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Cystinosis is an inherited metabolic disorder caused by recessive mutations in the CTNS gene. The disease primarily affects the kidneys followed by extra-renal organ involvement later in life. Azoospermia is one of the unclarified complications which is not improved by cysteamine treatment, the only available disease-modifying treatment. We aimed at unravelling the origin of azoospermia in cysteamine-treated cystinosis by confirming or excluding an obstructive factor, and investigating the effect of cysteamine on fertility in the Ctns-/- mice model compared to wild-type. Azoospermia was present in the vast majority of infantile type cystinosis patients. While spermatogenesis was intact either at testicular or epididymal level in cystinosis patients, an enlarged caput epididymis and reduced levels of seminal markers for obstruction Neutral α-Glucosidase (NAG) and extracellular matrix protein 1 (ECM1) pointed towards an epididymal obstruction. Transcriptomic analysis of CTNS KD in a fertile human caput epididymal cell line demonstrated upregulation of pathways related to inflammation and cell polarization. Interestingly, histopathological examination in human and mice revealed a disturbed blood-testis barrier (BTB) characterized by an altered zonula occludens-1 (ZO-1) protein expression. Animal studies ruled out a negative effect of cysteamine on fertility, and showed that cystine in the testes is irresponsive to regular cysteamine treatment. We conclude that the azoospermia in infantile cystinosis is due to an obstruction related to epididymal dysfunction, irrespective of the severity of an evolving primary hypogonadism as an additional non-obstructive process. Regular cysteamine treatment does not affect fertility but has subtherapeutic effects on cystine accumulation in testes. This article is protected by copyright. All rights reserved.

The common practice of therapeutic drug monitoring (TDM) involves the quantification of drug plasma concentrations at a specific time in a dosing window. Although TDM for antibiotics is not considered mandatory, it may represent a valid tool for clinicians in order to limit antibiotic resistance and avoid therapeutic failures. The aim of our study was to develop and validate a high-performance liquid chromatography-diode array detection method for simultaneous quantification of 10 antibiotics in plasma. This method has a fast analytical procedure that uses the same chromatographic conditions to quantify ceftazidime, ceftriaxone, meropenem, ertapenem, ciprofloxacin, tigecycline, ampicillin, levofloxacin and piperacillin, plus the β-lactamase inhibitor tazobactam. Method validation was ensured by testing selectivity, accuracy, precision, limits of detection and quantification, recovery and stability. The calibration ranges, established accordingly to the expected plasma concentration in patients, showed a coefficient of determination >0.996 for all compounds. Within- and between-days precisions reported a coefficient of variation >15%. Similarly, the accuracy evaluation reported a relative standard deviation of

Sildenafil is a selective inhibitor of cGMP-specific type 5 phosphodiesterase used for the treatment of pulmonary arterial hypertension (PAH) in the adults. In pediatrics, PAH treatment options include the off-label use of sildenafil. Sildenafil is metabolized in the liver by cytocrome P450 into its active metabolite, N-desmethyl sildenafil. The determination of plasma levels of sildenafil and N-desmethyl sildenafil could be useful for therapy optimization and pharmacokinetic studies. We have developed and validated a method for the quantification of sildenafil and its metabolite in plasma of children by rapid extraction, using high-performance liquid chromatography with ultraviolet detection. The calibration range was fitted at least square model (r2 ≥ 0.999), with an accuracy and an intra- and inter-day relative standard deviation

Culicoides imicola is the main biological vector in the transmission of the Bluetongue virus in the Mediterranean basin. Its geographical range is constrained by environmental characteristics, and soil moisture has been proposed as an important constraint because of its effect on C. imicola breeding habitat. The few field studies on breeding habitat of C. imicola indicate the favourability of (semi-)moist habitat that is not flooded. Data on C. imicola in Calabria revealed the presence of C. imicola at the eastern Ionian coastal area and the absence at the greater part of the western Tyrrhenian coastal area. A spatially distributed soil moisture model was applied to obtain daily soil moisture estimates for Calabria and to assess the relationship between soil moisture and the particular C. imicola distribution at the study region. The temporal soil moisture pattern was not significantly different between locations of contrasting C. imicola occurrence. The monthly average volumetric soil moisture content, however, was found to differ substantially. Soil moisture conditions of the topsoil at locations of C. imicola presence were consistently wetter. Particularly in August, at the onset of the season of high C. imicola abundance, soil moisture was significantly higher at the presence sites and sustained the larval stages of the C. imicola life cycle. This study provides evidence that soil moisture imposes an important constraint on the geographical distribution of C. imicola. Soil moisture may therefore be considered as a key environmental variable for the delineation of suitable C. imicola habitat. Copyright © 2013 John Wiley & Sons, Ltd.

Aim: To investigate adherence to dietary treatment and quality of life (QoL) in patients with phenylketonuria (PKU). Methods: In the setting of a tertiary paediatric hospital, 41 early-treated patients affected by PKU aged more than 3 years old were enrolled in a cross-sectional study. Three-days dietary assessment, QoL questionnaires for patients

SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

Biting midges of the genus Culicoides include vector species for orbiviral diseases, such as bluetongue and African horse sickness. Although the Afro-Asiatic species C. imicola is the major vector of bluetongue in the Mediterranean basin, recent outbreaks in regions where C. imicola is absent has incriminated other Culicoides, including those belonging to the Obsoletus Complex of the subgenus Avaritia Fox, 1955. The classical taxonomy of this species complex is unclear and this stimulated the molecular analysis of twenty Culicoides populations sampled from eighteen localities across Italy. Ribosomal internal transcribed spacer 2 sequences were used to characterize the intra- and interspecific variation between Italian members of the Obsoletus Complex and related species, by means of an analysis of molecular variance and phylogenetic analyses. Although morphological differentiation is often extremely difficult, the molecular analysis clearly demonstrated a high degree of divergence between most species. The study showed that at least seven species of the subgenus Avaritia occur in Italy; these are C. obsoletus, C. scoticus, C. montanus, C. dewulfi, C. imicola and two species that could not be identified with certainty, but one of which is similar to C. chiopterus. Finally, a simple polymerase chain reaction assay was developed that rapidly discriminates between four members of the Obsoletus Complex in Italy, a prerequisite for vector identification.

Following the first incursion of bluetongue virus (BTV) into Italy, the geographical and seasonal distribution of the biting midge Culicoides imicola Kieffer (Diptera: Ceratopogonidae), the main vector of BTV and African horse sickness virus, was investigated in two regions of central Italy (Lazio and Tuscany). Surveillance of Culicoides was carried out between July 2001 and December 2002 using light traps: 1917 collections were made in 381 trap sites, well distributed across both regions. During the survey, bluetongue outbreaks were recorded in both regions. Culicoides imicola was found in 89 (23%) trap sites, distributed fairly continuously along the whole western coastline, between 41.2697 degrees N and 44.05724 degrees N. It was found only occasionally inland and usually in low abundance, with catches of more than 1000 specimens per night found in only two sample sites and 74% of catches numbering fewer than 10 specimens. Adults were caught from March to mid December, with peaks ranging from the end of August to mid November. The coastal distribution and the presence of only few sites with year-round records of adult vectors suggests that colonization may have occurred recently, by passive wind-dispersal from external source areas (Sardinia and Corsica). Alternatively, the species may occur in established, previously undetected, autochthonous populations that are limited from extension inland and northern-ward within Lazio and Tuscany by cool winter temperatures.

A model was developed to classify the Italian territories in relation to their suitability to harbour populations of Culicoides imicola and, as a consequence, also able to sustain a bluetongue (BT) epidemic. Italy was subdivided into 3507 10 x 10 km cells. In 546 cells at least one collection was made. The cell was considered the unit for all subsequent analyses. Culicoides were collected using Onderstepoort-type blacklight traps. Some traps were operated weekly at chosen sites; the remainder were moved almost daily to new sites. Only the results obtained during the peak August-November period were used, to exclude bias caused by the seasonality of C. imicola. Climate data for the period 1999-2001 were obtained from 80 weather stations. Multiple logistic regression was performed using the presence or absence of C. imicola in a specific cell as the dependent variable. Annual means of daily values for minimum temperature and minimum relative humidity, and the mean altitude above sea level, were the independent variables. The probability of occurrence of C. imicola in each grid cell was used to create a prediction map for Italy. The model was able to correctly classify 77.5% of the 546 grid cells in which at least one collection had been made. Culicoides imicola was found frequently through much of Sardinia, in parts of southern Italy, and further north along the Tyrrhenian coast, but was absent from along most of the Adriatic coast, and the internal mainland, and from most of Sicily. Six detailed maps are provided. Also mapped are areas where the probability of the occurrence of C. imicola is lower than 5%. This identification of possible mountainous C. imicola-free areas in central Italy could facilitate safer animal trade and transhumance, even if BT infections in traded animals or moving stock, were to go undetected. Needless to say this depends upon no cool-adapted species of Culicoides being involved in the transmission of BT disease.

Summary In August 2000 bluetongue (BT) disease appeared amongst sheep on the island of Sardinia spreading later to Sicily and to mainland Italy. The majority of areas affected by BT were surveyed for Culicoides imicola, the only proven vector of the disease known to occur in the Mediterranean region. The data from 1456 light-trap collections, made in months with a mean temperature of 12.5°C, were used to test the accuracy of current models predicting the prevalence and abundance of C. imicola across the region. For Italy, the distribution of C. imicola was found to be very irregular and did not fit the modelled predictions. The possible reasons for this are discussed, and suggestions made as to which variables may improve this fit in the development of future risk models. In Italy, past surveys failed to reveal the presence of C. imicola, and so could be construed as evidence of its recent invasion, and thus rampant spread northwards. Although equivocal, historical records indicate that C. imicola was overlooked in the past. Six recommendations are made as to the possible future course of Culicoides research in southern Europe.

In addition to systemic manifestations with skeletal, pulmonary, renal, and haematological signs, lysinuric protein intolerance (LPI), a membrane transport defect of cationic amino acids, is often complicated by severe life-threatening immunological manifestations. A 10-year-old boy with LPI who exhibited a severe systemic immunohaematological disease is described here. This patient showed cutaneous lesions similar to the subacute form of systemic lupus erythematosus, severe anaemia and dysproteinaemia, and a marked reduction of circulating T lymphocytes, mainly the CD4+ cells. In vitro bone marrow cell culture studies showed that addition of patient's serum induced macrophage proliferation and inhibited erythroid progenitor cell growth. Treatment with high-dose intravenous immune globulin resolved most of the clinical and laboratory abnormalities.