception fields produced by the DT coil at 7T were similar to each other. Effective full-width-half-maximum of (23) Na image was ∼5 mm at 2-mm resolution. Mean [(23) Na] was 288.13 ± 29.50 mM (n = 7) in the anterior femoral cartilage of normal subjects.We developed a new high-sensitivity (23) Na RF coil for knee MRI at 7T. Our (1) H/(23) Na MRI allowed quantitative measurement of [(23) Na] in knee cartilage by measuring PSF and cartilage thickness from (23) Na and (1) H image, respectively.

We report on the measurements performed using a 22Na source on a detector element for an MRI-compatible TOF-PET endorectal prostate probe, with Depth-Of-Interaction sensitivity. It is made from a LYSO scintillator crystal, wrapped with Lumirror, readout at both ends by means of Silicon Photomultipliers. With a detailed description of the data analysis procedure we show that our results point to a 400 ps coincidence resolving time and, at the same time, to a Depth-Of-Interaction resolution of 1 mm. These appealing features, along with the tiny 1.5 mm x 1.5 mm x 10 mm crystal size, are quite promising in view of the realization of a prototype probe., 27 pages, 28 figures. arXiv admin note: substantial text overlap with arXiv:1203.0043

Apical membrane vesicles purified from mucosal scrapings obtained from distal segments of organ donor colons and a 22Na-uptake technique were used to characterize the mechanism(s) of Na+ transport into these vesicles. An outwardly directed H+ gradient (pH 5.5in/7.5out) markedly increased uptake of 22Na into these vesicles. Osmolarity studies demonstrated that 22Na was taken up into the intravesicular space with minimal binding observed to the surface of the vesicles. Voltage clamping in the presence of K+/valinomycin reduced the H+ gradient-dependent 22Na uptake into these vesicles by approximately 45% and generation of an inside negative membrane potential significantly increased 22Na uptake. Under non voltage clamped conditions, H+ gradient-dependent 22Na uptake into these vesicles was significantly inhibited by specific inhibitors of Na(+)-H+ exchange (DMA, HMA and EIPA) as well as by inhibitor of epithelial Na+ channels (phenamil). Under voltage clamped conditions, H+ gradient-dependent 22Na uptake, however, was unaffected by phenamil (20 microM), but was almost completely inhibited by DMA, HMA and EIPA (20 microM each). The mechanism of amiloride inhibition of electroneutral Na(+)-H+ exchange was noncompetitive with a Ki for amiloride of 340 microM. Electroneutral 22Na uptake exhibited saturation kinetics with an apparent Km for Na+ of 8.7 +/- 1.7 mM and a Vmax of 2.02 +/- 0.45 nmol/mg per 5 s. The Na(+)-H+ exchange demonstrated cation specificity similar to the Na(+)-H+ exchangers described in other epithelia. These studies demonstrate for the first time that Na+ transport across the apical membranes of human distal colon involves both conductive Na+ uptake and an electroneutral Na(+)-H+ exchange process.

1. Capillary permeability-surface area (PS) products for the low molecular weight radioactive tracers, 22Na, 51Cr-EDTA (relative molecular mass 357) and 57Co-cyanocobalamin (relative molecular mass 1353) were measured in the fetal circulation of isolated dually perfused lobules of normal term human placentae using the single circulation, multiple-tracer dilution technique. 2. In lobules perfused with M199 medium, containing dextran and 5 g l-1 bovine albumin, the extractions of all three tracers decreased as the flow was increased over the range of 2-8 ml min-1, and PS products for 51Cr-EDTA and 57Co-cyanocobalamin, but not for 22Na, reached constant values at flows above 0.1 ml min-1 g-1. 3. Flow-independent PS products in the presence of albumin were 0.025 +/- 0.002 ml min-1 g-1 (mean +/- S.E.M., n = 25) for 57Co-cyanocobalamin and 0.057 +/- 0.003 ml min-1 g-1 (n = 25) for 51Cr-EDTA. The ratio of PS values (51Cr-EDTA/57Co-cyanocobalamin) was 2.28, while the ratio of the corresponding free diffusion coefficients was 1.79, indicating substantial restriction to the diffusion of the 57Co-cyanocobalamin. 4. In another series of lobules perfused in the absence of albumin, extraction values for all three test tracers were constant over the same flow range. Values at high flow rates were therefore about twice those measured in the presence of albumin, and PS products for all three tracers failed to reach diffusion-limited values. 6. Lobules perfused with and without albumin were fixed using a glutaraldehyde fixative containing 1% Alcian Blue dye. An ultrastructural examination of the endothelium showed no significant changes in cell or cleft morphology, or in the glycocalyx, in the absence of albumin which might account for the observed permeability change. 7. These data are the first physiological measurements specifically characterizing fetal microvascular permeability in the human placenta. The results suggest that permeability resembles that found in skeletal muscle and, as such, the endothelium presents a significant barrier to the diffusion of large solutes. The observed 'protein effect' indicates that albumin can interact with elements of the solute pathway to increase its restrictiveness.

We investigated the effect of cromakalim, a K + channel opener, that activates indirectly the Na + -K + pump, in association with increased K + conductance in the mesenteric arteries. In 65% of human mesenteric arteries tested, the concentration-dependent relaxation curves for cromakalim were biphasic: the low concentration ( −7 M) effect was preferentially inhibited by ouabain, whereas the higher concentration effect was significantly inhibited by glibenclamide. In branches of canine mesenteric artery, the cromakalin-induced relaxation was inhibited by pretreatment with ouabain (1 μM) as well as by glibenclamide (1 μM). The reduction in contraction of human and canine mesenteric arterial strips caused by cromakalim was totally reversed by pretreatment with ouabain (1 μM) or glibenclamide (1 μM). On the other hand, in canine mesenteric artery, cromakalim caused a significant stimulation of 22 Na + influx and ouabain-sensitive 86 Rb + uptake in association with increased 86 Rb + efflux, all of which were inhibited by glibenclamide (1 μM). Thus, it is suggested that cromakalim possesses the additional property to stimulate the Na + -K + pump through an elevation in intracellular Na + , resulting in strong relaxation of blood vessels.

To examine the functional significance of epidermal growth factor (EGF) binding sites present on the human erythrocyte membrane [Engelmann et al. (1992) Am J Hematol 39:239-241], the effect of EGF on 45Ca2+ uptake and on 22Na+ efflux from these cells has been studied. In all cases media contained 1.25 mM Ca2+, whereas Na+ and K+ were varied. In 140 mM Na+/5 mM K+ medium EGF (250 ng/ml) stimulated 45Ca2+ uptake by 50%-90% in quin-2-loaded cells, and by up to threefold in untreated cells. Increasing extracellular K+ up to 75 mM at the expense of extracellular Na2+ stimulated the EGF-induced 45Ca2+ uptake by about twofold compared to 145 mM Na+ medium both in quin-2-loaded and in untreated cells. In 145 mM K+ medium, however, no EGF-induced 45Ca2+ uptake was detectable in quin-2-loaded cells, while in untreated cells Ca2+ entry was stimulated twofold by EGF. After increasing intracellular Na+ from 6 mmol/l cells to 18 mmol/l cells in untreated cells suspended in 145 mM K+ medium, 45Ca2+ uptake induced by EGF gradually increased. In contrast, in 140 mM Na+/5 mM K+ as well as in 70 mM Na+/75 mM K+ medium, 45Ca2+ uptake accelerated by EGF was largely unaffected by a modified red cell Na+ content. When 22Na-loaded untreated red cells were suspended in 145 mM K+ medium EGF stimulated red cell 22Na+ efflux by more than threefold. In 140 mM Na+/5 mM K+ as well as in 70 mM Na+/75 mM K+ medium, no 22Na+ efflux induced by the growth factor was evident.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic agonists, through activation of intestinal epithelial alpha2-adrenergic receptors (alpha2AR), inhibit electrolyte secretion and promote absorption. The mechanisms of action to promote basal Na(+) absorption and inhibit stimulated secretion are not understood completely. The effects of alpha2-agonists on Na(+) transport were studied in a cell line, Caco2-3B, derived from the Caco2 cell line engineered to permanently express human alpha2A-adrenergic receptors. Serosal, but not mucosal, addition of the alpha2AR agonist N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine (clonidine) increased Caco2-3B apical (22)Na(+) uptake, an effect not seen in the Caco2 parent line that lacks alpha2AR expression. This effect was blocked by the alpha2AR antagonist 17alpha-yohmban-16alpha-carboxylic acid methyl ester (yohimbine). Increased Na(+) uptake was paralleled by increased apical surface abundance of the sodium/hydrogen exchangers NHE2 and NHE3. No changes in total cell NHE2 and NHE3 expression were observed. Clonidine also inhibited both cAMP and Ca(2+)-induced decreases in apical Na(+) uptake and apical membrane NHE2 and NHE3 endocytosis stimulated by these agents. alpha2AR actions were mediated via stimulation of phospholipase C, and metabolism of arachidonic acid by an epoxygenase activity followed epidermal growth factor release and activation of the epidermal growth factor receptor, resulting in phosphatidylinositol-3-kinase and Akt stimulation. In summary, activation of intestinal epithelial alpha2AR significantly blocks the inhibition of apical Na(+) transporters by cAMP- and Ca(2+)-mediated pathways and also directly increases apical sodium/hydrogen exchange activities. By both blocking electrolyte secretion and promoting absorption, alpha2-agonists could be potent antidiarrheal agents that could directly counteract the actions of toxigenic pathogens and other secretagogues causing secretory diarrhea.

The red cell Na/K pump is known to continue to extrude Na when both Na and K are removed from the external medium. Because this ouabain-sensitive flux occurs in the absence of an exchangeable cation, it is referred to as uncoupled Na efflux. This flux is also known to be inhibited by 5 mM Nao but to a lesser extent than that inhibitable by ouabain. Uncoupled Na efflux via the Na/K pump therefore can be divided into a Nao-sensitive and Nao-insensitive component. We used DIDS-treated, SO4-equilibrated human red blood cells suspended in HEPES-buffered (pHo 7.4) MgSO4 or (Tris)2SO4, in which we measured 22Na efflux, 35SO4 efflux, and changes in the membrane potential with the fluorescent dye, diS-C3 (5). A principal finding is that uncoupled Na efflux occurs electroneurally, in contrast to the pump's normal electrogenic operation when exchanging Nai for Ko. This electroneutral uncoupled efflux of Na was found to be balanced by an efflux of cellular anions. (We were unable to detect any ouabain-sensitive uptake of protons, measured in an unbuffered medium at pH 7.4 with a Radiometer pH-STAT.) The Nao-sensitive efflux of Nai was found to be 1.95 +/- 0.10 times the Nao-sensitive efflux of (SO4)i, indicating that the stoichiometry of this cotransport is two Na+ per SO4=, accounting for 60-80% of the electroneutral Na efflux. The remainder portion, that is, the ouabain-sensitive Nao-insensitive component, has been identified as PO4-coupled Na transport and is the subject of a separate paper. That uncoupled Na efflux occurs as a cotransport with anions is supported by the result, obtained with resealed ghosts, that when internal and external SO4 was substituted by the impermeant anion, tartrate i,o, the efflux of Na was inhibited 60-80%. This inhibition could be relieved by the inclusion, before DIDS treatment, of 5 mM Cli,o. Addition of 10 mM Ko to tartrate i,o ghosts, with or without Cli,o, resulted in full activation of Na/K exchange and the pump's electrogenicity. Although it can be concluded that Na efflux in the uncoupled mode occurs by means of a cotransport with cellular anions, the molecular basis for this change in the internal charge structure of the pump and its change in ion selectivity is at present unknown.

The plasma membrane Na+/H+ exchanger 1 is activated in response to various extrinsic factors, and this process is regulated by an intracellular pH-sensing mechanism. To identify the candidate residues responsible for intracellular pH regulation, we analyzed the functional properties of engineered Na+/H+ exchanger 1 mutants with charge-reversal mutations of charged residues located in the intracellular loops. Na+/H+ exchanger 1 mutants with mutations at 11 positions were well expressed in the plasma membrane, but that with E247R was not, suggesting that Glu247 is important for the functional expression of Na+/H+ exchanger 1. Charge-reversal mutations of Glu131 (E131R, E131K) and Arg327 (R327E) resulted in a shift in the intracellular pH dependence of the exchange activity measured by 22Na+ uptake to the acidic side, and it abolished the response to growth factors and a hyperosmotic medium; however, mutations of Asp448 (D448R) and Arg500 (R500E) slightly shifted it to the alkaline side. In E131R, in addition to the change in intracellular pH dependence, the affinities for extracellular Na+, Li+ and the inhibitor 5-(N-ethyl-N-isopropyl)amiloride significantly increased. Furthermore, charge-conserved mutation of E131 (E131D) was found to have no effect, whereas charge neutralization (E131Q) resulted in a slight acidic shift of exchange. These results support the view that the multiple charged residues identified in this study, along with several basic residues reported previously, participate in the regulation of the intracellular pH sensing of Na+/H+ exchanger 1. In addition, Glu131 may also be important for cation transport.

The sodium concentration gradient in the kidney (from the cortex to the medulla) serves to regulate fluid homeostasis and is tightly coupled to renal function. It was previously shown that renal function and pathophysiology can be characterized in rat kidneys by measuring the sodium gradient with (23)Na MRI. This study demonstrates for the first time the ability of (23)Na MRI to map the distribution of sodium in the human kidney and to quantify the corticomedullary sodium gradient. The study was performed on a 3T Signa LX scanner (GE) using an in-house-built quadrature surface coil. (23)Na images of volunteers were acquired using a 3D coronal gradient-echo sequence at a spatial resolution of 0.3 x 0.3 x 1.5 cm(3) in a 25-min scan time. The signal intensity (relative to the noise) increased linearly from the cortex to each of the medullae with a mean slope of 1.6 +/- 0.2 in relative arbitrary units per mm (Rel.u./mm, N = 6) and then decreased, as expected, toward the renal pelvis. Water deprivation (12 hr) induced a significant increase of 25% (P < 0.05) in this gradient. Based on these results, we suggest that sodium MRI can serve as a valuable noninvasive method for functional imaging of the human kidney.

In this article, both sodium magnetic resonance (MR) and T1ρ relaxation mapping aimed at measuring molecular changes in cartilage for the diagnostic imaging of osteoarthritis are reviewed. First, an introduction to structure of cartilage, its degeneration in osteoarthritis (OA) and an outline of diagnostic imaging methods in quantifying molecular changes and early diagnostic aspects of cartilage degeneration are described. The sodium MRI section begins with a brief overview of the theory of sodium NMR of biological tissues and is followed by a section on multiple quantum filters that can be used to quantify both bi-exponential relaxation and residual quadrupolar interaction. Specifically, (i) the rationale behind the use of sodium MRI in quantifying proteoglycan (PG) changes, (ii) validation studies using biochemical assays, (iii) studies on human OA specimens, (iv) results on animal models and (v) clinical imaging protocols are reviewed. Results demonstrating the feasibility of quantifying PG in OA patients and comparison with that in healthy subjects are also presented. The section concludes with the discussion of advantages and potential issues with sodium MRI and the impact of new technological advancements (e.g. ultra-high field scanners and parallel imaging methods). In the theory section on T1ρ, a brief description of (i) principles of measuring T1ρ relaxation, (ii) pulse sequences for computing T1ρ relaxation maps, (iii) issues regarding radio frequency power deposition, (iv) mechanisms that contribute to T1ρ in biological tissues and (v) effects of exchange and dipolar interaction on T1ρ dispersion are discussed. Correlation of T1ρ relaxation rate with macromolecular content and biomechanical properties in cartilage specimens subjected to trypsin and cytokine-induced glycosaminoglycan depletion and validation against biochemical assay and histopathology are presented. Experimental T1ρ data from osteoarthritic specimens, animal models, healthy human subjects and as well from osteoarthritic patients are provided. The current status of T1ρ relaxation mapping of cartilage and future directions is also discussed. Copyright © 2006 John Wiley & Sons, Ltd.