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Effect of the chemical environment of the DNA guanine quadruplex on the free energy of binding of Na and K ions.
Sharawy, M, Consta, S
The Journal of chemical physics. 2018;(22):225102
Abstract
Guanine quadruplex (G-quadruplex) structures play a vital role in stabilizing the DNA genome and in protecting healthy cells from transforming into cancer cells. The structural stability of G-quadruplexes is greatly enhanced by the binding of monovalent cations such as Na+ or K+ into the interior axial channel. We computationally study the free energy of binding of Na+ and K+ ions to two intramolecular G-quadruplexes that differ considerably in their degree of rigidity and the presence or absence of terminal nucleotides. The goal of our study is two-fold. On the one hand, we study the free energy of binding every ion, which complements the experimental findings that report the average free energy for replacing Na+ with K+ ions. On the other hand, we examine the role of the G-quadruplex structure in the binding free energy. In the study, we employ all-atom molecular dynamics simulations and the alchemical transformation method for the computation of the free energies. To compare the cation-dependent contribution to the structural stability of G-quadruplexes, we use a two-step approach to calculate the individual free energy difference ΔG of binding two Na+ and two K+ to two G-quadruplexes: the unimolecular DNA d[T2GT2(G3T)3] (Protein Data Bank ID 2M4P) and the human telomeric DNA d[AGGG(TTAGGG)3] (PDB ID 1KF1). In contrast to the experimental studies that estimate the average free energy of binding, we find a varying difference of approximately 2-9 kcal/mol between the free energy contribution of binding the first and second cation, Na+ or K+. Furthermore, we found that the free energy of binding K+ is not affected by the chemical nature of the two quadruplexes. By contrast, Na+ showed dependency on the G-quadruplex structure; the relatively small size allows Na+ to explore larger configurational space than K+. Numerical results presented here may offer reference values for future design of cationic drug-like ligands that replace the metal ions in G-quadruplexes.
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2.
[Disturbances of Sodium Homeostasis].
Dresely, F
Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS. 2018;(7-08):492-502
Abstract
Sodium is the most important osmotically effective cation in the extracellular space and very important for the water balance of the organism. Disturbances in the sodium homeostasis are therefore usually closely associated with disturbances in the water balance. The most important organs involved in the regulation of the sodium homeostasis are the kidneys and the brain. Disturbances of sodium homeostasis are common electrolyte disturbances, which can cause serious complications, as well as their improper therapy. The aim of this article is to inform about the etiology of disturbances of sodium homeostasis and to present important therapeutic principles.The TUR syndrome is a complication that can occur in the context of transurethral resection of the prostate which can lead to the inundation of larger amounts of hypotonic, electrolyte-free rinsing solution into the circulation and severe hyponatremia. Central pontine myelinolysis is a dangerous complication of a too fast compensation of hyponatremia. Exercise-associated hyponatremia (EHA) is a severe complication due to an inappropriately high intake of hypotonic fluids (mineral water, "isotonic sports drinks") during endurance sports. Due to the increasing popularity of endurance sports competitions (marathon, triathlon), an increasing incidence of this potentially life-threatening electrolyte disorder is to be expected.
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Compact DD generator-based in vivo neutron activation analysis (IVNAA) system to determine sodium concentrations in human bone.
Coyne, MD, Neumann, C, Zhang, X, Byrne, P, Liu, Y, Weaver, CM, Nie, LH
Physiological measurement. 2018;(5):055004
Abstract
OBJECTIVE This study presents the development of a noninvasive method for monitoring Na in human bone. Many diseases, such as hypertension and osteoporosis, are closely associated with sodium (Na) retention in the human body. Na retention is generally evaluated by calculating the difference between dietary intake and excretion. There is currently no method to directly quantify Na retained in the body. Bone is a storage for many elements, including Na, which renders bone Na an ideal biomarker to study Na metabolism and retention. APPROACH A customized compact deuterium-deuterium (DD) neutron generator was used to produce neutrons for in vivo neutron activation analysis (IVNAA), with a moderator/reflector/shielding assembly optimized for human hand irradiation in order to maximize the thermal neutron flux inside the irradiation cave and to limit radiation exposure to the hand and the whole body. MAIN RESULTS The experimental results show that the system is able to detect sodium levels in the bone as low as 16 µg Na g-1 dry bone with an effective dose to the body of about 27 µSv. The simulation results agree with the numbers estimated from the experiment. SIGNIFICANCE This is expected to be a feasible method for measuring the change of Na in bone. The low detection limit indicates this will be a useful system to study the association between Na retention and related diseases.
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The ratio of urinary sodium and potassium and chronic kidney disease progression: Results from the KoreaN Cohort Study for Outcomes in Patients with Chronic Kidney Disease (KNOW-CKD).
Koo, H, Hwang, S, Kim, TH, Kang, SW, Oh, KH, Ahn, C, Kim, YH
Medicine. 2018;(44):e12820
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Abstract
The Na/K ratio in urine stands for the dietary of sodium and potassium intake in patients with chronic kidney disease remains unclear for the renal progression. We aimed to determine the risk of progression of chronic kidney disease based on the Na/K ratio in a 24-hour urine collection.We determined the association between the progression of renal disease and 24-hour urinary sodium and potassium (Na/K) ratios in 2238 patients over a 5-year timespan using data obtained from the KoreaN cohort study for Outcomes in patients With Chronic Kidney Disease (KNOW-CKD). Renal events were defined as a 50% decrease in the glomerular filtration rate (GFR) below baseline, or the onset of end-stage renal disease (ESRD). Patients were divided into 4 groups based on the quartile range of the 24-hour urinary sodium and potassium ratio. We analyzed those variables in the 4 groups. Multiple logistic regression analyses were performed using the data of 1001 patients to identify the independent factors associated with renal events.Age and male sex accounted for the greatest number of patients in the group with the highest values (group 4) of the 24-hour urinary Na/K ratio (≥3.85). There was no difference in the prevalence of hypertension or diabetes mellitus, the ratio of use of antihypertensive drugs, blood pressures, or estimated GFRs. In the group with the highest urinary Na/K ratio, the 24-hour urinary Na concentration mean ± standard deviation was 188.7 ± 70.6 mmol and that of urinary K was 39.9 ± 16.1 mmol. The urinary protein excretion was highest in the group with the highest urinary Na/K ratio. In the logistic regression analysis, the effect on renal events increased with increasing urinary Na/K ratios. After adjusting for other factors, the risk of renal events was 2.48 (95% confidence interval (CI) 1.30-4.90) in group 3, and 3.75 (95% CI: 1.35-11.27) in group 4. In the Kaplan-Meier analysis, the higher the urinary Na/K ratio, the higher the rate of CKD progression.Based on our analyses, we concluded that the higher the urinary Na/K ratio, the greater the risk of CKD progression.
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Wireless, intraoral hybrid electronics for real-time quantification of sodium intake toward hypertension management.
Lee, Y, Howe, C, Mishra, S, Lee, DS, Mahmood, M, Piper, M, Kim, Y, Tieu, K, Byun, HS, Coffey, JP, et al
Proceedings of the National Academy of Sciences of the United States of America. 2018;(21):5377-5382
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Abstract
Recent wearable devices offer portable monitoring of biopotentials, heart rate, or physical activity, allowing for active management of human health and wellness. Such systems can be inserted in the oral cavity for measuring food intake in regard to controlling eating behavior, directly related to diseases such as hypertension, diabetes, and obesity. However, existing devices using plastic circuit boards and rigid sensors are not ideal for oral insertion. A user-comfortable system for the oral cavity requires an ultrathin, low-profile, and soft electronic platform along with miniaturized sensors. Here, we introduce a stretchable hybrid electronic system that has an exceptionally small form factor, enabling a long-range wireless monitoring of sodium intake. Computational study of flexible mechanics and soft materials provides fundamental aspects of key design factors for a tissue-friendly configuration, incorporating a stretchable circuit and sensor. Analytical calculation and experimental study enables reliable wireless circuitry that accommodates dynamic mechanical stress. Systematic in vitro modeling characterizes the functionality of a sodium sensor in the electronics. In vivo demonstration with human subjects captures the device feasibility for real-time quantification of sodium intake, which can be used to manage hypertension.
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The Association of Dietary and Urinary Sodium With Bone Mineral Density and Risk of Osteoporosis: A Systematic Review and Meta-Analysis.
Fatahi, S, Namazi, N, Larijani, B, Azadbakht, L
Journal of the American College of Nutrition. 2018;(6):522-532
Abstract
OBJECTIVE Although some earlier studies have indicated an association between dietary/urinary sodium and bone mass density (BMD), bone mass content (BMC), and the risk of osteoporosis (OS), findings are still conflicting. The aim of this study was to summarize the relation of dietary/urinary sodium with BMD, BMC, and the risk of OS. METHODS We conducted a systematic search up to April 2017 in PubMed/MEDLINE, SCOPUS, and Web of Science to find relevant studies. Articles with cross-sectional and cohort designs in which odds ratios (ORs), correlations (r), or beta coefficients were reported for the association between dietary/urinary sodium and OS, BMD, or BMC were included. RESULTS Pooling 11 effect sizes with a total of 39,065 people showed that higher sodium consumption significantly increased the risk of OS (OR = 1.20; 95% confidence interval [CI], 1.02-1.41; p = 0.026), with high heterogeneity among studies (I2 = 68.0%; p = 0.001). Subgroup analyses showed significantly higher risk of OS in premenopausal women (OR = 1.31; 95% CI, 1.01-1.69; p = 0.036), in participants with a mean age older than 50 years (OR = 1.15; 95% CI, 1.04-1.28; p = 0.005), in dietary sodium intake subgroup (OR = 1.45; 95% CI, 1.19-1.77; p < 0.001), and in individuals with adjustment for energy (OR = 1.77; 95% CI, 1.38-2.27; p < 0.001). The correlation coefficients showed no significant association between urinary sodium and BMD (r = -0.46; 95% CI, -0.74 to -0.18; p = 0.02). CONCLUSIONS We found a positive association between sodium intake and the risk of OS, while no association was found with urinary sodium. Furthermore, there was no significant correlation between sodium intake and BMD. Due to high heterogeneity in this research, more studies are suggested.
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Errors in estimating usual sodium intake by the Kawasaki formula alter its relationship with mortality: implications for public health.
He, FJ, Campbell, NRC, Ma, Y, MacGregor, GA, Cogswell, ME, Cook, NR
International journal of epidemiology. 2018;(6):1784-1795
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BACKGROUND Several cohort studies with inaccurate estimates of sodium reported a J-shaped relationship with mortality. We compared various estimated sodium intakes with that measured by the gold-standard method of multiple non-consecutive 24-h urine collections and assessed their relationship with mortality. METHODS We analysed the Trials of Hypertension Prevention follow-up data. Sodium intake was assessed in four ways: (i) average measured (gold standard): mean of three to seven 24-h urinary sodium measurements during the trial periods; (ii) average estimated: mean of three to seven estimated 24-h urinary sodium excretions from sodium concentration of 24-h urine using the Kawasaki formula; (iii) first measured: 24-h urinary sodium measured at the beginning of each trial; (iv) first estimated: 24-h urinary sodium estimated from sodium concentration of the first 24-h urine using the Kawasaki formula. We included 2974 individuals aged 30-54 years with pre-hypertension, not assigned to sodium intervention. RESULTS During a median follow-up of 24 years, 272 deaths occurred. The average sodium intake measured by the gold-standard method was 3769 ± 1282 mg/d. The average estimated sodium over-estimated the intake by 1297 mg/d (95% confidence interval: 1267-1326). The average estimated value was systematically biased with over-estimation at lower levels and under-estimation at higher levels. The average measured sodium showed a linear relationship with mortality. The average estimated sodium appeared to show a J-shaped relationship with mortality. The first measured and the first estimated sodium both flattened the relationship. CONCLUSIONS Accurately measured sodium intake showed a linear relationship with mortality. Inaccurately estimated sodium changed the relationship and could explain much of the paradoxical J-shaped findings reported in some cohort studies.
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Significance of fluctuations in serum sodium levels following aneurysmal subarachnoid hemorrhage: an exploratory analysis.
Eagles, ME, Tso, MK, Macdonald, RL
Journal of neurosurgery. 2018;(2):420-425
Abstract
OBJECTIVE Fluctuations in patient serum sodium levels are common after aneurysmal subarachnoid hemorrhage (aSAH), but their effect on patient outcome is not well described in the literature. The goal of this work was to better characterize the relationship between fluctuations in serum sodium levels, outcome, and the development of delayed cerebral ischemia (DCI) after aSAH. METHODS The authors performed a post hoc analysis of data from the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial. Patients had their serum sodium values recorded daily for 14 days post-aSAH. Average and average absolute daily differences in sodium levels were calculated for each patient based on 3 reference points: admission sodium levels, a normal sodium level (defined as 140 mmol/L), and the previous day's sodium level. These variables were also calculated for the classic "vasospasm window" (days 3-12) post-aSAH. A stepwise logistic regression model, locally weighted scatterplot smoothing curves, and receiver operator characteristic curve analysis were used to evaluate the relationship between alterations in serum sodium levels and clinical outcome or the development of DCI after aSAH. Poor outcome was defined as a modified Rankin Scale (mRS) score of > 2 at 3 months. RESULTS The average daily difference in sodium values from baseline (p < 0.001), average daily difference from a normal sodium level (p < 0.001), average absolute daily difference from a normal sodium level (p = 0.015), and average absolute daily difference from the previous day's sodium level (p = 0.017) were significant predictors of poor outcome in a stepwise multivariate regression model. There was a trend toward significance for average absolute daily difference from admission sodium levels during the vasospasm window as an independent predictor of DCI (p = 0.052). There was no difference in the predictive capacity for DCI when sodium fluctuations from post-aSAH days 1-14 were compared with those from the classic vasospasm window (days 3-12). CONCLUSIONS Fluctuations in serum sodium levels may play a role in clinical outcome and the development of DCI after aSAH. The timing of these fluctuations appears to have no significant effect on the development of DCI.
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Role of Insulin-Mediated Antinatriuresis in Sodium Homeostasis and Hypertension.
Brands, MW
Hypertension (Dallas, Tex. : 1979). 2018;(6):1255-1262
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Prognostic Significance of Baseline Serum Sodium in Heart Failure With Preserved Ejection Fraction.
Patel, YR, Kurgansky, KE, Imran, TF, Orkaby, AR, McLean, RR, Ho, YL, Cho, K, Gaziano, JM, Djousse, L, Gagnon, DR, et al
Journal of the American Heart Association. 2018;(12)
Abstract
BACKGROUND The purpose of this study was to evaluate the relationship between serum sodium at the time of diagnosis and long term clinical outcomes in a large national cohort of patients with heart failure with preserved ejection fraction. METHODS AND RESULTS We studied 25 440 patients with heart failure with preserved ejection fraction treated at Veterans Affairs medical centers across the United States between 2002 and 2012. Serum sodium at the time of heart failure diagnosis was analyzed as a continuous variable and in categories as follows: low (115.00-134.99 mmol/L), low-normal (135.00-137.99 mmol/L), referent group (138.00-140.99 mmol/L), high normal (141.00-143.99 mmol/L), and high (144.00-160.00 mmol/L). Multivariable Cox regression and negative binomial regression were performed to estimate hazard ratios (95% confidence interval [CI]) and incidence density ratios (95% CI) for the associations of serum sodium with mortality and hospitalizations (heart failure and all-cause), respectively. The average age of patients was 70.8 years, 96.2% were male, and 14% were black. Compared with the referent group, low, low-normal, and high sodium values were associated with 36% (95% CI, 28%-44%), 6% (95% CI, 1%-12%), and 9% (95% CI, 1%-17%) higher risk of all-cause mortality, respectively. Low and low-normal serum sodium were associated with 48% (95% CI, 10%-100%) and 38% (95% CI, 8%-77%) higher risk of number of days of heart failure hospitalizations per year, and with 44% (95% CI, 32%-56%) and 18% (95% CI, 10%-27%) higher risk of number of days of all-cause hospitalizations per year, respectively. CONCLUSIONS Both elevated and reduced serum sodium, including values currently considered within normal range, are associated with adverse outcomes in patients with heart failure with preserved ejection fraction.