Active shape correction of a thin glass/plastic X-ray mirror

Optics for future X-ray telescopes will be characterized by very large aperture and focal length, and will be made of lightweight materials like glass or plastic in order to keep the total mass within acceptable limits. Optics based on thin slumped glass foils are currently in use in the NuSTAR telescope and are being developed at various institutes like INAF/OAB, aiming at improving the angular resolution to a few arcsec HEW. Another possibility would be the use of thin plastic foils, being developed at SAO and the Palermo University. Even if relevant progresses in the achieved angular resolution were recently made, a viable possibility to further improve the mirror figure would be the application of piezoelectric actuators onto the non-optical side of the mirrors. In fact, thin mirrors are prone to deform, so they require a careful integration to avoid deformations and even correct forming errors. This however offers the possibility to actively correct the residual deformation. Even if other groups are already at work on this idea, we are pursuing the concept of active integration of thin glass or plastic foils with piezoelectric patches, fed by voltages driven by the feedback provided by X-rays, in intra-focal setup at the XACT facility at INAF/OAPA. In this work, we show the preliminary simulations and the first steps taken in this project

Stem Cell Modeling of Neuroferritinopathy Reveals Iron as a Determinant of Senescence and Ferroptosis during Neuronal Aging

Neuroferritinopathy (NF) is a movement disorder caused by alterations in the L-ferritin gene that generate cytosolic free iron. NF is a unique pathophysiological model for determining the direct consequences of cell iron dysregulation. We established lines of induced pluripotent stem cells from fibroblasts from two NF patients and one isogenic control obtained by CRISPR/Cas9 technology. NF fibroblasts, neural progenitors, and neurons exhibited the presence of increased cytosolic iron, which was also detectable as: ferritin aggregates, alterations in the iron parameters, oxidative damage, and the onset of a senescence phenotype, particularly severe in the neurons. In this spontaneous senescence model, NF cells had impaired survival and died by ferroptosis. Thus, non-ferritin-bound iron is sufficient per se to cause both cell senescence and ferroptotic cell death in human fibroblasts and neurons. These results provide strong evidence supporting the primary role of iron in neuronal aging and degeneration

UN RARO CASO DI POLICONDRITE RICORRENTE A PREVALENTE ESPRESSIONE IPOGLOTTICA

La policondrite ricorrente è una malattia infiammatoria cronica, immunomediata e sistemica, caratterizzata da flogosi e progressiva alterazione della matrice cartilaginea. Si manifesta solitamente intorno alla V decade di vita, con una distribuzione equa fra M e F di razza caucasica e con una incidenza di 3.5 casi per mln/ab/anno. La eziopatogenesi permane sconosciuta ma il frequente riscontro con altre patologie autoimmuni e le caratteristiche microscopiche propendono per una patologia autoimmune. Clinicamente determina un ampio spettro di manifestazioni che variano da episodi intermittenti, dolorosi ed autolimitanti di condrite auricolare e nasale, ad espressioni deturpanti o potenzialmente fatali come il collasso tracheale, ampie perforazioni settali o patologie cardiovascolari, articolari ed oculari. La sua rarità e la mancanza di linee guida assolute comportano spesso ritardi diagnostici o difficoltà nella gestione clinica. I criteri diagnostici di riferimento, proposti da McAdam, definiscono Policondrite la positività in tre dei seguenti aspetti clinici: Condrite auricolare bilaterale, Poliartrite non erosiva, Condrite nasale, Infiammazione oculare, Condrite delle vie aeree, Disfunzione Cocleare o Vestibolare. Tali manifestazioni cliniche devono essere avallate dal riscontro istologico. E’ definita istologicamente dall’ infiltrazione di linfociti T (>CD4+), la presenza di depositi di immunocomplessi nelle aree coinvolte (IgG e C3) rivolti verso il collagene di tipo II, IX e XI , la matrillina1 e la proteina oligomerica della matrice cartilaginea (COMP). Gli esami di laboratorio evidenziano VES e PCR elevate, leucocitosi, anemia, trombocitosi, iperγglobulinemia ed elevati livelli urinari di cataboliti di cartilagine di tipo II. La terapia è modulata sulla gravità dei quadri clinici riscontrati, prevedendo trattamenti sintomatici a base di FANS, analgesici e colchicina a basse dosi in pazienti con manifestazioni limitate e poco invalidanti; l’uso di cortisonici, immunosoppressori (ciclofosfamide, azatioprina, ciclosporina A) e farmaci biologici (antiTNFα) nei pazienti resistenti ai precedenti trattamenti o con quadri clinici più severi. MATERIALI E METODI Si descrive il caso di A.F., donna, di anni 45. La paziente riferiva dispnea ingravescente nell’ultimo anno, dolenzia in regione auricolare e frequenti ma autolimitantesi dolori articolari condrosternali. Alla laringoscopia a fibre ottiche presentava plurime lesioni dall’aspetto nodulare, circoscritte e a mucosa indenne in regione sottoglottica, con motilità cordale conservata e spazio respiratorio ridotto. Si evidenziava, inoltre, iperemia ed edema dei padiglioni auricolari che apparivano dolenti e dolorabili alla palpazione, con esclusione del lobo. L’esame TC collo e torace senza e con mdc confermava tali irregolarità a carico dell’anello cricoideo, che si estendevano ai primi due anelli tracheali. Le lesioni avevano disposizione sottomucosa, di verosimile natura granulomatosa, considerato l’enhancement successivo al mdc. Si procedeva pertanto a biopsia delle suddetta lesione laringea, e, ipotizzando una probabile correlazione immunomediata, un’indagine laboratoristica sugli opportuni markers flogistico autoimmunitar

Osteocalcin (bone GLA protein) levels, vascular calcifications, vertebral fractures and mortality in hemodialysis patients with diabetes mellitus

Background and aims: Diabetes mellitus is recognized as one of the major causes of end stage kidney disease. Bone Gla protein (BGP) is a vitamin K-dependent protein involved in bone mineralization and vascular calcifications (VC). Our goal was to characterize BGP and undercarboxylated BGP (ucBGP) in DM patients on HD, compared to HD patients without DM, and their association with vascular and bone disease. Methods: 387 HD patients from 18 dialysis centers in Italy. Associations of DM, levels of BGP, vitamin D and VC were evaluated. Time-to-event analysis for all-cause mortality was performed by the Kaplan\u2013Meier. Results: Patients with DM had lower levels of total BGP (139.00 vs. 202.50 mcg/L, p < 0.001), 25(OH)D (23.4 vs. 30.2 ng/ml, p < 0.001), and ucBGP (9.24 vs. 11.32 mcg/L, p = 0.022). In regression models, the geometric means of total BGP and ucBGP were 19% (p = 0.009) and 26% (p = 0.034) lower in diabetic patients. In univariate Cox regression analysis, DM patients had a higher risk of all-cause mortality (HR:1.83, 95% CI 1.13\u20132.96, p = 0.014). Adjustment for confounders confirmed the significant DM-mortality link. We included VC and warfarin into the Cox model, the DM-mortality link was no longer significant, suggesting a role of these risk factors as causal mediators leading to increased mortality in dialysis patients. Conclusions: HD patients have an increased mortality risk associated with DM. Furthermore, we found an association between DM and decreased BGP levels. Although our study does not support the notion that BGP levels act as mediator in the DM-mortality link, to our knowledge this is the first study in HD patients suggesting a potential protective role of BGP in the bone, endocrine and vascular pathway

Trans-heterozygosity for mutations enhances the risk of recurrent/chronic pancreatitis in patients with Cystic Fibrosis

Background: Recurrent (RP) and chronic pancreatitis (CP) may complicate Cystic Fibrosis (CF). It is still unknown if mutations in genes involved in the intrapancreatic activation of trypsin (IPAT) or in the pancreatic secretion pathway (PSP) may enhance the risk for RP/CP in patients with CF.Methods: We enrolled: 48 patients affected by CF complicated by RP/CP and, as controls 35 patients with CF without pancreatitis and 80 unrelated healthy subjects. We tested a panel of 8 genes involved in the IPAT, i.e. PRSS1, PRSS2, SPINK1, CTRC, CASR, CFTR, CTSB and KRT8 and 23 additional genes implicated in the PSP.Results: We found 14/48 patients (29.2%) with mutations in genes involved in IPAT in the group of CF patients with RP/CP, while mutations in such genes were found in 2/35 (5.7%) patients with CF without pancreatitis and in 3/80 (3.8%) healthy subjects (p < 0.001). Thus, we found mutations in 12 genes of the PSP in 11/48 (22.9%) patients with CF and RP/CP. Overall, 19/48 (39.6%) patients with CF and RP/CP showed one or more mutations in the genes involved in the IPAT and in the PSP while such figure was 4/35 (11.4%) for patients with CF without pancreatitis and 11/80 (13.7%) for healthy controls (p < 0.001).Conclusions: The trans-heterozygous association between CFTR mutations in genes involved in the pathways of pancreatic enzyme activation and the pancreatic secretion may be risk factors for the development of recurrent or chronic pancreatitis in patients with CF

Gli inibitori della Neprilisina nei pazienti affetti da Malattia Renale Cronica e Sindrome Cardio-Renale

I pazienti affetti da malattia renale cronica (CKD) presentano una maggiore incidenza di eventi cardiovascolari (acuti e cronici) che, a loro volta, comportano un rischio aumentato di progressione verso la malattia renale cronica terminale (end \u2013 stage renal disease \u2013 ESRD) L\u2019inibizione della neprilisina, oltre ad offrire un nuovo target terapeutico nei pazienti affetti da scompenso cardiaco, potrebbero rappresentare una strategia di potenziale miglioramento negli outcomes, sia cardio-vascolari che renali, dei pazienti affetti da CKD. L\u2019inibizione della neprilisina, favorendo una maggiore biodisponibilit\ue0 dei peptidi natriuretici atriali, determina un incremento della diuresi e della natriuresi, oltre ad esercitare un\u2019azione di inibizione del sistema renina \u2013 angiotensina \u2013 aldosterone (RAAS). L\u2019inibizione del RAAS, a sua volta, genera una serie di controregolazioni in grado di bilanciarne gli effetti sfavorevoli in corso di CKD e di insufficienza cardiaca (HF). L\u2019idea del blocco della neprilisina non \ue8 recentissima, ma i primi farmaci impiegati, essendo molecole di associazione con antagonisti dell\u2019angiotensina II (ARBs), risultavano gravati da un\u2019incidenza inammissibile di angioedema. Tra le molecole di ultima generazione in grado di esercitare un\u2019azione inibente specifica sul recettore della neprilisina e su quello dell\u2019angiotensina II, grazie alla associazione con il valsartan, vi \ue8 l\u2019LCZ696 (sacubitril/valsartan) che ha mostrato evidenti benefici sia nel trattamento dell\u2019ipertensione arteriosa che nell\u2019insufficienza cardiaca.Patients with chronic kidney disease (CKD) have a higher incidence of cardiovascular (acute and chronic) events, which in turn have an increased risk of progression to end-stage renal disease (ESRD) Inhibition of neprilysin, in addition to offering a new therapeutic target in patients with heart failure, could represent a potential improvement strategy in cardiovascular and renal outcome of patients with CKD. Inhibition of neprilysin by inhibiting the breakdown of natriuretic peptides, increases their bioavailability resulting in an increase in diuresis and sodium excretion and, in addition to exerting an inhibition of the renin-angiotensin-aldosterone (RAAS) system. Inhibition of RAAS, in turn, generates a series of counter-regulations that can balance the adverse effects present in CKD and heart failure (HF). The idea of blocking neprilysin is not very recent, but the first drugs used as inhibitors had an inadmissible incidence of angioedema. Among the latest generation molecules that can perform a specific inhibitory action on the neprilysin receptor and, at the same time, on the angiotensin II receptor thanks to the association with valsartan there is the LCZ696 (sacubitril / valsartan). This drug has shown promising benefits both in the treatment arterial hypertension and heart failure. It is hoped that equally positive effects may occur in CKD patients, particularly those with macroproteinuria

Single-center open-label randomized study of anemia management improvement in ESRD patients with secondary hyperparathyroidism

Whether anemia and mineral bone abnormalities (chronic kidney disease\u2013mineral bone disorder [CKD-MBD]) are associated still remains to be elucidated. Both anemia and CKD-MBD have been associated with adverse cardiovascular outcome and poor quality of life. However, recent evidence suggests that use of large doses of erythropoietin-stimulating agents (ESAs) to correct hemoglobin (Hb) may be detrimental in CKD. The Optimal Anemia Treatment in End Stage Renal Disease (ESRD) (Optimal ESRD Treatment) study will assess whether lowering of parathyroid hormone (PTH) is associated with a reduction in ESA consumption. The Optimal ESRD Treatment study is a pilot single-center open-label study with blinded end point (a prospective randomized open blinded end-point [PROBE] design) enrolling 50 patients on maintenance dialysis. Eligible patients with intact PTH (iPTH) 300-540 pg/mL and Hb 10-11.5 g/dL will be randomized 1:1 to strict PTH control (150-300 pg/mL) versus standard care (PTH range 300-540 pg/mL). Available drugs for CKD-MBD and anemia treatment will be managed by the attending physician to maintain the desired levels of PTH (according to study arm allocation) and Hb (10-11.5 g/dL). Echocardiographic data for cardiac structure and function as well as arterial stiffness will be assessed at study inception and completion. The Optimal ESRD Treatment study should shed light on the complicated interplay of anemia and CKD-MBD and on the feasibility of clinical trials in this domain. The study results are expected in the spring of 2017

Gli inbitori della neprilisina nei pazienti affetti da malattia renale cronica sindrome cardio-renale

I pazienti affetti da malattia renale cronica (CKD) presentano una maggiore incidenza di eventi cardiovascolari (acuti e cronici) che, a loro volta, comportano un rischio aumentato di progressione verso la malattia renale cronica terminale (end \u2013 stage renal disease \u2013 ESRD) L\u2019inibizione della neprilisina, oltre ad offrire un nuovo target terapeutico nei pazienti affetti da scompenso cardiaco, potrebbero rappresentare una strategia di potenziale miglioramento negli outcomes, sia cardio-vascolari che renali, dei pazienti affetti da CKD. L\u2019inibizione della neprilisina, favorendo una maggiore biodisponibilit\ue0 dei peptidi natriuretici atriali, determina un incremento della diuresi e della natriuresi, oltre ad esercitare un\u2019azione di inibizione del sistema renina \u2013 angiotensina \u2013 aldosterone (RAAS). L\u2019inibizione del RAAS, a sua volta, genera una serie di controregolazioni in grado di bilanciarne gli effetti sfavorevoli in corso di CKD e di insufficienza cardiaca (HF). L\u2019idea del blocco della neprilisina non \ue8 recentissima, ma i primi farmaci impiegati, essendo molecole di associazione con antagonisti dell\u2019angiotensina II (ARBs), risultavano gravati da un\u2019incidenza inammissibile di angioedema. Tra le molecole di ultima generazione in grado di esercitare un\u2019azione inibente specifica sul recettore della neprilisina e su quello dell\u2019angiotensina II, grazie alla associazione con il valsartan, vi \ue8 l\u2019LCZ696 (sacubitril/valsartan) che ha mostrato evidenti benefici sia nel trattamento dell\u2019ipertensione arteriosa che nell\u2019insufficienza cardiaca.