Characterization of carrier females and affected males with X-linked recessive nephrolithiasis.

X-linked recessive nephrolithiasis (XRN) was described in a large kindred in which nephrolithiasis; proximal tubular dysfunction, proteinuria, nephrocalcinosis, and renal failure occur only in males. Carrier females are asymptomatic, but formal studies of them have not been done. The gene for XRN has been mapped to the pericentromeric region of the X chromosome, close to the loci for several eye disease genes. We studied six affected males, 13 carrier females, and 25 normal members of this family including 7 females whose genetic haplotype predicted them to be carriers. Studies were done in the Clinical Research Unit on a diet containing 400 mg of calcium and 2 g of sodium, and by an additional outpatient urine collection was obtained on a 1-g calcium intake. Hypercalciuria occurred in five of six affected males, 4 of 12 carrier females, and three of seven predicted carriers. Significant proteinuria was present in all affected males and in no other subjects. Low-molecular-weight proteinuria was present in all affected males: the excretion of alpha 1-microglobulin exceeded normal by 3- to 14-fold, of beta 2-microglobulin exceeded normal by 100- to 400-fold, and of retinol-binding protein exceeded normal by 1,000- to 3,000-fold. The excretion of these proteins was less strikingly elevated in carrier females, but the excretion of alpha 1-microglobulin was abnormal in 9 of 15 carriers, beta 2-microglobulin was abnormal in 12 of 15, and retinolbinding protein in was abnormal 12 of 13, and this pattern was similar in predicted carriers. The urinary concentrating ability was abnormal in four affected males with renal insufficiency but normal in all other subjects. Urinary wasting of potassium, phosphorous, and glucose occurred infrequently, and no subject was hypouricemic. Formal ophthalmologic studies were normal in five affected males. Thus, the most consistent urinary abnormalities in XRN are hypercalciuria and low-molecular-weight proteinuria, the latter of which appears to be a marker for the carrier state

El itinerario cristiano según Evagrio Póntico : sus proyecciones exegéticas en la Sagrada Escritura en general y en el libro del Eclesiastés en particular

En el cuadro de los actuales estudios acerca del pensamiento de Evagrio Póntico nos interesa profundizar en las proyecciones exegéticas que -a la zaga de una tradición clásico-cristiana bien identificada- posee la concepción evagriana del cristianismo como itinerario de salvación. Dichas proyecciones se extienden a la Sagrada Escritura en general y, de un modo particular, al libro del Eclesiastés. De este modo una vez desarrollado el sentido del itinerario evagriano y sus proyecciones exegéticas generales, nuestro trabajo centrará su atención en el comentario evagriano titulado Escolios al Eclesiastés y su lugar en el marco del pensamiento del filósofo del Ponto. Se trata de una obra poco estudiada que constituye, no obstante, una pieza exegética singular dentro del corpus evagriano en la medida en que con ella accedemos a una comprensión más profunda de lo que nuestro autor ha querido designar con el concepto de "contemplación natural". En este sentido, su profundización permite, asimismo -a nuestro modo de ver- una renovada comprensión del itinerario espiritual en el que Evagrio cifra la esencia del cristianismo en tanto "doctrina de Cristo, nuestro Salvador". De igual modo, la obra en cuestión permite comprender más cabalmente las particularidades del método exegético evagriano.In the context of current studies on the thought of Evagrius Ponticus we are interested in deepening the exegetical projections that -following a well- identified classical-Christian tradition- possesses the evagrian conception of Christianity as an itinerary of salvation. These projections extend to Sacred Scripture in general and, in a way, to the book of Ecclesiastes. Thus, after developing the sense of the evagrian itinerary and its general exegetical projections, our work will focus on the evagrian commentary entitled "Scholia on Ecclesiastes" and its place within the framework of the thought of the philosopher of Ponto. This work has been little studied but it constitutes a unique exegetical piece within the evagrian corpus. Through this work we access a deeper understanding of what Evagrius wanted to designate with the concept of "natural contemplation". In this sense, deepening this work allows -in our view- a renewed understanding of the spiritual itinerary that constitutes, for Evagrius, the essence of Christianity. Similarly, Scholia on Ecclesiastes allow us to understand more fully the particularities of the exegetical evagrian method

High-dose erythropoietin population pharmacokinetics in neonates with hypoxic–ischemic encephalopathy receiving hypothermia

BackgroundHigh-dose erythropoietin (Epo) is a promising neuroprotective treatment in neonates with hypoxic-ischemic encephalopathy (HIE) receiving hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of high-dose Epo in this population to inform future dosing strategies.MethodsWe performed a population pharmacokinetic analysis of 47 neonates with HIE treated with hypothermia who received up to six doses of Epo in two previous clinical trials. We compared the ability of different dosing regimens to achieve the target neuroprotective Epo exposure levels determined from animal models of hypoxic-ischemia (i.e., area under the curve during the first 48 h of treatment (AUC48 h) 140,000 mU*h/ml).ResultsBirth weight scaled via allometry was a significant predictor of Epo clearance and volume of distribution (P < 0.001). After accounting for birth weight, variation in Epo pharmacokinetics between neonates was low (CV% 20%). All 23 neonates who received 1,000 U/kg every 24 h for the first 2 d of therapy achieved the target AUC48 h 140,000 mU*h/ml. No neonate who received a lower dosing regimen achieved this target.ConclusionIn neonates with HIE receiving hypothermia, Epo 1,000 U/kg every 24 h for the first 2 d of therapy resulted in consistent achievement of target exposures associated with neuroprotection in animal models