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AbstractMaternal obesity is an established risk factor for poor infant neurodevelopmental outcomes; however, the link between maternal weight and fetal development in utero is unknown. We investigated whether maternal obesity negatively influences fetal autonomic nervous system (ANS) development. Fetal heart rate variability (HRV) is an index of the ANS that is associated with neurodevelopmental outcomes in the infant. Maternal–fetal magnetocardiograms were recorded using a fetal biomagnetometer at 36 weeks (n= 46). Fetal HRV was represented by the standard deviation of sinus beat-to-beat intervals (SDNN). Maternal weight was measured at enrollment (12–20 weeks) and 36 weeks. The relationships between fetal HRV and maternal weight at both time points were modeled using adjusted ordinary least squares regression models. Higher maternal weight at enrollment and 36 weeks were associated with lower fetal HRV, an indicator of poorer ANS development. Further study is needed to better understand how maternal obesity influences fetal autonomic development and long-term neurodevelopmental outcomes.

Conocer el estado actual de la actividad médico-quirúrgica y de la formación de los residentes de urología en España.

Aims. We identify and characterize low-mass stars in the ~3 Myr old Trumpler 16 region by means of a deep ChandraX-ray observation, and study their optical and near-IR properties. We compare the X-ray activity of Trumpler 16 stars with the known characteristics of Orion and Cygnus OB2 stars.

Aims. We report here on the first detection at X-ray wavelengths of the Supernova Remnant (SNR) G337.8-0.1, carried out with the XMM-NewtonObservatory.

Aims.Microquasars are ideal natural laboratories for understanding accretion/ejection processes, studying the physics of relativistic jets, and testing gravitational phenomena. Nevertheless, these objects are difficult to find in our Galaxy. The main goal of this work is to increase the number of known systems of this kind, which should allow better testing of high-energy phenomena and more realistic statistical studies of this galactic population to be made.

Aims.We characterize individual and ensemble properties of X-ray flares from stars in the Cygnus OB2 and ONC star-forming regions.

Aims.The aim of this work is to identify the so far unknown low mass stellar population of the ~2 Myr old Cygnus OB2  star forming region, and to investigate the X-ray and near-IR stellar properties of its members.

An analysis of the abundances of the Silicon star HD 206653 is presented using an ATLAS9 model atmosphere and observational material taken with a REOSC echelle spectrograph attached to the Jorge Sahade2.15 m telescope at CASLEO. The light elements are solar or deficient except silicon which is overabundant by a factor of 5. The iron peakelements are all overabundant by factors between 10 and 50. Sr and Y are around 1000 times the solar values. Among the Rare Earths only Ce and Eu are identified; both are overabundant by large factors.

We describe a 63-year-old patient with unrepaired tricuspid valve atresia and a hypoplastic right ventricle (single-ventricle physiology) who presented with progressive symptomatic hypoxia. Her anatomy resulted in parallel pulmonary and systemic circulations, pulmonary arterial hypertension, and uncoupling of the ventricle/pulmonary artery. Hemodynamic and coupling data were obtained before and after pulmonary vasoactive treatment, first inhaled nitric oxide and later inhaled treprostinil. The coupling ratio (ratio of ventricular to vascular elastance) shunt fractions and dead space ventilation were calculated before and after treatment. Treatment resulted in improvement of the coupling ratio between the ventricle and the vasculature with optimization of stroke work, equalization of pulmonary and systolic flows, a decrease in dead space ventilation from 75% to 55%, and a significant increase in 6-minute walk distance and improved hypoxia. Inhaled treprostinil significantly increased 6-minute walk distance and improved hypoxia. This is the first report to show that pulmonary vasoactive treatment can be used in a patient with unrepaired single-ventricle anatomy and describes the hemodynamic effects of inhaled therapy on ventriculovascular coupling and gas exchange in the pulmonary circulation in this unique physiology.

We describe a 63-year-old patient with unrepaired tricuspid valve atresia and a hypoplastic right ventricle (single-ventricle physiology) who presented with progressive symptomatic hypoxia. Her anatomy resulted in parallel pulmonary and systemic circulations, pulmonary arterial hypertension, and uncoupling of the ventricle/pulmonary artery. Hemodynamic and coupling data were obtained before and after pulmonary vasoactive treatment, first inhaled nitric oxide and later inhaled treprostinil. The coupling ratio (ratio of ventricular to vascular elastance) shunt fractions and dead space ventilation were calculated before and after treatment. Treatment resulted in improvement of the coupling ratio between the ventricle and the vasculature with optimization of stroke work, equalization of pulmonary and systolic flows, a decrease in dead space ventilation from 75% to 55%, and a significant increase in 6-minute walk distance and improved hypoxia. Inhaled treprostinil significantly increased 6-minute walk distance and improved hypoxia. This is the first report to show that pulmonary vasoactive treatment can be used in a patient with unrepaired single-ventricle anatomy and describes the hemodynamic effects of inhaled therapy on ventriculovascular coupling and gas exchange in the pulmonary circulation in this unique physiology.

Abstract: The ratios of Rb to Cs contents were studied in five fish species from seven lakes located in the Patagonia Andean Range, Argentina in order to trace fish diet. The species studied were native velvet catfish (Diplomistes viedmensis) and creole perch (Percichthys trucha), and exotic brown trout (Salmo trutta), rainbow trout (Oncorhynchus mykiss), and brook trout (Salvenilus fontinalis). Rainbow trout specimens from two farms were also studied, as well as fish food items and native mussels (Diplodon chilensis). Rb and Cs concentrations were determined by instrumental neutron activation analysis. A positive correlation of Cs concentration in the muscle of velvet catfish with fish length was observed, probably associated with the long biological half-life of this element in this species, whereas the Rb concentration remained constant, hence inhibiting the use of Rb-Cs ratios as a tracer in this case. Seasonal variations observed for rainbow trout and Cs concentration background bias in one of the lakes studied are also a limiting factor to the use of Rb-Cs ratios as a diet tracer. Rb-Cs ratios allowed clear differentiation of rainbow trout raised in farms from the natural specimens that lived in the same environment, in agreement with Rb-Cs ratios determined in both diets. Rb-Cs ratios in rainbow trout showed significant differences between Rivadavia and Futalaufquen lakes compared to Moreno and Nahuel Huapi lakes, which could be associated with a higher participation of plankton in the diet in the first case. No relevant variations in Rb-Cs ratios of brown trout were observed, probably because of the similarity in the diet.

N-Acetylglutamate synthase (NAGS) deficiency is a rare, autosomal recessive urea-cycle disease. Its clinical presentation is not different from the other hereditary hyperammonaemias. We report a new neonatal case with hyperammonaemic coma. A test by carbamylglutamate was performed at 25 days of life. Since then, the child was treated by carbamylglutamate three or four times a day with a total dose of 80–100 mg/kg per day. Today, the boy is 1 year old. He receives carbamylglutamate 200 mg four times a day. He has normal somatic and neurological development and good metabolic balance.

Orotic acid excretion in urine is increased in ornithine transcarbamylase deficiency, citrullinemia and argininemia; it is barely increased in argininosuccinic aciduria and normal in carbamylphosphate synthetase deficiency and in hyperammonemia due to organic aciduria. The determination of orotic acid excretion is useful in differentiating the causes of hyperammonemia and reduces the need for enzymatic assays on tissue biopsies for decisions on therapy. The data indicate that orotic acid does not merely reflect ammonia concentration in plasma, but depends on carbamylphosphate concentration. Arginine could play a key role in the regulation of ammonia detoxication.

We report the 9-year follow-up of a patient suffering from N-acetylglutamate synthetase deficiency, an urea cycle disorder leading to severe neonatal hyperammonaemia. Hitherto two patients from two families with this inborn error of metabolism had been observed. Our management consisted mainly of a protein-restricted diet and oral treatment with N-carbamylglutamate, an activator of carbamylphosphate synthetase, together with arginine or citrulline. The somatic development was normal whereas a moderate psychomotor retardation was diagnosed. The patient died after an episode of coma and prolonged generalized convulsions at the age of 9.5 years.

Pitfalls in organic acid analysis can originate from inadequate methodology, analytical interferences, in vivo interactions and from pre-analytical conditions which often are unknown to the specialized analytical laboratory. Among the latter, ingested food and additives, metabolites of food processing or medications have to be considered. Bacterial metabolites from the gastrointestinal or urogenital system or formed after sample collection can lead to pitfalls as well. An example of such a patient whose urinary metabolites mimick at first glance inherited propionic aciduria is described.

The aim of this collaborative study was to investigate whether guanidino compound analyses in the biologic fluids can be used as a complementary diagnostic parameter for hyperargininemia. Guanidino compounds were determined in the biologic fluids of all known living hyperargininemic patients using a cation exchange Chromatographie system with a fluorescence detection method. The serum arginine, homoarginine, α-keto-δ-guanidino-valeric acid, argininic acid, and N-α-acetylarginine levels of all the hyperargininemic patients are higher than the normal range. Similar increases were seen for the urinary excretion of α-keto-δ-guanidinovaleric acid and argininic acid. Untreated hyperargininemic patients have the highest guanidino compound levels in cerebrospinal fluid. However, even under therapy, the arginine, homoarginine, α-keto-δ-guanidinovaleric acid, and argininic acid levels in cerebrospinal fluid are still increased. Protein restriction alone is not sufficient to normalize the hyperargininemia, but protein restriction together with supplementation of essential amino acids with or without sodium benzoate decreases further the arginine levels. However, whereas the argininemia can be normalized, the catabolites of arginine are still increased. We conclude that the urinary amino acid levels may remain normal in hyperargininemia, whereas consistent increases of the guanidino compounds are observed. Thus, guanidino compound analyses can be used as a complementary biochemical diagnostic parameter for hyperargininemia. Although the argininemia can be normalized by therapy, the levels of the catabolites of arginine are still elevated.

A patient with Rett syndrome (cerebral atrophy associated with hyperammonemia) was studied. Primary defects of urea cycle enzymes were excluded as causes of the disorder. The analysis of urinary organic acids showed a moderate increase of lactate, methylcitrate, tiglylglycine and 3-hydroxisovalerate, indicating an abnormality of multiple carboxylases. Biotin supplementation reversed the urinary abnormalities. In fibroblasts grown with a low biotin medium propionylCoA and 3-methylcrotonylCoA carboxylase activities were reduced. Holocarboxylase synthetase activity was normal (Vmax and Km). Surprisingly the biotinidase in fibroblasts was not decreased. The data indicate that some patients with Rett syndrome might suffer from a biotin-dependent defect of unknown nature.

Immunocytochemistry to serotonin, dopamine beta hydroxylase (DBH), and tyrosine hydroxylase (TH) was studied in the brains of 2 cebus monkeys that had developed permanent hemiparkinsonism after intracarotid injection of 1.2 mg N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and were sacrificed after 10–12 months. A pronounced depletion of TH-immunoreactive neurons was found in the substantia nigra, caudate nucleus, and putamen, ipsilaterally to the injected side. In these dopamine-denervated structures, the number of serotonergic fibers was increased in the ipsilateral compared with the contralateral side, or with an untreated control monkey. Serotonergic neurons in the brainstem appeared to be unaffected. Topography and number of DBH-positive fibers in the control and the MPTP-injected sides were comparable.

Eight adult, untreated patients with classical phenylketonuria received L-dopa and a decarboxylase inhibitor for 2 weeks. No effect of l-dopa therapy on choice reaction time tasks, sustained attention, frontal lobal function as well as latencies of visual evoked potentials was found. The results raise the question if adult patients with phenylketonuria really suffer from functional dopamine deficiency.

1H nuclear magnetic resonance (NMR) was used to detect directly the signal from the aromatic protons of phenylaline (phe) in the brains of rabbits made hyperphenylalaninemic by administration of a diet high in phe and containing 0.4 a-methylphenylalanine. In addition to those resonances found in the region between 6.5 and 8.5 ppm in the 1H NMR spectra of control rabbits, a resonance centered at 7.37 ppm was observed in the spectra obtained from the brains of hyperphenylalaninemic rabbits in vivo or in situ postmortem. The chemical shift of this additional resonance was that expected for protons of the phenyl ring of phe. Its intensity correlated well with measurements of brain phe levels made on postmortem samples by amino acid analyzer. Both of these measurements correlated poorly with amino acid analyzer measurements of serum phe, especially at high values of the latter. High-resolution1H NMR spectra of the brain extracts showed that in most animals an unidentified aromatic compound, possibly yglutamyl- phe, was present in addition to phe. This study demonstrates the feasibility of measuring the concentration of brain phenyl and its metabolites noninvasively by 'H NMR. The method can be used for similar measurements in human brain. (Pediatr Res 27 566-570,1990)

Sparse-fur mice, 28 d of age with the x-chromosomal inherited defect of ornithine carbamoyltransferase, were used to investigate if tryptophan and the serotonin pathway in the brain are affected in this animal model which closely resembles the human inborn error of metabolism. Increased concentrations of tryptophan and 5-hydroxyindole acetic acid were found in forebrain and brainstem. Application of probenecid, which blocks the efflux of 5- hydroxyindole acetic acid from the brain, led to an augmented accumulation of this serotonin metabolite in the affected males. We conclude that the increased concentration of tryptophan in brain and the subsequent increased flux through the serotonin pathway are a consequence of hyperammonemia in this inherited defect of urea synthesis. Surprisingly, increased carbamoylphosphate synthetase was found in the liver of the male sparse-fur mice.

Two siblings are reported who were syptomatic in the neonatal period. The first died suddenly at 4 days of age after regurgitating a meal. The postmortem examination showed steatosis of the liver, kidney and muscle. In the second, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency was diagnosed at 3 days of age with muscular hypotonia, vomiting, hyperammonaemia and mild acidosis. Thus disorders of fatty acid oxidation should also be considered in newborns. The biochemical work up indicates that in neonates, analysis of serum medium-chain fatty acids and of acyl and free carnitine are more likely to lead to a diagnosis than determining dicarboxylic acids alone in urine. Long-term treatment was effective and monitored by the acyl/free carnitine ratio.

We have examined collagen from a patient with the rare type IIC form of perinatally lethal osteogenesis imperfecta, in whom biochemical characteristics of hypophosphatasia were also apparent. In addition to normal a1(I) and a2(I) chains, there were chains overmodified along their lengths. Unexpectedly, the thermal stability of molecules containing these chains was normal. This suggests the existence of a structural mutation causing delayed triple helix formation, situated in either the a1(I) or a2(I) C-terminal propeptide. Since collagen synthesised by fibroblasts from each of the patient's parents was normal, the mutation was probably newly arising and dominant. In contrast to other reported cases of lethal osteogenesis imperfecta, not only was the secretion of collagen by cultured fibroblasts considerably retarded, but that of non-collagenous proteins was also severely impaired.

Acetyl-CoA:L-glutamate N-acetyltransferase (amino acid acetyltransferase, EC 2.3.1.1) was isolated from human liver mitochondria by precipitation with (NH4)2SO4 and chromatography on hydroxyapatite, DEAE-cellulose and Sephacryl 300. This gave a 360-fold purification. The molecular weight was estimated to be approx. 190 000. The kinetic properties in the absence of arginine are compatible with a rapid-equilibrium random Bi Bi mechanism. The estimated constants are: for the substrates Km, acetyl-CoA 4.4 mM, Ki, acetyl-CoA 4.7 mM, Km, glutamate 8.1 mM, Ki, glutamate 8.8 mM; for the products, Ki, acetylglutamate 0.28 mM, Ki, CoA 5.6 mM. The rate constant for the forward direction is 1.24s-1. If in vivo the constants are of the same order of magnitude as in vitro, the synthesis of N-acetylglutamate, an obligate activator of the first step of urea synthesis, can be expected to occur in the mitochondrion under conditions where the amino acid acetyltransferase is not saturated by its substrates. The regulation of the first step of urea synthesis could thus depend mainly on the intramitochondrial substrate and perhaps product concentrations of amino acid acetyltransferase.

ABSTRACT: 1H nuclear magnetic resonance (NMR) was used to detect directly the signal from the aromatic protons of phenylaline (phe) in the brains of rabbits made hyperphenylalaninemic by administration of a diet high in phe and containing 0.4% a-methylphenylalanine. In addition to those resonances found in the region between 6.5 and 8.5 ppm in the 1H NMR spectra of control rabbits, a resonance centered at 7.37 ppm was observed in the spectra obtained from the brains of hyperphenylalaninemic rabbits in vivo or in situ postmortem. The chemical shift of this additional resonance was that expected for protons of the phenyl ring of phe. Its intensity correlated well with measurements of brain phe levels made on postmortem samples by amino acid analyzer. Both of these measurements correlated poorly with amino acid analyzer measurements of serum phe, especially at high values of the latter. High-resolution1H NMR spectra of the brain extracts showed that in most animals an unidentified aromatic compound, possibly ? glutamyl- phe, was present in addition to phe. This study demonstrates the feasibility of measuring the concentration of brain phenyl and its metabolites noninvasively by 'H NMR. The method can be used for similar measurements in human brain.

ABSTRACT: The aim of this collaborative study was to investigate whether guanidino compound analyses in the biologic fluids can be used as a complementary diagnostic parameter for hyperargininemia. Guanidino compounds were determined in the biologic fluids of all known living hyperargininemic patients using a cation exchange Chromatographie system with a fluorescence detection method. The serum arginine, homoarginine, a-keto-d-guanidino-valeric acid, argininic acid, and N-a-acetylarginine levels of all the hyperargininemic patients are higher than the normal range. Similar increases were seen for the urinary excretion of a-keto-d-guanidinovaleric acid and argininic acid. Untreated hyperargininemic patients have the highest guanidino compound levels in cerebrospinal fluid. However, even under therapy, the arginine, homoarginine, a-keto-d-guanidinovaleric acid, and argininic acid levels in cerebrospinal fluid are still increased. Protein restriction alone is not sufficient to normalize the hyperargininemia, but protein restriction together with supplementation of essential amino acids with or without sodium benzoate decreases further the arginine levels. However, whereas the argininemia can be normalized, the catabolites of arginine are still increased. We conclude that the urinary amino acid levels may remain normal in hyperargininemia, whereas consistent increases of the guanidino compounds are observed. Thus, guanidino compound analyses can be used as a complementary biochemical diagnostic parameter for hyperargininemia. Although the argininemia can be normalized by therapy, the levels of the catabolites of arginine are still elevated.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of fatty acid metabolism and typically presents in early childhood as potentially fatal hypoketotic, hypoglycaemic crisis often associated with Reye-like symptoms. Re-investigations of cases of sudden infant death syndrome (SIDS) have revealed in some instances a deficiency of MCAD, suggesting that this metabolic disorder may lead to sudden infant death without prior clinical symptoms. In the present study, we examined 142 infants who had suffered from an apparent life-threatening event (ALTE) or were otherwise considered at risk for SIDS for MCAD deficiency by phenylpropionate loading. In no case excretion of phenylpropionylglycine, the hallmark of MCAD deficiency, was increased. In contrast, 3 out of 55 children with symptoms of metabolic disorders showed increased phenylpropionylglycine excretion, and in all three cases MCAD deficiency was confirmed by DNA analysis. In addition, we investigated 142 cases of sudden unexplained child death and 100 control subjects for the A985G mutation in the MCAD gene which is associated with about 98% of enzyme deficiencies. We found one case of heterozygosity each in the patient and control group. Our data indicate that MCAD deficiency is not a major cause of ALTE and, in agreement with results from similar studies in other countries, its frequency is not increased in children who died of SIDS.

Abstract: In view of the importance of liver tests in the follow-up of patients under treatment with corticosteroid hormones, 20 mg of prednisolone were given by mouth to normal volunteers for 4 days and hepatic function was assessed before and during treatment. Despite significant falls in plasma cortisol and serum bilirubin concentrations, the galactose elimination capacity, the BSP tests, and the urinaryd-glucaric acid output remained essentially unchanged. Consequently no pharmacological effect of this corticosteroid hormone on the examined tests could be detected.

The efficacy and side effects of the new vasodilator carprazidil and the established vasodilator minoxidil were compared in 18 hypertensive patients inadequately controlled by 2 to 4 conventional drugs; the latter included diuretics, beta-blockers and/or sympatholytics and, in half the cases, vasodilators, such as hydralazine, diazoxide or the postsynaptic alpha-blocker prazosin. The vasodilators were withdrawn and, using a crossover design all patients received carprazidil (mean final dose 88 mg) and minoxidil (20 mg) for an average period of 5 to 6 months. The effects of the 2 agents appeared to be qualitatively and quantitatively similar. Both tended to cause sodium retention and an increase in heart rate, which required an increased dose of diuretic in one third of the cases or of a beta-blocker in a quarter. With this approach mean body weight and blood volume were not altered in the established phase of carprazidil or minoxidil treatment; heart rate and plasma norepinephrine tended to be only minimally increased, plasma renin was slightly increased, and plasma aldosterone and epinephrine were largely unchanged. Supine and upright blood pressure were reduced from initial values of 189/113 and 167/113 mm Hg, to 149/95 and 138/95 mm Hg (-18 and -17%), respectively, during carprazidil, and to 154/95 and 141/96 mm Hg (-17 and -15%) during minoxidil therapy. Hypertrichosis occurred with both agents in almost all patients, and limits their more prolonged use in females. No adverse side effects on haematological parameters, liver or renal function were observed, nor was antinuclear antibody detected. It is concluded that carprazidil and minoxidil are equivalent vasodilator agents in the treatment of severe hypertension, particularly in males.

N-Acetylglutamate synthase (NAGS) deficiency is a rare, autosomal recessive urea-cycle disease. Its clinical presentation is not different from the other hereditary hyperammonaemias. We report a new neonatal case with hyperammonaemic coma. A test by carbamylglutamate was performed at 25 days of life. Since then, the child was treated by carbamylglutamate three or four times a day with a total dose of 80–100 mg/kg per day. Today, the boy is 1 year old. He receives carbamylglutamate 200 mg four times a day. He has normal somatic and neurological development and good metabolic balance.