Fast Detection of a BRCA2 Large Genomic Duplication by Next Generation Sequencing as a Single Procedure: A Case Report.

The aim of this study was to verify the reliability of a next generation sequencing (NGS)-based method as a strategy to detect all possible BRCA mutations, including large genomic rearrangements. Genomic DNA was obtained from a peripheral blood sample provided by a patient from Southern Italy with early onset breast cancer and a family history of diverse cancers. BRCA molecular analysis was performed by NGS, and sequence data were analyzed using two software packages. Comparative genomic hybridization (CGH) array was used as confirmatory method. A novel large duplication, involving exons 4–26, of BRCA2 was directly detected in the patient by NGS workflow including quantitative analysis of copy number variants. The duplication observed was also found by CGH array, thus confirming its extent. Large genomic rearrangements can affect the BRCA1/2 genes, and thus contribute to germline predisposition to familial breast and ovarian cancers. The frequency of these mutations could be underestimated because of technical limitations of several routinely used molecular analysis, while their evaluation should be included also in these molecular testing. The NGS-based strategy described herein is an effective procedure to screen for all kinds of BRCA mutations

Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences

The introduction of atypical antipsychotics (AAPs) since the discovery of its prototypical drug clozapine has been a revolutionary pharmacological step for treating psychotic patients as these allow a significant recovery not only in terms of hospitalization and reduction in symptoms severity, but also in terms of safety, socialization and better rehabilitation in the society. Regarding the mechanism of action, AAPs are weak D2 receptor antagonists and they act beyond D2 antagonism, involving other receptor targets which regulate dopamine and other neurotransmitters. Consequently, AAPs present a significant reduction of deleterious side effects like parkinsonism, hyperprolactinemia, apathy and anhedonia, which are all linked to the strong blockade of D2 receptors. This review revisits previous and current findings within the class of AAPs and highlights the differences in terms of receptor properties and clinical activities among them. Furthermore, we propose a continuum spectrum of “atypia” that begins with risperidone (the least atypical) to clozapine (the most atypical), while all the other AAPs fall within the extremes of this spectrum. Clozapine is still considered the gold standard in refractory schizophrenia and in psychoses present in Parkinson's disease, though it has been associated with adverse effects like agranulocytosis (0.7%) and weight gain, pushing the scientific community to find new drugs as effective as clozapine, but devoid of its side effects. To achieve this, it is therefore imperative to characterize and compare in depth the very complex molecular profile of AAPs. We also introduce relatively new concepts like biased agonism, receptor dimerization and neurogenesis to identify better the old and new hallmarks of “atypia”. Finally, a detailed confrontation of clinical differences among the AAPs is presented, especially in relation to their molecular targets, and new means like therapeutic drug monitoring are also proposed to improve the effectiveness of AAPs in clinical practice.Fondazione ARPA (2016_2), a non-profitorganization founded in 1992 (http://www.fondazionearpa.it) and byProgetti di Ricerca di Ateneo (PRA 2015_008

Gli inibitori della Neprilisina nei pazienti affetti da Malattia Renale Cronica e Sindrome Cardio-Renale

I pazienti affetti da malattia renale cronica (CKD) presentano una maggiore incidenza di eventi cardiovascolari (acuti e cronici) che, a loro volta, comportano un rischio aumentato di progressione verso la malattia renale cronica terminale (end \u2013 stage renal disease \u2013 ESRD) L\u2019inibizione della neprilisina, oltre ad offrire un nuovo target terapeutico nei pazienti affetti da scompenso cardiaco, potrebbero rappresentare una strategia di potenziale miglioramento negli outcomes, sia cardio-vascolari che renali, dei pazienti affetti da CKD. L\u2019inibizione della neprilisina, favorendo una maggiore biodisponibilit\ue0 dei peptidi natriuretici atriali, determina un incremento della diuresi e della natriuresi, oltre ad esercitare un\u2019azione di inibizione del sistema renina \u2013 angiotensina \u2013 aldosterone (RAAS). L\u2019inibizione del RAAS, a sua volta, genera una serie di controregolazioni in grado di bilanciarne gli effetti sfavorevoli in corso di CKD e di insufficienza cardiaca (HF). L\u2019idea del blocco della neprilisina non \ue8 recentissima, ma i primi farmaci impiegati, essendo molecole di associazione con antagonisti dell\u2019angiotensina II (ARBs), risultavano gravati da un\u2019incidenza inammissibile di angioedema. Tra le molecole di ultima generazione in grado di esercitare un\u2019azione inibente specifica sul recettore della neprilisina e su quello dell\u2019angiotensina II, grazie alla associazione con il valsartan, vi \ue8 l\u2019LCZ696 (sacubitril/valsartan) che ha mostrato evidenti benefici sia nel trattamento dell\u2019ipertensione arteriosa che nell\u2019insufficienza cardiaca.Patients with chronic kidney disease (CKD) have a higher incidence of cardiovascular (acute and chronic) events, which in turn have an increased risk of progression to end-stage renal disease (ESRD) Inhibition of neprilysin, in addition to offering a new therapeutic target in patients with heart failure, could represent a potential improvement strategy in cardiovascular and renal outcome of patients with CKD. Inhibition of neprilysin by inhibiting the breakdown of natriuretic peptides, increases their bioavailability resulting in an increase in diuresis and sodium excretion and, in addition to exerting an inhibition of the renin-angiotensin-aldosterone (RAAS) system. Inhibition of RAAS, in turn, generates a series of counter-regulations that can balance the adverse effects present in CKD and heart failure (HF). The idea of blocking neprilysin is not very recent, but the first drugs used as inhibitors had an inadmissible incidence of angioedema. Among the latest generation molecules that can perform a specific inhibitory action on the neprilysin receptor and, at the same time, on the angiotensin II receptor thanks to the association with valsartan there is the LCZ696 (sacubitril / valsartan). This drug has shown promising benefits both in the treatment arterial hypertension and heart failure. It is hoped that equally positive effects may occur in CKD patients, particularly those with macroproteinuria

Gli inbitori della neprilisina nei pazienti affetti da malattia renale cronica sindrome cardio-renale

I pazienti affetti da malattia renale cronica (CKD) presentano una maggiore incidenza di eventi cardiovascolari (acuti e cronici) che, a loro volta, comportano un rischio aumentato di progressione verso la malattia renale cronica terminale (end \u2013 stage renal disease \u2013 ESRD) L\u2019inibizione della neprilisina, oltre ad offrire un nuovo target terapeutico nei pazienti affetti da scompenso cardiaco, potrebbero rappresentare una strategia di potenziale miglioramento negli outcomes, sia cardio-vascolari che renali, dei pazienti affetti da CKD. L\u2019inibizione della neprilisina, favorendo una maggiore biodisponibilit\ue0 dei peptidi natriuretici atriali, determina un incremento della diuresi e della natriuresi, oltre ad esercitare un\u2019azione di inibizione del sistema renina \u2013 angiotensina \u2013 aldosterone (RAAS). L\u2019inibizione del RAAS, a sua volta, genera una serie di controregolazioni in grado di bilanciarne gli effetti sfavorevoli in corso di CKD e di insufficienza cardiaca (HF). L\u2019idea del blocco della neprilisina non \ue8 recentissima, ma i primi farmaci impiegati, essendo molecole di associazione con antagonisti dell\u2019angiotensina II (ARBs), risultavano gravati da un\u2019incidenza inammissibile di angioedema. Tra le molecole di ultima generazione in grado di esercitare un\u2019azione inibente specifica sul recettore della neprilisina e su quello dell\u2019angiotensina II, grazie alla associazione con il valsartan, vi \ue8 l\u2019LCZ696 (sacubitril/valsartan) che ha mostrato evidenti benefici sia nel trattamento dell\u2019ipertensione arteriosa che nell\u2019insufficienza cardiaca.

Hepatitis C Virus Infection Increases the Risk of Developing Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Background and Rationale: Chronic kidney disease and hepatitis C virus are prevalent in the general population worldwide, and controversy exists about the impact of HCV infection on the development and progression of kidney disease. Design: A systematic review of the published medical literature was made to assess whether positive anti-HCV serologic status plays an independent impact on the development of chronic kidney disease in the adult general population. We used a random-effects model to generate a summary estimate of the relative risk of chronic kidney disease (defined by reduced glomerular filtration rate or detectable proteinuria) with HCV across the published studies. Meta-regression and stratified analysis were also conducted. Results: Twenty-three studies (n\ua0=\ua02,842,421 patients) were eligible, and separate meta-analyses were performed according to the outcome. Pooling results of longitudinal studies (n\ua0=\ua09; 1,947,034 unique patients) demonstrated a relationship between positive HCV serologic status and increased incidence of chronic kidney disease, the summary estimate for adjusted hazard ratio was 1.43 (95\ua0% confidence interval 1.23; 1.63, P\ua0=\ua00.0001), and between-studies heterogeneity was noted (P value by Q test <0.0001). The risk of the incidence of chronic kidney disease associated with HCV, in the subset of Asian surveys, was 1.31 (95\ua0% confidence interval 1.16; 1.45) without heterogeneity (P value by Q test\ua0=\ua00.6). HCV positive serology was an independent risk factor for proteinuria; adjusted odds ratio, 1.508 (95\ua0% confidence intervals 1.19; 1.89, P\ua0=\ua00.0001) (n\ua0=\ua06 studies; 107,356 unique patients). Conclusions: HCV infection is associated with an increased risk of developing chronic kidney disease in the adult general population

Efficiency and sustainability indicators for passenger and commodities transportation systems. The case of Siena, Italy

Three different energy analysis approaches (energy and embodied energy, exergy and emergy analysis) have been applied to the road and railway systems of a medium size district of central Italy, in order to shed light on the dynamics of the local transport sector and develop a tool for analysis capable of taking the system complexity into account. Road and railway systems, respectively, support passenger flows of 3.57E9 p-km (passengers per km) per year and 0.17E9 p-km per year and commodity flows of 2.5E9 t-km (tonnes per km) per year and 0.35E9 t-km per year, generating a total energy consumption equal to 1.84E5 tonnes of oil equivalent per year. The passenger mass transport on road (buses) shows globally the best performance among the patterns investigated, while railway ranks higher for commodity transport, according to most of the calculated intensity indicators. Several improvement options are also evaluated on the basis of the first- and second-order exergy efficiency. Some of the suggested improvements, even showing high theoretical possibility, do not match the transport needs of the investigated area, as indicated by their huge material and emergy intensities (measures of ecological footprints) even if it cannot be excluded that they may appear more appropriate to nationwide transportation patterns. In conclusion, although data and indicators refer to a well identified region under specific geographic and socio-economic conditions, results suggest that a complex system such as transport is very unlikely to be described by a linear relation between input resource and output service delivered. Even when thermodynamically based approaches are properly used to describe the system behavior, findings very often do not converge, and require that different indicators are compared to yield a comprehensive picture of the system dynamics. An integrated approach is therefore suggested to support decision making in the presence of diverging results

Crystalluria: prevalence, different types of crystals and the role of infrared spectroscopy

Background: Studies on the frequency of the different types of urinary crystals and the role of Fourier transform infrared microspectroscopy (FTIRM) for identification are few. We describe the results of a retrospective study on the prevalence and typology of crystalluria and on the role of FTIRM. Methods: Urinary crystals were identified using the combined knowledge of crystal morphology, birefringence features and urine pH (combined approach). When this was inconclusive, FTIRM was performed. Results: Crystalluria was found in 807 out of 9834 samples (8.2%). In 793, the combined approach identified "typical'' crystals, while in 14 FTIRM was needed to identify "atypical'' crystals. Among "typical crystals'', calcium oxalate (75.9%), uric acid (25.9%) and amorphous urates (7.9%), alone or in combination, were the most frequent. Brushite, ammonium biurate and cystine were the most rare (0.1%-0.7%). FTIRM identified 12 of 14 atypical crystals: three crystals were due to a drug (amoxicillin, indinavir, doubtful phenytoloxamine); four were due to calcium oxalate mono-or bihydrate, uric acid bihydrate or struvite; five were due to calcium carbonate, Tamm-Horsfall glycoprotein, or rare salt combinations. Conclusions: Crystalluria is not rare and most crystals can be identified by the combined approach. Occasionally, identification of crystals will require FTIRM