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In persons with congenital severe hemophilia A (HA) living in high-income countries, twice weekly intravenous infusions of extended half-life (EHL) factor VIII (FVIII) products, or weekly/biweekly/monthly subcutaneous injections of emicizumab are the gold standard home treatments to grant days without hurdles and limitations. Once weekly/twice monthly infusions of EHL Factor IX (FIX) products achieve the same target in severe hemophilia B (HB). Gene therapy, which is likely to be licensed for clinical use within 1–2 years, embodies a shift beyond these standards. At an individual patient level, a single functional gene transfer leads to a > 10-yr almost full correction of the hemostatic defect in HB and to a sustained (3–6-yrs) expression of FVIII sufficient to discontinue exogenous clotting factor administrations. At the doses employed, the limited liver toxicity of systemically infused recombinant adeno-associated virus (rAAV) vectors is documented by long-term (12–15 yrs) follow-ups, and pre-existing high-titer neutralizing antibodies to the AAV5 vector are no longer an exclusion criterion for effective transgene expression with this vector. A safe durable treatment that converts a challenging illness to a phenotypically curable disease, allows persons to feel virtually free from the fears and the obligations of hemophilia for years/decades. Along with patient organizations and health care professionals, communicating to government authorities and reimbursement agencies the liberating potential of this substantial innovation, and disseminating across the Centers updated information on benefits and risks of this strategy, will align expectations of different stakeholders and establish the notion of a potentially lifelong cure of hemophilia. [ABSTRACT FROM AUTHOR]

Summary Psoriasis is a chronic disease associated with overweight/obesity and related cardiometabolic complications. The link between these diseases is likely the inflammatory background associated with adipose tissue, particularly the visceral one. Accordingly, previous studies have demonstrated that in the long-term weight loss may improve the response to systemic therapies. We report a case report of a woman in her 40s suffering from relapsing moderate-to-severe plaque psoriasis and obesity-related metabolic syndrome, in whom adequate response to ongoing treatment with biological therapy (adalimumab) was restored after only 4 weeks of very low-calorie, carbohydrate-free (ketogenic), protein-based diet. Accordingly, through rapid and consistent weight loss, very low calorie ketogenic diet may allow restoring a quick response to systemic therapy in a patient suffering from relapsing psoriasis. This intervention should be considered in overweight/obese patients before the rearrangement of systemic therapy. Nonetheless, studies are required to evaluate whether very low calorie ketogenic diets should be preferred to common low-calorie diets to improve the response to systemic therapy at least in patients with moderate-to-severe psoriasis. [ABSTRACT FROM AUTHOR]

Summary Background In morbid obesity, optimisation of nutritional strategies impacting cardiovascular and metabolic risk profile is a desirable target in clinical practice. Objective To assess in morbid obesity the feasibility, safety and efficacy of a nutritional cycle comprising a short-term carbohydrates-free diet delivered by nasogastric tube followed by an almost equivalent oral diet. Design In our clinical practice, adults with body mass index (BMI) ≥ 45 kg/m 2 , otherwise clinically healthy, signed informed consent for a 14-day stint of continuous and controlled carbohydrates-free nutritional regiment delivered via 8-Fr nasogastric tube (enteral nutrition, EN), followed by a 14-day stint of almost comparable oral nutrition (ON). Body metrics, insulin resistance, blood pressure (BP) and heart rate (HR), as well as parameters for safety were monitored. Results In 112 patients, EN significantly reduced BMI and waist circumference (WC), BP, insulin resistance while it increased urine ketones and uric acid increased (all p < 0.01 independent to confounders), but had no clinically significant impact on kidney and renal function, and coagulation parameters as well. With ON, findings were consistent. No major safety concerns were recorded during the nutritional treatment. In a subset of patients sharing clinical characteristics with the whole sample, the nutritional strategy reduced the mesenteric fat assessed by ultrasound. Conclusions In morbid obesity, an aggressive nutritional cycle comprising a short-term ketogenic EN followed by an almost carbohydrates-free ON may be feasible, safe, and highly effective in reducing body weight, WC, BP and insulin resistance. [ABSTRACT FROM AUTHOR]

Abstract: Cystic fibrosis (CF) is one of the most common inherited life-shortening diseases with an incidence of 1:2.500–3500 and a carrier frequency of 4–5% . It is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a protein expressed in the apical membrane of exocrine epithelial cells, resulting in changes to the fluid and electrolytes on cell surface. More than 1500 mutations have been described so far in the CFTR gene, grouped in 5 classes on the basis of the impact on protein synthesis or activity . In the last years a mounting number of reports described patients that did not meet all diagnostic criteria for CF ; in particular, atypical or nonclassic CF is characterized by normal or borderline sweat test, pancreatic sufficiency and a monosymptomatic phenotype; the most studied forms are: congenital bilateral absence of vasa deferentes, acute or chronic recurrent pancreatitis, idiopathic bronciectasis . These patients typically bear a severe and a mild (classes 4–5) CFTR mutation, the latter being dominant . The involvement of upper airways is observed in up to 100% of classic CF patients, including recurrent sinusitis and rhinitis. Nasal polyps are present in 6–48% of overall CF patients and in 5–15.2% of less than 10 years old CF patients. Surgery is required for syntomatic polyps. It is the second most common class of operations performed on CF patients. In spite of the best of operations CF patients will have recurrence, because of systemic disease. We describe a patient diagnosed as “atypical CF” on the basis of persisting chronic rhinosinusitis, that showed a very rare CFTR genotype. [ABSTRACT FROM AUTHOR]

In cystic fibrosis, deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel causes misfolding and premature degradation. One possible approach to reducing the detrimental health effects of cystic fibrosis could be the identification of proteins whose suppression rescues F508del-CFTR function in bronchial epithelial cells. However, searches for these potential targets have not yet been conducted, particularly in a relevant airway background using a functional readout. To identify proteins associated with F508del-CFTR processing, we used a highthroughput functional assay to screen an siRNA library targeting 6,650 different cellular proteins. We identified 37 proteins whose silencing significantly rescued F508del-CFTR activity, as indicated by enhanced anion transport through the plasma membrane. These proteins included FAU, UBE2I, UBA52, MLLT6, UBA2, CHD4, PLXNA1, and TRIM24, among others. We focused our attention on FAU, a poorly characterized protein with unknown function. FAU knockdown increased the plasma membrane targeting and function of F508del-CFTR, but not of wildtype CFTR. Investigation into the mechanism of action revealed a preferential physical interaction of FAU with mutant CFTR, leading to its degradation. FAU and other proteins identified in our screening may offer a therapeutically relevant panel of drug targets to correct basic defects in F508del-CFTR processing. [ABSTRACT FROM AUTHOR]

Objectives Sweat chloride test is the gold standard test for cystic fibrosis (CF) diagnosis. In 2014 the Istituto Superiore di Sanità established the Italian pilot external quality assessment program for CF sweat test (IEQA-ST). Design and methods Ten laboratories, included among the 33 Italian CF Referral Centers, were selected and enrolled on the basis of their attitude to perform sweat test (ST) analysis by using methods recommended by the Italian Guidelines. They received three different sweat-like samples (normal, borderline and pathologic chloride concentration), with mock clinical indications, for analysis according to routine procedures. Assessment, performed by a panel of experts, covered analytical performance, interpretation and reporting of results; categories of “poor” and “satisfactory” performance were not defined. All data were managed through a web utility. Results The program identified important areas of interest and, in some case, of concern. It is important to underline that results are referred to a small proportion, i.e. about 30%, of Italian laboratories performing CF ST in the context of the Referral Centers. Conclusions Data collected highlight the importance of participation in EQA programs as it may improve laboratory/clinical performance; our study represents a model for the setting up of a large-scale EQA scheme for ST. [ABSTRACT FROM AUTHOR]

In this study we assessed the BDNF promoter IV methylation state of a large genomic region surrounding promoter IV and evaluated BDNF transcript IV expression from prefrontal cortex and striatum of 15 schizophrenic and 15 control subjects. In prefrontal cortex, a single CpG site at −93, appeared to be undermethylated in patients׳group. BDNF mRNA levels in frontal cortex and striatum were variable among individuals but did not associate with disease. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Serum Fetuin A has been identified as an inhibitor of ectopic calcification. It is reduced in subjects with chronic kidney disease (CKD) and it has been proposed as a potential link between CKD and the higher prevalence of arterial calcification observed in these patients. During aging both the stiffening of arterial wall due to calcification and a decline in kidney function are frequent. The aim of the study is to investigate if Fetuin A serum levels are associated with aging and with AHSG T256S polymorphism. Moreover, we aim at investigate whether serum Fetuin A is correlated to kidney function in this setting of senescence. Design and methods: 256 health long-lived subjects (age 92 [81–100]) were recruited for the study. Serum Fetuin A was evaluated by ELISA, Cystatin C by immune-nephelometry. AHSG T256S was determinated by PCR-RFLP. Results: Serum Fetuin A shows a significant correlation with age (r =0.20; P =0.0048). AHSG TS and SS genotypes are associated to lower levels of serum protein (0.27 [0.19–0.29] g/L vs 0.42 [0.32–0.49] g/L; P <0.027 and 0.34 [0.25–0.41] g/L vs 0.42 [0.32–0.49] g/L; P <0.001, respectively). No significant correlation between Fetuin A and Cystatin C was observed. Conclusions: Serum Fetuin A increases with age in elder individuals and subjects with the TS or SS AHSG polymorphism have lower levels of the circulating protein. No correlation with kidney function decline was observed. Other mechanisms should be investigated to explain the increase of Fetuin A with age. [Copyright &y& Elsevier]

Objective: To describe the ocular phenotype in patients with ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome (MIM#604292) and to determine the pathogenic basis of visual morbidity. Design: Retrospective case series. Participants: Nineteen families (23 patients) affected by EEC syndrome from the United Kingdom, Ireland, and Italy. Methods: General medical examination to fulfill the diagnostic criteria for EEC syndrome and determine the phenotypic severity. Mutational analysis of p63 was performed by polymerase chain reaction–based bidirectional Sanger sequencing. All patients with EEC syndrome underwent a complete ophthalmic examination and ocular surface assessment. Limbal stem cell deficiency (LSCD) was diagnosed clinically on the basis of corneal conjunctivalization and anatomy of the limbal palisades of Vogt. Impression cytology using immunofluorescent antibodies was performed in 1 individual. Histologic and immunohistochemical analyses were performed on a corneal button and corneal pannus from 2 EEC patients. Main Outcome Measures: The EEC syndrome phenotypic severity (EEC score), best-corrected Snellen visual acuity (decimal fraction), slit-lamp biomicroscopy, tear function index, tear breakup time, LSCD, p63 DNA sequence variants, impression cytology, and corneal histopathology. Results: Eleven heterozygous missense mutations in the DNA binding domain of p63 were identified in all patients with EEC syndrome. All patients had ocular involvement and the commonest was an anomaly of the meibomian glands and lacrimal drainage system defects. The major cause of visual morbidity was progressive LSCD, which was detected in 61% (14/23). Limbal stem cell deficiency was related to advancing age and caused a progressive keratopathy, resulting in a dense vascularized corneal pannus, and eventually leading to visual impairment. Histologic analysis and impression cytology confirmed LSCD. Conclusions: Heterozygous p63 mutations cause the EEC syndrome and result in visual impairment owing to progressive LSCD. There was no relationship of limbal stem cell failure with the severity of EEC syndrome, as classified by the EEC score, or the underlying molecular defect in p63. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. [ABSTRACT FROM AUTHOR]

Summary: Factors related to bacterial virulence and/or to the host have been implicated in the pathogenesis of recurrent urinary tract infections (rUTI), but in most cases the cause is unknown. Mannose binding lectin (MBL) is an acute phase glycoprotein that exerts immunological functions by binding to the surface of a variety of pathogens. Some human gene variants reduce MBL activity thereby predisposing the host to bacterial and viral infections. The aim of this study was to investigate MBL2 gene variants in relation to rUTI risk. Six MBL gene variants and seven haplotypes were analyzed by PCR and direct sequencing in rUTI patients (n = 83) and in healthy subjects from southern Italy (n = 642). The frequencies of the L allele (−550) and the HYPA haplotype were higher in controls than in patients stratified according to sex (p < 0.05). Our data indicate that the HYPA haplotype in the MBL2 gene could be associated with a minor risk of developing rUTI in males. [Copyright &y& Elsevier]

This study aims to cast light on immunocytometric alterations in COVID-19, a potentially fatal viral infection with heterogeneous clinical expression and a not completely defined pathophysiology. We studied 35 COVID patients at hospital admission testing by cytofluorimetry a large panel of lymphocyte subpopulations and serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-17A and the soluble receptor of IL-17A (IL-17RA). At hospital admission, total lymphocytes and most T and B subpopulations were reduced in 50–80% of patients, with close relationship to disease severity. While activated T helper 1 (TH1) and TH17 cells resulted normal or higher. Serum IL-6 was increased in all patients, while TNF-α and IL-17A were higher in advanced stages. A patient subset with low severity had very high IL-17RA levels. Tocilizumab treatment caused an increase of IL-17A in 3/6 patients and a reduction in 3 others, while the lymphocyte number increased in 3 patients and did not change in the others. Cytofluorimetry revealed a functional exhaustion of most lymphocyte populations in COVID patients not involving activated TH1 and TH17. Consequently, there was a relevant cytokines production that contributes to impair the respiratory inflammation. The increase of TH17 and IL-17 in a subset of cases and the evidence of a significant increase of IL-17RA (that prevents the interaction of IL-17 with the cell receptor) in patients with low severity suggest that some patients could benefit from monoclonal antibodies treatment targeting IL-17 pathway. Immunocytofluorimetric markers may contribute to a personalized therapy in COVID patients. • Total lymphocytes and most T and B sub-clusters were reduced in COVID-19 patients. • Activated TH1 and TH17 cells resulted normal or higher in COVID-19 patients. • Serum IL-6 levels were increased in all patients. • Serum TNF-α and IL-17A were higher in advanced stages. • Evidence of a significant increase of serum IL-17RA in patients with low severity. [ABSTRACT FROM AUTHOR]