Transition to glycerol phenylbutyrate for the management of urea cycle disorders: clinical experiences.

BACKGROUND: Urea cycle disorders (UCDs) are a group of rare inborn diseases caused by a deficiency in one of the six enzymes or one of the two transporters involved in the urea cycle. The most common biochemical feature is elevated blood ammonia levels, which can be toxic at high levels, especially to the brain and may manifest as encephalopathy if left untreated. Glycerol phenylbutyrate (GPB) is currently approved for use in the USA and Europe for patients of all ages with UCD who cannot be managed with protein restriction and/or amino acid supplementation alone. This article presents the author's experience in different exemplary settings and depicts the most efficient management of UCDs with GPB. CASE PRESENTATION: Six patient histories are described. 4 had OCT, one citrullinemia, and one argininosuccinic aciduria. Treatment with GPB was started between 2 days and 14 years of age. Before GPB, one patient had not been treated, 4 had received sodium phenylbutyrate (NaPB), and one Na benzoate. CONCLUSIONS: Overall, treatment with GPB was followed by a relevant metabolic improvement, resulting in better therapeutic compliance, reduced hospitalization, and improved quality of life.

Effects of six months of vitamin D supplementation in patients with heart failure: a randomized double-blind controlled trial.

BACKGROUND AND AIM: Low plasma vitamin D levels have been associated with heart failure (HF). This research attempts to explain the role of vitamin D supplementation on myocardial function in elderly patients with HF. METHODS AND RESULTS: Twenty-three chronic HF patients were randomized in a small parallel group, double-blind, placebo-controlled trial. All patients, with a mean age of 74 years and vitamin D levels <30 ng/mL, received 800,000 IU (4000 IU/daily) of cholecalciferol or placebo for 6 months. The outcomes measured at baseline and after 6 months were ejection fraction (EF) and other echocardiography parameters, carboxyterminal propeptide of procollagen type I (PIP), natriuretic peptides, lipid profile, renin, parathyroid hormone, blood pressure, and body mass index (BMI). In 13 patients under active treatment for 6 months, mean plasma 25-hydroxy vitamin D concentrations (15.51 vs. -1.40 ng/mL, p < 0.001) and plasma calcium (from 9.3 to 9.6 mmol/L, p < 0.05) increased significantly. However, other biomarkers of bone metabolism did not differ between the treatment and placebo groups. EF increased significantly in the intervention group (6.71 vs. -4.3%; p < 0.001), and the serum concentration of PIP increased only in the placebo group after 6 months (1140.98 vs. -145 mcg/L; p < 0.05). Systolic blood pressure was lower after 6 months of cholecalciferol treatment (from 129.6 to 122.7 mm Hg, p < 0.05). No significant variations were observed for other parameters. CONCLUSIONS: Six months of vitamin D supplementation significantly improves EF in elderly patients with HF and vitamin D deficiency.

Newborn screening of inherited metabolic disorders by tandem mass spectrometry: past, present and future.

Inborn errors of metabolism are inherited biochemical disorders caused by lack of a functional enzyme, transmembrane transporter, or similar protein, which then results in blockage of the corresponding metabolic pathway. Taken individually, inborn errors of metabolism are rare. However, as a group these diseases are relatively frequent and they may account for most of neonatal mortality and need of health resources. The detection of genetic metabolic disorders should occur in a pre-symptomatic phase. Recently, the introduction of the tandem mass spectrometric methods for metabolite analysis has changed our ability to detect intermediates of metabolism in smaller samples and provides the means to detect a large number of metabolic disorders in a single analytical run. Screening panels now include a large number of disorders that may not meet all the criteria that have been used as a reference for years. The rationale behind inclusion or exclusion of a respective disorder is difficult to understand in most cases and it may impose an ethical dilemma. The current organization is an important tool of secondary preventive medicine, essential for children's healthcare, but the strong inhomogeneity of the regional models of screening applied today create in the Italian neonatal population macroscopic differences with regards to healthcare, which is in effect mainly diversified by the newborn's place of birth, in possible violation of the universal criterion of the equality of all citizens. Carefully weighed arguments are urgently needed since patient organizations, opinion leaders and politicians are pressing to proceed with expansion of neonatal population screening.

The oligomeric integrity of toposome is essential for its morphogenetic function.

Sea urchin embryos are uniquely suitable for the study of morphogenetic cell interactions. Efforts to identify the molecules responsible for morphogenetic cell adhesion led to the isolation of a 22S glycoprotein complex from Paracentrotus lividus sea urchin embryo, that has been called toposome. The biological activity of toposome in mediating cellular adhesion has been fully documented. Its function in determining positional guidance during the development of the sea urchin embryo has been proposed. Here studies on the molecular structure of toposome are reported showing that, under non-reducing conditions, it is resolved in sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) in a major band with an apparent molecular weight of 260 kDa, a doublet of 180-160 kDa and a lower band of 80 kDa. Digestion with EndoH endoglycosidase reduced the molecular sizes of the bands of 10%, 20% and 40%, respectively. In order to establish if the oligomeric integrity of toposome was essential for its function, the biological activity of each subunit on cells dissociated from sea urchin blastula embryos was tested. The resulting swimming embryoids were lacking skeleton, while reaggregating cells supplemented with native toposome developed into pluteus-like structures with skeletal elements.