Search

Background: Metabolic and bariatric surgery (MBS) is an effective treatment for adolescents with severe obesity. Objectives: This study examined the safety of MBS in adolescents during the coronavirus disease 2019 (COVID-19) pandemic. Methods: This was a global, multicentre and observational cohort study of MBS performed between May 01, 2020, and October 10,2020, in 68 centres from 24 countries. Data collection included in-hospital and 30-day COVID-19 and surgery-specific morbidity/mortality. Results: One hundred and seventy adolescent patients (mean age: 17.75 ± 1.30 years), mostly females (n=122, 71.8%), underwent MBS during the study period. The mean pre-operative weight and body mass index were 122.16 ± 15.92 kg and 43.7± 7.11 kg/m2, respectively. Although majority of patients had pre-operative testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n=146; 85.9%), only 42.4% (n=72) of the patients were asked to self-isolate pre-operatively. Two patients developed symptomatic SARS-CoV-2 infection post-operatively (1.2%). The overall complication rate was 5.3% (n=9). There was no mortality in this cohort. Conclusions: MBS in adolescents with obesity is safe during the COVID-19 pandemic when performed within the context of local precautionary procedures (such as pre-operative testing). The 30-day morbidity rates were similar to those reported pre-pandemic. These data will help facilitate the safe re-introduction of MBS services for this group of patients.

Background To investigate timely access to and the time needed to complete the diagnostic path of children and adolescents with suspected attention deficit hyperactivity disorder (ADHD) in the 18 Italian Lombardy Region ADHD reference centers. Methods Data of children and adolescents enrolled in the Regional ADHD disease-oriented Registry for suspected ADHD who requested their first visit in 2013–2017 were analyzed. Results The sample comprised 2262 children and adolescents aged 5–17 years who accessed the ADHD centers for diagnostic classification and management. The median waiting time was of 177 days (range 66–375) from the request for the initial appointment to the completion of the diagnostic path, with a three - fold difference between centers. In addition to the center, the strongest significant predictors of long waiting times were age comorbidities, the severity of the disorder, and having already completed some diagnostic procedures provided by the common standard path. Conclusions To guarantee an equal standard of care in ADHD centers for all children and adolescents there is a pressing need to reduce the times to complete the diagnostic path. It is the task of both policymakers and each center to optimize the quality of the service and of the care delivered.

International experts suggest tailoring antibiotic duration in community-acquired pneumonia (CAP) according to patients' characteristics. We aimed to assess the effectiveness of an individualized approach to antibiotic duration based on time in which CAP patients reach clinical stability during hospitalization. In a multicenter, non-inferiority, randomized, controlled trial hospitalized adult patients with CAP reaching clinical stability within 5 days after hospitalization were randomized to a standard vs. individualized antibiotic duration. In the Individualized group, antibiotics were discontinued 48 h after the patient reached clinical stability, with at least five days of total antibiotic treatment. Early failure within 30 days was the primary composite outcome. 135 patients were randomized to the Standard group and 125 to the Individualized group. The trial was interrupted by the safety committee because of an apparent inferiority of the Individualized group over the Standard treatment: 14 (11.2%) patients in the Individualized group experienced early failure vs. 10 (7.4%) patients in the Standard group, p = 0.200, at the intention-to-treat analysis. 30-day mortality rate was four-time higher in the Individualized group than the Standard group. Shortening antibiotic duration according to patients' characteristics still remains an open question.

Chylomicron retention disease is a recessive inherited disorder characterized by fat malabsorption and steatorrhea and is associated with failure to thrive in infancy. We describe a kindred carrying a mutation of Sara2 gene causing a chylomicron retention phenotype. The proband was a 5-month-old baby, born of consanguineous, apparently healthy parents from Morocco, with failure to thrive. There was a large quantity of fats in feces and malabsorption of fat-soluble vitamins. Intestinal biopsies showed a diffused enterocyte vacuolization with large cytosolic lipid droplets. Chylomicron retention disease or Anderson disease was hypothesized, and the Sara2 gene was analyzed by direct sequencing. Analysis of the Sara2 gene in the proband identified a 2-nucleotide homozygous deletion in exon 3 leading to a premature stop codon (c.75-76 del TG-L28fsX34). The father was heterozygous for the same mutation, whereas the proband's mother was homozygous, suggesting a variable phenotypic expression of the molecular defect. More studies are needed to understand the reasons of the phenotypic variability of the same molecular defect in the same family.

Aims: To assess toxicity and clinical outcomes of moderately hypofractionated helical tomotherapy (HT) for the curative treatment of localized prostate cancer (PC). Methods: From December 2012 to May 2018, 170 patients were treated with definitive intent for PC. Thirty-four percent were low risk, 30% intermediate risk (IR) and 36% high risk (HR). All patients received 70Gy in 28 fractions to the prostate; 61.6Gy were delivered to the seminal vesicles for IR; pelvic lymph nodes irradiation for a total dose of 50.4Gy was added in the HR subgroup. Toxicity was assessed using CTCAE V4.0, and biochemical failure was defined following Phoenix criteria. Time-to-event data were analyzed using the Kaplan–Meier method and log-rank test. Results: The median follow-up was 36months (range 12–78); acute toxicity was as follows: G1 and G2 in 27.6% and 19.4% for GI; 53% and 24% for GU. No G ≥ 3 event was observed. For late toxicity, G ≥ 3 GI and GU rates were, respectively, 3% and 2.4% at 3years and 3% and 4.8% at 4years; no G4 occurred. A statistical correlation between acute or late G3 incidence and clinical or dosimetric parameters was not found. At the time of analysis, 2- and 3-year biochemical relapse-free survival rates were 90% and 87.5% and 2- and 3-year overall survival rates were 96.4% and 90%, respectively. The log-rank test revealed no difference between the risk groups in terms of biochemical control (p = 0.16). Conclusions: Moderately hypofractionated RT with HT for localized prostate cancer reported excellent outcomes with mild acute and late toxicity incidence, with promising biochemical control rates.

Introduction New treatments have improved the overall survival of patients with multiple myeloma (MM). At diagnosis and during the course of the disease, patients often report pain and other symptoms. Given the long disease trajectory, psychological and social issues are also frequent. Recently, the potential usefulness of early palliative care (EPC) was hypothesized in the area of hematology. We conducted a retrospective analysis of patients with MM referred to our institute for a palliative care (PC) consultation between January 2017 and June 2020. Our aim was to evaluate the main reasons (pain or other clinical symptoms) for the referral for a first PC consultation. Methods We examined the main reasons for the first PC consultation, the number of PC consultations carried out, and the period of time between diagnosis, first and subsequent PC visits, and death. We also recorded information on the type of pain experienced and the treatments administered. Results Of the 325 patients with MM followed at our hematology unit during the study period, 43 were referred for a PC consultation (39 for pain management and 4 to determine the most appropriate care setting (hospice or palliative homecare service)). Nineteen (44.2%) of the 43 patients reported other symptoms in addition to pain. The median time between MM diagnosis and the first PC consultation was 473 days. Fifteen patients died, with a median 332 days between the first PC visit and death. Conclusion Randomized studies on MM involving larger patient populations with access to EPC are needed to identify an effective clinical model to improve the management of patients with MM.

Predictive models based on radiomics and machine-learning (ML) need large and annotated datasets for training, often difficult to collect. We designed an operative pipeline for model training to exploit data already available to the scientific community. The aim of this work was to explore the capability of radiomic features in predicting tumor histology and stage in patients with non-small cell lung cancer (NSCLC). We analyzed the radiotherapy planning thoracic CT scans of a proprietary sample of 47 subjects (L-RT) and integrated this dataset with a publicly available set of 130 patients from the MAASTRO NSCLC collection (Lung1). We implemented intra- and inter-sample cross-validation strategies (CV) for evaluating the ML predictive model performances with not so large datasets. We carried out two classification tasks: histology classification (3 classes) and overall stage classification (two classes: stage I and II). In the first task, the best performance was obtained by a Random Forest classifier, once the analysis has been restricted to stage I and II tumors of the Lung1 and L-RT merged dataset (AUC = 0.72 ± 0.11). For the overall stage classification, the best results were obtained when training on Lung1 and testing of L-RT dataset (AUC = 0.72 ± 0.04 for Random Forest and AUC = 0.84 ± 0.03 for linear-kernel Support Vector Machine). According to the classification task to be accomplished and to the heterogeneity of the available dataset(s), different CV strategies have to be explored and compared to make a robust assessment of the potential of a predictive model based on radiomics and ML.

Purpose or objective: To evaluate toxicity and outcomes of moderately hypofractionated helical tomotherapy for the curative treatment of a cohort of patients aged ≥ 75years with localized prostate cancer (PC). Materials and methods: From January 2013 to February 2017, 95 patients with median age 77years (range 75–88) were treated for PC. 39% were low risk, 33% intermediate risk (IR), 28% high risk (HR). Median iPSA was 9.42ng/ml (1.6–107). Androgen deprivation was prescribed according to NCCN recommendations. All patients received 70Gy in 28 fractions to theprostate; 61.6Gy were delivered to the seminal vesicles for IR; whole pelvis irradiation with a total dose of 50.4Gy was added in the HR group.Toxicity evaluation was based on CTCAE V4.0 criteria, biochemical failure was defined following Phoenix criteria. Quality of Life was assessed with the EPIC-26 index. Overall survival and biochemical failure-free survival were analysed with Kaplan–Meier method. Results: With a median follow-up of 36months (range 24–73), acute and late toxicity were acceptable. No correlation between toxicity patterns and clinical or dosimetric parameter was registered. EPIC-26 showed a negligible difference in urinary and bowel function post-treatment that did not reach statistical significance. The 2- and 3-years OS were 93% and 87% with cancer specific survival of 97.9% and 96.2%. Conclusion: Moderate hypofractionated RT reported excellent outcomes in our cohort of older patients. Shorter schedules may be proposed regardless of chronological age facilitating the treatment compliance in the older population.

Background Community-acquired pneumonia (CAP) has a potential complication of bacteremia. The objective of this study was to define the clinical outcomes of patients with CAP and bacteremia treated with and without a macrolide. Materials and methods Secondary analysis of the Community-Acquired Pneumonia Organization database of hospitalized patients with CAP. Patients with a positive blood culture were categorized based on the presence or absence of a macrolide in their initial antimicrobial regimen, and severity of their CAP. Outcomes included in-hospital all-cause mortality, 30-day mortality, length of stay, and time to clinical stability. Results Among 549 patients with CAP and bacteremia, 247 (45%) were treated with a macrolide and 302 (55%) were not. The primary pathogen was Streptococcus pneumoniae (74%). Poisson regression with robust error variance models were used to compare the adjusted effects of each study group on the outcomes. The unadjusted 30-day mortality was 18.4% in the macrolide group, and 29.6% in the non-macrolide group (adjusted relative risk (aRR)0.81; 95% confidence interval (CI)0.50–1.33; P = 0.41). Unadjusted in-hospital all-cause mortality was 7.3% in the macrolide group, and 18.9% in the non-macrolide group (aRR 0.54, 95% CI 0.30–0.98; P = 0.043). Length of stay and time to clinical stability were not significantly different. Conclusions In-hospital mortality, but not 30-day mortality, was significantly better in the macrolide group. Our data support the use of a macrolide in hospitalized patients with CAP and bacteraemia.

Background Autosomal recessive hypercholesterolemia (ARH) is a rare inherited lipid disorder. In Sardinia, differently from other world regions, the mutated allele frequency is high. It is caused by mutations in the low-density lipoprotein receptor adaptor protein 1 gene. Fourteen different mutations have been reported so far; in Sardinia, 2 alleles (ARH1 and ARH2) explain most of the cases. Four ARH patients, all carriers of the ARH1 mutation, have been identified in mainland Italy and 2 in Sicily. Objective The objectives of the study were to improve the molecular diagnosis of familial hypercholesterolemia (FH) and to estimate the frequency of the ARH1 allele in 2 free-living Sicilian populations. Methods We sequenced by targeted next-generation sequencing 20 genes related to low-density lipoprotein metabolism in 50 hypercholesterolemic subjects. Subjects from 2 free-living populations from Northern (Ventimiglia Heart Study, 848 individuals) and Southern Sicily (Zabut Zabut Aging Project, 1717 individuals) were genotyped for ARH1 allele. Results We identified 1 homozygous carrier of the ARH1 mutation among the 50 hypercholesterolemic outpatients. Population-based genotyping of ARH1 in 2565 subjects allowed the identification of 1 heterozygous carrier. The overall estimated allele frequency of ARH1 in Sicily was 0.0002 (0.02%). Conclusions The identification of a new case of ARH in Sicily among 50 clinically diagnosed FH highlights the importance of next-generation sequencing analysis as tool to improve the FH diagnosis. Our results also indicate that ARH1 carrier status is present in ∼1:2500 of Sicilian inhabitants, confirming that ARH is extremely rare outside Sardinia.

Although ADHD comorbidity has been widely studied, some issues remain unsolved. This multicenter observational study aims to examine comorbid psychiatric disorders in a clinical sample of newly diagnosed, treatment naive children and adolescents with and without ADHD and, to compare treatment efficacy based on the type of comorbidity. We performed an analysis of the medical records of patients identified from the Regional ADHD Registry database, enrolled in 18 ADHD centers in the 2011-2016 period. 1919 of 2861 subjects evaluated (67%) met the diagnostic criteria for ADHD: 650 (34%) had only ADHD, while 1269 (66%) had at least one comorbid psychiatric disorder (learning disorders, 56%; sleep disorders, 23%; oppositional defiant disorder, 20%; anxiety disorders, 12%). Patients with ADHD of combined type and with severe impairment (CGI-S ≥5) were more likely to present comorbidity. 382 of 724 (53%) followed up patients improved after 1 year of treatment. ADHD with comorbidity showed greater improvement when treated with combined interventions or methylphenidate alone. Specifically, combined treatment showed significant superiority for ADHD with learning disorders (ES 0.66) and ODD (ES 0.98), lower for ADHD with sleep or anxiety disorders. Training intervention alone showed only medium efficacy (ES 0.50) for ADHD and learning disorders. This study was the first describing comorbidity patterns of ADHD in Italy, confirming, in a multicenter clinical setting, that ADHD is more often a complex disorder. Findings highlight important diagnostic, therapeutic, and service organization aspects that should be broadly extended to ensure an appropriate and homogenous ADHD management.

Background and aims Obesity is predictive of metabolic syndrome (metS), type 2 diabetes, cardiovascular (CV) disease and cancer. The aim of the study is to assess the risk of incident cancer connected to obesity and metS in a Mediterranean population characterized by a high prevalence of obesity. Methods and results As many as 1133 subjects were enrolled in two phases and followed for 25 years (859 subjects) or 11 years (274 subjects) and incident cancer was registered in the follow-up period. Anthropometric measures and biochemical parameters were filed at baseline and evaluated as predictors of incident cancer by measuring hazards ratios (HR) using multivariate Cox parametric hazards models. Best predictive threshold for metabolic parameters and metS criteria were recalculated by ROC analysis. Fasting Blood Glucose >5.19 mmol/L [HR = 1.58 (1.0–2.4)] and the TG/HDL ratio (log 10 ) (Males > 0.225, Females > 0.272) [HR = 2.44 (1.3–4.4)] resulted independent predictors of survival free of cancer with a clear additive effect together with age classes [45–65 years, HR = 2.47 (1.3–4.4), 65–75 years HR = 3.80 (2.0–7.1)] and male gender [HR = 2.07 (2.3–3.1)]. Conclusions Metabolic disturbances are predictive of cancer in a 25 years follow-up of a Mediterranean population following a traditional Mediterranean diet. The high prevalence of obesity and metS and the observed underlying condition of insulin resistance expose this population to an increased risk of cardiovascular disease and cancer despite the healthy nutritional habits.

Objective Familial hypobetalipoproteinemia (FHBL) is characterized by inherited low plasma levels of apolipoprotein B (apoB)-containing lipoproteins. In this paper we investigated whether the already described APOB R463W missense mutation, a FHBL mutation able to impair the activity of microsomal triglyceride transfer protein (MTP), may cause intestinal fat accumulation and reduced postprandial lipemia. Methods Four out of five probands harboring APOB R463W mutation were compared with six healthy controls and six patients with celiac disease (CD). An oral fat load supplemented with retinyl palmitate (RP) was administered and a gastro-duodenal endoscopy with biopsy was performed. Results Plasma triglyceride area under curves was significantly reduced in FHBL probands compared to controls and CD patients; the proportion of absorbed RP was similar to that of CD patients. Only the intestinal biopsies of FHBL patients showed lipids accumulating within the duodenal mucosa. Conclusions FHBL due to R463W apoB mutation is a cause of intestinal fat accumulation and postprandial lipid absorption impairment.

The aim of the present study was to define the prevalence, characteristics, risk factors and impact on clinical outcomes of acute myocardial infarction (AMI) versus other cardiovascular events (CVEs) in patients with community-acquired pneumonia (CAP).This was an international, multicentre, observational, prospective study of CAP patients hospitalised in eight hospitals in Italy and Switzerland. Three groups were identified: those without CVEs, those with AMI and those with other CVEs.Among 905 patients, 21 (2.3%) patients experienced at least one AMI, while 107 (11.7%) patients experienced at least one other CVE. Patients with CAP and either AMI or other CVEs showed a higher severity of the disease than patients with CAP alone. Female sex, liver disease and the presence of severe sepsis were independent predictors for the occurrence of AMI, while female sex, age >65 years, neurological disease and the presence of pleural effusion predicted other CVEs. In-hospital mortality was significantly higher among those who experienced AMI in comparison to those experiencing other CVEs (43% versus 21%, p=0.039). The presence of AMI showed an adjusted odds ratio for in-hospital mortality of 3.57 (p=0.012) and for other CVEs of 2.63 (p=0.002).These findings on AMI versus other CVEs as complications of CAP may be important when planning interventional studies on cardioprotective medications.

Objective— Cyclic AMP responsive element–binding protein 3–like 3 ( CREB3L3 ) is a novel candidate gene for dominant hypertriglyceridemia. To date, only 4 kindred with dominant hypertriglyceridemia have been found to be carriers of 2 nonsense mutations in CREB3L3 gene (245fs and W46X). We investigated a family in which hypertriglyceridemia displayed an autosomal dominant pattern of inheritance. Approach and Results— The proband was a 49-year-old woman with high plasma triglycerides (≤1300 mg/dL; 14.68 mmol/L). Her father had a history of moderate hypertriglyceridemia, and her 51-year-old brother had triglycerides levels as high as 1600 mg/dL (18.06 mmol/L). To identify the causal mutation in this family, we analyzed the candidate genes of recessive and dominant forms of primary hypertriglyceridemia by direct sequencing. The sequencing of CREB3L3 gene led to the discovery of a novel minute frame shift mutation in exon 3 of CREB3L3 gene, predicted to result in the formation of a truncated protein devoid of function (c.359delG–p.K120fsX20). Heterozygosity for the c.359delG mutation resulted in a severe phenotype occurring later in life in the proband and her brother and a good response to diet and a hypotriglyceridemic treatment. The same mutation was detected in a 13-year-old daughter who to date is normotriglyceridemic. Conclusions— We have identified a novel pathogenic mutation in CREB3L3 gene in a family with dominant hypertriglyceridemia with a variable pattern of penetrance.

A 13-yr-old Caucasian female was referred to the Dept of Paediatric Diseases (Havana, Cuba) with shortness of breath and pleuritic chest pain located in her right hemithorax. The pain had occurred the day before while doing physical activity and lasted ∼1 h. The patient reported a 2-month history of recurrent episodes of pleuritic chest pain, which were either self-limited or relieved by paracetamol, as well as growing fatigue in the previous few weeks. Her past history was remarkable for a diagnosis of pneumonia after exposure to fumigation during a dengue haemorrhagic fever epidemic 2 yrs earlier, which was treated with steroids and antibiotics. On admission, the patient had no weight loss, no fever or dyspnoea. Physical examination showed decreased breathing sounds in the inferior part of both hemithoraces. Cardiovascular, abdominal and neurological examination, as well as ear, nose and ophthalmologic investigations were unremarkable. The chest radiograph showed bilateral pneumonia with moderate right-sided pleural effusion. The leukocyte count was 9.8×109 cells·L−1 with 54% neutrophils and 32% lymphocytes. The erythrocyte sedimentation rate was 85 mm·h−1. Serum chemistry, renal and liver function tests were in the normal range. Blood cultures were negative. Antibiotic therapy with ceftriaxone and amikacin was started. During the treatment the patient reported 2 days of moderate fever and various episodes of left-sided pleuritic chest pain, which occurred especially during forceful diaphragm contractions ( i.e. sneezing, laughing and coughing). Following a short stay in the Cuban hospital, the patient was transferred to an Italian hospital (Como). Amikacin was discontinued and clarithromycin added. A new chest radiograph (fig. 1⇓), 14 days after the previous one, and a computed tomography (CT) scan of the thorax were performed. Echocardiography and abdominal ultrasound were both negative. An increased value of the tumour marker CA-125 (220 U·mL−1, versus a normal value

Telithromycin is a ketolide, a semisynthetic derivative of the 14-membered ring macrolide antibiotics, with an expanded spectrum of activity relative to macrolides. Its good tissue pharmacokinetic characteristics allows once-daily administration, and it has been successfully employed in lower respiratory tract infections. Recent data indicate that telithromycin may exert anti-inflammatory/immunomodulatory effects that may be of use in the treatment of both acute and chronic airway diseases. This review examines the role of telithromycin in lower respiratory tract infections, analyzing published data on exacerbations of chronic bronchitis, community-acquired pneumonia and asthma in adults. In addition, pharmacokinetic and pharmacodynamic properties of the drug are considered.

Summary Background Lipoid proteinosis (LP), also known as Urbach–Wiethe disease, is a rare autosomal recessive disorder characterized by a hoarse voice, warty skin infiltration and scarring. Mutations within the extracellular matrix protein 1 (ECM1) gene cause LP. Objectives We report the molecular analysis of the ECM1 gene in a Sicilian patient with LP in order to extend the mutation spectrum of this genodermatosis. Methods We studied a 32-year-old female born from consanguineous parents who was diagnosed at the age of 11 years as having LP. She has a clinical phenotype corresponding to Urbach–Wiethe disease characterized by papules/nodules, indurated plaques and sometimes ulcerated lesions primarily involving the skin and mucous membranes, and extracutaneous features such as epilepsy, hoarseness of the voice and neuropsychiatric abnormalities. Samples of clinically affected skin obtained by biopsies were analysed after staining with haematoxylin and eosin, periodic acid–Schiff (PAS), and PAS–diastase. The whole ECM1 gene was analysed by direct sequencing. Results We identified a homozygous nonsense mutation in exon 6 of the ECM1 gene, C589T (Q197Ter). Conclusions Over 60% of mutations occur in exons 6 and 7. Exon 7 is alternatively spliced and frameshift mutations in exon 7 lead to ablation of the ECM1a transcript, but not the shorter ECM1b transcript that normally lacks this exon. Homozygous nonsense or frameshift mutations in exon 6 are predicted to affect both full-length ECM1a and ECM1b transcripts, whereas ECM1b should be unaffected for similar types of mutation in exon 7. It has been suggested that individuals with mutations in exon 7 have a slightly milder phenotype than those with exon 6 mutations. This is the first report with respect to a novel mutation of the ECM1 gene responsible for recessive LP in Sicily.

SummaryWe analyzed 795 sputa from 315 patients (233 males, mean age 69.3±8.8 years, mean number of exacerbations 2.52/patient) with acute exacerbations of moderate-to-severe chronic obstructive pulmonary disease (COPD) (mean steady-state FEV1 42.5±7.8% of predicted). 581/795 sputa were considered adequate. Sputum was analyzed by a quali-quantitative colorimetric scale allowing both color distinction and color degree of intensity. Quantitative culture was then performed (threshold: >106CFU/mL). Samples were distinguished in mucoid (145) and purulent (436) sputa. Absence of bacterial growth was observed in 22% and 5% of mucoid and purulent sputa, respectively. Among mucoid sputa, Gram positive bacterial growth occurred more commonly compared to Gram negative and Pseudomonas aeruginosa/Enterobacteriaceae (56%, 24%, 20%, respectively). In purulent sputa, Gram positives were found in 38% of cases, Gram negatives in 38%, and P. aeruginosa/Enterobacteriaceae in 24%. We evaluated whether functional impairment (FEV1) orientates as to the infectious etiology of exacerbations. Significant differences were observed in the distribution of pathogens. Gram negative and P. aeruginosa/Enterobacteriaceae were isolated more frequently in the sputum when FEV1 was

Objective— Mutations of the ANGPTL3 gene have been associated with a novel form of primary hypobetalipoproteinemia, the combined hypolipidemia (cHLP), characterized by low total cholesterol and low HDL-cholesterol levels. The aim of this work is to define the role of ANGPTL3 gene as determinant of the combined hypolipidemia phenotype in 2 large cohorts of 913 among American and Italian subjects with primary hypobetalipoproteinemia (total cholesterol Methods and Results— The combined hypolipidemia cut-offs were chosen according to total cholesterol and HDL-cholesterol levels reported in the ANGPTL3 kindred described to date: total cholesterol levels, ANGPTL3 and APOB genes. We identified nonsense and/or missense mutations in ANGPTL3 gene in 8 subjects; no mutations of the APOB gene were found. Mutated ANGPTL3 homozygous/compound heterozygous subjects showed a more severe biochemical phenotype compared to heterozygous or ANGPTL3 negative subjects, although ANGPTL3 heterozygotes did not differ from ANGPTL3 negative subjects. Conclusion— These results demonstrated that in a cohort of subjects with severe primary hypobetalipoproteinemia the prevalence of ANGPTL3 gene mutations responsible for a combined hypolipidemia phenotype is about 10%, whereas mutations of APOB gene are absent.

OBJECTIVES: In the past years, several risk charts have been created to increase the accuracy of cardiovascular risk stratification. The most widely used and validated algorithms do not included target organ damage as risk prediction. The aim of the present study was to evaluate whether preclinical renal damage is associated with cardiovascular diseases independently of individual risk profile assessed by risk charts. METHODS: The study population was that of Italy-Developing Education and awareness on MicroAlbuminuria in patients with hypertensive Disease, a large observational study conducted on hypertensive patients in Italy. The Framingham Risk Score (FRS), Systematic COronary Risk Estimation (SCORE) and Progetto Cuore Risk Score (Progetto Cuore RS) were computed in each eligible patient. Chronic kidney disease was defined by the presence of albuminuria or by a reduction of glomerular filtration rate. RESULTS: Study participants were categorized to have low, medium and high risk according to the tertiles of the three charts. Prevalence of total cardiovascular diseases progressively and significantly increased according to the degrees of risk assessed by the three charts, the highest prevalence being in participants with a high-risk profile (both high and medium vs. low risk

Background and aim Cardiovascular (CV) risk factors present in childhood predict future CV events. Few data regarding the metabolic syndrome (MS) prevalence are available in adolescents from Mediterranean areas where obesity is becoming a social emergency. This study presents data of MS prevalence in a student cohort from southern Italy. Methods and results 1629 students between 7 and 14 years of age underwent anthropometric measurements and a blood sample was obtained to assess biochemical parameters. MS risk factors were calculated based on age and gender adjusted percentiles of parameter distributions. MS prevalence rate was 0.022 using paediatric, age-adjusted criteria; the rate increased to 0.029 using a 90th percentile criteria for fasting blood glucose instead of >100 mg/dL. Using the criteria issued by the International Diabetes Federation the MS prevalence rate dropped to 0.005. The exploratory factor analysis identified four factors: age/fat related, lipids, blood pressure and blood glucose. Family history of type 2 diabetes mellitus was associated with triglyceride [OR = 1.55 (1.0–2.3)] and BMI [OR = 1.71 (1.2–2.4)] but not to blood glucose by logistic regression analysis. Conclusions In a student cohort from Southern Italy, obesity is associated with the features of MS.

Objectives— The PCSK9 gene, encoding a pro-protein convertase involved in posttranslational degradation of low-density lipoprotein receptor, has emerged as a key regulator of plasma low-density lipoprotein cholesterol. In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. The aim of this study was to assess whether loss of function mutations of PCSK9 were a cause of familial hypobetalipoproteinemia and a determinant of low-plasma low-density lipoprotein cholesterol in whites. Methods and Results— We sequenced PCSK9 gene in 18 familial hypobetalipoproteinemia subjects and in 102 hypocholesterolemic blood donors who were negative for APOB gene mutations known to cause familial hypobetalipoproteinemia. The PCSK9 gene variants found in these 2 groups were screened in 42 subjects in the lowest (th ) percentile, 44 in the highest (>95 th ) percentile, and 100 with the average plasma cholesterol derived from general population. In one familial hypobetalipoproteinemia kindred and in 2 hypocholesterolemic blood donors we found a novel PCSK9 mutation in exon 1 (c.202delG) resulting in a truncated peptide (Ala68fsLeu82X). Two familial hypobetalipoproteinemia subjects and 4 hypocholesterolemic blood donors were carriers of the R46L substitution previously reported to be associated with reduced low-density lipoprotein cholesterol as well as other rare amino acid changes (T77I, V114A, A522T and P616L) not found in the other groups examined. Conclusions— We discovered a novel inactivating mutation as well as some rare nonconservative amino acid substitutions of PCSK9 in white hypocholesterolemic individuals.

Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease caused by mutations in the gene coding for the low density lipoprotein receptor (LDL-R). It is characterized by a high concentration of low density lipoprotein (LDL), which frequently gives rise to premature coronary artery disease. We studied the probands of five FH Sicilian families with 'definite' FH and one proband of Paraguayan descent with homozygous FH who has been treated with an effective living-donor liver transplantation. In order to seek the molecular defect in these six families, we used direct sequencing to define the molecular defects of the LDL-R gene responsible for the disease. We described three novel missense mutations (C100Y, C183Y and G440C), two frameshift mutations (g.1162delC in exon 8 and g.2051delC in exon 14) and one mutation (g.2390-1Gright curved arrow A) at splicing acceptor consensus sequences located in intron 16 of the LDL-R gene; the analysis of cDNA of this splicing mutation showed the activation of a cryptic splice site in intron 16 and the binding studies showed a reduction in internalisation of LDL-DIL in the proband's cultured fibroblasts. Moreover, a g.2051delC in exon 14 was identified in the proband of Paraguayan ancestry with clinical features of homozygous FH. The mutation identified in the South American patient represents the first description of a variant in South American patients other than Brazilian FH patients. The 5 mutations identified in the Sicilian patients confirm the heterogeneity of LDL-R gene mutations in Sicily.