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Background The role of prothrombotic gene variants as risk factors for venous thrombotic diseases is controversial and the ordering of tests for thrombophilia in the clinical context is scarcerly respective of evidence-based data. Methods We studied FVL, FVR2, FII G20210A, MTHFR C677T and A1298C, beta-fibrinogen -455 G>A, FXIII V34L, HPA-1 L33P variants and PAI-1 4G/5G alleles in: 343 patients with deep vein thrombosis (DVT), 164 with pulmonary embolism (PE), 126 with superficial vein thrombosis (SVT), 118 with portal vein thrombosis (PVT), 75 with cerebral vein thrombosis (CVT), 119 with retinal vein thrombosis (RVT) in comparison with 430 subjects from the general population (GP) of the same geographical area (Southern Italy). Results About 40% of patients with DVT, PE and SVT have a prothrombotic predisposition represented by FVL, FVR2 and FII G20210A variants (significantly more frequent than in the general population), significantly higher in PE males. While, in patients with PVT and CVT only FII G20210A variant is more frequent particularly in females. Finally, RVT is poorly related to prothrombotic risk factors, confirming that local vascular and other factors have a pivotal role in its pathogenesis. Conclusions Our data indicate that only FVL, FVR2 and FII G20210A are related to vein thrombotic diseases while all the other gene variants, frequently ordered in the clinical context, do not have a role as risk factors. Furthermore, the evidence of a sex difference for some variants, once confirmed in larger populations, may help to promote sex-specific prevention of such diseases.

Background Acute myocardial infarction (AMI) in young women represent an extreme phenotype associated with a higher mortality compared with similarly aged men. Prothrombotic gene variants could play a role as risk factors for AMI at young age. Methods We studied Factor V Leiden, FII G20210A, MTHFR C677T and beta-fibrinogen -455G>A variants by real-time PCR in 955 young AMI (362 females) and in 698 AMI (245 females) patients. The data were compared to those obtained in 909 unrelated subjects (458 females) from the general population of the same geographical area (southern Italy). Results In young AMI females, the allelic frequency of either FV Leiden and of FII G20210A was significantly higher versus the general population (O.R.: 3.67 for FV Leiden and O.R.: 3.84 for FII G20210A; p Discussion and conclusion Our data confirm that young AMI in females is a peculiar phenotype with specific risk factors as the increased plasma procoagulant activity of FV and FII. On the contrary, the homozygous state for the 677T MTHFR variant may cause increased levels of homocysteine and/or an altered folate status and thus an increased risk for AMI, particularly in males. The knowledge of such risk factors (that may be easily identified by molecular analysis) may help to improve prevention strategies for acute coronary diseases in specific risk-group subjects.

The aim of this study was to evaluate the influence of traditional and nontraditional (oxidation markers) cardiovascular risk factors on the degree of adaptive response of the carotid wall to atherosclerotic disease, a process known as arterial enlargement. Five thousand sixty-two clinically healthy, middle-aged women living in the area of Naples participated in the “Progetto Atena” study; 310 of these women (potentially at higher atherosclerotic risk) underwent a high-resolution ultrasound scan of the carotid arteries. In addition to routine biochemical tests, these women had the determination of serum IgG antibody titer against oxidized LDL and measurement of thiobarbituric acid reactive substances and total radical-trapping activity potential of plasma. Age, systolic blood pressure, body mass index, and radical-trapping activity were all positively correlated with external and internal common carotid diameters, whereas triglycerides (positively) and HDL cholesterol (inversely) were related only to external diameter. After controlling for traditional cardiovascular risk factors, associations still persisted for age, systolic blood pressure, and plasma radical-trapping activity with external carotid diameters. However, in the quartile of women with highest total cholesterol (>7.38 mmol/L), the slope of the regression line between systolic blood pressure and external diameter was significantly flatter than in the three other quartiles (test for difference, P =0.014). Outward carotid enlargement is related to traditional and nontraditional risk factors and comes even before plaque development. Women with poor resistance to oxidative stress potentially have a difficulty to remodel their arteries in response to atherosclerotic stimuli.

Background and objectives: ischemic stroke (IS) is among the most frequent causes of death worldwide, thus, it is of paramount relevance to know predisposing factors that may help to identify and treat the high-risk subjects. Materials and Methods:we tested nine variants in genes involved in thrombotic pathway in 282 patients that experienced IS and 87 that had transient ischemic attacks (TIA) in comparison to 430 subjects from the general population (GP) of the same geographic area (southern Italy). We included cases of young and child IS to evaluate the eventual differences in the role of the analyzed variants. Results: we did not observe significant differences between TIA and the GP for any of the variants, while the allele frequencies of methylene-tetrahydrofolate reductase (MTHFR) C677T, beta-fibrinogen -455G&gt, A and factor (FXIII) V34L were significantly higher in patients with IS than in the subjects from the GP. No significant interaction was observed with sex. Conclusions: the present data argue that some gene variants have a role in IS and this appears to be an interesting possibility to be pursued in large population studies to help design specific strategies for IS prevention.

Background: Cystic fibrosis (CF) is one of the most common inherited diseases. It is characterised by a severe decline in pulmonary function associated with metabolic perturbations and an increased production of inflammatory cytokines. The key role of physical activity (PA) in improving the health status of CF patients and reducing lung function decline has recently been demonstrated. This study evaluated interleukin-6 (IL-6) and tumour necrosis factor α (TNFα) expression in two subgroups of CF patients classified based on PA. Methods: We selected 85 CF patients, half of them regularly undertook supervised PA in the three years leading up to the study and half of them were not physically active. Patients were analysed for serum IL-6 and TNFα levels using enzyme-linked immunosorbent assays. Results: We found that the expression levels of IL-6 and TNFα differed in terms of their regulation by PA. In particular, TNFα levels negatively correlated with FEV1% decrease/year and FEV1% decrease (p = 0.023 and p = 0.02, respectively), and positively correlated with serum fasting glucose (p = 0.019) in PA CF patients. In contrast, in the NPA subgroup, TNFα levels were positively correlated with IL-6 (p = 0.001) and negatively correlated with adiponectin (p = 0.000). In addition, multiple logistic regression analysis confirmed that PA is an independent modulator of the inflammatory state. Conclusions: PA modulates inflammatory processes in CF patients by regulating the secretion of pro-inflammatory cytokines and thus ameliorating lung function. Our data show that PA is a useful complementary strategy in the management of CF and that TNFα may be a marker of these effects of PA.

The defective mucociliary clearance due to CFTR malfunctioning causes predisposition to the colonization of pathogens responsible for the recurrent inflammation and rapid deterioration of lung function in patients with cystic fibrosis (CF). This has also a profound effect on the lung microbiome composition, causing a progressive reduction in its diversity, which has become a common characteristic of patients affected by CF. Although we know that the lung microbiome plays an essential role in maintaining lung physiology, our comprehension of how the microbial components interact with each other and the lung, as well as how these interactions change during the disease’s course, is still at an early stage. Many challenges exist and many questions still to be answered, but there is no doubt that manipulation of the lung microbiome could help to develop better therapies for people affected by CF.

Because of the progression of genetics and genomics, the demand for prenatal diagnosis (PD) for inherited genetic diseases has increased. However, several incidental findings may emerge during PD, like misattributed paternity, the evidence of disease in a parent, and the possible misinterpretation of the results because of complex alleles or de novo mutations that have several implications. In a retrospective observational study on all the couples referred to our Medical School (1993&ndash, 2018) for PD of genetic inherited diseases (n = 1502), we selected the cases of PD for cystic fibrosis (CF, n = 239) and hemophilia A and B (HA, HB, n = 47), revising all incidental findings previously mentioned. We found one case in which a technical error led to PD of carrier in two siblings that were born affected by CF, four cases of misattributed paternity, eight cases of asymptomatic parents revealed as affected by CF transmembrane regulator (CFTR)-related disorders, a case of a novel complex allele that could have caused the diagnosis of CF in a carrier fetus, and a case of a de novo mutation in a mother (already a carrier) that caused hemophilia in a child that PD had revealed as healthy. We present these conditions as clinical cases and discuss the technical, clinical, ethical, and legal aspects to be considered.

Cystic fibrosis (CF) is a genetic disease characterized by progressive decline of lung function and chronic airway inflammation. Adipose tissue, through adiponectin and leptin, exerts several effects on energy metabolism and inflammatory processes. This study evaluated the levels of adiponectin and leptin in adult healthy subjects, in patients with CF and their correlation with long-term physical activity. CF patients were divided into two groups (sedentary versus active) based on their regular physical activity over 3 years. Anthropometric and serum biochemical profiles of CF patients and controls were evaluated and compared. Total serum adiponectin and leptin levels were measured by ELISA; adiponectin oligomeric profiles were analysed by western blot. Adiponectin levels were significantly higher while leptin levels were lower in patients with CF than in healthy controls. Furthermore, adiponectin was significantly lower in active compared to sedentary CF (p=0.047), while leptin was slightly increased in active compared to sedentary CF. In addition, C-reactive protein levels were significantly lower in active than in sedentary CF patients (p=0.048). Interestingly, only in the active group adiponectin levels were inversely correlated with forced expiratory volume (FEV) 1% decrease/year and FEV1% decrease. Moreover, adiponectin levels negatively correlated with lipid profiles. Our findings indicated that regular, long-term physical activity in CF improves respiratory function, metabolism, and inflammation status. These improvements in patients’ conditions are associated with immunometabolic processes involving adiponectin, leptin, and C-reactive protein. Therefore, we propose that both adipokines may be a useful biomarker in the evaluation of metabolic and inflammatory status in patients with CF.

Background Recurrent (RP) and chronic pancreatitis (CP) may complicate Cystic Fibrosis (CF). It is still unknown if mutations in genes involved in the intrapancreatic activation of trypsin (IPAT) or in the pancreatic secretion pathway (PSP) may enhance the risk for RP/CP in patients with CF. Methods We enrolled: 48 patients affected by CF complicated by RP/CP and, as controls 35 patients with CF without pancreatitis and 80 unrelated healthy subjects. We tested a panel of 8 genes involved in the IPAT, i.e. PRSS1, PRSS2, SPINK1, CTRC, CASR, CFTR, CTSB and KRT8 and 23 additional genes implicated in the PSP. Results We found 14/48 patients (29.2%) with mutations in genes involved in IPAT in the group of CF patients with RP/CP, while mutations in such genes were found in 2/35 (5.7%) patients with CF without pancreatitis and in 3/80 (3.8%) healthy subjects (p

Objectives: Cluster headache (CH) is characterized by severe, recurrent, unilateral attacks of extreme intensity and brief duration. Variants in a myriad of genes were studied in sporadic CH patients, often with conflicting results. Methods: We studied gene mutations in some candidate genes, hypocretin receptor 2, Clock, and alcohol dehydrogenase 4 (ADH4), in 54 unrelated sporadic CH patients and in 200 controls in 8 kindreds/families that included more affected and nonaffected cases. Furthermore, we performed the whole-genome scanning by comparative genomic hybridization, searching for rearrangements associated with DNA gain or loss in a subset of sporadic and familial CH and control participants. Results: The analysis of candidate genes revealed that only allele and genotype frequency of the 2 ADH4 mutations resulted significantly between sporadic CH and controls; the same mutations were homozygous in CH patients from 2 families. The comparative genomic hybridization analysis revealed 2 novel rearrangements that involved the intron regions of thyrotropin-releasing hormone-degrading enzyme and neurexin 3 (NRXN3) genes, respectively. The first arrangement was present either in CH or in controls, whereas the second one was specifically found in some sporadic and familial CH cases. Conclusions: Our data (although obtained on a small number of cases) confirm the genetic heterogeneity of CH, suggesting that mutations in the ADH4 gene and a novel rearrangement involving NRXN3 gene might be related to CH in a subset of cases.

Background: Haemophilia A and B (HA, HB) are the most frequent X-linked bleeding diseases; two-thirds of cases are severe. Methods: We counselled 51 couples for prenatal diagnosis (PD) of haemophilia. In 7/51 (13.7%) cases, the couple decided not to undergo PD because counselling revealed that they were carriers of a mild form of the disease, while we performed 44 PD for severe HA (36 cases) or HB (8 cases). The indication for PD was a haemophilic child (30/44, 68.2%) or an affected family member (12/44, 27.3%); in two cases the non-carrier mother of isolated haemophilic patients requested PD because of the risk of mosaicism. Results: We completed PD in 43/44 cases; in one case, the prenatal sample was contaminated by maternal DNA; however, molecular analysis revealed the female sex of the foetus. We performed PD for 16 of the 36 couples at risk of HA (44.4%) by analysing the intron (IVS)22 inversion; in 1/36 cases (2.8%) the mother had the IVS1 inversion, and in 8/36 (22.2%) the family mutation was identified by sequencing; in 11/36 (30.6%) cases the family mutation was unknown, and PD was performed by linkage (no recombination nor uninformative cases occurred). For HB, in 6/8 (75.0%) cases, PD was performed by DHPLC or by sequencing; in 2/8 cases we tested intragenic markers (again with no cases of recombination or uninformative families). Conclusions: PD in well-equipped laboratories, and multidisciplinary counselling are an aid to planning reproductive and early therapeutic strategies in families with severe haemophilia.

No abstract available

Background and Purpose— The association between obesity and atherosclerotic disease is controversial. In the present analysis, we evaluated whether common carotid intima-media thickness (IMT) and area, 2 markers of preclinical atherosclerosis, were increased in obese subjects. Methods— More than 5000 middle-aged women (n=5062; age, 30 to 69 years) living in the area of Naples, Southern Italy, were recruited for a prospective, currently ongoing study on the etiology of cardiovascular disease and cancer in the female population (the Progetto ATENA study). A subsample of 310 participants underwent high-resolution B-mode ultrasound examination, and the IMTs, intima-media areas, and lumen diameters of common carotid arteries were measured with a semiautomated computerized program. Subjects were divided into 3 groups on the basis of the recently published obesity guidelines for body mass index (BMI), a marker of general obesity, and tertiles of waist-to-hip ratio (WHR), a marker of regional obesity. Results— Women with a BMI ≥30 kg/m 2 showed higher systolic and diastolic blood pressures, triglycerides, and fasting glucose and insulin, as well as lower high-density lipoprotein concentrations, than subjects with lower BMI. A gradual increase in common carotid IMT and intima-media area was observed when lean women (0.94±0.01 mm and 19.8±0.5 mm 2 , respectively) were compared with overweight (0.98±0.01 mm and 21.0±0.4 mm 2 ) and obese (1.02±0.02 mm and 22.6±0.8 mm 2 , P 0.85) had adverse risk factor profiles and thicker carotid intima-media complex than those in the first 2 tertiles ( P P Conclusions— The present results indicate a graded and independent association between general and abdominal obesity—reflected by high BMI and WHR—and carotid artery wall thickening in a population of middle-aged women.

The aim of this study was to determine whether impaired glucose regulation, defined according to the new American Diabetes Association (ADA) criteria, is associated with early signs of carotid atherosclerosis. We examined 310 clinically healthy women from southern Italy, aged 30 to 69 years, recruited for a prospective study, currently ongoing, on the etiology of cardiovascular disease and cancer in the female population (Progetto Atena). All subjects underwent cardiovascular risk factor assessment and high resolution B-mode ultrasound to measure intima-media thickness (IMT) of common carotid arteries and carotid bifurcations. At the time of our survey, fasting glucose levels [ge ] 7.0 mmol/L had already been found in 7 women, 17 participants were diagnosed on that occasion as having new diabetes, 38 had impaired fasting glucose (IFG), and the remaining 248 presented normal fasting glucose values (NFG). Diabetic women showed a worse cardiovascular risk profile, with higher values of triglycerides, body mass index, and diastolic blood pressure than either normoglycemic or IFG subjects. The frequency of atherosclerotic plaques (IMT [gt ] 1.2 mm) increased as glucose homeostasis worsened. In multivariate logistic regression analyses, only diabetes mellitus was associated with a significantly increased risk of carotid atherosclerosis (odds ratio [OR], 11.5; 95% confidence interval [CI], 1.4 to 92.7). Our findings suggest a definite association between diabetes mellitus, as defined by the new ADA diagnostic criteria and early carotid structural changes. Furthermore, the condition of IFG does not seem to identify subjects at significantly increased atherosclerotic risk.