Lumbar spine bone mineral density and trabecular bone score-adjusted FRAX, but not FRAX without bone mineral density, identify subclinical carotid atherosclerosis

Purpose: Osteoporosis and atherosclerosis share common risk factors. Aim of this study was to test if FRAX (which is an algorithm that can identify subjects at risk of fracture), without or with BMD values, also adjusted for trabecular bone score (TBS) was able to identify subclinical atherosclerosis, evaluated by measurement of carotid intima media thickness (cIMT ≥ 0.9 mm) as compared to DXA values. Methods: Ninety postmenopausal women underwent DXA measurement and cIMT evaluation. For each patient, the FRAX algorithm for major osteoporotic fracture (M) and for hip fracture (H) without BMD was computed, together with FRAX with BMD and TBS-adjusted FRAX. Serum levels of osteoprotegerin, sRANKL, and interleukin-6 were also measured. Results: There were no differences in anthropometric parameters and cardiovascular risk factors between subjects with cIMT ≥ 0.9 mm (35% of subjects, group A) compared to those with cIMT < 0.9 mm (group B). The prevalence of osteoporosis and FRAX BMD, TBS-adjusted FRAX both for M and H were higher in group A compared to group B. The best ROC curves to identify subjects with a cIMT ≥ 0.9 mm were: lumbar spine T-score, with a threshold of − 2.5 SD (area under the curve, AUC 0.64; p = 0.02) with a sensibility of 50% and a specificity of 76%; TBS-adjusted FRAX H with a sensibility of 50% and a specificity of 72% (AUC 0.64; p = 0.01 with a threshold of 3%). Interleukin-6 positively correlated with FRAX BMD H and M. Conclusions: FRAX without BMD does not identify subclinical carotid atherosclerosis, while lumbar spine T-score and TBS-adjusted FRAX H similarly detected it with higher specificity for T-score

A QUANTITATIVE ASSESSMENT OF DInSAR TIME SERIES ACCURACY IN VOLCANIC AREAS: FROM THE FIRST TO SECOND GENERATION SAR SENSORS

We perform a quantitative assessment of the accuracy of Differential SAR Interferometry (DInSAR) time series in volcanic areas, retrieved through “first” and “second generation” SAR data. In particular, we analyze the impact that the wavelengths and looking geometries may have in the DInSAR measurement retrieval depending on the radar system. To this aim, we focus on the DInSAR algorithm referred to as Small BAseline Subset (SBAS) to generate mean deformation velocity maps and corresponding time series starting from sequences of SAR images. Moreover, we consider collections of SAR data acquired by the ERS-1/2 and ENVISAT (C-band), and COSMO-SkyMed (Xband) sensors over the volcanic area of the Campi Flegrei caldera, Southern Italy. We invert these SAR data sequences through the SBAS-DInSAR technique, thus obtaining C- and X- band deformation time series that we compare to continuous GPS measurements, the latter assumed as reference. The achieved results provide, in addition to a clear picture of the surface deformation phenomena already occurred and occurring in the selected case study, relevant indications for the analysis of the SBAS-DInSAR time series accuracies in volcanic areas passing from the first to second generation SAR sensors.PublishedMünich1IT. Reti di monitoraggio e Osservazionirestricte

Role of Nuclear Lamin A/C in the Regulation of Nav1.5 Channel and Microtubules: Lesson From the Pathogenic Lamin A/C Variant Q517X

In this work, we studied an lmna nonsense mutation encoding for the C-terminally truncated Lamin A/C (LMNA) variant Q517X, which was described in patients affected by a severe arrhythmogenic cardiomyopathy with history of sudden death. We found that LMNA Q517X stably expressed in HL-1 cardiomyocytes abnormally aggregates at the nuclear envelope and within the nucleoplasm. Whole-cell patch clamp experiments showed that LMNA Q517X-expressing cardiomyocytes generated action potentials with reduced amplitude, overshoot, upstroke velocity and diastolic potential compared with LMNA WT-expressing cardiomyocytes. Moreover, the unique features of these cardiomyocytes were 1) hyper-polymerized tubulin network, 2) upregulated acetylated α-tubulin, and 3) cell surface Nav1.5 downregulation. These findings pointed the light on the role of tubulin and Nav1.5 channel in the abnormal electrical properties of LMNA Q517X-expressing cardiomyocytes. When expressed in HEK293 with Nav1.5 and its β1 subunit, LMNA Q517X reduced the peak Na+ current (INa) up to 63% with a shift toward positive potentials in the activation curve of the channel. Of note, both AP properties in cardiomyocytes and Nav1.5 kinetics in HEK293 cells were rescued in LMNA Q517X-expressing cells upon treatment with colchicine, an FDA-approved inhibitor of tubulin assembly. In conclusion, LMNA Q517X expression is associated with hyper-polymerization and hyper-acetylation of tubulin network with concomitant downregulation of Nav1.5 cell expression and activity, thus revealing 1) new mechanisms by which LMNA may regulate channels at the cell surface in cardiomyocytes and 2) new pathomechanisms and therapeutic targets in cardiac laminopathies

Targeting unfolded protein response reverts ER stress and ER Ca2+ homeostasis in cardiomyocytes expressing the pathogenic variant of Lamin A/C R321X

Background: We previously demonstrated that an Italian family affected by a severe dilated cardiomyopathy (DCM) with history of sudden deaths at young age, carried a mutation in the Lmna gene encoding for a truncated variant of the Lamin A/C protein (LMNA), R321X. When expressed in heterologous systems, such variant accumulates into the endoplasmic reticulum (ER), inducing the activation of the PERK-CHOP pathway of the unfolded protein response (UPR), ER dysfunction and increased rate of apoptosis. The aim of this work was to analyze whether targeting the UPR can be used to revert the ER dysfunction associated with LMNA R321X expression in HL-1 cardiac cells. Methods: HL-1 cardiomyocytes stably expressing LMNA R321X were used to assess the ability of 3 different drugs targeting the UPR, salubrinal, guanabenz and empagliflozin to rescue ER stress and dysfunction. In these cells, the state of activation of both the UPR and the pro-apoptotic pathway were analyzed monitoring the expression levels of phospho-PERK, phospho-eIF2α, ATF4, CHOP and PARP-CL. In addition, we measured ER-dependent intracellular Ca2+ dynamics as indicator of proper ER functionality. Results: We found that salubrinal and guanabenz increased the expression levels of phospho-eIF2α and downregulated the apoptosis markers CHOP and PARP-CL in LMNA R321X-cardiomyocytes, maintaining the so-called adaptive UPR. These drugs also restored ER ability to handle Ca2+ in these cardiomyocytes. Interestingly, we found that empagliflozin downregulated the apoptosis markers CHOP and PARP-CL shutting down the UPR itself through the inhibition of PERK phosphorylation in LMNA R321X-cardiomyocytes. Furthermore, upon empagliflozin treatment, ER homeostasis, in terms of ER ability to store and release intracellular Ca2+ was also restored in these cardiomyocytes. Conclusions: We provided evidence that the different drugs, although interfering with different steps of the UPR, were able to counteract pro-apoptotic processes and to preserve the ER homeostasis in R321X LMNA-cardiomyocytes. Of note, two of the tested drugs, guanabenz and empagliflozin, are already used in the clinical practice, thus providing preclinical evidence for ready-to-use therapies in patients affected by the LMNA R321X associated cardiomyocytes

La letteratura dal punto di vista degli scrittori

La storia della critica letteraria è stata generalmente esaminata dal punto di vista degli studiosi di teoria. Manca, a tutt’oggi, una visione d’insieme che esamini in maniera sistematica la critica letteraria dal punto di vista interno, ovvero degli autori stessi. Muovendo da tali premesse, il volume propone un’articolata analisi dei «discorsi» sulla letteratura prodotti da scrittori di lingua inglese, dalla seconda metà del Cinquecento a oggi. Allo scopo di dare ordine a una materia ampia e frastagliata, sono state individuate tre principali tipologie discorsive, o forme testuali, attraverso cui gli autori hanno dato voce alle proprie idee sulla letteratura. A tali tipologie discorsive corrispondono le tre sezioni in cui è stata suddivisa la materia critica del volume. La prima sezione, «Saggi e paratesti», esamina le teorie letterarie esposte in forma di saggi, prefazioni, commenti da parte dell’autore. La seconda sezione, «Disseminazioni», analizza le idee sulla letteratura sparse all’interno di romanzi, drammi, poesie. La terza sezione, infine, «Maschere d’autore», si concentra sulle teorie letterarie la cui esposizione è affidata a un alter ego dello scrittore, ovvero a una maschera parzialmente autobiografica. Ne emerge un quadro ricco e composito all’interno del quale teoria e prassi letteraria si arricchiscono reciprocamente, fino a fondersi in una più complessa unità i cui confini appaiono labili, indefiniti, negoziabili

Genetic aspects underlying the normocalcemic and hypercalcemic phenotypes of primary hyperparathyroidism

purpose: hypercalcemic primary hyperparathyroidism (PHPT) is a common endocrine disorder that has been very well characterized. In contrast, many aspects of normocalcemic primary hyperparathyroidism (NPHPT) such as natural history, organ damage, and management are still matter of debate. In addition, both the pathophysiology and molecular basis of NPHPT are unclear. we investigated whether PHPT and NPHPT patient cohorts share the same pattern of genetic variation in genes known to be involved in calcium and/or bone metabolism. Research design and methods: Genotyping for 9 single nucleotide polymorphisms (SNPs) was performed by Real-Time PCR (TaqMan assays) on 27 NPHPT and 31 PHPT patients evaluated in a tertiary referral center. the data of both groups were compared with 54 in house-controls and 503 subjects from the 1,000 genomes Project. All groups were compared for allele/haplotype frequencies, on a single locus, two loci and multi-locus basis. Results: The NPHPT group differed significantly at SNPs in OPG and ESR1. also, the NPHPT cohort was peculiar for pairwise associations of genotypes and for the overrepresentation of unusual multilocus genotypes. Conclusions: Our NPHPT patient set harboured a definitely larger quota of genetic diversity than the other samples. Specific genotypes may help in defining subgroups of NPHPT patients which deserve ad hoc clinical and follow-up studies

Transcatheter aortic valve implantation with the novel-generation Navitor device. Procedural and early outcomes

Transcatheter aortic valve implantation (TAVI) has proved beneficial in patients with severe aortic stenosis, especially when second-generation devices are used. We aimed at reporting our experience with Navitor, a third-generation device characterized by intrannular, large cell, and cuffed design, as well as high deliverability and minimization of paravalvular leak. Between June and December 2021, a total of 39 patients underwent TAVI with Navitor, representing 20% of all TAVI cases. Mean age was 80.0 +/- 6.7 years, and 14 (36.8%) women were included. Severe aortic stenosis was the most common indication to TAVI (37 [97.4%] cases), whereas 2 (5.3%) individuals were at low surgical risk. Device and procedural success was obtained in all patients, with a total hospital stay of 6.6 +/- 4.5 days. One (2.9%) patient required permanent pacemaker implantation, but no other hospital events occurred. At 1-month follow-up, a cardiac death was adjudicated in an 87-year-old man who had been at high surgical risk. Echocardiographic follow-up showed no case of moderate or severe aortic regurgitation, with mild regurgitation in 18 (47%), and none or trace regurgitation in 20 (53%). The Navitor device, thanks to its unique features, is a very promising technology suitable to further expand indications and risk-benefit profile of TAVI

life threatening acute myocardial infarction due to left main dissection during radiofrequency transcatheter ablation of atrial tachycardia

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