Search

congenital bleeding disorders

Background - In Italy, the National Register of Congenital Coagulopathies (NRCC) collects epidemiological and therapeutic data from patients affected by haemophilia A (HA), haemophilia B (HB), von Willebrand's disease (vWD) and other rare coagulation disorders. Here we present data from the 2016 annual survey. Materials and methods - Data are provided by the Italian Haemophilia Centres, on a voluntary basis. Information flows from every Centre to a web-based platform of the Italian Association of Haemophilia Centres, shared with the Italian National Institute of Health, in accordance with current privacy laws. Patients are classified by diagnosis, disease severity, age, gender and treatment-related complications. Results - In 2016, the total number of patients with congenital coagulopathies in the NRCC was 10,360: 39.8% of these patients had HA, 31.5% had vWD, 8.5% had HB, and 20.2% had less common factor deficiencies. The overall prevalence of HA and HB was 13.9/100,000 males and 3.0/100,000 males, respectively. The overall prevalence of vWD was 5.4/100,000 inhabitants. During 2016, 126 patients had current alloantibodies to factor VIII (FVIII) or factor IX (FIX) and were under treatment with bypassing agents and/or immune tolerance induction. Overall, 388 patients with a history of alloantibodies were recorded in the NRCC of whom 337 with severe HA and 12 with severe HB. Coagulation factor use, evaluated from treatment plans, was approximately 451,000,000 IU of FVIII for HA patients (7.5 IU/inhabitant), and approximately 53,000,000 IU of FIX for HB patients (0.9 IU/inhabitant). Discussion - The prevalences of HA and HB fall within the ranges reported in more developed countries; the consumption of FVIII and FIX was in line with that of other European countries (France, United Kingdom) and Canada. The NRCC, with its bleeding disorder dataset, is a helpful tool for shaping public health policies, as well as planning clinical and epidemiological research projects.

Objectives: HbS/β+ patients’ presence in Italy increased due to immigration; these patients are clinically heterogeneous, and specific guidelines are lacking. Our aim is to describe a cohort of HbS/β+ patients, with genotype-phenotype correlation, in order to offer guidance for clinical management of such patients. Methods: Retrospective cohort study of HbS/β+ patients among 15 AIEOP Centres. Results: A total of 41 molecularly confirmed S/β+ patients were enrolled (1-55years, median 10.9) and classified on β+ mutation: IVS-I-110, IVS-I-6, promoter, and “others.” Prediagnostic events included VOC 16/41 (39%), ACS 6/41 (14.6%), sepsis 3/41 (3.7%), and avascular necrosis 3/41 (7,3%). Postdiagnostic events were VOC 22/41 (53.6% %), sepsis 4/41 (9.7%), ACS 4/41 (9.7%), avascular necrosis 3/41 (7.3%), aplastic crisis 2/41 (4.8%), stroke 1/41 (2.4%), ACS 1/41 (2.4%), and skin ulcerations 1/41 (2.4%). The IVS-I-110 group presented the lowest median age at first SCD-related event (P=.02 vs promoter group) and the higher median number of severe events/year (0.26 events/patient/year) (P=.01 vs IVS-I-6 and promoter groups). Promoter group presented a specific skeletal phenotype. Treatment regimen applied was variable among the centers. Conclusions: HbS/β+ is not always a mild disease. Patients with IVS-I-110 mutation could benefit from a standard of care like SS and S/β° patients. Standardization of treatment is needed.

TAVOLA ROTONDA - L'argomento della Tavola Rotonda è di grande attualità poiché all'interno del Recovery Plan vi sono fondi specifici destinati alla parità di genere e alla coesione, e il loro opportuno indirizzo potrà contribuire a un cambiamento sostanziale della grave situazione generata dalla pandemia e che ha colpito in particolare le donne. E un tema che coinvolge il mondo della formazione, della ricerca, delle imprese, delle politiche sociali e il CPO-SIF qui propone una discussione tra le varie parti in un tavolo di eccellenza al femminile, per confrontarsi e ripartire investendo nelle donne.

Vaccination against communicable diseases is crucial for disease prevention, but this practice poses challenges to healthcare professionals in patients with haemophilia. Poor knowledge of the vaccination requirements for these patients and safety concerns often result in vaccination delay or avoidance. In order to address this issue, a panel of 11 Italian haemophilia and immunization experts conducted a Delphi consensus process to identify the main concerns regarding the safe use of vaccines in patients with haemophilia. The consensus was based on a literature search of the available evidence, which was used by the experts to design 27 consensus statements. A group of clinicians then rated these statements using the 5‐point Likert‐type scale (1 = strongly disagree; 5 = strongly agree). The main issues identified by the expert panel included vaccination schedule for haemophilic patients; protocol and optimal route of vaccine administration; vaccination of haemophilic patients with antibodies inhibiting coagulation factor VIII (inhibitors); and vaccination and risk of inhibitor development. This manuscript discusses these controversial areas in detail supported by the available literature evidence and provides evidence‐ and consensus‐based recommendations. Overall, participants agreed on most statements, except those addressing the potential role of vaccination in inhibitor formation. Participants agreed that patients with haemophilia should receive vaccinations according to the institutional schedule for individuals without bleeding disorders; however, vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk. Data also suggest vaccination timing does not need to take into consideration when the patient received factor VIII replacement.

Summary: Giant lipomas affecting the retroperitoneum and pelvis are quite rare. The surgical management of these lesions may be technically demanding and controversies exist with respect to diagnosis, competences being involved, type of surgical approach, radicality, and timing. A unique case presentation of a giant lipoma occupying the whole pelvis and the gluteal region is presented. Due to its size, many anatomical areas are involved, requiring the expertise of multiple specialists to treat. After multidisciplinary counseling, the lesion is radically resected in one stage by using a new videolaparoscopically assisted transperineal access to the pelvis. This type of surgical approach may be of interest for resecting pelvic tumors in women and men.

Long non-coding RNAs (lncRNAs), an emerging group of gene expression regulators in normal and cancer cells, are defined as endogenous RNAs consisting of more than 200 nucleotides and lacking an ope...

Primary myelofibrosis (PMF) is a Philadelphia-negative (Ph-) myeloproliferative disorder, showing abnormal CD34+ progenitor cell trafficking, splenomegaly, marrow fibrosis leading to extensive extramedullary haematopoiesis, and abnormal neoangiogenesis in either the bone marrow or the spleen. Monocytes expressing the angiopoietin-2 receptor (Tie2) have been shown to support abnormal angiogenic processes in solid tumors through a paracrine action that takes place in proximity to the vessels. In this study we investigated the frequency of Tie2 expressing monocytes in the spleen tissue samples of patients with PMF, and healthy subjects (CTRLs), and evaluated their possible role in favouring spleen angiogenesis. We show by confocal microscopy that in the spleen tissue of patients with PMF, but not of CTRLs, the most of the CD14+ cells are Tie2+ and are close to vessels; by flow cytometry, we found that Tie2 expressing monocytes were Tie2+CD14lowCD16brightCDL62-CCR2- (TEMs) and their frequency was higher (p = 0.008) in spleen tissue-derived mononuclear cells (MNCs) of patients with PMF than in spleen tissue-derived MNCs from CTRLs undergoing splenectomy for abdominal trauma. By in vitro angiogenesis assay we evidenced that conditioned medium of immunomagnetically selected spleen tissue derived CD14+ cells of patients with PMF induced a denser tube like net than that of CTRLs; in addition, CD14+Tie2+ cells sorted from spleen tissue derived single cell suspension of patients with PMF show a higher expression of genes involved in angiogenesis than that found in CTRLs. Our results document the enrichment of Tie2+ monocytes expressing angiogenic genes in the spleen of patients with PMF, suggesting a role for these cells in starting/maintaining the pathological angiogenesis in this organ.

The anelastic behavior of 5N-Al thin foils with three different thicknesses (10, 50 and 125 µm) was investigated in the temperature range from 300 to 720 K through Mechanical Spectroscopy (MS) measurements performed by using a completely automated vibrating reed analyser. Two relaxation peaks P1 and P2 and a relevant high temperature background were observed in the thinnest samples whereas only the grain boundary peak (PGB) was observed in the thickest ones. Detailed TEM observations and X-ray diffraction (XRD) measurements indicate that defective structures depend on foil thickness and suggest that the origin of P1 and P2 peaks is connected to the vibration dynamics of isolated dislocations not organized in networks. P1 has been attributed to the combination of dislocatio n motion through the stress field of other dislocations and thermally activated cross slip, while P2 is due to the movement of jogs assisted by pipe diffusion. In addition to anelastic effects due to dislocation vibration, permanent grain boundary sliding seems to contribute to the high temperature background observed in the thinnest foils.

Background: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN. Methods: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines. Results: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models. Conclusions: Trabectedin could be good candidate for clinical studies in JMML/CMML patients.

L'articolo analizza sinteticamente i processi di costruzione, conflitto e negoziazione del patrimonio del Museo dell’Arte Fabbrile e delle Coltellerie (MAFC) di Maniago, in Friuli Venezia Giulia. Nell'arco di dieci anni di ricerca museografica sul campo il Museo è stato influenzato dalle politiche di patrimonializzazione, passando dalla fase di Museo tecnico, partecipativo, commerciale e turistico trasformandosi in un'arena sociale dove i vari stakeholder e attori sociali mettono in gioco strategie e tattiche che interpretano e declinano il patrimonio materiale e immateriale con diversi usi e funzioni. Il museo diventa un'area di frizione e di mediazione politica tra heritage, etnologia e turismo a geometrie variabili dal livello identitario locale a quello globale delle liste di patrimonializzazione Unesco.

In this paper we introduce a model describing diffusion of species by a suitable regularization of a "forward-backward" parabolic equation. In particular, we prove existence and uniqueness of solutions, as well as continuous dependence on data, for a system of partial differential equations and inclusion, which may be interpreted, e.g., as evolving equation for physical quantities such as concentration and chemical potential. The model deals with a constant mobility and it is recovered from a possibly non-convex free-energy density. In particular, we render a general viscous regularization via a maximal monotone graph acting on the time derivative of the concentration and presenting a strong coerciveness property., Key words: diffusion of species, forward-backward parabolic equation, non-smooth regularization, initial-boundary value problem, well-posedness, hysteresis

Endothelial progenitor cells could be implicated in the aberrant neoangiogenesis that occurs in bone marrow and spleen in patients with primary myelofibrosis (PMF). However, antivascular endothelial growth factor (VEGF) monotherapy had only a modest and transient effect in these individuals. Recently it was found that VEGF-induced proangiogenic intracellular Ca 2+ oscillations could be impaired in endothelial progenitor cells of subjects with malignancies. Therefore, we employed Ca 2+ imaging, wavelet analysis, and functional assays to assess whether and how VEGF-induced Ca 2+ oscillations are altered in PMF-derived endothelial progenitor cells. We focused on endothelial colony-forming cells (ECFCs), which are the only endothelial progenitor cell subtype capable of forming neovessels both in vivo and in vitro. VEGF triggers repetitive Ca 2+ spikes in both normal ECFCs (N-ECFCs) and ECFCs obtained from PMF patients (PMF-ECFCs). However, the spiking response to VEGF is significantly weaker in PMF-ECFCs. VEGF-elicited Ca 2+ oscillations are patterned by the interaction between inositol-1,4,5-trisphosphate-dependent Ca 2+ mobilization and store-operated Ca 2+ entry. However, in most PMF-ECFCs, Ca 2+ oscillations are triggered by a store-independent Ca 2+ entry pathway. We found that diacylglycerol gates transient receptor potential canonical 1 channel to trigger VEGF-dependent Ca 2+ spikes by recruiting the phospholipase C/inositol-1,4,5-trisphosphate signaling pathway, reflected as a decrease in endoplasmic reticulum Ca 2+ content. Finally, we found that, apart from being less robust and dysregulated as compared with N-ECFCs, VEGF-induced Ca 2+ oscillations modestly stimulate PMF-ECFC growth and in vitro angiogenesis. These results may explain the modest effect of anti-VEGF therapies in PMF.

Background The number of patients with sickle cell disease (SCD) has increased in Italy in the past decade due to immigration. In spite of the established efficacy of hydroxyurea (HU) in childhood, population-based data regarding its prescription and effectiveness come mainly from studies performed in adults or outside Europe. Population and methods The Hydroxyurea in SCD: A Large Nation-wide Cohort Study from Italy was a retrospective cohort study of adult and pediatric patients with SCD attending 32 centers. Pediatric data are analyzed separately. Results Out of 504 children followed in 11 centers, 206 (40%) were on HU (194 SS/Sβ°, 12 SC/Ss+); 74% came from Sub-Saharian Africa and 18% from Europe. HU therapy indications for SS/Sβ° patients were as follows: 57% painful vaso-occlusive crisis, acute chest syndrome or both, 24% anemia, 8% anemia, and other reasons (the majority had Hb ≤ 8–8.5 g/dl, revealing scarce acceptance of low Hb values by pediatric hematologist). Mean starting dose was 15.5 mg/kg, and dose at full regimen was 17.1 mg/kg. Mean age at HU therapy was 7.68 years, although it was lower for SS/Sβ° patients. Only 10% started HU before 3 years. In 92%, 500 mg capsule was used; in 6%, the galenic was used; and in 2%, 100 mg tablet was used. Significant reduction of clinical events and inpatients admissions, with improvement in hematological parameters, was observed for SS/Sβ° patients and a trend toward improvement for SC/Ss+ patients was also observed. Conclusions HU effectiveness is demonstrated in a national cohort of children with SCD living in Italy, even at a lower dose than recommended, revealing good adherence to a treatment program by a socially vulnerable group of patients such as immigrants.