Search

Mutations in presenilin 1 gene (PSEN1) are the most common causes of autosomal dominant early-onset Alzheimer's disease (EOAD). We report a novel PSEN1 mutation (I213S) that was discovered in an Italian patient with a family history of early-onset dementia, who developed a slowly progressive cognitive decline since the age of 40 years. Clinical investigations, including neuropsychological assessment, brain MRI and 18-fluorodeoxyglucose PET, as well as cerebrospinal fluid biomarkers, supported the diagnosis of EOAD. Genetic studies identified a novel missense mutation at codon 213 (I213S). Three other mutations at the same codon have been described in association with EOAD. Previous in silico, in vitro and in vivo studies indicated that these mutations affect the functional properties of γ-secretase and are most likely pathogenic. In silico algorithms suggested that even the I213S mutation has similar deleterious effects on PSEN1 structure and function. Overall, these data strongly support a role of hotspot site for the codon 213 of PSEN1, and provide evidence that the genetic variants located on this site cause EOAD., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Autosomal dominant Alzheimer's disease (AD) is caused by mutations in amyloid precursor protein, presenilin 1 (PSEN1), and presenilin 2 genes and is mostly associated with early-onset form of AD (EOAD), whereas very few mutations were also found in late-onset AD (LOAD) cases. Because of the clinical overlapping between AD and other degenerative dementias such as frontotemporal dementias, a wide-spectrum genetic analysis should be envisaged in the differential diagnosis of this group of disorders. We used next-generation sequencing techniques to analyze 10 genes involved in dementia on a cohort of 20 EOAD and 20 LOAD cases. We found 5 rare coding variants (frequency <1%). PSEN1 H214N mutation, identified in a case of familial EOAD and PSEN1 R220P, found in a case of familial LOAD, are predicted to be pathogenic. These findings confirm the contribution of PSEN1 genetic variants also to LOAD, underlining the need of extending the genetic screening of presenilin mutations to LOAD patients. Two variants in microtubule-associated protein tau and 1 in progranulin appeared to be benign polymorphisms, showing no major contribution of these genes to AD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Adrenal insufficiency is often present in cirrhosis. We hypothesize that a prolonged adrenocorticotropic hormone (ACTH) stimulus can restore cellular capacity of adrenal glands to secrete cortisol. Aim of our study was to assess adrenal responsiveness to prolonged ACTH stimulation in cirrhotics., Methods: Prospective observational study in 121 consecutively admitted cirrhotic patients undergoing a low dose short synacthen test and plasma ACTH measurement using a chemiluminescence immunoassay. Long synacthen test was performed if the low dose was abnormal., Results: 46 patients had abnormal low dose short test (38%), and 29 underwent the long test: 41% showed normal response (Group 1), 55% showed delayed response (Group 2) and 1 had abnormal response (4%). Baseline ACTH levels did not significantly differ between the two groups. Median basal cortisol was higher in Group 1 (296 vs. 198 nmol/L; p=0.02). Using ROC curve basal cortisol <254 nmol/L was associated with a delayed long synacthen test response (AUC 0.78, p=0.001) with good accuracy (sensitivity 67%, specificity 81%)., Conclusion: A delayed cortisol response after a prolonged ACTH stimulation is found in over fifty percent of cirrhotics with abnormal low dose short synacthen test, confirming that the mechanism of hypoadrenalism in these patients could be related both to adrenal cellular dysfunction and hypothalamus-pituitary adrenal axis impairment., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: To evaluate renal failure (RF) in cirrhosis to determine and quantify its prognostic significance., Methods: Studies were identified by MEDLINE, EMBASE, Cochrane, ISI Web of Science (1977-2010); search terms included renal failure, mortality, and cirrhosis. Included studies (n=74) reported >10 patients and mortality data (8088 patients). Mortality at 1, 3, and 12 months was evaluated with respect to Child-Pugh score, serum creatinine, ascites, ICU status or sepsis, prospective study design, and publication year. Pooled odds ratio (POR) for death was compared for RF vs. non-RF (5668 patients)., Results: Overall median mortality for RF patients was 67%: 58% at 1 month and 63% (IQR 54-79) at 12 months. POR for death RF vs. non-RF patients was 7.6 (95%CI 5.4-10.8). Overall mortality before 2005 (1264 patients) was 74% and after 2005 (2833 patients) was 63% with a marked reduction only at 30 days (71% vs. 52%)., Conclusions: This study provides a measure of the increased risk of death in cirrhosis with renal failure. RF increases mortality 7-fold, with 50% of patients dying within one month. Preventative strategies for RF are needed., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Gerstmann-Sträussler-Scheinker disease Pro102Leu (GSS102) is a rare autosomal dominant inherited prion disease due to a substitution of proline for leucine at codon 102 in the Prion Protein gene, and characterized by early walking difficulties and much later occurring dementia. We report clinical, electrophysiological and neuroradiological features of seven novel Italian cases of GSS102. The findings in our series support the thesis that early signs of GSS102 (including areflexia, ataxia, lower limb weakness, and painful dysesthesias) are likely due to a caudal myelopathic process, and suggest that GSS102 should be included among the causes of ataxia with areflexia. Moreover, our observations show that in patients with GSS102, as opposed to Friedreich's ataxia and other forms of ataxia with areflexia, nerve conduction studies and somato-sensory evoked potentials are normal, despite the presence of lower limb areflexia. Hence, in subjects with walking difficulties, the presence of lower limb areflexia without central and peripheral conduction abnormalities is highly suggestive or possibly pathognomonic of GSS102, and can easily guide the clinicians to make the diagnosis of this rare neurodegenerative disease., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background & Aims: Adrenal insufficiency (AI) is reported in critically ill patients with cirrhosis and is associated with increased mortality. It is unclear if AI is an underlying condition or triggered by critical events (e.g. sepsis). We investigated AI in cirrhosis without infection or hemodynamic instability., Methods: A total of 101 consecutive patients with cirrhosis were studied. AI was defined by a total serum cortisol (TC) <18 μg/dl at 20 or 30 min after injection of 1 μg of tetracosactrin. Transcortin, calculated free cortisol (cFC), and free cortisol index (FCI) were assessed in a subgroup of 41 patients, with FCI>12 representing normal adrenal function., Results: AI was present in 38 patients (38%). Child score (median, 10 vs 7, p<0.0001), MELD score (median, 17 vs 12, p<0.0001), ascites (68% vs 37%, p<0.01), basal TC (median,7.6 vs 14.9 μg/dl, p<0.001), albumin (28 ± 0.8 vs 33 ± 0.7 g/L, p<0.0001), INR (median, 1.6 vs 1.2, p<0.0001), total bilirubin (median, 51 vs 31 μmol/L, p<0.05), total cholesterol (median, 120 vs 142, p<0.05), and LDL (median, 76 vs 81, p<0.05) were significantly different between those with and without AI. ROC curves showed a basal TC ≤ 12.8 μg/dl to be a cut-off value closely associated with AI. The cFC was significantly related to TC for baseline values (R=0.94, p<0.0001), peak values (R=0.90, p<0.0001), and delta values (R=0.95, p<0.0001), in patients with and without AI. However, no patient had a FCI<12., Conclusions: AI defined by an abnormal response to 1 μg tetracosactrin is frequent in stable patients with cirrhosis, in the absence of infections or hemodynamic instability and is related to the severity of liver disease. However, evaluation of the true incidence of AI should comprise direct assays of free cortisol. Clinical consequences of AI need to be explored., (Copyright © 2010 European Association for the Study of the Liver. All rights reserved.)

Background: Natural or induced variations in the noxiousness of gluten proteins for celiac disease (CD) patients are currently being investigated for their potential in breeding wheat crops with reduced toxicity., Aims: We evaluated the bread wheat line C173 for its effects on the in vitro-grown duodenal mucosa of CD patients., Methods: In vitro-grown duodenal mucosa biopsies of 19 CD patients on a gluten-free diet were exposed to peptic/tryptic-digested prolamins from bread wheat line C173 lacking gliadin-glutenin subunits, analyzed for morphology, cytokine and anti-tTG antibody production, and compared with mucosa biopsies exposed to prolamins from wild-type cv. San Pastore., Results: Duodenal mucosa biopsies exposed to prolamins from C173 and San Pastore released higher amounts of IFN-γ, IL-2, IL-10 and anti-tTG antibodies in the culture medium than untreated controls. The line C173 differed from cv. San Pastore as it did not produce negative effects on enterocyte height, suggesting that manipulating prolamin composition can affect innate immune responses of CD mucosa to wheat gluten., Conclusions: Our data demonstrated that this gliadin-deficient wheat has a lower direct toxicity but activates an immunologic reaction of the duodenal mucosa like that of the common wheat species., (Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: Growing evidence suggests that the metabolic syndrome (MetS) has both a genetic and environmental basis. To evaluate the possibility of a further genetic analysis, we estimated prevalence rates and heritabilities for the MetS and its individual traits in the adult population of Linosa, a small and isolated Italian Island in the southern-central part of the Mediterranean Sea., Methods and Results: The Linosa Study (LiS) group consisted of 293 Caucasian native subjects from 51 families (123 parents; 170 offsprings). The MetS was defined according to NCEP/ATP III criteria and the following prevalence rates were calculated: hyperglycaemia 20.3%; central obesity 34.9%; hypertension 43.4%; hypertriglyceridaemia 29.9%; "low HDL" 56.6%; MetS 29.9%. Waist circumference was significantly related to all the quantitative parameters included in the NCEP/ATP III MetS definition. The MetS showed a heritability of 27% (p=0.0012) and among its individual components, treated as continuous and discrete traits, heritability ranged from 10% for blood glucose to 54% for HDL-cholesterol. Among MetS subtypes, the clustering of central obesity, hypertriglyceridaemia and "Iow HDL" had the highest heritability (31%; p<0.001)., Conclusion: These data showed high prevalence rates for the MetS and its related traits in an isolated and small Caucasian population. The appreciable heritability estimates for the MetS and some of its components/clusters in the LiS population might support the observation of genetic factors underlying the pathogenesis of the MetS and encourage further analysis to identify new susceptibility genes.

Background: Recent findings have suggested that subjects with non-coronary atherosclerosis may show elevated prevalence of atherogenic dyslipidemia, including higher triglyceride levels, reduced HDL-cholesterol concentrations and increased levels of small, dense low-density lipoproteins (LDL). These three lipid abnormalities constitute the so-called "atherogenic-lipoprotein-phenotype" (ALP) but its predictive role in these patients still remains to be established., Methods: We performed a 2-year follow-up study to assess clinical and biochemical predictors of cardiovascular events in 44 male patients (64+/-5 years, BMI: 27+/-3), 26 with peripheral arterial disease and 18 with abdominal aortic aneurysm. Beyond traditional cardiovascular risk factors, we measured LDL size and subclasses by gradient gel electrophoresis., Results: Clinical events were registered in the 43% of patients. At univariate analysis we found that patients with events had increased prevalence of hypertension (p=.0098), diabetes (p=.0089), family history of cardiovascular diseases (p=.0089), of elevated small, dense LDL (p=.0222) and ALP (p=.0224). At multivariate analysis (including all clinical and laboratory variables) we found the following independent predictors of events: hypertension (OR 8.9, p=.0347), diabetes (OR 9.4, p=.0270), elevated small, dense LDL (OR 6.9, p=.0488) and ALP (OR 8.7, p=.0497)., Conclusions: This is the first study that evaluated the predictive role of ALP beyond traditional cardiovascular risk factors in patients with peripheral arterial disease or abdominal aortic aneurysm. We confirmed that hypertension and diabetes are strong predictors of cardiovascular events in these subjects but ALP seems to be an independent predictor too. Yet, the therapeutical consequences of these findings need to be tested by future studies.

Genetic Creutzfeldt-Jakob disease (gCJD) is caused by a range of mutations in the prion protein gene (PRNP). We describe the first Italian case of gCJD associated with the rare PRNP E196K mutation. The disease showed an atypical presentation featuring dementia without motor signs in a 75-year-old woman. The case lacked both a known family history of a similar neurological disease and the typical EEG pattern; it was misdiagnosed as frontotemporal dementia. The present case emphasizes that vigilance must be kept high to avoid missing gCJD cases falling outside a typical phenotypical presentation and a known family history, especially in the elderly, in whom an alternative, more common, but incorrect diagnosis may be made.

Aims: Oral mucosal lesions may be markers of chronic gastrointestinal disorders, such as those causing malabsorption. Our objectives were to assess the prevalence of recurrent oral aphthous-like ulcers in coeliac disease patients living in the Mediterranean area, and to evaluate the impact of a gluten-free diet., Methods: A test group of 269 patients (age range 3-17 years) with coeliac disease confirmed both serologically and histologically was compared with a control group of 575 otherwise clinically healthy subjects for the presence, or a positive history of aphthous-like ulcers. Coeliac disease patients with aphthous-like ulcers were re-evaluated 1-year after starting a gluten-free diet., Results: Aphthous-like ulcers were found significantly more frequently in coeliac disease, in 22.7% (61/269) of patients with coeliac disease versus 7.1% (41/575) of controls (p=<0.0001; chi-square=41.687; odds ratio=4.3123; 95% confidence interval=2.7664:6.722). Most coeliac disease patients with aphthous-like ulcers and adhering strictly to gluten-free diet (71.7%; 33/46) reported significant improvement on gluten-free diet, with no or reduced episodes of aphthous-like ulcers (p=0.0003; chi-square=13.101; odds ratio=24.67; 95% confidence interval=2.63:231.441)., Conclusions: The epidemiological association found between coeliac disease and aphthous-like ulcers suggests that recurrent aphthous-like ulcers should be considered a risk indicator for coeliac disease, and that gluten-free diet leads to ulcer amelioration.

Background: Epidemiologic studies have demonstrated that elderly patients with fixed airflow obstruction can be affected by asthma or chronic obstructive pulmonary disease (COPD)., Methods: We studied 49 consecutive elderly outpatients, presenting fixed airflow obstruction, by clinical history (smoking), pulmonary function tests, blood gas analysis, and induced sputum., Results: The age was not different in patients with COPD (n=28) and asthma (n=21) (70.2+/-3.9 years vs. 69.6+/-3.7 years), also the degree of fixed airflow obstruction was similar (FEV1: 58.3+/-1.5% vs. 59.0+/-1.4% of predicted). Patients with asthma had significantly more eosinophils in peripheral blood (0.43+/-0.05x10(-3)microL vs. 0.27+/-0.1x10(-3)microL, P<0.0001), and in induced sputum (5.0% [(p25th and p75th) 5.0-6.0%] vs. 1.0% [(p25th and p75th) 0.01-1.0%]; P<0.0001), as well as serum ECP (18.6+/-4.9ng/mL vs. 7.7+/-4.7ng/mL, P<0.0001) and ECP in the induced sputum (31.6+/-2.9ng/mL vs. 5.6+/-4.9ng/mL, P<0.0001). Finally, in induced sputum the eosinophils EG2+ were higher in patients with asthma than in patients with COPD (40.5 [(p25th and p75th) 39.3-44.3] MFI vs. 3.9 [(p25th and p75th) 0-11.4] MFI, P<0.0001). They also had significantly higher diffusing capacity, and a greater reversibility to steroids, after 14-day course of therapy, whereas the reversibility to 400microg of salbutamol was similar., Conclusion: Despite similar fixed airflow obstruction, elderly patients with asthma have distinct characteristics compared with patients with COPD.

Background: Diagnosing asthma cannot be always easy. It is important to consider the validity of the diagnostic tests, and/or how much more commonly they are positive in patients with asthma compared to healthy subjects and, particularly, to patients with asthma-like symptoms., Objective: To evaluate the validity of diagnostic tests for asthma, in terms of sensitivity, specificity, positive and negative predictive values, in patients with bronchial asthma compared to patients affected by gastro-oesophageal reflux disease (GERD) with asthma-like symptoms, and healthy control subjects without asthma and gastro-oesophageal reflux (GER)., Design: Single-center, cross-sectional, observational study., Patients: We studied 60 patients with mild asthma, 30 patients with GERD and asthma-like symptoms and 25 healthy control subjects., Measurements: We measured provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in 1s (MCh PC(20)/FEV(1)), the amplitude percent mean of peak expiratory flow (A%M of PEF), derived from twice-daily readings for >2 weeks, the FEV(1)/forced vital capacity (FEV(1)/FVC) ratio, the eosinophil count in blood and in induced sputum and the serum eosinophil cationic protein (ECP) levels., Results: FEV(1)/FVC ratio, A%M of PEF, blood eosinophils counts and serum ECP levels were less sensitive and specific when the reference population was composed of patients with asthma-like symptoms by GER. While, MCh PC(20)/FEV(1) and induced sputum eosinophils count were the most sensitive (both 90%) and specific (89% and 92%, respectively) tests., Conclusion: Our findings demonstrate that MCh PC(20)/FEV(1) and the induced sputum eosinophil count are the most useful objective tests in patients with mild asthma. All patients with asthma presented both an MCh PC(20)/FEV(1) <1500 microg and eosinophils count in the induced sputum >1%.

Background: Despite the improvement in detection and surgical therapy in the last years, the outcome of patients affected by colorectal carcinoma (CRC) remains limited by metastatic relapse. The aim of this study was to investigate the presence of free tumor DNA in the plasma of CRC patients in order to understand its possible prognostic role., Patients and Methods: Ki-Ras, TP53 mutations and p16(INK4A) methylation status were prospectively evaluated in tumor tissues and plasma of 66 CRC patients., Results: In 50 of the 66 primitive tumor cases (76%) at least one significant alteration was identified in Ki-Ras and/or TP53 and/or p16(INK4A) genes. Eighteen of the 50 patients presented the same alteration both in the plasma and in the tumor tissue. At univariate analysis, Ki-Ras mutations proved to be significantly related to quicker relapse (P <0.01), whereas only a trend towards statistical significance (P = 0.083) was observed for the TP53 mutations, Conclusions: Detection of Ki-Ras and TP53 mutation in plasma should be significantly related to disease recurrence. These data suggest that patients with a high risk of recurrence can be identified by means of the analysis of tumor-derived plasma DNA with the use of fairly non-invasive techniques.

Background: Methylation of the p16 promoter is one of the most frequent mechanisms of gene inactivation; its incidence is extremely variable according to the type of tumor involved. Our purpose was to analyze the hypermethylation of the p16 promoter in laryngeal squamous cell carcinomas (LSCC), salivary gland (SG) tumors and in colorectal cancer (CRC), to detect any possible association with the clinicopathological features and to determine the prognostic significance of the p16 gene in the tumors analyzed., Patients and Methods: The hypermethylation of the p16 promoter was prospectively analyzed, by MSP, in a consecutive series of 64 locally advanced LSCC patients, in a consecutive series of 33 SG tumor patients and in a consecutive series of 66 sporadic CRC patients., Results: Hypermethylation was observed in 9% of the LSCC cases, in all cases of SG cancer and in 21% of the CRC cases. No significant association was observed between p16 hypermethylation and clinicopathological variables in all the tissue samples analyzed. Moreover at univariate analysis p16 mutations were not independently related at disease relapse and death in LSCC and CRC., Conclusions: The results of this study suggest that the lack of p16 function could happen in advanced stage of SG tumors.

Background: Mammaglobin is expressed mainly in mammary tissue, overexpressed in breast cancer (BC) and rarely in other tissue. The aim of this study was to assess the sensitivity and specificity of transcript MGB1 detection and to evaluate the role of MGB1 as potential clinical marker for the detection of disseminated cancer cells in the blood of BC patients., Patients and Methods: A consecutive series of 23 BC tissues, 36 peripheral blood BC samples and 35 healthy peripheral blood samples was prospectively recruited to investigate MGB1 expression by means of a quantitative Real Time RT-PCR assay., Results: MGB1 overexpression in tissue samples of BC patients is significantly associated only with high level of Ki67 (P <0.05). None of the samples from peripheral blood of 35 healthy female individuals were positive for MGB1 transcript. In contrast MGB1 mRNA expression was detected in three of 36 (8%) peripheral blood of BC patients., Conclusions: Our preliminary results demonstrate that the detection of MGB1 transcript in peripheral blood of BC patients was specific but with low sensitivity. MGB1 overexpression by itself or in combination with Ki67 might be considered an index of BC progression.

Background: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity., Materials and Methods: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation., Results: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability., Conclusions: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.