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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. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Organic acidurias (OAs) are a group of rare metabolic disorders that disrupt the regular amino acid metabolism. OAs are characterized by recurrent episodes of acidemia, ketonuria and hyperammonemia which can result in brain/liver damage and renal failure, and despite the life-long protein-restricted diet, impaired growth and long-term complications can occur. Consequently, a longterm management of OAs patients is required, aimed principally at reducing the frequency and duration of metabolic decompensation/hyperammonemia episodes. Nevertheless, unlike the acute phase, evidence on the chronic management of OAs patients is less consolidated. SUBJECTS AND METHODS: To expand the knowledge on this field, 13 Italian referral centers for the management of OAs were involved in a survey focused on the long-term use of carglumic acid (Carbaglu®, Recordati Rare Diseases). RESULTS: Participating centers reported a reduction between 69% and 81% in the annual number of metabolic decompensations with the chronic use of carglumic acid and an improvement in protein intake. Most centers reported no difficulty using carglumic acid as a long-term therapy, along with a great compliance. CONCLUSIONS: Taken together, obtained data align with the available literature and support a positive clinical experience with the long-term carglumic acid administration. Additional studies aimed at better defining a proper dosage for the chronic administration of carglumic acid and the clinical and biochemical characteristics of patients treated chronically are needed. In addition, the potential impact of this treatment regimen on the neurological development and growth of patients should be elucidated. [ABSTRACT FROM AUTHOR]

The waste-to-energy (WTE) incinerator plant located in the Turin area (Italy) started to recover energy from the combustion of municipal solid waste in 2013. A health surveillance program was implemented to evaluate the potential health effects on the population living near the plant. This program included a longitudinal biomonitoring to evaluate temporal changes of some environmental pollutants, including polycyclic aromatic hydrocarbons (PAHs), in residents living in areas near the Turin incinerator (exposed group, E) compared to those observed in subjects living far from the plant (not exposed group, NE). Ten monohydroxy-PAHs (OH-PAHs), consisting in the principal metabolites of naphthalene, fluorine, phenanthrene, and pyrene, were analyzed in urines collected from the E and NE subjects after one (T 1) and three years (T 2) of plant activity and compared with those determined in the same cohort established before the plant start-up (T 0). Spearman correlation analysis was undertaken to explore possible associations between OH-PAHs and personal characteristics, lifestyle variables, and dietary habits. A linear mixed model (LMM) approach was applied to determine temporal trends of OH-PAHs observed in the E and NE subjects and to evaluate possible differences in trend between the two groups. Temporal trends of OH-PAHs determined by LMM analysis demonstrated that, at all times, the E group had concentrations lower than those assessed in the NE group, all other conditions being equal. Moreover, no increase in OH-PAH concentrations was observed at T 1 and T 2 either in E or in NE group. Significant positive correlations were found between all OH-PAHs and smoking habits. Regarding variables associated to outdoor PAH exposure, residence near high traffic roads and daily time in traffic road was positively correlated with 1-hydroxynaphthalene and 1-hydroxypyrene, respectively. In conclusion, no impact of the WTE plant on exposure to PAHs was observed on the population living near the plant. [Display omitted] • Human exposure to waste incinerator emissions is of great concern. • No impact of the WTE plant was observed on human exposure to PAHs. • OH-PAH levels did not increase after one and three years of incinerator activity. • Temporal trends of OH-PAH levels did not differ among exposed and not-exposed group. [ABSTRACT FROM AUTHOR]

Introduction The pathology of abdominal aortic aneurysm (AAA) is a life-threatening disease, with no treatment able to stop or slow the growth and rupture of AAAs; the only medical option is surgery. A better understanding of the mechanisms triggering this pathology is therefore needed to design new treatments. Immune effectors play a role in the pathology. In particular, it has been shown that IgE antibodies, mast cells (MCs) and germinal center (GC) B cells, which are known to form an axis of the immune system, accumulate in the adventitia of AAA. Objective Our goal is to test if the MC-B cell-IgE axis triggers a local amplification loop that precipitates the rupture of AAAs. Method To assess the effect of MCs on AAA healing in vivo, we created a mouse model that develop aneurysm and can be depleted in MCs. In parallel, we characterized the MC–B cell–IgE axis in blood and arterial samples collected from AAA and control patients. We tested, in vitro, the ability of adventitial soluble molecules, especially IgEs, to activate human MCs. Results We observed that mice which are depleted in MCs during the healing phase of AAA develop smaller aneurysms with elevated collagen density. In human AAA adventitia, MCs are activated, covered by IgEs, and located in the vicinity of GCs, which suggest that they can interact with GC B cells in AAAS. The GC B cells from the adventitia are absent from paired patient blood and some adventitial GC stained positive for IgE. Therefore, adventitial GC probably arise from a local differentiation of B cells and support a local production of IgE. AAA adventitial soluble factors trigger the degranulation of MC and their IgE-dependent production of IL-4, a cytokine required for B cells to produce IgEs (Fig. 1). Conclusion Our data suggest that locally produced IgE directed against lesion-specific antigens activate MCs, which prevent AAA healing and promote the production of more IgEs, leading to an amplification loop of the pathology. [ABSTRACT FROM AUTHOR]

Vaccination with phosphorylcholine (PC) reduces experimental atherosclerosis by raising the titer of PC-specific IgM in Apolipoprotein E knockout (ApoEKO) mice. The epitope of the antibodies elicited by the PC-Vaccine coincides with that of 'natural' anti-pneumococcal antibodies and strikingly similar results can be obtained by vaccination with Prevenar®. The aim of the present study was therefore to assess whether the atheroprotective effects carried by PC-Vaccine and Prevenar@ are linked to the activation of the germline encoded B cell pool, which is responsible for the production of natural antibodies. AID Cre mice were crossed with ApoEKO mice and double transgenic mice were immunized with PC-Vaccine or with Prevenar® as previously reported (DOI:10.1016/j.atherosclerosis.2018.06.903). Three months later, atherosclerotic lesions and natural anti-PC IgM antibodies values were compared to the AID+ (affinity maturated) IgM+ (B1-like) cell pool in the peritoneal cavity and draining lymph nodes. Discriminant analysis showed that the rise of natural anti-PC IgM antibodies (AB1-2 IgM), the proportion of affinity matured (AID +) B1-like cells (CD19+ CD5+ CD43+ CD1d+ IgM +) having migrated from the draining lymph node to the peritoneal cavity and the lesion size (AUC) were interdependent from each other and that atheroprotection in both PC-Vaccine and Prevenar® mouse groups was proportional to the fraction of affinity matured B1-like cells in the peritoneal cavity and the rise of natural anti-PC IgM antibody production (individual data and bivariate plots are displayed in Fig. 1). Phosphorylcholine-targeting vaccination boosts affinity maturation of B lymphocytes involved in the production of natural antibodies and prevents experimental atherosclerosis progression. [ABSTRACT FROM AUTHOR]