Early posterior vitreous detachment is associated with LAMA5 dominant mutation

Background: Extracellular matrix molecular components, previously linked to multisystem syndromes include collagens, fibrillins and laminins. Recently, we described a novel multisystem syndrome caused by the c.9418G>A p.(V3140M) mutation in the laminin alpha-5 (LAMA5) gene, which affects connective tissues of all organs and apparatus in a three generation family. In the same family, we have also reported a myopic trait, which, however, was linked to the Prolyl 4-hydroxylase subunit alpha-2 (P4HA2) gene. Results of investigation on vitreous changes and their pathogenesis are reported in the present study.Materials and Methods: Nineteen family individuals underwent complete ophthalmic examination including best-corrected visual acuity (BCVA), fundus examination, fundus photography, intraocular pressure measurement, axial length measurement using ocular biometry, Goldmann visual field examination, standard electroretinogram, SD-OCT. Segregation analysis of LAMA5 and P4HA2 mutations was performed in enrolled members.Results: The vitreous alterations fully segregated with LAMA5 mutation in both young and adult family members. Slight reduction of retinal thickness and peripheral retinal degeneration in only two patients were reported.Conclusions: In this work we showed that PVD is a common trait of LAMA5 multisystem syndrome, therefore occurring as an age-unrelated trait. We hypothesize that the p.(V3140M) mutation results in a reduction of retinal inner limiting membrane (ILM) stability, leading to a derangement in the macromolecular structure of the vitreous gel, and PVD. Further investigations will be necessary to elucidate the role of wild type and mutated LAMA5 in the pathogenesis of PVD.     

MEMRI and tumors: a method for the evaluation of the contribution of Mn(II) ions in the extracellular compartment

The purpose of the work was to set‐up a simple method to evaluate the contribution of Mn²⁺ ions in the intra‐ and extracellular tumor compartments in a MEMRI experiment. This task has been tackled by “silencing” the relaxation enhancement arising from Mn²⁺ ions in the extracellular space. In vitro relaxometric measurements allowed assessment of the sequestering activity of DO2A (1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid) towards Mn²⁺ ions, as the addition of Ca‐DO2A to a solution of MnCl₂ causes a drop of relaxivity upon the formation of the highly stable and low‐relaxivity Mn‐DO2A. It has been proved that the sequestering ability of DO2A towards Mn²⁺ ions is also fully effective in the presence of serum albumin. Moreover, it has been shown that Mn‐DO2A does not enter cell membranes, nor does the presence of Ca‐DO2A in the extracellular space prompt migration of Mn ions from the intracellular compartment. On this basis the in vivo, instantaneous, drop in SE% (percent signal enhancement) in T₁‐weighted images is taken as evidence of the sequestration of extracellular Mn²⁺ ions upon addition of Ca‐DO2A. By applying the method to B16F10 tumor bearing mice, T₁ decrease is readily detected in the tumor region, whereas a negligible change in SE% is observed in kidneys, liver and muscle. The relaxometric MRI results have been validated by ICP‐MS measurements. Copyright © 2015 John Wiley & Sons, Ltd.     

Results From a Large,Multicenter, Retrospective Analysis On Radium223 Use in Metastatic Castration-resistant Prostate Cancer (mCRPC) in the Triveneto Italian Region

Background

Radium 223 was introduced for metastatic castration-resistant prostate cancer based on the results of a randomized controlled trial showing risk reduction for death and skeletal events. Our aim was to evaluate the outcome of patients receiving radium 223 in a real-world setting.

Cardiopulmonary exercise testing for personalized job reintegration after acute cardiovascular attacks: a pilot cross-sectional study

Background:Cardiovascular diseases (CVD), particularly the ischemic heart disease, are a growing public health issue. In addition, the return to work after an acute cardiovascular attack represents a complex challenge.Objectives:To evaluate utility and safety of cardiopulmonary exercise testing (CPET), particularly performed “on site”, to promote a return to work in line with the residual working capacity.Methods:Fifty-nine workers affected by a major cardiovascular event, aged 18-63 years, have been enrolled between 2015 and 2018. All the patients underwent a CPET in outpatient clinic. Eleven workers also underwent the “on site” CPET, recorded during their working activities.Results:Outpatient clinic CPET outcomes (i.e. normal, mild impairment or moderate/severe impairment of cardiopulmonary function) were associated with the subjective perception of workers’ health status after returning to work. The “on site” CPET was found to be safe and reliable to promote a personalized return to work of patients. In 7 out of 11 patients, the values of O₂ consumption (VO₂) during the working activity were higher than 40% of VO₂ max as obtained from laboratory CPET.Conclusions:This study provides evidence for safety and usefulness of “on site” CPET for a personalized statement of fitness for work. This may facilitate the job retention of patients characterized by a high risk of unnecessary job loss. The use of CPET represents a first step of energy expenditure evaluation associated with specific working tasks.Key words: Acute coronary syndrome, cardiopulmonary exercise testing, return to work     

Augmentation technique with semitendinosus and gracilis tendons in chronic partial lesions of the ACL: clinical and arthrometric analysis

Most of the techniques described in the literature for the repair of chronic partial ACL tears, don’t spare the intact portion of the ligament. The aim of this study was to perform a prospective analysis of the results of augmentation surgery using gracilis and semitendinosus tendons to treat partial sub-acute lesions of the ACL. This technique involves an “over the top” femoral passage, which enables salvage and strengthening of the intact portion of the ACL. The study included 47 patients treated consecutively at our institute from 1993 to 1998, with a mean injury-surgery interval of 18 weeks (range 12–36). The patients were followed up by clinical and instrumental assessment criteria at 3 months, 1 and 5 years after surgery. Clinical assessment was performed using the IKDC form. Subjective and functional parameters were assessed by the Tegner activity scale. Instrumental evaluation was done using the KT-2000 instrument: the 30-pound passive test and the manual maximum displacement test were performed. We obtained good or excellent results in 95.7% of cases. No recurrences in ligamentous laxity were observed. We believe that the described technique has the advantage of being compatible with ACL anatomy, and enables very rapid functional recovery.     

ReProComet: a new in vitro method to assess DNA damage in mammalian sperm.

The increasing request of chemical safety assessment demands for the validation of alternative methods to reduce the resort to animal experimentation. Methods that evaluate reproductive toxicity are among those requiring the largest use of animals. Presently, no validated in vitro alternative exists for the assessment of reproductive toxicity. Mammalian sperm are sensitive targets of DNA-reactive chemicals, which form premutagenic adducts. Here, we propose a new method based on comet assay to detect DNA damage induced by potential germ cell mutagens in bull sperm available from assisted reproduction practices. In somatic cells, chemical-induced adducts can be revealed by comet assay that detects DNA breaks produced during adduct repair. Mature sperm, however, are devoid of repair enzymes, and adducts are processed only after fertilization. For this reason, comet assay is not sensitive to detect DNA lesions induced in sperm by most chemicals. To overcome such limitation, we developed a modified comet assay based on the addition of a protein extract from HeLa cells to agarose-embedded sperm on microscopic slides. To test the method, sperm were treated in vitro with methyl methanesulfonate (MMS) or melphalan (MLP) and comet assay was conducted both with and without protein supplementation. No effect of MMS or MLP was detected without protein supplementation; on the contrary, a clear-cut dose-dependent effect was measured after addition of the cell extract. These results represent a proof of concept of a novel in vitro mutagenicity test on sperm that could offer a promising approach to complement previously validated in vivo germ cell genotoxicity assays.     

Synthesis and biological evaluation of new antimuscarinic compounds with amidine basic centers. A useful bioisosteric replacement of classical cationic heads

Amidines (guanidine, formamidine, and acetamidine) were introduced as substitutes for the cationic heads present in atropine, scopolamine, and corresponding quaternary derivatives. Amidine systems are intermediate in structure between tertiary amines and quaternary compounds, at least as regards ionization and electronic properties, but differ from the latter in shape (planar not tetrahedral). They have additional binding opportunities on account of their hydrogen-bond-forming capacity. The effect of the introduction of these cationic heads on the affinity for different muscarinic acetyl choline receptor (m-AcChR) subtypes was investigated in vitro, in binding displacement studies, and in functional tests on isolated organs. All new compounds (3a,b-5a,b) showed high affinity for the m-AcChR considered, comparable or slightly inferior to that of the parent drugs (1a-e). The new amidine derivatives proved effective as spasmolytic agents, with little tendency to cause central effects. However, no separation was achieved of spasmolytic and other untoward effects, like inhibition of salivation. Thus, amidine moieties are effective bioisosteric substitutes for conventional cationic heads present in antimuscarinic agents. Their unusual physical-chemical properties make them useful tools when modulation of pharmacokinetic or pharmacodynamic effects is required.