Delphi consensus on the current clinical and therapeutic knowledge on Anderson-Fabry disease

BACKGROUND: Management of Anderson-Fabry disease (AFD) is contentious, particularly regarding enzyme replacement therapy (ERT). We report results of a Delphi consensus panel on AFD management. METHODS: A survey to gauge consensus among AFD experts was distributed online and responses were analysed. Statements on: 1) diagnosis; 2) when starting ERT; 3) management of ERT infusion and adverse reactions; and 4) follow-up/monitoring response to therapy and progression of disease were included. Responses without consensus were discussed with an enlarged panel and modified to reach consensus. RESULTS: 15 experts responded to the survey. After plenary discussion among the enlarged panel, consensus was reached on most statements. Key points were the use of a target organ biopsy to show Gb3 deposits in symptomatic women with negative molecular analysis, the need for ERT in symptomatic women and in all patients with persistent signs and symptoms±organ damage. It was agreed to assess vital signs before ERT administration and use a 0.2μL filter on infusion to reduce the risk of adverse reactions, that serum should be drawn prior to the first infusion for anti-agalsidase antibody analysis to have a baseline value if a subsequent adverse reaction appears, and that pre-medication is required in those with prior infusion reactions. Holter ECG monitoring, cardiac and brain MRI, renal parameters, and abdominal ultrasound were considered important for the assessment of disease progression and response at ERT. CONCLUSIONS: This consensus supplies guidance to healthcare providers on best practice in the management of patients with AFD and indicates a need for more guidanc

Infarct-like myocarditis with coronary vasculitis and aneurysm formation caused by epstein–barr virus infection

Myocardial infection by Epstein–Barr virus (EBV) may manifest with inflammatory cardiomyopathy, coronary syndrome X, and rarely with infarct-like myocarditis. The aim of the report is to describe a case of myocardial EBV infection causing acute myocarditis with heart failure, necrotizing coronary vasculitis, and multiple left ventricular (LV) aneurysms. A 67-year-old woman presented with fever, chest pain, and heart failure. She underwent non-invasive cardiac studies including electrocardiography, 2D-echocardiography, cardiac magnetic resonance, hematochemical exams with Troponin T determination, and invasive studies including cardiac catheterization, coronary angiography, and LV endomyocardial biopsy. Five endomyocardial samples were processed for histology and immunohistochemistry for inflammatory cells characterization and detection of viral antigens. Two additional frozen samples were evaluated by real-time polymerase chain reaction for the presence of cardiotropic viral genomes. Routine laboratory tests revealed the presence of elevated white blood cells (17 000 103/μL) and increased Troponin T. Electrocardiogram showed sinus tachycardia with ST elevation in V2–V5. Two-dimensional echocardiography showed normal LV dimension with reduced LV contractility (LVEF = 40%) with mild pericardial effusion. Cardiac magnetic resonance revealed the presence of a micro-aneurism in the inferior LV wall, a diffuse oedematous imbibition of LV myocardium suggested by hyper-intensity of T2 mapping, and increased fibrosis as suggested by areas of late gadolinium enhancement signals. Coronary arteries were normal while several micro-aneurysms were observed at LV angiography. At histology, a lymphocytic myocarditis with necrotizing coronary vasculitis sustained by a positive real-time polymerase chain reaction for EBV, detectable in cardiomyocytes and inflamed intramural vessels by positive immunohistochemistry for EBV latent membrane protein 1 antigen, was observed. Myocardial EBV infection is an unusual cause of acute heart failure and cardiac aneurysms, increasing the risk of electrical instability, cardiac perforation, and sudden death

Hypoxia and inflammation as a consequence of β-fibril accumulation. A perspective view for new potential therapeutic targets

Amyloidoses are heterogeneous diseases that result from the deposition of toxic insoluble β-sheet fibrillar protein aggregates in different tissues. The cascade of molecular events leading to amyloidoses and to the related clinical manifestations is not completely understood. Nevertheless, it is known that tissue damage associated to this disease involves alteration of tissue architecture, interaction with cell surface receptors, inflammation elicited by the amyloid protein deposition, oxidative stress, and apoptosis. However, another important aspect to consider is that systemic protein massive deposition not only subverts tissue architecture but also determines a progressive cellular hypertrophy and dilation of the extracellular space enlarging the volume of the organ. Such an alteration increases the distance between cells and vessels with a drop in pO2 that, in turn, causes both necrotic cell death and activation of the hypoxia transcription factor HIF-1α. Herewith, we propose the hypothesis that both cell death and hypoxia represent two important events for the pathogenesis of damage and progression of amyloidoses. In fact, molecules released by necrotic cells activate inflammatory cells from one side while binding to HIF-1α-dependent membrane receptors expressed on hypoxic parenchymal cells on the other side. This latter event generates a signaling cascade triggering NFκB activation and chronic inflammation. Finally, we also suggest that this scenario, once proved and detailed, might suggest important targets for new therapeutic interventions

SNOWFALL ANALYSIS OVER PENINSULAR ITALY IN RELATIONSHIP TO THE DIFFERENT TYPES OF SYNOPTIC CIRCULATION: FIRST RESULTS

The time series of snow data for a sample of Italian meteorological stations have been analyzed taking into account, for the time series, an acceptable continuity and quality of meteorological data. The data set is that of the Italian Meteorological Service (UGM), and refer to the period 1982–2004. The Slovenian station of Kredarica, located in the Julian Alps, has been added for convenience. The study is composed of two different parts: - Climatologic analysis of the snow parameters during the last 20 years. In particular, the height of the fresh snow and the number of days with permanence of snow at the ground have been analyzed. - Evidence of the synoptic situations in which snowfalls are observed with at least a thickness of 10 cm in at least a third of the total number of analyzed stations in Central, Southern and insular Ital

THE ROLE OF IMMUNITY SUPPRESSION IN TREATMENT OF MYOCARDITIS

Regardless the common consensus on the benefits of immunity suppression in eosinophilic, granulomatous, giant cell and lymphocyte myocarditis, associated with systemic connective tissue diseases, and in rejection of transplanted heart, role of immune suppression therapy (IST) in treatment of lymphocyte inflammatory cardiomyopathy remains controversial. Previous retrospective studies revealed clinical improvement in 90% of patients with virus-negative inflammatory cardiomyopathy and absence of response or worsening of heart function in 85% of virus-positive inflammatory cardiomyopathy after immunity suppression. Other studies identified the enhanced expression of HLA in cardiomyocytes as an additional indicator of sensitivity of inflammatory cardiomyopathy to IST. Recently, the singlecenter randomized study was performed with double blind application of prednisone and azatioprin as addition to maintenance therapy in 85 patients with virus-negative inflammatory cardiomyopathy. The results of the study showed significant improvement of the left ventricle ejection fraction and decrease of the left ventricle dimensions in 88% patients among 43 of treated comparing to 42 patients on placebo demonstrated worsening of cardiac functioning in 83% cases (the TIMIC study). This data confirms the efficacy of immunity suppression in virus-negative inflammatory cardiomyopathy. Insufficiency of response in 12% cases undermines existence of non-revealed viruses and mechanisms of damage and inflammation, non-sensitive to immunity suppression. Restoring of cardiac function in patients actively responded to immunity suppression, was determined by inhibition of cardiomyocytes death and increase of cells proliferation with ad novo synthesized contractile material

Myocarditis and intramural coronary vasculitis in polyarteritis nodosa: an unusual treatable form of heart failure

We describe an uncommon cardiac presentation of polyarteritis nodosa. A 68-year-old woman, with a history of fatigue, weight loss, and myalgia of the lower extremities, was admitted for congestive heart failure. Coronary arteries were normal. Endomyocardial biopsy showed active lymphocytic myocarditis with associated intramural small vessels necrotizing vasculitis. The overexpression of TLR-4 and the negativity for myocardial viruses suggested an immune mediated mechanism of cardiac damage. These histologic findings associated to weight loss >4 kg not due to dieting or other factors, myalgias, and polyneuropathy, were consistent with the diagnosis of polyarteritis nodosa. Immunosuppressive treatment, consisting of cyclophosphamide and prednisolone, led to a significant improvement of cardiac function. Polyarteritis nodosa can be the cause of unexplained heart failure due to myocarditis and intramural vessels vasculitis. Its recognition is crucial to obtain a cardiac recovery with a tailored immunosuppressive treatment

Mutational Landscape of Bone Marrow CD19 and CD138 Cells in Waldenström Macroglobulinemia (WM) and IgM Monoclonal Gammopathy of Undetermined Significance (IgM MGUS)

Despite recurrent and activating mutations, including MYD88, CXCR4, ARID1A, KMT2D, and CD79B were identified, the genetic basis for Waldenström’s Macroglobulinemia (WM) and the risk of progression of IgM MGUS to WM remain to be fully elucidated. We investigated the mutation status of WM (n=8), sWM (n=7), and IgM MGUS (n=5) patients, by performing high-throughput targeted AmpliSeq NGS on 117 target genes. We detected the classic mutation MYD88L265P in 93% of WM/sWM and in 60% of IgM MGUS patients. The CXCR4S338Ter mutation was identified in 26% of WM/sWM patients, whereas it was undetectable in IgM MGUS subjects. Interestingly, we identified new mutated genes, including WNK2 somatic mutations affecting 46% of WM/sWM patients, for which a recurrent allelic variant (V1635Ter) was observed in this cohort, and BCL9 with a frameshift variant (P516Lfs) in 26% of WM/sWM and in one IgM MGUS patient. Moreover, sequencing evaluation revealed recurrently frameshift or missense mutations involving NFKB2 (L473Afs), PTPN13 (P1546Tfs), CARD11 (S622del), KMT2C (I823T), and ATM in WM and IgM MGUS patients

Physical and chemical mechanisms involved in adhesion of orthodontic bonding composites: in vitro evaluations

BackgroundBond strength of orthodontic composite is strongly influenced by molecular and structural mechanisms. Aim of this in vitro study was to compare bond strength of light-cure orthodontic composites by measuring debonding forces and evaluating locations of bond failure. Investigations on chemical compositions clarified adhesive behaviors and abilities, exploring effects of ageing processes in this junction materials.MethodsTwelve enamel discs, from human premolars, were randomly coupled to one orthodontic adhesive system (Transbond XT (TM) 3 M UNITEK, USA, Light-Cure Orthodontic Paste, LEONE, Italy and Bisco Ortho Bracket Paste LC, BISCO, Illinois) and underwent to Shear Bond Strength test. Metallic brackets were bonded to twenty-seven human premolar, with one of the adhesive systems, to quantify, at FE-SEM magnifications, after debonding, the residual material on enamel and bracket base surfaces. Raman Spectroscopy analysis was performed on eight discs of each composites to investigate on chemical compositions, before and after accelerated aging procedures in human saliva and sugary drink.ResultsOrthodontic adhesive systems showed similar strength of adhesion to enamel. The breakage of adhesive-adherent bond occurs in TXT at enamel-adhesive interface while in Bisco and Leone at adhesive-bracket interface. Accelerated in vitro aging demonstrated good physical-chemical stability for all composites, Bisco only, was weakly contaminated with respect to the other materials.ConclusionA similar, clinically adequate and acceptable bond strength to enamel for debonding maneuvers was recorded in all orthodontic adhesive systems under examination. No significant chemical alterations are recorded, even in highly critical situations, not altering the initial mechanical properties of materials