the study of familial hypercholesterolemia in italy a narrative review

Abstract In this review we outline our experience in the clinical and molecular diagnosis of familial hypercholesterolemia (FH), built up over more than three decades. We started our work by selecting FH patients on the basis of stringent clinical criteria, including extensive family studies. In most patients we confirmed the clinical diagnosis by showing a reduced LDLR activity in skin fibroblasts. After the isolation of LDLR cDNA and the characterization of the corresponding gene by the Dallas group, we started a systematic molecular investigation of our patients first using Southern blotting, and, subsequently Sanger sequencing. Up to now we have been able to identify 260 mutations of LDLR gene in more than 1000 genotyped FH patients, including 68 homozygotes. During this survey we identified 13 mutation clusters located in different geographical districts, which gave us the chance to compare the phenotype of patients carrying the most common mutations. We also found that mutations in APOB and PCSK9 genes were a rare cause of FH in our cohort. Despite our efforts, we failed to identify mutations in candidate genes in ∼20% of cases of definite FH. An exome-wide study, conducted within the context of an international collaboration, excluded the presence of other major genes in our unexplained FH cases. Recently, we have adopted sequencing technology of the next generation (NGS) with the parallel sequencing of a panel of FH targeted genes as a way of obtaining a more comprehensive picture of the gene variants potentially involved in the disease

Studio multidisciplinare finalizzato alla riqualificazione ambientale della valle del Rio della Rocca (Comune di Castellarano, Provincia di Reggio Emilia)

La valle del Rio della Rocca nel Comune di Castellarano (Reggio Emilia) è stata interessata a partire dagli anni ‘50 del secolo scorso da attività estrattive che in parte ne hanno profondamente modificato le caratteristiche ambientali, in particolare quelle geomorfologiche. In considerazione dell’interesse paesaggistico della valle e ai fini di una riqualificazione ambientale del territorio, è stato realizzato uno studio multidisciplinare volto a delineare i principali aspetti geologici, paleontologici, floristici e faunistici. Specifica attenzione è stata posta alla valutazione dell’instabilità dei versanti e alla individuazione dei geositi presenti nell’area. Sulla scorta dei risultati delle ricerche effettuate sono state elaborate proposte di riqualificazione del territorio che prevedono una valorizzazione della valle a fini geoturistici e ricreativi

Post-partum surgical wound infections: incidence after caesarean section in an Italian hospital

Introduction. Despite international recommendations and gen- eral agreement on the fact that more complications arise after caesarean section, Italy ranks first in the number of caesarean sections performed each year. Aim of this cohort study was to estimate the incidence of post-partum wound infections following caesarean section in a sample of low-risk women and to examine the main risk factors correlated. Methods. 430 mothers were included in the study. A data col- lection form was completed with woman?s obstetric history, details of the operation and of any infection that occurred during hospital staying. A post-discharge telephone call-up surveillance after delivery was also performed Results. A total of 20 (4.7%) SSIs were recorded. Through post-discharge surveillance, 85% of infections were identified. The time between membrane rupture and start of the operation was found to be associated with the development of infection (p = 0.04). No statistically significant association with any of the other risk factors was found. Discussion and conclusion. From the comparison of current practices with international guideline recommendations we could identify critical points that will need to be addressed in correc- tive and training interactions, specifically, choice and timing of administration of antibiotics in antimicrobial prophylaxis and timing of showering and shaving

Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family

Abstract: Next-generation sequencing (NGS) is nowadays commonly used for clinical purposes, and represents an efficient approach for the molecular diagnosis of familial hypercholesterolemia (FH). Although the dominant form of the disease is mostly due to the low-density lipoprotein receptor (LDLR) small-scale pathogenic variants, the copy number variations (CNVs) represent the underlying molecular defects in approximately 10% of FH cases. Here, we reported a novel large deletion in the LDLR gene involving exons 4–18, identified by the bioinformatic analysis of NGS data in an Italian family. A long PCR strategy was employed for the breakpoint region analysis where an insertion of six nucleotides (TTCACT) was found. Two Alu sequences, identified within intron 3 and exon 18, could underlie the identified rearrangement by a nonallelic homologous recombination (NAHR) mechanism. NGS proved to be an effective tool suitable for the identification of CNVs, together with small-scale alterations in the FH-related genes. For this purpose, the use and implementation of this cost-effective, efficient molecular approach meets the clinical need for personalized diagnosis in FH cases

Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy

Immune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy

Ottimizzazione del sistema di controllo di una pompa di calore dual-source (aria/terreno) abbinata ad impianto fotovoltaico.

In questo lavoro di tesi è stata studiata e ottimizzata la logica di controllo di un prototipo di pompa di calore dual-source (aria/terreno-acqua), con l’obiettivo di permettere alla macchina di operare nella modalità di funzionamento che attesti i migliori coefficienti di prestazione annuali. Tale lavoro è stato svolto nell’ambito del Progetto HEGOS. Lo studio è stato condotto con l’utilizzo del software di simulazione dinamica TRNSys. Per l’analisi del comportamento dell’impianto con le diverse logiche di controllo si è sfruttato un edificio test; è stato installato un impianto di condizionamento avente fan coil come terminali di emissione e il prototipo di pompa di calore multisorgente come generatore. L’impianto presenta un sistema di sonde geotermiche verticali che fungono da eventuale sorgente esterna, possibili configurazioni: sonda singola da 60, 80, 100 m e sonda doppia da 60,80,100 m. Le varie logiche di controllo studiate impongono alla macchina la modalità di funzionamento, aria o terreno, sulla base di: temperatura dell’aria esterna, confronto tra temperatura dell’aria esterna (bulbo secco o bulbo umido) e temperatura del fluido lato sonde (in ingresso alla PdC o media del circuito), temperatura del terreno. Le simulazioni hanno coperto un periodo temporale di 16 anni al fine di valutare la sostenibilità sul lungo periodo del sistema in caso di carichi stagionali sbilanciati. I risultati ottenuti sono stati confrontati in termini di indici prestazionali e temperature del terreno. È stato integrato un impianto fotovoltaico, per favorire l’autoproduzione dell’energia elettrica richiesta dalla pompa di calore e da una ipotetica utenza. È stata condotta un’analisi economica al variare del numero di moduli basata su una funzione costo per stabilire la configurazione più conveniente: il risparmio annuo prodotto dall’intervento di miglioramento dell’efficienza energetica è stato quantificato in base ad autoconsumo e scambio sul posto

A 3-day-old neonate with severe hypertriglyceridemia from novel mutations of the GPIHBP1 gene

Background Familial chylomicronemia is a genetic defect of the intravascular lipolysis of triglyceride (TG)-rich lipoproteins. Intravascular lipolysis involves the TG-hydrolase lipoprotein lipase (LPL) as well as other factors such as apolipoprotein CII and apolipoprotein AV (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL). Methods We sequenced the familial chylomicronemia candidate genes in a neonate with chylomicronemia. Results A 3-day-old newborn was found to have chylomicronemia (plasma TG 18.8 mmol/L, 1.667 mg/dL). The discontinuation of breastfeeding for 24 hours reduced plasma TG to 2.3 mmol/L (201 mg/dL), whereas its resumption induced a sharp TG increase (7.9 mmol/L, 690 mg/dL). The child was switched to a low-fat diet, which was effective in maintaining TG level below 3.5 mmol/L (294 mg/dL) during the first months of life. The child was found to be a compound heterozygous for 2 novel mutations in GPIHBP1 gene. The first mutation was a 9-bp deletion and 4-bp insertion in exon 2, causing a frameshift that abolished the canonical termination codon TGA. The predicted translation product of the mutant messenger RNA is a peptide that contains 51 amino acids of the N-terminal end of the wild-type protein followed by 252 novel amino acids. The second mutation was a nucleotide change (c.319T>C), causing an amino acid substitution p.(Ser107Pro) predicted in silico to be damaging. Conclusions GPIHBP1 mutations should be considered in neonates with chylomicronemia negative for mutations in LPL gene