Pathophysiology of cough with angiotensin-converting enzyme inhibitors: How to explain within-class differences?

: Angiotensin converting enzyme inhibitors (ACEi) have consistently demonstrated improved survival and reduced risk of major cardiovascular events, across the spectrum of cardiovascular disease, including hypertension, coronary artery disease, myocardial infarction, and heart failure. The cardioprotective effects of ACEi result from inhibiting the conversion of angiotensin I to angiotensin II, and inhibition of bradykinin degradation. They are generally well tolerated but may cause the onset of a dry cough in some patients. This review presents current evidence on the incidence and mechanisms of cough associated with ACEi use, and then considers how to manage ACEi-related cough in clinical practice. The incidence of ACEi-induced cough in the published literature varies widely due to heterogeneity in the source data and lack of adequate controls. Incidence also varies among individual ACEi with agents such as perindopril, which has a high tissue ACE affinity, associated with a lower rate of cough. Evidence from real-world studies shows that the incidence of ACEi-associated cough is lower than rates reported in clinical trials. Patients who experience any dry cough are often switched to angiotensin- receptor blockers or other classes of antihypertensive drugs, regardless of cough severity. To avoid inappropriate discontinuation of ACEi in clinical practice, an alternative approach in patients with persistent cough is to perform a challenge/re-challenge to determine if re-introduction of ACEi is associated with recurrence of symptoms. Incidence of cough should not be considered a class effect for ACEi, and the patient may benefit by a switch from one ACEi to another. Every effort should be made to enable patients to continue ACEi therapy to reduce adverse cardiovascular outcomes and improve survival

San Carlo dei Barnabiti: restoration and reinforcement of the roofing of a florentine baroque masterpiece

The church of San Carlo dei Barnabiti houses one of the most important examples of Baroque illusionistic painting in Florence. Given the level of deterioration of the vault, the preliminary investigations required a 3D survey of the current geometry to detect the mainly damaged areas. A point cloud obtained by laser scanning is employed to investigate the deformations and the state of conservation of the vault. The acquired data also revealed some unknown aspects concerning the construction of the structure and its pictorial decoration useful to design the restoration project

Monitoring and Computation of the Volumes of Stockpiles of Bulk Material by Means of UAV Photogrammetric Surveying

The monitoring and metric assessment of piles of natural or man-made materials plays a fundamental role in the production and management processes of multiple activities. Over time, the monitoring techniques have undergone an evolution linked to the progress of measure and data processing techniques; starting from classic topography to global navigation satellite system (GNSS) technologies up to the current survey systems like laser scanner and close-range photogrammetry. Last-generation 3D data management software allow for the processing of increasingly truer high-resolution 3D models. This study shows the results of a test for the monitoring and computing of stockpile volumes of material coming from the differentiated waste collection inserted in the recycling chain, performed by means of an unmanned aerial vehicle (UAV) photogrammetric survey and the generation of 3D models starting from point clouds. The test was carried out with two UAV flight sessions, with vertical and oblique camera configurations, and using a terrestrial laser scanner for measuring the ground control points and as ground truth for testing the two survey configurations. The computations of the volumes were carried out using two software and comparisons were made both with reference to the different survey configurations and to the computation software

La vite nel Medioevo in Maremma: caratterizzazione morfologica e genotipizzazione di vinaccioli del quindicesimo secolo attraverso marcatori molecolari a DNA

In a recent excavation carried out under the Cathedral of Grosseto, was found a "well throw" dating back to the fifteenth century, containing several archaeological finds and plant material belonging to various botanical species, mainly tree fruit species, including the grapevine. There were recovered more than 200 seeds, which were individually cataloged and photographed to be subjected to ampelometrical analysis. Some of these seeds have been subjected to the analysis of SSR profiles. The DNA was extracted from each seed, quantified by real-time PCR and used to amplify the 14 SSR loci including the 9 selected at international level. The results show considerable variability in both the quantity and quality of DNA between different seeds, and it was possible to obtain reliable SSR profiles and postulate some relationships with the varieties currently grown in Tuscany

A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type γ in chronic myeloid leukemia patients

Background: Protein tyrosine phosphatase receptor gamma (PTPRG) is a ubiquitously expressed member of the protein tyrosine phosphatase family known to act as a tumor suppressor gene in many different neoplasms with mechanisms of inactivation including mutations and methylation of CpG islands in the promoter region. Although a critical role in human hematopoiesis and an oncosuppressor role in chronic myeloid leukemia (CML) have been reported, only one polyclonal antibody (named chPTPRG) has been described as capable of recognizing the native antigen of this phosphatase by flow cytometry. Protein biomarkers of CML have not yet found applications in the clinic, and in this study, we have analyzed a group of newly diagnosed CML patients before and after treatment. The aim of this work was to characterize and exploit a newly developed murine monoclonal antibody specific for the PTPRG extracellular domain (named TPγ B9-2) to better define PTPRG protein downregulation in CML patients. Methods: TPγ B9-2 specifically recognizes PTPRG (both human and murine) by flow cytometry, western blotting, immunoprecipitation, and immunohistochemistry. Results: Co-localization experiments performed with both anti-PTPRG antibodies identified the presence of isoforms and confirmed protein downregulation at diagnosis in the Philadelphia-positive myeloid lineage (including CD34+/CD38bright/dim cells). After effective tyrosine kinase inhibitor (TKI) treatment, its expression recovered in tandem with the return of Philadelphia-negative hematopoiesis. Of note, PTPRG mRNA levels remain unchanged in tyrosine kinase inhibitors (TKI) non-responder patients, confirming that downregulation selectively occurs in primary CML cells. Conclusions: The availability of this unique antibody permits its evaluation for clinical application including the support for diagnosis and follow-up of these disorders. Evaluation of PTPRG as a potential therapeutic target is also facilitated by the availability of a specific reagent capable to specifically detect its target in various experimental conditions

Missense PDSS1 mutations in CoenzymeQ10 synthesis cause optic atrophy and sensorineural deafness

CoenzymeQ10 is one of the main cellular antioxidants and an essential lipid involved in numerous cell reactions, such as energy production and apoptosis modulation. A large number of enzymes are involved in CoQ10 biosynthesis. Mutations in the genes encoding for these enzymes cause a CoQ10 deficiency, characterized by neurological and systemic symptoms. Here we describe two young sisters with sensorineural deafness followed by optic atrophy, due to a novel homozygous pathogenic variant in PDSS1. The visual system seems to be mainly involved when the first steps of CoQ10 synthesis are impaired (PDSS1, PDSS2, and COQ2 deficiency)

Enabling personalised medical support for chronic disease management through a hybrid robot-cloud approach

n/

Expanding the Clinical Spectrum of UBTF-Related Neurodevelopmental Disorder

Objectives: UBTF1 gene encodes for Upstream Binding Transcription Factor, an essential protein for RNA metabolism. A recurrent de novo variant (c.628G>A; p.Glu210Lys) has recently been associated with a childhood-onset neurodegenerative disorder characterized by motor and language regression, ataxia, dystonia, and acquired microcephaly. In this study, we report the clinical, metabolic, molecular genetics and neuroimaging findings and histologic, histochemical, and electron microscopy studies in muscle samples of 2 patients from unrelated families with a neurodevelopmental disorder. Methods: Data were retrospectively analyzed by medical charts revision. Results: Patient 1, a 16-year-old boy, presented a childhood-onset slowly progressive neurodegenerative disorder mainly affecting language skills, behavior, and motor coordination. Patient 2, a 22-year-old woman, presented with a severe and rapidly progressive disease with dystonic tetra paresis, acquired microcephaly, and severe cognitive deficit complicated by pseudobulbar syndrome characterized by involuntary and uncontrollable outbursts of laughing, dysphagia requiring tube feeding, and nocturnal hypoventilation treated with noninvasive ventilation. Both patients carried the recurrent previously described UBTF1 de novo variant and had signs of mitochondrial dysfunction at muscle biopsy. The metabolic profile of patient 2 also revealed a decrease in CSF biopterin. Discussion: These case reports add new insights to the UBTF1 disease spectrum instrumental to improving the diagnostic rate in neurodevelopmental disorders

Rapamycin rescues mitochondrial dysfunction in cells carrying the m.8344A > G mutation in the mitochondrial tRNALys

Background: Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently affecting the tRNALys gene at position m.8344A > G. Defective tRNALys severely impairs mitochondrial protein synthesis and respiratory chain when a high percentage of mutant heteroplasmy crosses the threshold for full-blown clinical phenotype. Therapy is currently lim- ited to symptomatic management of myoclonic epilepsy, and supportive measures to counteract muscle weakness with co-factors/supplements. Methods: We tested two therapeutic strategies to rescue mitochondrial function in cybrids and fibroblasts carry- ing different loads of the m.8344A > G mutation. The first strategy was aimed at inducing mitochondrial biogenesis directly, over-expressing the master regulator PGC-1α, or indirectly, through the treatment with nicotinic acid, a NAD+ precursor. The second was aimed at stimulating the removal of damaged mitochondria through prolonged rapamy- cin treatment. Results: The first approach slightly increased mitochondrial protein expression and respiration in the wild type and intermediate-mutation load cells, but was ineffective in high-mutation load cell lines. This suggests that induction of mitochondrial biogenesis may not be sufficient to rescue mitochondrial dysfunction in MERRF cells with high-muta- tion load. The second approach, when administered chronically (4 weeks), induced a slight increase of mitochondrial respiration in fibroblasts with high-mutation load, and a significant improvement in fibroblasts with intermediate- mutation load, rescuing completely the bioenergetics defect. This effect was mediated by increased mitochondrial biogenesis, possibly related to the rapamycin-induced inhibition of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and the consequent activation of the Transcription Factor EB (TFEB). Conclusions: Overall, our results point to rapamycin-based therapy as a promising therapeutic option for MERRF