Mechanistic understanding of salt-induced drug encapsulation in nanosuspension via acid-base neutralization as a nanonization platform technology to enhance dissolution rate of pH-dependent poorly water-soluble drugs.

An acid-base neutralization technique has generated interest for the ability to achieve an enhanced dissolution of pH-dependent weakly basic or acidic poorly water-soluble drugs. However, the underlying nanonization mechanism, following acid-base neutralization, requires further elucidation. We hypothesized that the nanosuspensions (NSPs) via nanonization of drug particles could be attributed to the "salt-induced effect" and surfactant-driven micellization after acid-base neutralization. Rebamipide (RBM) and valsartan (VAL) were chosen as model drugs owing to poor water solubility and pH-dependent aqueous solubility. The drug NSP was rapidly obtained via salt formation (NaCl) after neutralization of the drug in basic NaOH solution and poloxamer 407 (POX 407) in acidic HCl solution. The NSP surrounded by NaCl salt was further stabilized by POX 407. The resulting NaCl salt modulated the critical micelle aggregation of POX 407, stabilizing the drug-loaded NSP in a cage of salt and micellar surfactant. In non-assisted homogenization, size analysis indicated the relationship between salt concentration and size reduction. Fourier transform infrared (FTIR) spectra revealed that the existence of hydrogen bonding between the drug and surfactant after neutralization, attributed to NSP size reduction. Changes in drug crystallinity to the nano-amorphous state were confirmed by powder X-ray diffraction (PXRD). Overall, the salt-induced drug NSP synergistically enhanced the dissolution rate, narrowing a gap between drug dissolution profiles in different pH environments.

Investigation of Various Intramuscular Volumes Delivered to the Semimembranosus Muscle of Cavia porcellus.

The goal of this study is to provide quantitative data on the ideal volume for intramuscular (IM) injections into the semimembranosus muscle of guinea pigs weighing between 320 to 410 grams. This evaluation comprised 2 experiments. The first was to assess dispersion leakage of intramuscularly injected iohexol, a radiocontrast agent commonly used in Computed Tomography (CT), based on analysis of in vivo imaging. The second used varying volumes of intramuscularly injected sodium chloride (0.9% NaCl) to assess pain and pathology associated with IM injection. Hartley guinea pigs were injected IM with varying volumes of either iohexol or sodium chloride (150, 300, 500, 1000 and 1500 µL). In the iohexol experiment, results suggest IM volumes of 150 and 300 µL remain within the target muscle. In the experiment using sodium chloride, pain and pathology did not increase as IM volume increased. The pathology noted was related to needle tract through the musculature rather than the volume size of the injectate. The results did not reveal a correlation between volume of IM 0.9% NaCl and pain levels. We conclude that volume size correlates more with precision and accuracy of delivery into the intended muscle tissue. Regarding tissue distribution, our findings also suggest that the optimal capacity for IM injection in the semimembranosus muscle should be less than 500 µL.

A randomised controlled trial of amnioexchange for fetal gastroschisis.

OBJECTIVE: Morbidity in fetuses affected by gastroschisis is mainly the result of bowel ischaemic and inflammatory processes. Experimental studies on animal models show that clearing amniotic fluid from the digestive secretions by amnioexchange procedures reduces the inflammatory process. We evaluated the benefit of the amnioexchange procedure for fetal gastroschisis in humans. DESIGN: Prospective, interventional, randomised study. SETTING: Eight referral centres for fetal medicine. POPULATION: Pregnant women carrying a fetus with gastroschisis. METHODS: We compared, in utero, amnioexchange with a sham procedure. The protocol included, in both arms, steroid injections at 30 weeks of gestation and the use of postnatal minimal enteral feeding. MAIN OUTCOME MEASURES: The primary outcome was a composite variable based on the duration of ventilation and parenteral nutrition. Secondary outcomes were the effectiveness and safety of the amnioexchange procedure, including the rate of perinatal death, time to full enteral feeding, primary closure, and late feeding disorders. RESULTS: Sixty-four patients were randomised. There was no difference in the composite criteria between the amnioexchange and control groups. Based on an intention-to-treat analysis, there were no significant between-group differences in pregnancy outcome or complications. When studying the relationship between digestive compounds and amniotic fluid inflammatory markers, a clear correlation was found between bile acid and both ferritin and interleukin 1ß (IL1ß). CONCLUSIONS: In humans, amnioexchange, as described in our protocol, is not an option for fetal care; however, we provide supplementary proof of the involvement of inflammation in the pathogenicity of gastroschisis and suggest that future research should aim at reducing inflammation. ClinicalTrials.gov: NCT00127946. TWEETABLE ABSTRACT: A prospective, interventional, randomised study shows no benefit of amnioexchange for fetal gastroschisis in humans.

Effects of three infusion fluids with different sodium chloride contents on steady-state serum concentrations of bromide in dogs.

Potassium bromide overdose (bromism) in the management of canine epilepsy has been known. However, a protocol to reduce bromide concentrations rapidly has not been previously established. The effects of three infusion fluids with different chloride contents on the steady-state serum concentrations of bromide in beagles were determined. After stabilization of the serum bromide concentrations, seven dogs were infused with saline (Na+ 154 mmol/L; Cl- 154 mmol/L), lactated Ringer's (Na+ 131 mmol/L; Cl- 110 mmol/L), or maintenance solutions (Na+ 35 mmol/L; Cl- 35 mmol/L) at a rate of 2 or 10 ml kg-1  hr-1 for 5 hr. Serum and urine were collected hourly, and the bromide concentrations were measured. When saline and lactated Ringer's solutions were infused at a rate of 10 ml kg-1  hr-1 for 5 hr, serum bromide concentrations were decreased by 14.24% and urine bromide concentrations by 17.63%, respectively. Of all compositions of infusion fluids, only sodium and chloride contents were associated with the decreased serum concentrations and the increased renal clearance of bromide. In summary, saline and lactated Ringer's solutions reduced serum bromide concentrations in a sodium chloride-dependent manner in dogs were found when infused at 10 ml kg-1  hr-1 for 5 hr.

UCP3 Ablation Exacerbates High-Salt Induced Cardiac Hypertrophy and Cardiac Dysfunction.

BACKGROUND/AIMS: Excessive salt intake and left ventricular hypertrophy (LVH) are both critical for the development of hypertension and heart failure. The uncoupling protein 3 (UCP3) plays a cardio-protective role in early heart failure development. However, the potential role for UCP3 in salt intake and LVH is unclear. METHODS: UCP3-/- and C57BL/6 mice were placed on either a normal-salt (NS, 0.5%) or a high-salt (HS, 8%) diet for 24 weeks. The cardiac function, endurance capacity, energy expenditure, and mitochondrial functional capacity were measured in each group. RESULTS: Elevated blood pressure was only observed in HS-fed UCP3-/- mice. High salt induced cardiac hypertrophy and dysfunction were observed in both C57BL/6 and UCP3-/- mice. However, the cardiac lesions were more profound in HS-fed UCP3-/- mice. Furthermore, HS-fed UCP3-/-mice experienced more severe mitochondrial respiratory dysfunction compared with HS-fed C57BL/6 mice, represented by the decreased volume of oxygen consumption and heat production at the whole-body level. CONCLUSION: UCP3 protein was involved in the incidence of high-salt induced hypertension and the progression of cardiac dysfunction in the early stages of heart failure. UCP3 ablation exacerbated high-salt-induced cardiac hypertrophy and cardiac dysfunction.

Time Course of Change in Blood Pressure From Sodium Reduction and the DASH Diet.

Both sodium reduction and the Dietary Approaches to Stop Hypertension (DASH) diet lower blood pressure (BP); however, the patterns of their effects on BP over time are unknown. In the DASH-Sodium trial, adults with pre-/stage 1 hypertension, not using antihypertensive medications, were randomly assigned to either a typical American diet (control) or DASH. Within their assigned diet, participants randomly ate each of 3 sodium levels (50, 100, and 150 mmol/d, at 2100 kcal) over 4-week periods. BP was measured weekly for 12 weeks; 412 participants enrolled (57% women; 57% black; mean age, 48 years; mean systolic BP [SBP]/diastolic BP [DBP], 135/86 mm Hg). For those assigned control, there was no change in SBP/DBP between weeks 1 and 4 on the high-sodium diet (weekly change, -0.04/0.06 mm Hg/week) versus a progressive decline in BP on the low-sodium diet (-0.94/-0.70 mm Hg/week; P interactions between time and sodium <0.001 for SBP and DBP). For those assigned DASH, SBP/DBP changed -0.60/-0.16 mm Hg/week on the high- versus -0.42/-0.54 mm Hg/week on the low-sodium diet (P interactions between time and sodium=0.56 for SBP and 0.10 for DBP). When comparing DASH to control, DASH changed SBP/DBP by -4.36/-1.07 mm Hg after 1 week, which accounted for most of the effect observed, with no significant difference in weekly rates of change for either SBP (P interaction=0.97) or DBP (P interaction=0.70). In the context of a typical American diet, a low-sodium diet reduced BP without plateau, suggesting that the full effects of sodium reduction are not completely achieved by 4 weeks. In contrast, compared with control, DASH lowers BP within a week without further effect thereafter. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000608.

Assessing the kinetics of microbubble appearance in cirrhotic patients using transthoracic saline contrast-enhanced echocardiography.

BACKGROUND: The number of cardiac cycles that need to be reviewed by echocardiography before a significant intrapulmonary shunt can be excluded remains unclear. METHODS: We retrospectively identified patients with cirrhosis who underwent technetium-99 m-labeled macroaggregated albumin scanning. The kinetics of bubble appearance after the injection of agitated saline during transthoracic echocardiograms were assessed in these patients. RESULTS: For the 64 eligible patients, the mean ± SD age was 56 ± 9 years. The median (IQR) shunt fraction by radionuclide scanning was 7.7% (2.8%-19.9%). Microbubbles were seen in the left atrium (LA) and left ventricle (LV) at a median (IQR) of 4 (2-5) and 4 (2-5) beats, respectively. The number of heart cycles before microbubbles appeared in the LA or LV was inversely associated with the nuclear scanning shunt fraction (R = -0.42, P = .001, R = -0.46, P < .001, respectively). If no microbubbles were detected by heart cycle 7, the shunt fraction was uniformly less than 3%. Patients with arterial oxygen <60 mm Hg, compared to ≥60 mm Hg, had earlier appearance of microbubbles in the left heart chambers (2.6 ± 1.9 vs 4.0 ± 2.3 beats, P = .046). CONCLUSIONS: In patients with advanced cirrhosis suspected of having hepatopulmonary syndrome, a greater shunt fraction during nuclear scanning was associated with more pronounced hypoxemia and a prompt and more intense appearance of microbubbles in the left-sided heart chambers. Patients with a shunt fraction above 3% have microbubbles in the LA or LV at some point during the first seven heart cycles.

Uptake and desorption of hydrophilic compounds from human stratum corneum.

Small, polar compounds, both ionic and uncharged, partition into human stratum corneum immersed in aqueous solutions to an extent comparable to the water volume fraction of the tissue, then desorb in two phases. The fast phase has a time constant on the order of a few minutes, whereas the slow phase occurs over many hours. A physical model for this behavior involving a combination of tranverse diffusion through the tissue and lateral diffusion and exchange with skin appendages is presented. This concept is probed using excised human stratum corneum exposed to aqueous solutions of radiolabeled sodium chloride, tetraethyl ammonium bromide and mannitol, plus previously published data on six other compounds of varying molecular size and polarity. The fast phase desorption process becomes unimportant for lipophilic compounds. Slow phase desorption rates are size-selective, with larger species desorbing much more slowly than smaller ones. Interpreting the size-selectivity in terms of smooth cylindrical pores using the centerline approximation leads to an optimum pore radius of about 8-12Å, depending on the model chosen.

Effects of vasoactive drugs on crystalloid fluid kinetics in septic sheep.

PURPOSE: Crystalloid fluid and vasoactive drugs are used in the early treatment of sepsis. The purpose of the present study was to examine how these drugs alter plasma volume expansion, peripheral edema, and urinary excretion. METHODS: Twenty-five anesthetized sheep were made septic by cecal puncture and a short infusion of lipopolysaccharide. After 50 min, a slow infusion of isotonic saline was initiated: the saline either contained no drug, norepinephrine (1 µg/kg/min), phenylephrine (3 µg/kg/min), dopamine (50 µg/kg/min), or esmolol (50 µg/kg/min). Ten min later, 20 mL/kg Ringer´s lactate solution was given over 30 min. Central hemodynamics, acid-base balance, and the urinary excretion were monitored. Frequent measurements of the blood hemoglobin concentration were used as input in a kinetic analysis, using a mixed effects modeling software. RESULTS: The fluid kinetic analysis showed slow distribution and elimination of Ringer´s lactate, although phenylephrine and dopamine accelerated the distribution. Once distributed, the fluid remained in the peripheral tissues and did not equilibrate adequately with the plasma. Overall, stimulation of adrenergic alpha1-receptors accelerated, while beta1-receptors retarded, the distribution and elimination of fluid. A pharmacodynamic Emax model showed that Ringer´s lactate increased stroke volume by 13 ml/beat. Alpha1-receptors, but not beta1-receptors, further increased stroke volume, while both raised the mean arterial pressure. Modulation of the beta1-receptors limited the acidosis. CONCLUSIONS: Stimulation of adrenergic alpha1-receptors with vasoactive drugs accelerated, while beta1-receptors retarded, the distribution and elimination of fluid. The tendency for peripheral accumulation of fluid was pronounced, in particular when phenylephrine was given.

Molecular mechanisms underlying active desalination and low water permeability in the esophagus of eels acclimated to seawater.

Marine teleosts can absorb imbibed seawater (SW) to maintain water balance, with esophageal desalination playing an essential role. NaCl absorption from luminal SW was enhanced 10-fold in the esophagus of SW-acclimated eels, and removal of Na+ or Cl- from luminal SW abolished the facilitated absorption, indicating coupled transport. Mucosal/serosal application of various blockers for Na+/Cl- transporters profoundly decreased the absorption. Among the transporter genes expressed in eel esophagus detected by RNA-seq, dimethyl amiloride-sensitive Na+/H+ exchanger (NHE3) and 4,4'-diisothiocyano-2,2'-disulfonic acid-sensitive Cl-/[Formula: see text] exchanger (AE) coupled by the scaffolding protein on the apical membrane of epithelial cells, and ouabain-sensitive Na+-K+-ATPases (NKA1α1c and NKA3α) and diphenylamine-2-carboxylic acid-sensitive Cl- channel (CLCN2) on the basolateral membrane, may be responsible for enhanced transcellular NaCl transport because of their profound upregulation after SW acclimation. Upregulated carbonic anhydrase 2a (CA2a) supplies H+ and [Formula: see text] for activation of the coupled NHE and AE. Apical hydrochlorothiazide-sensitive Na+-Cl- cotransporters and basolateral Na+-[Formula: see text] cotransporter (NBCe1) and AE1 are other possible candidates. Concerning the low water permeability that is typically seen in marine teleost esophagus, downregulated aquaporin genes (aqp1a and aqp3) and upregulated claudin gene (cldn15a) are candidates for transcellular/paracellular route. In situ hybridization showed that these upregulated transporters and tight-junction protein genes were expressed in the absorptive columnar epithelial cells of eel esophagus. These results allow us to provide a full picture of the molecular mechanism of active desalination and low water permeability that are characteristic to marine teleost esophagus and gain deeper insights into the role of gastrointestinal tracts in SW acclimation.

Distribution of Flunixin Residues in Muscles of Dairy Cattle Dosed with Lipopolysaccharide or Saline and Treated with Flunixin by Intravenous or Intramuscular Injection.

Twenty dairy cows received flunixin meglumine at 2.2 mg/kg bw, administered once daily by either the intravenous (IV) or intramuscular (IM) route for three consecutive days with either intravenous normal saline (NS) or lipopolysaccharide (LPS) providing a balanced design with five animals per group. Cows were sacrificed after a 4 day withdrawal period, and 13 muscle types were collected and assayed for flunixin by LC-MS/MS. After elimination of sample outliers, the main effects of route of administration (IV or IM), treatment (NS or LPS), and tissue type significantly (P < 0.05) affected flunixin residues, with no interaction (P > 0.05). Intramuscular (nonlabel) flunixin administration produced greater (P < 0.05) flunixin residues in muscle than the IV (label) administration, whereas LPS resulted in lower flunixin levels. Differences among the tissue levels indicate it is necessary to specify the tissue to be used for any monitoring of drug levels for consumer protection.

Positioning the Intracellular Salt Potassium Glutamate in the Hofmeister Series by Chemical Unfolding Studies of NTL9.

In vitro, replacing KCl with potassium glutamate (KGlu), the Escherichia coli cytoplasmic salt and osmolyte, stabilizes folded proteins and protein-nucleic acid complexes. To understand the chemical basis for these effects and rank Glu- in the Hofmeister anion series for protein unfolding, we quantify and interpret the strong stabilizing effect of KGlu on the ribosomal protein domain NTL9, relative to the effects of other stabilizers (KCl, KF, and K2SO4) and destabilizers (GuHCl and GuHSCN). GuHSCN titrations at 20 ° C, performed as a function of the concentration of KGlu or another salt and monitored by NTL9 fluorescence, are analyzed to obtain R-values quantifying the Hofmeister salt concentration (m3) dependence of the unfolding equilibrium constant K(obs) [r-value = −d ln K(obs)/dm3 = (1/RT) dΔG(obs) ° /dm3 = m-value/RT]. r-Values for both stabilizing K+ salts and destabilizing GuH+ salts are compared with predictions from model compound data. For two-salt mixtures, we find that contributions of stabilizing and destabilizing salts to observed r-values are additive and independent. At 20 ° C, we determine a KGlu r-value of 3.22 m(−1) and K2SO4, KF, KCl, GuHCl, and GuHSCN r-values of 5.38, 1.05, 0.64, −1.38, and −3.00 m(−1), respectively. The KGlu r-value represents a 25-fold (1.9 kcal) stabilization per molal KGlu added. KGlu is much more stabilizing than KF, and the stabilizing effect of KGlu is larger in magnitude than the destabilizing effect of GuHSCN. Interpretation of the data reveals good agreement between predicted and observed relative r-values and indicates the presence of significant residual structure in GuHSCN-unfolded NTL9 at 20 ° C.

Measurement of Procedure-Specific Irrigation-Fluid Absorption in Transurethral Therapy of Lower Urinary Tract Syndrome, Using Ethanolic Saline and Breath Alcometry.

INTRODUCTION: Transurethral resection risks excessive absorption of irrigating fluid with potentially severe or life-threatening consequences. We determined the amount of absorbed saline irrigation fluid during photoselective vaporisation of the prostate (PVP) and bipolar transurethral resection of the prostate (bTURP). PATIENTS AND METHODS: Patients at our institution treated by one of these methods were monitored by the alcometric method: ethanol is added to the irrigation fluid and blood alcohol is measured with a breathalyser. Various possible correlations were investigated. RESULTS: Data from 71 patients (36 PVP, 35 bTURP) were analysed. Detection of any absorption was more frequent under bTURP (71% of patients) than under PVP (39%; p = 0.006). Absorption in the volume range 500-1,000 ml was conspicuously more frequent in the bTURP procedure than in PVP. CONCLUSIONS: Presence of absorption was more frequent under bTURP than under PVP. However, high-volume absorption was more frequent during bTURP than in PVP.

Regional Ventilation and Aerosol Deposition with Helium-Oxygen in Bronchoconstricted Asthmatic Lungs.

BACKGROUND: Theoretical models suggest that He-O2 as carrier gas may lead to more homogeneous ventilation and aerosol deposition than air. However, these effects have not been clinically consistent and it is unclear why subjects may or may not respond to the therapy. Here we present 3D-imaging data of aerosol deposition and ventilation distributions from subjects with asthma inhaling He-O2 as carrier gas. The data are compared with those that we previously obtained from a similar group of subjects inhaling air. METHODS: Subjects with mild-to-moderate asthma were bronchoconstricted with methacholine and imaged with PET-CT while inhaling aerosol carried with He-O2. Mean-normalized-values of lobar specific ventilation sV* and deposition sD* were derived and the factors affecting the distribution of sD* were evaluated along with the effects of breathing frequency (f) and regional expansion (FVOL). RESULTS: Lobar distributions of sD* and sV* with He-O2 were not statistically different from those previously measured with air. However, with He-O2 there was a larger number of lobes having sV* and sD* closer to unity and, in those subjects with uneven deposition distributions, the correlation of sD* with sV* was on average higher (p < 0.05) in He-O2 (0.84 ± 0.8) compared with air (0.55 ± 0.28). In contrast with air, where the frequency of breathing during nebulization was associated with the degree of sD*-sV* correlation, with He-O2 there was no association. Also, the modulation of f on the correlation between FVOL and sD*/sV* in air, was not observed in He-O2. CONCLUSION: There were no differences in the inter-lobar heterogeneity of sD* or sV* in this group of mild asthmatic subjects breathing He-O2 compared with patients previously breathing air. Future studies, using these personalized 3D data sets as input to CFD models, are needed to understand if, and for whom, breathing He-O2 during aerosol inhalation may be beneficial.

Absorption of irrigation fluid during XPS™ GreenLight laser vaporization of the prostate: results from a prospective breath ethanol monitoring study.

PURPOSE: To assess whether and to what extent irrigation fluid absorption occurs during laser vaporization (LV) of the prostate using the 180 W XPS™ GreenLight laser. METHODS: This prospective investigation was performed in a tertiary care center with a consecutive series of patients undergoing 180 W LV of the prostate. Intraoperative irrigation was performed with isotonic saline containing 1 % ethanol. The volume of irrigation fluid absorption was calculated from periodically performed breath ethanol measurements during LV. Additionally, intraoperative changes in biochemical and hematological blood parameters were assessed. RESULTS: Positive breath ethanol tests were detectable in 22 of 54 patients. The median absorption volume in these patients was 950 ml (range 208-4579 ml). Ten patients absorbed more than 2000 ml. Absorbers had smaller prostates, more capsular perforations and injuries to venous sinuses, and more total energy was applied with higher output power. Five patients had transient symptoms potentially related to fluid absorption. A significant drop in hemoglobin, hematocrit, venous pH and bicarbonate and an increase in chloride were detectable in the absorber group. These changes were significantly different in the non-absorber group. CONCLUSIONS: Absorption of irrigation fluid did occur in a relevant proportion of patients undergoing XPS™ GreenLight LV. High-volume absorption (≥2000 ml), which might be clinically relevant, was detectable in almost 20 % of all procedures. Absorption of saline irrigation fluid does not result in a classical TUR syndrome, but fluid and chloride overload can lead to serious complications, particularly in cardiovascular high-risk patients. Thus, patients with symptoms potentially related to fluid absorption should be monitored carefully.

In vivo photoacoustic flowmetry at depths of the diffusive regime based on saline injection.

We propose a saline injection-based method to quantify blood flow velocity in vivo with acoustic-resolution photoacoustic tomography. By monitoring the saline­blood interface propagating in the blood vessel, the flow velocity can be resolved. We first demonstrated our method in phantom experiments, where a root mean square error of prediction of 0.29 mm/s was achieved. By injecting saline into a mouse tail vein covered with 1 mm chicken tissue, we showed that the flow velocity in the tail vein could be measured at depths, which is especially pertinent to monitoring blood flow velocity in patients undergoing intravenous infusion.

Is absorption of irrigation fluid a problem in Thulium laser vaporization of the prostate? A prospective investigation using the expired breath ethanol test.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a prevalent entity in elderly men. If medical treatment fails, monopolar transurethral resection of the prostate (TUR-P) is still considered as the standard treatment. The proportion of high-risk patients with cardiac comorbidities increases and TUR-P goes along with a relevant perioperative risk. Especially large volume influx of irrigation fluid and transurethral resection syndrome (TUR syndrome) represent serious threats to these patients. Using isotonic saline as irrigation fluid like in transurethral laser vaporization (TUV-P), TUR syndrome can be prevented. However, no prospective trial has ever assessed occurrence or extent of irrigation fluid absorption in Thulium Laser TUV-P. METHODS/DESIGN: This is a single-center prospective trial, investigating, if absorption of irrigation fluid occurs during Thulium Laser TUV-P by expired breath ethanol test. The expired breath ethanol technique is an established method of investigating intraoperative absorption of irrigation fluid: A tracer amount of ethanol is added to the irrigation fluid and the absorption of irrigation fluid can be calculated by measuring the expiratory ethanol concentrations of the patient with an alcohol breathalyzer. Fifty consecutive patients undergoing TUV-P at our tertiary referral center are included into the trial. Absorption volume of irrigation fluid during Thulium Laser TUV-P is defined as primary endpoint. Pre- to postoperative changes in bladder diaries, biochemical and hematological laboratory findings, duration of operation and standardized questionnaires are assessed as secondary outcome measures. DISCUSSION: The aim of this study is to assess the safety of Thulium Laser TUV-P in regard to absorption of irrigation fluid.

Intravenous solutions in the care of patients with volume depletion and electrolyte abnormalities.

Infusion fluids are often given to restore blood pressure (volume resuscitation), but may also be administered to replace ongoing losses, match insensible losses, correct electrolyte or acid-base disorders, or provide glucose. The development of new infusion fluids has provided clinicians with a wide range of products. Although the choice for a certain infusion fluid is often driven more by habit than by careful consideration, we believe it is useful to approach infusion fluids as drugs and consider their pharmacokinetic and pharmacodynamic characteristics. This approach not only explains why infusion fluids may cause electrolyte and acid-base disturbances, but also why they may compromise kidney function or coagulation. In this teaching case, we present a 19-year-old patient in whom severe hypernatremia developed as a result of normal saline solution infusion and explore the pharmacokinetic and pharmacodynamic effects of frequently used infusion fluids. We review clinical evidence to guide the selection of the optimal infusion fluid.

Integrated compensatory network is activated in the absence of NCC phosphorylation.

Thiazide diuretics are used to treat hypertension; however, compensatory processes in the kidney can limit antihypertensive responses to this class of drugs. Here, we evaluated compensatory pathways in SPAK kinase-deficient mice, which are unable to activate the thiazide-sensitive sodium chloride cotransporter NCC (encoded by Slc12a3). Global transcriptional profiling, combined with biochemical, cell biological, and physiological phenotyping, identified the gene expression signature of the response and revealed how it establishes an adaptive physiology. Salt reabsorption pathways were created by the coordinate induction of a multigene transport system, involving solute carriers (encoded by Slc26a4, Slc4a8, and Slc4a9), carbonic anhydrase isoforms, and V-type H⁺-ATPase subunits in pendrin-positive intercalated cells (PP-ICs) and ENaC subunits in principal cells (PCs). A distal nephron remodeling process and induction of jagged 1/NOTCH signaling, which expands the cortical connecting tubule with PCs and replaces acid-secreting α-ICs with PP-ICs, were partly responsible for the compensation. Salt reabsorption was also activated by induction of an α-ketoglutarate (α-KG) paracrine signaling system. Coordinate regulation of a multigene α-KG synthesis and transport pathway resulted in α-KG secretion into pro-urine, as the α-KG-activated GPCR (Oxgr1) increased on the PP-IC apical surface, allowing paracrine delivery of α-KG to stimulate salt transport. Identification of the integrated compensatory NaCl reabsorption mechanisms provides insight into thiazide diuretic efficacy.