Uremic Toxins Inhibit Transport by Breast Cancer Resistance Protein and Multidrug Resistance Protein 4 at Clinically Relevant Concentrations

During chronic kidney disease (CKD), there is a progressive accumulation of toxic solutes due to inadequate renal clearance. Here, the interaction between uremic toxins and two important efflux pumps, viz. multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP) was investigated. Membrane vesicles isolated from MRP4- or BCRP-overexpressing human embryonic kidney cells were used to study the impact of uremic toxins on substrate specific uptake. Furthermore, the concentrations of various uremic toxins were determined in plasma of CKD patients using high performance liquid chromatography and liquid chromatography/tandem mass spectrometry. Our results show that hippuric acid, indoxyl sulfate and kynurenic acid inhibit MRP4-mediated [3H]-methotrexate ([3H]-MTX) uptake (calculated Ki values: 2.5 mM, 1 mM, 25 µM, respectively) and BCRP-mediated [3H]-estrone sulfate ([3H]-E1S) uptake (Ki values: 4 mM, 500 µM and 50 µM, respectively), whereas indole-3-acetic acid and phenylacetic acid reduce [3H]-MTX uptake by MRP4 only (Ki value: 2 mM and IC50 value: 7 mM, respectively). In contrast, p-cresol, p-toluenesulfonic acid, putrescine, oxalate and quinolinic acid did not alter transport mediated by MRP4 or BCRP. In addition, our results show that hippuric acid, indole-3-acetic acid, indoxyl sulfate, kynurenic acid and phenylacetic acid accumulate in plasma of end-stage CKD patients with mean concentrations of 160 µM, 4 µM, 129 µM, 1 µM and 18 µM, respectively. Moreover, calculated Ki values are below the maximal plasma concentrations of the tested toxins. In conclusion, this study shows that several uremic toxins inhibit active transport by MRP4 and BCRP at clinically relevant concentrations

Miotonia congênita: relato de sete pacientes Congenital myotonia: report of seven patients

Miotonia é o fenômeno da diminuição da velocidade de relaxamento muscular após contração, estímulo mecânico ou elétrico. As miotonias congênitas são afecções hereditárias e não apresentam distrofia muscular. Atualmente, a tendência é agrupá-las como doenças de canais iônicos, juntamente com as paralisias periódicas. Foram acompanhados sete pacientes, seis do sexo masculino e um do sexo feminino, com idade entre 16 e 48 anos (média 27 anos) e início dos sintomas entre 1 e 10 anos (média S anos), que apresentavam fenômeno miotônico desencadeado por contração intensa e hipertrofia muscular global. Três pacientes foram diagnosticados como miotonia generalizada tipo Becker por apresentarem herança autossômica recessiva e/ou episódios transitórios de fraqueza muscular. Dois pacientes correspondiam à miotonia congênita de Thomsen, com padrão de herança autossômica dominante e/ou ausência de episódios de fraqueza ou fatores de piora. Dois pacientes apresentavam miotonia flutuante, piorando com o frio e/ou ingestão de potássio. O diagnóstico clínico foi confirmado através de exames complementares (eletroneuromiografia, biópsia muscular e estudo do DNA). Cada paciente fez uso de diferentes drogas, no sentido de procurar o máximo de melhora da miotonia. Houve cinco relatos de melhora com difenil-hidantoína, um com carbamazepina, três com acetazolamida, um com bloqueador de canal de cálcio, um com beta-adrenérgico, um com tiazídico e nenhum com quinidina/procainamida.<br>Myotonia is the phenomenon of decrease of muscular relaxation rate, after either a contraction or a mechanical or electrical stimulus. Congenital myotonias are hereditary affections and do not present muscular dystrophy. The current trend is to group them as ionic channels diseases, together with the periodic paralysis.The authors accompanied the cases of seven patients, six males and one female, with ages ranging from 16 to 48 years (average 27 years) and onset of symptons between 1 and 10 years (average 5 years). These patients presented a myotonic phenomenon unleashed by intensive contraction and global muscular hypertrophy. Three patients were diagnosed as cases of Becker type generalized myotonia because they presented a recessive autosomic heredity and/or transient episodes of muscular weakness. Two patients fitted the description of Thomsen congenital myotonia, with a pattern of dominating autosomic heredity and/or absence of weakness episodes or worsening factors for their condition.Two patients presented fluctuating myotonia, which became worse in cold weather or at potassium intake. The clinical diagnosis was confirmed through complementary tests (electroneuromyography, muscle biopsy and DNA study). Each of the patients made use of different drugs, in the search of optimal lessening of their myotonia. There were five reports of amelioration with the use of diphenilhydantoine; one report with the use of carbamazepine; three reports with the use of acetazolamide; one report with the use of a calcium channel blocker; one report with the use of a beta-adrenergic; one report with the use of thiazide; and none with the use of quinidine/procainamide

Hook selectivity of the pacu Piaractus mesopotamicus (Holmberg, 1887) in the Pantanal, the state of Mato Grosso do Sul, Brazil

The Pacu Piaractus mesopotamicus is the most captured fish species in the Pantanal, Mato Grosso do Sul State, and since 1994, its maximum sustainable yield had already been exceeded. Its capture is carried out only by hooks, as mesh gears are forbidden either for professional or for recreational fishing. The aim of this study was to determine selectivity for different hook sizes used in P. mesopotamicus fishing and to verify which sizes capture only adults. Data were collected in the rivers Miranda, Aquidauana, and Vermelho, in January, March, and April 2002. Six longlines with eight hook sizes were used and we adopted the hook opening as a measure related to selectivity. Different hooks captured individuals of the same length and their medians were similar, evidencing the great overlap among sizes. Regression results showed no significant relationship between ln[c2 (l)/c1 (l)] and total length of captured individuals. In addition, the Kolmogorov-Smirnov test also did not detect significant differences in the size of captured fish. Several hypotheses, such as the selectivity models, shape of selection curves, scarcity of large fishes, and behavior are used in order to explain the absence of hook selectivity for this species. Size of recruitment for this gear was 28 cm of total length, when individuals are still immature

Preoperative scallop-by-scallop assessment of mitral prolapse using 2D-transthoracic echocardiography

<p>Abstract</p> <p>Background</p> <p>This study was conducted to assess the accuracy of harmonic imaging 2D-transthoracic echocardiography (2D-TTE) segmental analysis compared to surgical findings, in degenerative mitral regurgitation (MR).</p> <p>Methods</p> <p>Seventy-seven consecutive patients with severe degenerative MR were prospectively enrolled. Preoperative 2D-TTE with precise localization of prolapsing or flailing scallops/segments was performed. All patients underwent mitral valve surgical repair. Surgical reports (SR), including valve description, were used as references for comparisons. A postoperative control 2D-TTE was performed.</p> <p>Results</p> <p>Out of 462 scallops/segments studied, surgical inspection identified 102 prolapses or flails (22%), 92 of which had previously been detected by 2D-TTE (90.2% sensitivity, 100% specificity). Agreement between preoperative 2D-TTE segmental analysis and SR was 97.8% (k = 0.93; p < 0.0001). Sixty-nine out of 77 2D-TTE reports were completely concordant with SR (89.6% diagnostic accuracy). None of the 8 non-concordant 2D-TTE reports were in complete disagreement with SR. P2 scallop was always involved in posterior leaflet prolapse or flail and was described correctly by 2D-TTE in 68 out of 69 patients (98,7% agreement, k = 0,93; 98.5% sensitivity). The anterior leaflet was involved in 14 patients (18%); A2 segment was involved in all of those cases and was correctly detected by 2D-TTE in 13 (98,7% agreement, k = 0,95; 92,8% sensitivity). Antero-lateral and postero-medial para-commissural prolapse or flail had a lower prevalence (14% and 10% respectively), with 2D-TTE sensitivity respectively of 64% and 50%.</p> <p>Conclusions</p> <p>2D-TTE, performed by an experienced echo-lab, has very good diagnostic accuracy in localizing the scallops/segments involved in degenerative MR, particularly for the middle ones (P2-A2), which represent almost the totality of prolapses. More invasive, time consuming and expensive exams should be reserved to selected cases.</p