A kilonova as the electromagnetic counterpart to a gravitational-wave source.

Gravitational waves were discovered with the detection of binary black-hole mergers and they should also be detectable from lower-mass neutron-star mergers. These are predicted to eject material rich in heavy radioactive isotopes that can power an electromagnetic signal. This signal is luminous at optical and infrared wavelengths and is called a kilonova. The gravitational-wave source GW170817 arose from a binary neutron-star merger in the nearby Universe with a relatively well confined sky position and distance estimate. Here we report observations and physical modelling of a rapidly fading electromagnetic transient in the galaxy NGC 4993, which is spatially coincident with GW170817 and with a weak, short γ-ray burst. The transient has physical parameters that broadly match the theoretical predictions of blue kilonovae from neutron-star mergers. The emitted electromagnetic radiation can be explained with an ejected mass of 0.04 ± 0.01 solar masses, with an opacity of less than 0.5 square centimetres per gram, at a velocity of 0.2 ± 0.1 times light speed. The power source is constrained to have a power-law slope of -1.2 ± 0.3, consistent with radioactive powering from r-process nuclides. (The r-process is a series of neutron capture reactions that synthesise many of the elements heavier than iron.) We identify line features in the spectra that are consistent with light r-process elements (atomic masses of 90-140). As it fades, the transient rapidly becomes red, and a higher-opacity, lanthanide-rich ejecta component may contribute to the emission. This indicates that neutron-star mergers produce gravitational waves and radioactively powered kilonovae, and are a nucleosynthetic source of the r-process elements.

ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain.

KEY POINTS: Gain-of-function mutations in the highly selective Ca2+ channel ORAI1 cause tubular aggregate myopathy (TAM) characterized by muscular pain, weakness and cramping. TAM-associated mutations in ORAI1 first and third transmembrane domain facilitate channel opening by STIM1, causing constitutive Ca2+ influx and increasing the currents evoked by Ca2+ store depletion. Mutation V107M additionally decreases the channel selectivity for Ca2+ ions and its inhibition by acidic pH, while mutation T184M does not alter the channel sensitivity to pH or to reactive oxygen species. The ORAI blocker GSK-7975A prevents the constitutive activity of TAM-associated channels and might be used in therapy for patients suffering from TAM. ABSTRACT: Skeletal muscle differentiation relies on store-operated Ca2+ entry (SOCE) mediated by STIM proteins linking the depletion of endoplasmic/sarcoplasmic reticulum Ca2+ stores to the activation of membrane Ca2+ -permeable ORAI channels. Gain-of-function mutations in STIM1 or ORAI1 isoforms cause tubular aggregate myopathy (TAM), a skeletal muscle disorder with muscular pain, weakness and cramping. Here, we characterize two overactive ORAI1 mutants from patients with TAM: V107M and T184M, located in the first and third transmembrane domain of the channel. When ectopically expressed in HEK-293T cells or human primary myoblasts, the mutated channels increased basal and store-operated Ca2+ entry. The constitutive activity of V107M, L138F, T184M and P245L mutants was prevented by low concentrations of GSK-7975A while the G98S mutant was resistant to inhibition. Electrophysiological recordings confirmed ORAI1-V107M constitutive activity and revealed larger STIM1-gated V107M- and T184M-mediated currents with conserved fast and slow Ca2+ -dependent inactivation. Mutation V107M altered the channel selectivity for Ca2+ ions and conferred resistance to acidic inhibition. Ca2+ imaging and molecular dynamics simulations showed a preserved sensitivity of T184M to the negative regulation by reactive oxygen species. Both mutants were able to mediate SOCE in Stim1-/- /Stim2-/- mouse embryonic fibroblasts expressing the binding-deficient STIM1-F394H mutant, indicating a higher sensitivity for STIM1-mediated gating, with ORAI1-T184M gain-of-function being strictly dependent on STIM1. These findings provide new insights into the permeation and regulatory properties of ORAI1 mutants that might translate into therapies against diseases with gain-of-function mutations in ORAI1.

Effect of low dose supplementation of L-carnitine on lipid metabolism in hemodialyzed children.

Long-term intravenous supplementation with low dose L-carnitine (5 mg/kg body wt) was investigated in seven hemodialyzed children with type IV hyperlipoproteinemia. Carnitine was given at the completion of each hemodialysis treatment (3 times a week) over a period of five months. This treatment resulted in a rise in total plasma carnitine concentrations (117.7 +/- 33.0 microM) as compared to before therapy (37.9 +/- 15.8 microM); the free fraction was the chief portion of this elevation. Prior to therapy the patients had high plasma triglyceride concentrations (3.82 +/- 1.6 mM) which were markedly reduced after five months of carnitine therapy (1.86 +/- 0.7 mM; P less than or equal to 0.05). The initially low HDL-cholesterol levels (0.91 +/- 0.2 mM) were increased (1.13 +/- 0.2 mM; P less than or equal to 0.05) after supplementation. Thus, long-term low-dose carnitine supplementation improves the disturbed lipid metabolism; this suggests an important role for carnitine in uremic children and may justify the use of supplemental carnitine.

Renal insufficiency in the neonatal period.

Prevalence of renal insufficiency and renal failure of newborns in an intensive care unit is considerably high. Most patients have prerenal failure which is associated with the underlying disease, some have had heart surgery and only few patients have congenital renal malformation. In a retrospective analysis in our institution main risk factors were: prematurity, age < 10 days, obstetric complications, male gender, Cesarean delivery and pulmonary disease. We could not confirm, however, that asphyxia is significant for renal failure. Much more common than manifest renal failure is renal insufficiency in diseased newborns during intensive care. The cause is sometimes primary renal insufficiency as a harbinger of renal failure, but it is often iatrogenic, because fluid intake is inadequate, either unintentional or for a purpose. This strategy, however, conflicts with a conservative approach to renal insufficiency, which requires adequate fluid and caloric intake. A skilled approach to this situation demands a daily re-evaluation of the fluid regimen with regard to possible liberalization. If renal failure progresses dialysis may be indicated, but this remains controversial in neonates. However, with growing expertise, skill and adequate equipment, different techniques of dialysis nowadays can be applied even to small infants. Mortality in infants with acute renal failure ranges from 25 to 78%, but death is seldom caused primarily by renal disease. In our survey 0.9% in a total of 34% mortality was attributed to renal disease. Attention has to be paid to the bulk of diseased newborns, who experience only slight increase in serum creatinine in their early life with only mild (or even without) oliguria, who may be prone to residual renal morbidity as well as those, who have manifest renal failure.

The addition of aminoacids and phosphate to hemodiafiltration solutions in newborns with hyperammonemic coma.

A child with carbamyl-phosphate-synthetase defect who died after prolonged continuous hemodiafiltration in deep coma proved to have high aminoacid losses despite aminoacid infusion. We think that this results from high small-solute clearance during hemodialysis. In order to prevent these inevitable catabolic side-effects we decided to add aminoacids to the dialysate and substitution fluid in these children with metabolic diseases. Additionally we propose to add phosphate in order to avoid depletion. The aim is to achieve anabolic or at least non-catabolic hemodiafiltration.

Familial hypomagnesemia-hypercalciuria in 2 siblings.

Familial hypomagnesemia-hypercalciuria with nephrocalcinosis and renal insufficiency in childhood is a rarely described disease. Two siblings of consanguineous Tunesian parents (first cousins), a 2-year-old boy and a 4-year-old girl presented with renal insufficiency and severe bilateral nephrocalcinosis. Both were found to have decreased serum and intracellular magnesium concentrations, increased urinary excretion of magnesium and calcium, mild glomerular and severe tubular proteinuria and low citrate excretion in urine. Pathological biochemical findings and the severity of nephrocalcinosis of the boy compared to findings of the sister were strongly marked, Histology of the boy's kidney showed severe medullary nephrocalcinosis, tubular atrophy, focal lymphoplasmacellulary infiltration, focal cortical fibrosis, immature glomerula, segmental and global glomerulosclerosis. Subsequent mutation analysis revealed a homozygous frameshift mutation in the gene paracellin-1 in both affected individuals. Therapy consisted of sodium bicarbonate, cholecalciferol, calcitriol, hydrochlorothiazide, citrate salts and oral magnesium administration. Hypercalciuria decreased in both children by therapy with thiazide diuretics, but hypomagnesemia was unresponsive to magnesium administration. After a 32-month follow-up the boy commenced hemodialysis at the age of 5 years, whereas his sister showed no decline in renal function.

Thyroid hormone concentrations in dialysate during hemodialysis in children.

Thyroxine (T4) concentration in dialysate in the course of hemodialysis was determined in 15 children. Concentrations were measured by a modified radioimmunoassay. During hemodialysis there was a slight increase in T4 concentration. At the end of hemodialysis T4 concentration was about 50% higher than soon after the onset of hemodialysis. The loss of T4 into dialysate during hemodialysis was 19.2 microgram; the loss of T3 was less than 75 ng. The amount of the daily loss of thyroid hormones into dialysate was found to be in the range of normal urinary excretion. The lowering of serum thyroid hormone concentrations in children on hemodialysis cannot be explained by the loss of hormones into dialysate.

Kinetics of intravenously administered carnitine in haemodialysed children.

The pharmacokinetics of low-dose bolus L-carnitine (5 mg kg-1 body wt) in five haemodialysed children were investigated. Kinetic variables were obtained by applying a two-compartment open model. The elimination half-life was very short, 2.43 +/- 0.35 h, despite the reduced plasma clearance of 41.2 +/- 5.7 ml min-1, compared with healthy adults. The apparent volume of distribution, 0.27 +/- 0.07 1 kg-1 body wt, corresponds well to the size of the extracellular space. The kinetic behaviour of intravenously supplied carnitine may assist in future evaluations of the therapeutic application of this drug in uraemic children.

[25 years kidney replacement therapy in childhood and adolescence--success of somatic and psychosocial rehabilitation]. / 25 Jahre Nierenersatztherapie im Kindes- und Jugendlichenalter--Ein Erfolg der somatischen und psychosozialen rehabilitation.

In the late sixties, renal replacement therapy (RRT) was started in terminal renal insufficient children and adolescents. The high mortality rate and extreme therapeutic difficulties gave doubts to the possibility of longterm survival as well as somatic and psychosocial rehabilitation in these patients. But nowadays due to improvements in medical and technical possibilities of dialysis and kidney transplantation as well as to individually adapted treatment of the metabolic problems 5-years survival rate is more than 90%, body growth and development is in the lower normal range. Successful psychosocial rehabilitation despite RRT has also improved over time. In the beginning only 29% dialysed patients and 51% transplanted children attended school and 65% completed school. A recent analysis of educational status employment rate and social situation in 617 patients between 20 and 35 year of age who started RRT as children in Europe and 276 terminal renal insufficient adolescents in Germany, gave following results: one third went to vocational training, 11-17% attended university. Thereafter 40-65% of all patients were employed. Unemployment was a big problem in dialysed adolescents and young adults. With increasing age the patients gained independence in their life style. About 20% lived in their own houses, 28% were either married, divorced or widowed, 8% had children of their own.

[Fetal nephro-/uropathy: a retrospective analysis of 124 cases seen in the period from 1996 to 2002]. / Fetale Nephro-/Uropathien: Retrospektive Analyse von 124 Fällen, erfasst im Zeitraum von 1996 bis 2002.

BACKGROUND: The embryological development of the kidneys and the urinary tract follows a complex choreography. Disorders are quite common. The incidence of disorders amounts to 0.3 - 0.8 % of live-born infants. In addition, several chromosomal anomalies are combined with renal malformations. The poor prognosis of some of these diseases is reflected in a perinatal mortality of 6.3 %. PATIENTS AND METHODS: Retrospectively 124 cases with fetal nephro-/uropathy detected by prenatal ultrasonography between 1996 and 2002 were analyzed. Features of hypo-dysplastic kidneys (uni- or bilateral) were seen in 21 cases. Multicystic kidney disease (uni- or bilateral) existed in 40 fetuses. In some cases of multicystic or dysplastic kidney diseases, extrarenal malformations were combined. 21 fetuses suffered from autosomal recessive polycystic kidney disease. 18 male unborns showed the typical picture of intravesical obstruction due to posterior uretheral valves. The prune belly syndrome was seen 4 times. Hydronephrotic kidneys with more than 5 mm pelvic dilatation were detected in 13 cases. Renal agenesis led to a lethal outcome perinatally in 5 cases. One child died of bilateral thrombosis of renal artery and venous system. RESULTS: The high incidence of diseases with a poor prognosis accounts for the high mortality of 50.8 % (intrauterine or postnatal death, induced abortion). Such a fatal outcome was observed in autosomal recessive polycystic kidney disease, bilateral multicystic dysplastic kidney disease, bilateral renal dysplasia combined with severe extrarenal malformations, intravesical obstruction, renal agenesis and bilateral thrombosis of the renal vessels. Only 60 children survived. Of these 26 needed urological surgery. 15 suffered from progressive renal insufficiency. During a follow-up of 8 - 58 months only 44 exhibited a normal renal function. CONCLUSIONS: Such complex renal and urological diseases in the fetus require an interdisciplinary management of the pregnancy.