A population pharmacokinetic study to accelerate early phase clinical development for a novel drug, teriflunomide sodium, to treat systemic lupus erythematosus.

PURPOSE: To accelerate early phase clinical development of a novel drug, teriflunomide sodium, to treat systemic lupus erythematosus (SLE) based on the data of leflunomide. METHODS: Based on a pharmacokinetic (PK) study assessing the relative bioavailability of teriflunomide sodium compared to leflunomide, a population pharmacokinetic (Pop PK) analysis was firstly conducted using non-linear mixed effect model. Covariates were thoughtfully screened after Pop PK model evaluation and qualification using various diagnostic plots, visual predicted check (VPC) and bootstrap method. In order to predict teriflunomide PK profiles for multiple dosing of teriflunomide sodium in SLE patients, a model integrating enterohepatic circulation (EHC) mechanism was utilized to simulate the teriflunomide PK profile after multiple dosing of 20 mg/day leflunomide, and compare it to the teriflunomide PK profile in a 20 mg/day leflunomide multiple dose study in rheumatoid arthritis patients. Validated EHC PK model was applied to optimize dose regimen for teriflunomide sodium in SLE patients. RESULTS: A population one-compartment model with pulsed EHC characteristic was developed to capture teriflunomide PK profiles after administration of leflunomide and teriflunomide sodium. Body weight and male sex were found to significantly increase apparent volume of central compartment. ABCG2 34G>A polymorphism was found to significantly change apparent clearance and absorption rate. The Pop PK model was evaluated and validated. After this model was confirmed to capture EHC characteristics of teriflunomide in both healthy subjects and patients with rheumatoid arthritis after single and multiple dosing leflunomide, it was applied to suggest dose regimen of teriflunomide sodium in phase II study. CONCLUSIONS: The pulsed EHC Pop PK model characterized the teriflunomide PK processes well in both healthy subjects and patients. Body weight, sex, and ABCG2 34G>A genotype were identified to significantly affect PK characteristics. The developed EHC Pop PK model exhibited the ability to predict PK profiles of teriflunomide in patients after long-term dosing and could be utilized to support phase II trial design.

Ion uptake pathways in European sea bass Dicentrarchus labrax.

Ion uptake mechanisms are diverse in fish species, certainly linked to duplication events that have led to the presence of a multitude of paralogous genes. In fish, Na+ uptake involves several ion transporters expressed in different ionocyte subtypes. In the European sea bass Dicentrarchus labrax, several key transporters potentially involved in Na+ uptake have been investigated in seawater (SW) and following a 2 weeks freshwater (FW) acclimation. Using gel electrophoresis, we have shown that the Na+/H+-exchanger 3 (nhe3, slc9a3) is expressed in gills and kidney at both salinities. Quantitative realtime PCR analysis showed a significantly higher nhe3 expression in fresh water (FW) compared to SW. Its apical localization in a subset of gill ionocytes in freshwater-acclimated fish supports the role of NHE3 in Na+ uptake. Interestingly, NHE3-immunopositive cells also express basolateral Na+/K+/2Cl- cotransporter 1 (NKCC1) and are mainly localized in gill lamella. Among the three nhe2 (slc9a2) paralogs, only nhe2c shows differential branchial expression levels with higher mRNA levels in SW than in FW. The increased branchial expression of the ammonia transporter rhcg1 (Rhesus protein), nhe3 and cytoplasmic carbonic anhydrase (cac) in FW could indicate the presence of a functional coupling between ion transporters to form a Na+/NH4+ exchange complex. Acid-sensing ion channel 4 (asic4) seems not to be expressed in sea bass gills. Na+/Cl- cotransporter (ncc2a or ncc-like) is about three times more expressed in FW compared to SW suggesting coupled Na+ and Cl- uptake in a subset of gill ionocytes. Besides the main pump Na+/K+-ATPase, branchial NCC2a and NHE3 may be key players in ion uptake in sea bass following a long-term freshwater challenge.

The coastal environment affects lead and sodium uptake by the moss Hypnum cupressiforme used as an air pollution biomonitor.

Several studies suggest that potential competition exists between marine cations and heavy metals for binding sites on the cell wall of mosses. This competition would impact the heavy metal concentration measured in mosses by biomonitoring programs, which may underestimate air pollution by heavy metals in a coastal environment. In the present study, we aim to identify possible mechanisms affecting lead uptake by mosses in a coastal environment, specifically, the competition between lead (Pb2+) and sodium (Na+) for binding sites in Hypnum cupressiforme (Hc). We also compared the response of continental and coastal Hc populations to Pb2+ exposure by immersing the moss samples in artificial solutions that comprised six experimental treatments and subsequently locating and quantifying Pb2+ and Na+ using the sequential elution technique and X-ray microanalyses with a scanning electron microscope. We demonstrated that high concentrations of Pb2+ prevented Na+ from binding to the cell wall. We also examined the effect of the salt acclimation of Hc on Pb2+ and Na+ accumulation. Coastal Hc populations accumulated more Na and less Pb than continental Hc populations in all treatments. Moreover, our results showed treatment effects on the intra/extracellular distribution of Na+, as well as site. This feedback on the influence of salt stress tolerance on Pb2+ uptake by mosses requires further study and can be investigated for other heavy metals, leading to a better use of mosses as biomonitoring tools.

Validation of spot urine in predicting 24-h sodium excretion at the individual level.

Background: Evidence for the effect of dietary sodium intake on the risk of cardiovascular disease has been controversial. One of the main explanations for the conflicting results lies in the great variability associated with measurement methods for sodium intake. Spot urine collection is a convenient method commonly used for sodium estimation, but its validity for predicting 24-h urinary sodium excretion at the individual level has not been well evaluated among the general population.Objective: The aim of this study was to evaluate the validity of the Kawasaki, the International Cooperative Study on Salt, Other Factors, and Blood Pressure (INTERSALT), and the Tanaka formulas in predicting 24-h urinary sodium excretion by using spot urine samples in Chinese adults.Design: We analyzed the relative and absolute differences and misclassification at the individual level from 3 commonly used methods for estimating sodium intake among 141 Chinese community residents.Results: The mean measured 24-h sodium excretion was 220.8 mmol/d. The median (95% CIs) differences between measured sodium and those estimated from the Kawasaki, INTERSALT, and Tanaka methods were 6.4 mmol/d (-17.5, 36.8 mmol/d), -67.3 mmol/d (-96.5, -46.9 mmol/d), and -42.9 mmol/d (-59.1, -24.8 mmol/d), respectively. The proportions of relative differences >40% with the Kawasaki, INTERSALT, and Tanaka methods were 31.2%, 41.1%, and 22.0%, respectively; and the absolute difference for the 3 methods was >51.3 mmol/d (3 g salt) in approximately half of the participants. The misclassification rate was 63.1% for the Kawasaki method, 78.7% for the INTERSALT method, and 66.0% for the Tanaka method at the individual level.Conclusion: The results from our study do not support the use of spot urine to estimate 24-h urinary sodium excretion at the individual level because of its poor performance with respect to misclassification. This trial was registered at www.chictr.org.cn as ChiCTR-IOR-16010278.

Quality of tube well water intended for irrigation and human consumption with special emphasis on arsenic contamination at the area of Punjab, Pakistan.

In the present study, the tube well water quality and the associated health risks, emphasizing on arsenic contamination, were investigated in rural and urban samples from Tehsil Mailsi located in Punjab, Pakistan. Arsenic concentrations (µg/L) were ranged from 12 to 448.5 and which exceeded the WHO recommended limit (10 µg/L) in all cases. The calculated average daily dose (3.3 × 10-0.4 to 1.2 × 10-0.2 mg/kg day) and hazard quotient (1.1-40) reflected the potential health risk to local population due to tube well water consumption as drinking purpose. Sodium percent (Na%), sodium absorption ratio, residual sodium carbonate, Kelly's index and magnesium absorption ratio were also determined to assess the suitability of tube well water for irrigation purpose. The resulting piper plot revealed the Na-Ca-HCO3 type water chemistry of the area and generally alkaline environment. The spatial distribution of arsenic in the tube well waters pinpoints the significant contribution of anthropogenic activities to arsenic pollution. Nevertheless, different statistical tools, including principal component analysis, hierarchical cluster analysis and correlation matrices, revealed the contribution of both natural and anthropogenic activities and alkaline type of aquifers toward the high level of arsenic contamination.

Identification of structural elements involved in fine-tuning of the transport activity of the rice ammonium transporter OsAMT1;3.

Ammonium transporters (AMTs) are major routes for plant uptake of the NH4+-form nitrogen. Plant AMTs mediate predominantly the uptake of NH4+ and to a lesser extent, its organic analog methylammonium (MeA+). Mutagenesis studies on potential phosphorylation residues have achieved solid recognition that alteration of the phosphorylation status can result in allosteric regulation and impair the functionality of plant AMTs. However, molecular insights to the fine-tuning of a functional ammonium transporter remain less clear. In this report, we demonstrate that the rice root expressed OsAMT1;3 (Oryza sativa ammonium transporter 1;3) functions as a typical high-affinity NH4+ transporter and is weakly permeable to MeA+ using growth assays in NH4+ uptake defective yeast cells and electrophysiological measurements in Xenopus oocytes. Upon screening of six point mutations generated with the transporter, we identified two amino acid residues involved in the functional modulation of OsAMT1;3. The H199E mutation caused loss of transport activity whereas other five mutations retained the functionality of OsAMT1;3. Furthermore, the L56F mutation enabled respectively 5- and 3.5 -fold increased capability for NH4+ and MeA+ uptake with several-fold decreased affinity (Km) and accelerated Vmax values. Surprisingly, yeast cells expressing the L56F mutation shown increased Na+ toxicity leading to a speculation that enhanced Na+ permeation occurred with this mutation. The phenomenon was further supported by the observation of significant Na+ uptake current in oocytes. Our results seemingly support a speculation that the L56F mutation of OsAMT1;3 widens the substrate passage tunnel and allows enhanced permeability to NH4+ and larger ions MeA+ and Na+.

Exploring novel genetic sources of salinity tolerance in rice through molecular and physiological characterization.

BACKGROUND AND AIMS: Agricultural productivity is increasingly being affected by the build-up of salinity in soils and water worldwide. The genetic base of salt-tolerant rice donors being used in breeding is relatively narrow and needs broadening to breed varieties with wider adaptation to salt-affected areas. This study evaluated a large set of rice accessions of diverse origins to identify and characterize novel sources of salt tolerance. METHODS: Diversity analysis was performed on 107 germplasm accessions using a genome-wide set of 376 single-nucleotide polymorphism (SNP) markers, along with characterization of allelic diversity at the major quantitative trait locus Saltol Sixty-nine accessions were further evaluated for physiological traits likely associated with responses to salt stress during the seedling stage. KEY RESULTS: Three major clusters corresponding to the indica, aus and aromatic subgroups were identified. The largest group was indica, with the salt-tolerant Pokkali accessions in one sub-cluster, while a set of Bangladeshi landraces, including Akundi, Ashfal, Capsule, Chikirampatnai and Kutipatnai, were in a different sub-cluster. A distinct aus group close to indica contained the salt-tolerant landrace Kalarata, while a separate aromatic group closer to japonica rice contained a number of traditional, but salt-sensitive Bangladeshi landraces. These accessions have different alleles at the Saltol locus. Seven landraces - Akundi, Ashfal, Capsule, Chikirampatnai, Jatai Balam, Kalarata and Kutipatnai - accumulated less Na and relatively more K, maintaining a lower Na/K ratio in leaves. They effectively limit sodium transport to the shoot. CONCLUSIONS: New salt-tolerant landraces were identified that are genetically and physiologically distinct from known donors. These landraces can be used to develop better salt-tolerant varieties and could provide new sources of quantitative trait loci/alleles for salt tolerance for use in molecular breeding. The diversity observed within this set and in other donors suggests multiple mechanisms that can be combined for higher salt tolerance.

Comparison of multiple quantitative MRI parameters for characterization of the goat cartilage in an ongoing osteoarthritis: dGEMRIC, T1ρ and sodium.

RATIONALE AND OBJECTIVES: Osteoarthritis (OA) is a degenerative joint disease leading to cartilage deterioration by loss of matrix, fibrillation, formation of fissures, and ultimately complete loss of the cartilage surface. Here, three magnetic resonance imaging (MRI) techniques, dGEMRIC (delayed Gadolinium enhanced MRI of cartilage; dG1=T1,post; dG2=1/T1,post-1/T1,pre), T1ρ,and sodium MRI, are compared in a preclinical in vivo study to evaluate the differences in their potential for cartilage characterization and to establish an examination protocol for a following clinical study. MATERIALS AND METHODS: OA was induced in 12 caprine knees (6 control, 6 therapy). Adipose derived stem cells were injected afterwards as a treatment. The animals were examined healthy, 3 and 16 weeks postoperatively with all three MRI methods. Using statistical analysis, the OA development and the degree of correlation between the different MRI methods were determined. RESULTS: A strong correlation was observed between the dGEMRIC indices dG1 and dG2 (r=-0.87) which differ only in considering or not considering the T1 baseline. Moderate correlations were found between T1ρ and dG1 (r=0.55), T1ρ and dG2 (r=0.47) and at last, sodium and dG1 (r=0.45). The correlations found in this study match to the biomarkers which the methods are sensitive to. CONCLUSION: Even though the goat cartilage is significantly thinner than the human cartilage and even more in a degenerated cartilage, all three methods were able to characterize the cartilage over the whole period of time during an ongoing OA. Due to measurement and post processing optimizations, as well as the correlations detected in this work, the overall measurement time in future goat studies can be minimized. Moreover, an examination protocol for characterizing the cartilage in a clinical study was established.

New parameters for a better evaluation of vegetative bioremediation, leaching, and phytodesalination.

Vegetative bioremediation of calcareous sodic and saline-sodic soils is a biological approach for soil desalination by plants. It is based on three main processes: (i) sodium release from cation exchange sites, (ii) its leaching, and/or (iii) phytodesalination (Na(+) uptake by plant roots and its accumulation in shoots). Leaching needs sufficient rainfall and/or adequate irrigation. Thus, under non-leaching conditions, phytodesalination is the only existing process in terms of sodium removal. Several works tried to evaluate these processes; used plants were grown in field, in lysimeters, or in non-perforated pots. The evaluation of vegetative bioremediation, leaching, and phytodesalination was mainly based on plant analyses (including biomass production, sodium accumulation, test culture, and co-culture) and soil analyses (porosity, salinity, sodicity...). Nevertheless, used parameters are not enough to ensure comparisons between results found in different investigations. The present study introduces new parameters like phytodesalination efficiency, yield, and rate as well as vegetative bioremediation and leaching yields and rates. Our study is also illustrated by an estimation of all parameters for several previously-published data from our own works and those of other authors. Obtained results showed usefulness of these parameters and some of them can be extended to heavy metal phytoexraction.

Efficient Tailoring of Upconversion Selectivity by Engineering Local Structure of Lanthanides in Na(x)REF(3+x) Nanocrystals.

Efficient tailoring of upconversion emissions in lanthanide-doped nanocrystals is of great significance for extended optical applications. Here, we present a facile and highly effective method to tailor the upconversion selectivity by engineering the local structure of lanthanides in Na(x)REF(3+x) nanocrystals. The local structure engineering was achieved through precisely tuning the composition of nanocrystals, with different [Na]/[RE] ([F]/[RE]) ratio. It was found that the lattice parameter as well as the coordination number and local symmetry of lanthanides changed with the composition. A significant difference in the red to green emission ratio, which varied from 1.9 to 71 and 1.6 to 116, was observed for Na(x)YF(3+x):Yb,Er and Na(x)GdF(3+x):Yb,Er nanocrystals, respectively. Moreover, the local structure-dependent upconversion selectivity has been verified for Na(x)YF(3+x):Yb,Tm nanocrystals. In addition, the local structure induced upconversion emission from Er(3+) enhanced 9 times, and the CaF2 shell grown epitaxially over the nanocrystals further promoted the red emission by 450 times, which makes it superior as biomarkers for in vivo bioimaging. These exciting findings in the local structure-dependent upconversion selectivity not only offer a general approach to tailoring lanthanide related upconversion emissions but also benefit multicolor displays and imaging.

High-resolution quantitative sodium imaging at 9.4 Tesla.

PURPOSE: Investigation of the feasibility to perform high-resolution quantitative sodium imaging at 9.4 Tesla (T). METHODS: A proton patch antenna was combined with a sodium birdcage coil to provide a proton signal without compromising the efficiency of the X-nucleus coil. Sodium density weighted images with a nominal resolution of 1 × 1 × 5 mm(3) were acquired within 30 min with an ultrashort echo time sequence. The methods used for signal calibration as well as for B0, B1, and off-resonance correction were verified on a phantom and five healthy volunteers. RESULTS: An actual voxel volume of roughly 40 µL could be achieved at 9.4T, while maintaining an acceptable signal-to-noise ratio (8 for brain tissue and 35 for cerebrospinal fluid). The measured mean sodium concentrations for gray and white matter were 36 ± 2 and 31 ± 1 mmol/L of wet tissue, which are comparable to values previously reported in the literature. CONCLUSION: The reduction of partial volume effects is essential for accurate measurement of the sodium concentration in the human brain. Ultrahigh field imaging is a viable tool to achieve this goal due to its increased sensitivity.

Scan time reduction in ²³Na-Magnetic Resonance Imaging using the chemical shift imaging sequence: Evaluation of an iterative reconstruction method.

AIM: To evaluate potential scan time reduction in (23)Na-Magnetic Resonance Imaging with the chemical shift imaging sequence (CSI) using undersampled data of high-quality datasets, reconstructed with an iterative constrained reconstruction, compared to reduced resolution or reduced signal-to-noise ratio. MATERIALS AND METHODS: CSI (23)Na-images were retrospectively undersampled and reconstructed with a constrained reconstruction scheme. The results were compared to conventional methods of scan time reduction. The constrained reconstruction scheme used a phase constraint and a finite object support, which was extracted from a spatially registered (1)H-image acquired with a double-tuned coil. The methods were evaluated using numerical simulations, phantom images and in-vivo images of a healthy volunteer and a patient who suffered from cerebral ischemic stroke. RESULTS: The constrained reconstruction scheme showed improved image quality compared to a decreased number of averages, images with decreased resolution or circular undersampling with weighted averaging for any undersampling factor. Brain images of a stroke patient, which were reconstructed from three-fold undersampled k-space data, resulted in only minor differences from the original image (normalized root means square error < 12%) and an almost identical delineation of the stroke region (mismatch < 6%). CONCLUSION: The acquisition of undersampled (23)Na-CSI images enables up to three-fold scan time reduction with improved image quality compared to conventional methods of scan time saving.

Intrarenal ghrelin receptor antagonism prevents high-fat diet-induced hypertension in male rats.

Excess weight gain contributes up to 65% of the risk of primary hypertension, and the increase in blood pressure in response to high-fat diet (HFD) is preceded by significant increases in renal tubular sodium (Na(+)) reabsorption. In normal rats, intrarenal ghrelin infusion increases distal nephron-dependent Na(+) reabsorption via activation of the intrarenal ghrelin receptor (GHSR). This study focusses on the role of intrarenal GHSR-mediated Na(+) reabsorption in HFD-induced hypertension. Dahl salt-sensitive rats received standard diet or HFD for 6 weeks. Rats underwent uninephrectomy and osmotic minipump implantation for chronic intrarenal delivery of vehicle (0.25 µL/h × 28 d), selective GHSR antagonist [D-Lys-3]-growth hormone releasing peptide-6 (0.2µM/d), or GHSR inverse agonist [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P (SUB-P) (3.6µM/d). HFD rats with vehicle pumps had significantly increased renal GHSR expression compared with standard diet (0.092 ± 0.005 vs 0.065 ± 0.004 arbitrary units; P < .05), whereas acyl ghrelin levels were similar (16.3±6.2 vs 15.7±8.7 pg/g tissue). HFD rats with vehicle pumps became hypertensive after 2 weeks (P < .05) and showed a significant reduction in 24-hour urine Na(+) before hypertension. At this time, these rats showed an increase in collecting duct α-epithelial Na(+) channel, thereby providing a potential mechanism for the excess Na(+) reabsorption. In contrast, HFD rats with [D-Lys-3]-growth hormone releasing peptide-6 or SUB-P pumps never became hypertensive and did not show the reduction in urine Na(+). Because SUB-P blocks the constitutive, but not ghrelin-dependent, activity of the GHSR, and HFD-induced α-epithelial Na(+) channel up-regulation was abolished during GHSR antagonism, these data suggest that HFD increases the constitutive activity of renal GHSR to increase Na(+) reabsorption and induce hypertension in rats.

[6]-gingerol induces electrogenic sodium absorption in the rat colon via the capsaicin receptor TRPV1.

[6]-Gingerol possesses a variety of beneficial pharmacological and therapeutic properties, including anti-carcinogenic, anti-inflammatory, and anti-emetic activities. Although [6]-gingerol is known to regulate the contraction of the intestine, its effect on intestinal ion transport is unclear. The aim of this study was to examine the role of [6]-gingerol in the regulation of electrogenic ion transport in the rat intestine by measuring the transmural potential difference (ΔPD). [6]-Gingerol induced significant positive ΔPD when administered to the serosal but not mucosal side of the colon, ileum, and jejunum; the highest effect was detected in the colon at a concentration of 10 µM. [6]-Gingerol-induced increase in ΔPD was suppressed by ouabain, an inhibitor of Na(+)/K(+)-ATPase, whereas no effect was observed in response to bumetanide, an inhibitor of the Na(+)-K(+)-2Cl(-) co-transporter. In addition, ΔPD induction by [6]-gingerol was greatly diminished by capsazepine, an inhibitor of the capsaicin receptor TRPV1. These results suggest that [6]-gingerol induced the electrogenic absorption of sodium in the rat colon via TRPV1.

The role of transforming growth factor ß1 in the regulation of blood pressure.

Although human association studies suggest a link between polymorphisms in the gene encoding transforming growth factor (TGF) ß1 and differing blood pressure levels, a causative mechanism for this correlation remains elusive. Recently we have generated a series of mice with graded expression of TGFß1, ranging from approximately 10% to 300% compared to normal. We have found that blood pressure and plasma volume are negatively regulated by TGFß1. Of note, the 10% hypomorph exhibits primary aldosteronism and markedly impaired urinary excretion of water and electrolytes. We here review previous literature highlighting the importance of TGFß signaling as a natriuretic system, which we postulate is a causative mechanism explaining how polymorphisms in TGFß1 could influence blood pressure levels.

Osmotic diuresis-induced hypernatremia: better explained by solute-free water clearance or electrolyte-free water clearance?

Hypernatremia may result from inadequate water intake, excessive water loss or a combination of the two. Osmotic diuresis leads to losses of both solute and water. The relationship between solute and water losses determines the resulting changes in serum osmolality and sodium concentration. Total solute loss is routinely higher than loss of water in osmotic diuresis. Theoretically, then, decreases in serum osmolality (and serum sodium concentration) should follow. In clinical situations of osmotic diuresis, however, reduction in osmolality can take place, but not reduction in serum sodium concentration. It is of note that serum sodium concentration changes are related to urinary losses of sodium and potassium but not to the loss of total solute. In osmotic diuresis, the combined loss of sodium and potassium per liter of urine is lower than the concurrent serum sodium level. Consequently, hypernatremia can ensue. A patient who presented with osmotic diuresis and hypernatremia is described here. In this patient, we have shown that electrolyte-free water clearance is a better index of the effect of osmotic diuresis on serum sodium concentration than the classic solute-free water clearance.

Bilateral kidney sodium-MRI: Enabling accurate quantification of renal sodium concentration through a two-element phased array system.

PURPOSE: To develop a sodium-MRI ((23) Na-MRI) method for bilateral renal sodium concentration (RSC) measurements in rat kidneys at 9.4 Tesla (T). MATERIALS AND METHODS: To simultaneously achieve high B1 -field homogeneity and high receive sensitivity a dual resonator system composed of a double-tuned linearly polarized (1) H/(23) Na volume resonator and a newly developed two-element (23) Na receive array was used. In conjunction with three-dimensional (3D) ultra-short Time-to-Echo sequence a quantification accuracy of ± 10% was achieved for a nominal spatial resolution of (1 × 1 × 4) mm(3) in 10 min acquisition time. The technique was applied to study the RSC in six kidneys before and after furosemide-induced diuresis. RESULTS: The loop diuretic agent induced an increase of cortical RSC by 22% from 86 ± 16 mM to 105 ± 18 mM (P = 0.02), whereas the RSC in the inner medulla decreased by 38% from 213 ± 24 mM to 132 ± 25 mM (P = 0.8×10(-4) ). The RSC changes measured in this study agreed well with the qualitative sodium signal intensity variations reported elsewhere. CONCLUSION: Furosemide-induced diuresis has been investigated accurately with herein presented quantitative (23) Na-MRI technique. In the future, RSC quantification could allow for defining pathological and nonpathological RSC ranges to assess sodium concentration changes, e.g., induced by drugs.

Pseudohypoaldosteronism.

Pseudohypoaldosteronism (PHA) is a rare syndrome of mineralocorticoid resistance. PHA type 1 (PHA1) can be divided into two different forms, showing either a systemic or a renal form of mineralocorticoid resistance. The first is caused by mutations of the genes coding the epithelial sodium channel, the latter is caused by mutations in the mineralocorticoid receptor coding gene NR3C2. The clinical manifestation of systemic PHA1 is overt dehydration and hyponatremia due to systemic salt loss and severe hyperkalemia. The leading clinical sign of the less severe renal PHA1 is insufficient weight gain due to chronic dehydration. Hyperkalemia is generally mild. The patients manifest clinical signs mainly in early infancy. In both entities, plasma renin and aldosterone concentrations are highly elevated, reflecting a resistance of the kidney and other tissues to mineralocorticoids. PHA2 is characterized by hyperkalemia and hypertension. It has been described by Gordon's group as a syndrome with highly variable plasma aldosterone concentrations, suppressed plasma renin activity, various degrees of hyperchloremia and metabolic acidosis. PHA3 comprises transient and secondary forms of salt-losing states caused by various pathologies. Urinary tract infections and obstructive uropathies are the most frequent cause. Contrary to PHA1 and PHA2, the glomerular filtration rate is decreased in PHA3.

Hydrothermal synthesis of NaLuF4:153Sm,Yb,Tm nanoparticles and their application in dual-modality upconversion luminescence and SPECT bioimaging.

Upconversion luminescence (UCL) properties and radioactivity have been integrated into NaLuF(4):(153)Sm,Yb,Tm nanoparticles by a facile one-step hydrothermal method, making these nanoparticles potential candidates for UCL and single-photon emission computed tomography (SPECT) dual-modal bioimaging in vivo. The introduction of small amount of radioactive (153)Sm(3+) can hardly vary the upconversion luminescence properties of the nanoparticles. The as-designed nanoparticles showed very low cytotoxicity, no obvious tissue damage in 7 days, and excellent in vitro and in vivo performances in dual-modal bioimaging. By means of a combination of UCL and SPECT imaging in vivo, the distribution of the nanoparticles in living animals has been studied, and the results indicated that these particles were mainly accumulated in the liver and spleen. Therefore, the concept of (153)Sm(3+)/Yb(3+)/Tm(3+) co-doped NaLuF(4) nanoparticles for UCL and SPECT dual-modality imaging in vivo of whole-body animals may serve as a platform for next-generation probes for ultra-sensitive molecular imaging from the cellular scale to whole-body evaluation. It also introduces an easy methodology to quantify in vivo biodistribution of nanomaterials which still needs further understanding as a community.