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Wilson's Disease: A Review for the General Pediatrician.
Capone, K, Azzam, RK
Pediatric annals. 2018;(11):e440-e444
Abstract
Wilson's disease, also known as hepatolenticular degeneration, is an autosomal recessive genetic disorder due to a mutation of the ATP7B gene resulting in impaired hepatic copper excretion and copper accumulation in various tissues. It is associated with the classic triad of cirrhosis, neurological manifestations, and the ocular finding of Kayser-Fleischer rings; however, the clinical presentation can vary greatly from incidental findings of abnormal liver enzymes to acute liver failure necessitating liver transplant. Pediatric patients may present with subtle findings including asymptomatic hepatomegaly, transaminitis, changes in behavior, movement disorders, or school failure. The general pediatrician may be the first to recognize these symptoms and should consider Wilson's disease in their differential diagnosis. Wilson's disease can be managed with lifelong chelation or zinc therapy in patients who present early in the disease; therefore, pediatricians should have a low threshold for referral to a pediatric hepatologist for further evaluation when it is suspected. [Pediatr Ann. 2018;47(11):e440-e444.].
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Conformationally locked lanthanide chelating tags for convenient pseudocontact shift protein nuclear magnetic resonance spectroscopy.
Joss, D, Walliser, RM, Zimmermann, K, Häussinger, D
Journal of biomolecular NMR. 2018;(1-2):29-38
Abstract
Pseudocontact shifts (PCS) generated by lanthanide chelating tags yield valuable restraints for investigating protein structures, dynamics and interactions in solution. In this work, dysprosium-, thulium- and terbium-complexes of eight-fold methylated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tags [DOTA-M8-(4R4S)-SSPy] are presented that induce large pseudocontact shifts up to 5.5 ppm and adopt exclusively the square antiprismatic conformation. This is in contrast to our earlier findings on complexes of the stereoisomeric DOTA-M8-(8S)-SSPy, where significant amounts of the twisted square antiprismatic conformer for the Dy tag were observed. The Dy-, Tm-, Tb- and Lu-complexes of DOTA-M8-(4R4S)-SSPy were conjugated to ubiquitin S57C and selectively 15N leucine labeled human carbonic anhydrase II S50C, resulting in only one set of signals. Furthermore, we investigated the conformation of the thulium- and dysprosium-complexes in vacuo and with implicit water solvent using density functional theory calculations. The calculated energy differences between the two different conformations (7.0-50.5 kJ/mol) and experimental evidence from the corresponding ytterbium- and yttrium-complexes clearly suggest a SAP [Λ(δδδδ)] geometry for the complexes presented in this study. The lanthanide chelating tag studied in this work offer insights into the solution structure of proteins by inducing strong pseudocontact shifts, show different tensor properties compared to its predecessor, enables a convenient assignment procedure, is accessed by a more economic synthesis than its predecessor and constitutes a highly promising starting point for further developments of lanthanide chelating tags.
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3.
A meta-analysis of phosphate binders lanthanum carbonate versus sevelamer hydrochloride in patients with end-stage renal disease undergoing hemodialysis.
Zhou, T, Li, H, Xie, W, Lin, Z
African health sciences. 2018;(3):689-696
Abstract
BACKGROUND AND OBJECTIVES The purpose of this study was to compare the effects of phosphate binders lanthanum carbonate (LC) versus sevelamer hydrochloride (SH) in end-stage renal disease (ESRD) patients undergoing hemodialysis. METHODS Studies including randomized controlled trials (RCTs) comparing phosphate binders lanthanum carbonate versus sevelamer hydrochloride, in ESRD patients undergoing hemodialysis, were identified using a pre-defined search strategy. Phosphate, calcium, calcium-phosphorus product, intact parathyroid hormone, alkaline phosphatase, total cholesterol, and triglyceride were extracted and compared by RevMan 5.1 (The Cochrane Collaboration, Oxford, UK). RESULTS Six studies were identified. Meta-analysis showed that SH treatment reduced levels of phosphate, intact parathyroid hormone, and total serum alkaline phosphatase (ALP) when compared with LC treatment. Furthermore, patients on SH treatment tended to have reduced calcium levels, calcium-phosphorus product, total cholesterol, and triglyceride when compared to patients treated with LC, but there was no statistical difference. CONCLUSION SH treatment of patients with ESRD is more effective compared to LC treatment. However, more well-designed random control trails are required for confirmation.
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4.
Calcium-Polystyrene Sulfonate Decreases Inter-Dialytic Hyperkalemia in Patients Undergoing Maintenance Hemodialysis: A Prospective, Randomized, Crossover Study.
Wang, J, Lv, MM, Zach, O, Wang, LY, Zhou, MY, Song, GR, Zhang, X, Lin, HL
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2018;(6):609-616
Abstract
Hyperkalemia is a life-threatening emergency in maintenance hemodialysis (MHD) patients. This clinical trial investigated the efficacy and safety of calcium-polystyrene sulfonate (Ca-PS) in MHD patients with interdialytic hyperkalemia. A total of 58 hemodialysis patients with hyperkalemia (≥5.5 mol/L) were selected and administered either a 3-week Ca-PS (3 × 5 g/day) or a blank control following the model of a prospective, randomized, crossover clinical trial with a 1-week washout period. All patients were followed up for another 3 weeks for safety evaluations. The primary outcome was the magnitude of the change in serum potassium levels. The secondary outcomes were electrocardiography (ECG) changes and treatment safety (volume overload, electrolyte imbalance). Compared with the control group, Ca-PS treatment significantly reduced serum potassium levels (P <0.01). More patients in the Ca-PS group had lower serum potassium levels than the safety level of <5.5 mmol/L (32% for control vs. 61% for Ca-PS, P <0.01). Peaked T-wave occurred less frequently in patients in the Ca-PS group (13.8% for Ca-PS vs. 31.03% for control, P <0.01). In addition, Ca-PS reduced serum phosphorus levels with no effects on serum levels of calcium and sodium, fluid volume, blood pressure, or interdialytic weight gain. Ca-PS treatment decreases serum levels of potassium and phosphorus in MHD patients with interdialytic hyperkalemia. Ca-PS does not induce volume overload or disrupt electrolyte balance.
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5.
Site-specific chelator-antibody conjugation for PET and SPECT imaging with radiometals.
Morais, M, Ma, MT
Drug discovery today. Technologies. 2018;:91-104
Abstract
Antibodies and their derivatives radiolabelled with positron- and gamma-emitting radiometals enable sensitive and quantitative molecular Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging of antibody distribution in vivo. Chelators that are covalently attached to antibodies allow radiolabelling with metallic PET and SPECT radioisotopes. Conventional strategies for chelator-protein conjugation generate heterogeneous mixtures of bioconjugates that can exhibit reduced affinity for their receptor targets, and undesirable biodistribution and pharmacokinetics. Recent advances in bioconjugation technology enable site-specific modification to generate well-defined constructs with superior properties. Herein we survey existing site-specific chelator-protein conjugation methods. These include chelator attachment to cysteines/disulfide bonds or the glycan region of the antibody, enzyme-mediated chelator conjugation, and incorporation of sequences of amino acids that chelate the radiometal. Such technology will allow better use of PET and SPECT imaging in the development of antibody-based therapies.
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Intensified treatment of hyperphosphatemia associated with reduction in parathyroid hormone in patients on maintenance hemodialysis.
Chen, L, He, JX, Chen, YY, Ling, YS, Lin, CH, Guan, TJ
Renal failure. 2018;(1):15-21
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Abstract
BACKGROUND This study investigated the therapeutic effect of intensive phosphorus-lowering therapy on intact-parathyroid hormone (iPTH) levels in hemodialysis patients. METHODS Ninety-five hemodialysis patients with serum phosphorus ≥1.78 mmol/L and iPTH ≥300 pg/dL were apportioned to either the treatment or control group (n = 43 and 52, respectively) based on patient commitment to treatment. The treatment group was given phosphorus-lowering therapies with phosphate binders (lanthanum, sevelamer or/and calcium reagent) combined with dietary phosphate restriction and intensified hemodialysis. The control individuals were given low doses of calcium agents, if serum calcium was <2.54 mmol/L. Percent changes in serum phosphorus and iPTH levels were compared between the two groups. In addition, based on the time required to achieve >20% decrease in serum phosphorus, the patients in the treatment group were further stratified as rapid responders (≤2 months; 27 patients) or slow responders (>2 months; 16 patients) and percent changes in iPTH were compared. RESULTS Serum phosphorus and iPTH levels decreased from baseline in the treatment group (-24.08 ± 1.93% and -9.92 ± 3.70%, respectively) but increased in the control group (22.00 ± 3.63% and 104.21 ± 23.89%; both p < .001). In the rapid responders subgroup, the iPTH decreased (-16.93 ± 3.49%), but in the slow responders subgroup the iPTH increased slightly (0.68 ± 7.37%, p < .05). CONCLUSIONS For these patients on maintenance hemodialysis, intensive treatment of hyperphosphatemia was associated with a decrease in iPTH levels, especially for those who had achieved substantial reduction in serum phosphorus within 2 months.
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Patiromer to Enable Spironolactone Use in the Treatment of Patients with Resistant Hypertension and Chronic Kidney Disease: Rationale and Design of the AMBER Study.
Agarwal, R, Rossignol, P, Garza, D, Mayo, MR, Warren, S, Arthur, S, Romero, A, White, WB, Williams, B
American journal of nephrology. 2018;(3):172-180
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Abstract
BACKGROUND While chronic kidney disease (CKD) is common in resistant hypertension (RHTN), prior studies -evaluating mineralocorticoid receptor antagonists excluded patients with reduced kidney function due to risk of hyperkalemia. AMBER (ClinicalTrials.gov identifier NCT03071263) will evaluate if the potassium-binding polymer patiromer used concomitantly with spironolactone in patients with RHTN and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management. METHODS Randomized, double-blind, placebo-controlled parallel group 12-week study of patiromer and spironolactone versus placebo and spironolactone in patients with uncontrolled RHTN and CKD. RHTN is defined as unattended systolic automated office blood pressure (AOBP) of -135-160 mm Hg during screening despite taking ≥3 antihypertensives, including a diuretic, and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker -(unless not tolerated or contraindicated). The CKD inclusion criterion is an estimated glomerular filtration rate (eGFR) of 25 to ≤45 mL/min/1.73 m2. Screening serum potassium must be 4.3-5.1 mEq/L. The primary efficacy endpoint is the between-group difference (spironolactone plus patiromer versus spironolactone plus placebo) in the proportion of patients remaining on spironolactone at Week 12. RESULTS Baseline characteristics have been analyzed as of March 2018 for 146 (of a targeted 290) patients. Mean (SD) baseline age is 69.3 (10.9) years; 52.1% are male, 99.3% White, and 47.3% have diabetes. Mean (SD) baseline serum potassium is 4.68 (0.25) mEq/L, systolic AOBP is 144.3 (6.8) mm Hg, eGFR is 35.7 (7.7) mL/min/1.73 m2. CONCLUSION AMBER will define the ability of patiromer to facilitate the use of spironolactone, an effective antihypertensive therapy for patients with RHTN and CKD.
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Iron chelation destabilizes bacterial biofilms and potentiates the antimicrobial activity of antibiotics against coagulase-negative Staphylococci.
Coraça-Huber, DC, Dichtl, S, Steixner, S, Nogler, M, Weiss, G
Pathogens and disease. 2018;(5)
Abstract
OBJECTIVES The ability of certain bacteria to form biofilms underlies their capacity to cause medical device-associated infections. Most bacteria need the metal iron for their proliferation but also to form biofilms. The aim of this in vitro study was to investigate whether iron restriction upon application of the iron chelator deferiprone (DFP) impacts on bacterial biofilm formation and whether such an intervention can exert synergistic effects towards the antibacterial activity of three antibiotic compounds against coagulase-negative staphylococci (CNS) residing on titanium plates. METHODS Bacteria were seeded on titanium discs and cultured to obtain biofilms. Biofilms were then exposed to DFP and/or antibiotic treatment with clindamycin, gentamycin or vancomycin. Fluorescence microscopy and scanning electron microscopy (SEM) were used for morphological analysis of the biofilms before and after treatment. RESULTS Whereas DFP alone had only a moderate inhibitory effect on biofilm growth, the combination of DFP with the respective antibiotics resulted in a significant decline of bacterial numbers by two to three logs as compared to the effect of antibiotics alone. Fluorescence staining and SEM demonstrated severe damage to even complete destruction of biofilms after combined treatment with DFP and antibiotics that was not the case upon sole treatment with antibiotics. CONCLUSION Iron chelation is able to potentiate the antibacterial activity of conventional antibiotics by destroying bacterial biofilms that recommends this combination as a promising strategy for the treatment of chronic device infections with biofilm producing CNS.
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Phosphorus binders: The new and the old, and how to choose.
Sekar, A, Kaur, T, Nally, JV, Rincon-Choles, H, Jolly, S, Nakhoul, GN
Cleveland Clinic journal of medicine. 2018;(8):629-638
Abstract
In caring for patients with chronic kidney disease, it is important to prevent and treat hyperphosphatemia with a combination of dietary restrictions and phosphorus binders. This review describes the pathophysiology and control of hyperphosphatemia and the different classes of phosphorus binders with respect to their availability, cost, side effects, and scenarios in which one class of binder may be more beneficial than another.
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Synthesis, nature and utility of universal iron chelator - Siderophore: A review.
Khan, A, Singh, P, Srivastava, A
Microbiological research. 2018;:103-111
Abstract
Siderophores, the secondary metabolite of various microorganisms are ferric ion specific chelators secreted under iron stressed condition. These non-ribosomal peptides have been classified as catecholate, hydroxamate, carboxylate and mixed types. Recent studies focus on discovery of possible mammalian siderophores. The biosynthesis pathway including non-ribosomal dependent as well as non-ribosomal independent pathways are of great interest now a days. Many significant roles of siderophores such as virulence in pathogens, oxidative stress tolerance, classification of organisms etc. are being discovered. Studies on siderophore utilization in bioremediation and other heavy metal chelation have increased in past decade. The iron chelation ability of siderophores is being recently studied with regards to malignant cancerous cells. Not only this, it has been found that they possess antimicrobial properties which can be utilized against number of microbes. This review covers all recent aspects of siderophore and its applications.