Severe reduction of blood lysosomal acid lipase activity in cryptogenic cirrhosis: A nationwide multicentre cohort study.

Background And Aims: Blood lysosomal acid lipase (LAL) is reduced in non-alcoholic steatohepatitis, which is the major cause of cryptogenic cirrhosis (CC); few data on LAL activity in CC do exist. We investigated LAL activity in a cohort of patients with liver cirrhosis.

Methods: This is a multicentre cohort study including 274 patients with liver cirrhosis of different aetiology from 19 centres of Internal Medicine, Gastroenterology and Hepatology distributed throughout Italy.

Carotid plaque detection improves the predictive value of CHADS-VASc score in patients with non-valvular atrial fibrillation: The ARAPACIS Study.

Background And Aims: Vascular disease (VD), as assessed by history of myocardial infarction or peripheral artery disease or aortic plaque, increases stroke risk in atrial fibrillation (AF), and is a component of risk assessment using the CHADS-VASc score. We investigated if systemic atherosclerosis as detected by ultrasound carotid plaque (CP) could improve the predictive value of the CHADS-VASc score.

Methods: We analysed data from the ARAPACIS study, an observational study including 2027 Italian patients with non-valvular AF, in whom CP was detected using Doppler Ultrasonography.

An Optical System to Monitor the Displacement Field of Glass-fibre Posts Subjected to Thermal Loading.

Endocanalar posts are necessary to build up and retain coronal restorations but they do not reinforce dental roots. It was observed that the dislodgement of post-retained restorations commonly occurs after several years of function and long-term retention may be influenced by various factors such as temperature changes. Temperature changes, in fact, produce micrometric deformations of post and surrounding tissues/materials that may generate high stress concentrations at the interface thus leading to failure.

Aspirin and renal insufficiency progression in patients with atrial fibrillation and chronic kidney disease.

Background: In experimental models, thromboxane (Tx)A reduced renal perfusion and accelerated renal failure. The aim of the study was to investigate the association between the use of aspirin, which inhibits TxA production, and the incidence of an estimated Glomerular Filtration Rate (eGFR) <60 and <45ml/min/1.73m in patients with atrial fibrillation (AF) and chronic kidney disease (CKD).

Disruptions of network connectivity predict impairment in multiple behavioral domains after stroke.

Deficits following stroke are classically attributed to focal damage, but recent evidence suggests a key role of distributed brain network disruption. We measured resting functional connectivity (FC), lesion topography, and behavior in multiple domains (attention, visual memory, verbal memory, language, motor, and visual) in a cohort of 132 stroke patients, and used machine-learning models to predict neurological impairment in individual subjects. We found that visual memory and verbal memory were better predicted by FC, whereas visual and motor impairments were better predicted by lesion topography.

Indazole, Pyrazole, and Oxazole Derivatives Targeting Nitric Oxide Synthases and Carbonic Anhydrases.

Nitric oxide (NO) is an essential endogenous mediator with a physiological role in the central nervous system as neurotransmitter and neuromodulator. A growing number of studies have demonstrated that abnormal nitrergic signaling is a crucial event in the development of neurodegeneration. In particular, the uncontrolled production of NO by neuronal nitric oxide synthase (nNOS) is observed in several neurodegenerative diseases.

Dissociated functional connectivity profiles for motor and attention deficits in acute right-hemisphere stroke.

Strokes often cause multiple behavioural deficits that are correlated at the population level. Here, we show that motor and attention deficits are selectively associated with abnormal patterns of resting state functional connectivity in the dorsal attention and motor networks. We measured attention and motor deficits in 44 right hemisphere-damaged patients with a first-time stroke at 1-2 weeks post-onset.

Oxidative stress in chronic vascular disease: From prediction to prevention.

This review article is intended to describe the strong relationship between oxidative stress and vascular disease. Reactive oxygen species (ROS) play an important role in the pathogenesis of vascular disease: oxidative stress is intimately linked to atherosclerosis, through oxidation of LDL and endothelial dysfunction, to diabetes, mainly through advanced glycation end-products (AGEs)/receptor for AGE (RAGE) axis impairment, protein kinase C (PKC), aldose reductase (AR) and NADPH oxidase (NOX) dysfunction, and to hypertension, through renin–angiotensin system(RAS) dysfunction. Several oxidative stress biomarkers have been proposed to detect oxidative stress levels and to improve our current understanding of the mechanisms underlying vascular disease.

Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy.

Introduction: Protein aggregation is a common cause of neuropathology. The protein aggregation myopathy Limb-Girdle Muscular Dystrophy 1D (LGMD1D) is caused by mutations of amino acids Phe89 or Phe93 of DNAJB6, a co-chaperone of the HSP70 anti-aggregation protein. Another DNAJB6 mutation, Pro96Arg, was found to cause a distal-onset myopathy in one family.

Homocysteine, methylenetetrahydrofolate reductase, folate status and atherothrombosis: A mechanistic and clinical perspective.

Observational studies consistently reported an association between plasma total homocysteine concentrations and the risk of vascular events. In contrast, data from randomized trials largely support the hypothesis that mild elevations in homocysteine level have a modest effect on cardiovascular risk. A substantial body of evidence suggests that platelet activation is, at least in part, a transducer of the effects of high homocysteine in promoting atherothrombosis.

Selective Acetamidine-Based Nitric Oxide Synthase Inhibitors: Synthesis, Docking, and Biological Studies.

N-[(3-Aminomethyl)benzyl]acetamidine derivatives were synthesized and in vitro evaluated as inhibitors of the inducible isoform of nitric oxide synthase (iNOS). Because of the high potency of action and the excellent selectivity over the endothelial nitric oxide synthase (eNOS), compound 10 was ex vivo evaluated on isolated and perfused resistance arteries. The results confirm that compound 10 selectively inhibits the iNOS, without affecting the endothelial isoform.

Nucleophosmin contains amyloidogenic regions that are able to form toxic aggregates under physiological conditions.

Nucleophosmin (NPM)-1 is a multifunctional protein involved in a variety of biologic processes and has been implicated in the pathogenesis of several human malignancies. To gain insight into the role of isolated fragments in NPM1 activities, we dissected the C-terminal domain (CTD) into its helical fragments. In this study, we observed the unexpected structural behavior of the peptide fragment corresponding to helix (H)2 (residues 264-277).

RANK/RANKL/OPG signaling pathways in necrotic jaw bone from bisphosphonate-treated subjects.

Osteonecrosis of the jaw (ONJ) is a chronic complication affecting long-term bisphosphonate-treated subjects, recognized by non-healing exposed bone in the maxillofacial region. The pathophysiological mechanism underlying ONJ has not been fully elucidated. The aim of the present study was to investigate the role of RANK/RANKL/OPG signaling pathway and, in parallel, to evaluate angiogenic and matrix mineralization processes in jaw bone necrotic samples obtained from bisphosphonate-treated subjects with established ONJ.

Oxidative stress-related mechanisms affecting response to aspirin in diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a major cardiovascular risk factor. Persistent platelet activation plays a key role in atherothrombosis in T2DM. However, current antiplatelet treatments appear less effective in T2DM patients vs nondiabetics at similar risk.

Gel-embedded niosomes: preparation, characterization and release studies of a new system for topical drug delivery.

In the present paper physical gels, prepared with two polysaccharides, Xanthan and Locust Bean Gum, and loaded with non-ionic surfactant vesicles, are described. The vesicles, composed by Tween20 and cholesterol or by Tween85 and Span20, were loaded with Monoammonium glycyrrhizinate for release experiments. Size and zeta (ζ)-potential of the vesicles were evaluated and the new systems were characterized by rheological and dynamo-mechanical measurements.

Possible protective role of the 489C>T P2X7R polymorphism in Alzheimer's disease.

Inflammation is a key factor in the onset and progression of Alzheimer's disease (AD). The P2X7 receptor (P2X7R) is increasingly recognized as key pro-inflammatory receptor. A recent study has shown that activation of microglia by amyloid β (Aβ) and associated release of IL-1β, requires P2X7R expression.

Large-scale changes in network interactions as a physiological signature of spatial neglect.

The relationship between spontaneous brain activity and behaviour following focal injury is not well understood. Here, we report a large-scale study of resting state functional connectivity MRI and spatial neglect following stroke in a large (n=84) heterogeneous sample of first-ever stroke patients (within 1-2 weeks). Spatial neglect, which is typically more severe after right than left hemisphere injury, includes deficits of spatial attention and motor actions contralateral to the lesion, and low general attention due to impaired vigilance/arousal.

Circulating myeloid-related protein-8/14 is related to thromboxane-dependent platelet activation in patients with acute coronary syndrome, with and without ongoing low-dose aspirin treatment.

Background: Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low-dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11-dehydro-TXB2) is predictive of vascular events in high-risk patients. Myeloid-related protein (MRP)-8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events.

Functional and structural analysis of four novel mutations of CYP21A2 gene in Italian patients with 21-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder mainly caused by defects in the 21-hydroxylase gene (CYP21A2), coding for the enzyme 21-hydroxylase (21-OH). About 95% of the mutations arise from gene conversion between CYP21A2 and the inactive pseudogene CYP21A1P: only 5% are novel CYP21A2 mutations, in which functional analysis of mutant enzymes has been helpful to correlate genotype-phenotype. In the present study, we describe 3 novel point mutations (p.

The fine-tuning of TRAF2-GSTP1-1 interaction: effect of ligand binding and in situ detection of the complex.

We provide the first biochemical evidence of a direct interaction between the glutathione transferase P1-1 (GSTP1-1) and the TRAF domain of TNF receptor-associated factor 2 (TRAF2), and describe how ligand binding modulates such an equilibrium. The dissociation constant of the heterocomplex is K(d)=0.3 μM; however the binding affinity strongly decreases when the active site of GSTP1-1 is occupied by the substrate GSH (K(d)≥2.

Effects of a pulsatile electrostatic field on ischemic injury to the diabetic foot: evaluation of refractory ulcers.

Aims: The macro- and microcirculation disease, in patients with type 2 diabetes mellitus (T2DM), induces ischemic wounds of the lower limbs. We have tried to reduce the aggregation of red blood cells and to improve the O2 supply to the tissues and speed the healing of ulcers in T2DM patients.

Methods: We enrolled 25 obese subjects without glucose intolerance (group A; BMI greater than 30 kg/m2), 20 obese adults intolerant to glucose (group B) and two subgroups, groups C and D, with T2DM and with leg ulcers.

Exhaled breath condensate, nasal eosinophil cationic protein level and nasal cytology during immunotherapy for cypress allergy.

Interest in cypress allergy is widely rising: an increasing number of studies have pointed out the efficacy of immunotherapy to reduce cypress-related symptoms and drug use. Cypress immunotherapy is well tolerated, but there are few studies dealing with its sub-clinical effects on the airways. The aim of this investigation is to assess the effects of immunotherapy on airways by the analysis of exhaled breath condensate (EBC), nasal lavage fluid (NAL) and nasal cytology.

Nucleophosmin mutations in acute myeloid leukemia: a tale of protein unfolding and mislocalization.

Nucleophosmin (NPM1) is an abundant, ubiquitously expressed protein mainly localized at nucleoli but continuously shuttling between nucleus and cytoplasm. NPM1 plays a role in several cellular functions, including ribosome biogenesis and export, centrosome duplication, chromatin remodeling, DNA repair, and response to stress stimuli. Much of the interest in this protein arises from its relevance in human malignancies.