In silico analysis and theratyping of an ultra-rare CFTR genotype (W57G/A234D) in primary human rectal and nasal epithelial cells

Mutation targeted therapy in cystic fibrosis (CF) is still not eligible for all CF subjects, especially for cases carrying rare variants such as the CFTR genotype W57G/A234D (c.169T>G/c.701C>A). We performed in silico analysis of the effects of these variants on protein stability, which we functionally characterized using colonoids and reprogrammed nasal epithelial cells. The effect of mutations on cystic fibrosis transmembrane conductance regulator (CFTR) protein was analyzed by western blotting, forskolin-induced swelling (FIS), and Ussing chamber analysis. We detected a residual CFTR function that increases following treatment with the CFTR modulators VX661±VX445±VX770, correlates among models, and is associated with increased CFTR protein levels following treatment with CFTR correctors. In vivo treatment with VX770 reduced sweat chloride concentration to non-CF levels, increased the number of CFTR-dependent sweat droplets, and induced a 6% absolute increase in predicted FEV1% after 27 weeks of treatment indicating the relevance of theratyping with patient-derived cells in CF

Anodal Transcranial Direct Current Stimulation Promotes Frontal Compensatory Mechanisms in Healthy Elderly Subjects

Recent studies have demonstrated that transcranial direct current stimulation (tDCS) is potentially useful to improve working memory. In the present study, young and elderly subjects performed a working memory task (n-back task) during an electroencephalogram recording before and after receiving anodal, cathodal, and sham tDCS over the left dorsolateral prefrontal cortex (DLPFC). We investigated modulations of behavioral performance and electrophysiological correlates of working memory processes (frontal and parietal P300 event-related potentials). A strong tendency to modulated working memory performance was observed after the application of tDCS. In detail, young, but not elderly, subjects benefited from additional practice in the absence of real tDCS, as indicated by their more accurate responses after sham tDCS. The cathodal tDCS had no effect in any group of participants. Importantly, anodal tDCS improved accuracy in elderly. Moreover, increased accuracy after anodal tDCS was correlated with a larger frontal P300 amplitude. These findings suggest that, in elderly subjects, improved working memory after anodal tDCS applied over the left DLPFC may be related to the promotion of frontal compensatory mechanisms, which are related to attentional processes

Quantitative analysis of HBsAg, IgM anti-HBc and anti-HBc avidity in acute and chronic hepatitis B.

Background and objectives: We evaluated hepatitis B virus (HBV) serological markers by novel, quantitative immunoassays in order to study their behaviours and possible role in the various phases of HBV infection. Study design: The quantitative determination of HBsAg and anti-HBc/IgM by chemiluminescent immunoassays (Abbott Architect) and the calculation of anti-HBc avidity index have been carried out on repository specimens from patients with acute or chronic hepatitis B. Results: In acute hepatitis the levels of HBsAg were generally >10,000 UI/mL and decreased sharply in the recovery phase. In 35 anti-HBepositive chronic hepatitis cases HBsAg levels were generally lower than 10,000 UI/mL (mean: 2655), whereas in five HBeAg-positive chronic hepatitis patients the mean value was 78,756 UI/mL and 90% of specimens exceeded 10,000 UI/mL. The lowest values (mean: 1029 IU/mL) were found in the seven patients with minimal hepatic damage. IgM anti-HBc antibodies were positive in all acute cases and in 68/207 samples (32.85%) from patients with chronic hepatitis, with significantly lower levels (average sample/cutoff (S/CO) ratio: 2.95 in chronic cases versus 25.96 in acute cases; p < 0.005). A S/CO value of 10 for anti-HBc IgM had a 100% negative predictive value and a 99.13% positive predictive value for acute hepatitis B. The study of anti-HBc avidity by an experimental procedure showed that an avidity index (AI) threshold of 0.7 had a good efficacy to discriminate the cases of chronic hepatitis, among whom only 2 specimens out of 193 (1.04%) had an AI < 0.7. Conclusion: The quantitative determination of HBsAg, anti-HBc/IgM and anti-HBc avidity provides additional information and may be useful in the differential diagnosis of acute and chronic HBV infections and in the follow-up of chronically infected patients

Prognostic Role of 2-[18F]FDG PET/CT Metabolic Volume Parameters in Patients Affected by Differentiated Thyroid Carcinoma with High Thyroglobulin Level, Negative 131I WBS and Positive 2-[18F]-FDG PET/CT

The clinical and prognostic role of 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography/computed tomography (2-[(18)F]FDG PET/CT) in the study of patients affected by differentiated thyroid carcinoma (DTC) with positive serum thyroglobulin (Tg) level and negative [(131)I] whole-body scan ([(131)I]WBS) has already been demonstrated. However, the potential prognostic role of semi-quantitative PET metabolic volume features, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), has not yet been clearly investigated. The aim of this retrospective study was to investigate whether the main metabolic PET/CT parameters may predict the prognosis. We retrospectively included 122 patients with a positive 2-[(18)F]FDG PET/CT for DTC disease after a negative [(131)I]WBS with Tg > 10 ng/mL. The maximum and mean standardized uptake value (SUVmax and SUVmean), MTV and TLG of the hypermetabolic lesion, total MTV (tMTV) and total TLG (tTLG) were measured for each scan. Progression-free survival (PFS) and overall survival (OS) curves were plotted according to the Kaplan–Meier analysis. After a median follow up of 53 months, relapse/progression of disease occurred in 87 patients and death in 42. The median PFS and OS were 19 months (range 1–132 months) and 46 months (range 1–145 months). tMTV and tTLG were the only independent prognostic factors for OS. No variables were significantly correlated with PFS. The best thresholds derived in our sample were 6.6 cm(3) for MTV and 119.4 for TLG. In patients with negative WBS and Tg > 10 ng/mL, 2-[(18)F]FDG PET/CT metabolic volume parameters (tMTV and tTLG) may help to predict OS

Correlation between human nervous system development and acquisition of fetal skills: An overview

Understanding the association between fetal nervous system structure and functioning should be an important goal in neurodevelopmental sciences, especially when considering the emerging knowledge regarding the importance of prenatal onset. Intrauterine development of the human central nervous system consists of specific processes: neurogenesis, neuronal migration, synaptogenesis, and myelination. However, as extensively shown by the neurobehavioral studies in the last century, the development of the central nervous system involves both structure and functioning. It is now recognised that the developing motor and sensory systems are able to function long before they have completed their neural maturation and that the intrauterine experience contributes to neurobehavioral development. This review analyzes the recent literature, looking at the association between the human nervous system maturation and fetal behavior. This article will follow the development and skill acquisition of the anatomical nervous system across the three trimesters of the gestation period

Clinical and prognostic role of detection timing of distant metastases in patients with differentiated thyroid cancer

Distant metastases (DM) from DTC occur in 5-25% of cases and are correlated to lower survival; the prognostic significance of the temporal onset of DM is unclear. Our aim was to retrospectively analyze the prevalence of DM and to assess the prognostic role of the timing of manifestation of DM regarding the outcome

Nuclear cardiology and heart failure

Abstract The prevalence of heart failure in the adult population is increasing. It varies between 1% and 2%, although it mainly affects elderly people (6-10% of people over the age of 65 years will develop heart failure). The syndrome of heart failure arises as a consequence of an abnormality in cardiac structure, function, rhythm, or conduction. Coronary artery disease is the leading cause of heart failure and it accounts for this disorder in 60-70% of all patients affected. Nuclear techniques provide unique information on left ventricular function and perfusion by gated-single photon emission tomography (SPECT). Myocardial viability can be assessed by both SPECT and PET imaging. Finally, autonomic dysfunction has been shown to increase the risk of death in patients with heart disease and this may be applicable to all patients with cardiac disease regardless of aetiology. MIBG scanning has a very promising prognostic value in patients with heart failure

Prognostic role of pretreatment 18F-FDG PET/CT in primary brain lymphoma

Primary brain lymphoma is an aggressive extranodal non-Hodgkin lymphoma with poor prognosis. Many possible prognostic factors are investigated with controversial results, but possible prognostic role of 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) features remains unclear. Our aim was to study the metabolic behavior of brain lymphoma at 18F-FDG PET/CT and the prognostic impact of qualitative and semiquantitative PET/CT parameters