Phenotypic definition and genotype-phenotype correlates in pmpca-related disease

Background: Peptidase mitochondrial processing alpha (PMPCA) biallelic mutations cause a spectrum of disorders ranging from severe progressive multisystemic mitochondrial encephalopathy to a milder non-progressive cerebellar ataxia with or without intellectual disability. Recently, we and others described an intermediate phenotype in two unrelated patients. Methods: We report a second Italian patient carrying novel PMPCA variants (p.Trp278Leu; p.Arg362Gly). Molecular modeling, dynamics simulation, RT-qPCR, and Western blotting were performed to predict the pathogenic impact of variants in the two Italian patients and attempt genotype-phenotype correlates. Results: In line with the two patients with intermediate phenotypes, our case presented global psychomotor delay with regression, intellectual disability, spastic-ataxic gait, and hyperkinetic movements, with cerebellar atrophy and bilateral striatal hyperintensities. However, blood lactate, muscle biopsy, and MRI spectroscopy were normal. PMPCA protein levels were significantly higher than controls despite normal cDNA levels. Dynamics simulation of several PMPCA missense variants showed a variable impact on the flexibility of the glycine rich loop and, for some cases, on the overall protein stability, without clear genotype-phenotype correlates. Conclusion: We confirm the expansion of PMPCA phenotypic spectrum including an intermediate phenotype of progressive encephalopathy without systemic involvement. The association of cerebellar atrophy with “Leigh-like” striatal hyperintensities may represent a “red flag” for this condition

Loss of renal function in the elderly italians: a physiologic or pathologic process?

Abstract BACKGROUND: Nowadays it seems that chronic kidney disease (CKD) is outbreaking, mostly in the elderly participants. The aim of this study was to assess the progression of CKD in different ages. METHODS: We conducted a monocentric, retrospective, observational study enrolling 116 patients afferent to our outpatient clinic. INCLUSION CRITERIA: age >18 years, follow-up ≥5 years, estimated glomerular filtration rate (eGFR) <60mL/min/1.73 m(2), and/or diagnosed renal disease and/or presence of renal damage. Patients were divided into four groups according to their age: 25-55 years (n = 27), 56-65 (25), 66-75 (42), and 76-87 (22). eGFR was calculated using the modification of diet in renal disease and the CKD-epidemiology collaboration formulas. RESULTS: Younger patients had a significantly longer follow-up and less comorbidities, evaluated by the cumulative illness rating scale score, compared with the other groups. There was no difference between creatinine at baseline and at the end-of-follow-up period among the groups. Even though renal function significantly decreased in all groups, we noticed a slower progression as the age increased, and the difference between basal and end-of-follow-up eGFR was minimal in the group of patients aged 76-87 years. Analyzing the eGFR of every ambulatory control plotted against the year of follow-up, we showed a more rapid loss of filtrate in the younger group. Instead, loss of renal function decreased as the age of patients increased. CONCLUSIONS: This study demonstrates that, in elderly Italian participants, progression of CKD occurs more slowly than in younger patients. This implies that we may probably face an epidemic of CKD but that most of elderly patients diagnosed with CKD may not evolve to end-stage renal disease and require renal replacement therapy

The chemical etching as a method for post-processing of 3D cellular structures obtained by electron-beam melting: limitations and difficulties

Chemical etching is a promising method for post-surface treatment and the removal of residual powder from implants obtained using electron beam cladding. Partially sintered powder particles that remained on the implants surface can be difficult to remove from the internal structure of the additively manufactured specimens. In order to remove residual powder from scaffolds' interior, an aqueous solution of HF and HNO3 acids was used. Multiple immersion was more effective to remove the remaining powder, which was explained from the chemical point of view. The influence of the chemical etching on mechanical properties, mechanical behavior, fracture modes, and morphology was investigated

SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.

Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies. We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes. Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents. Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk

Ground Water Chemistry Changes before Major Earthquakes and Possible Effects on Animals

Prior to major earthquakes many changes in the environment have been documented. Though often subtle and fleeting, these changes are noticeable at the land surface, in water, in the air, and in the ionosphere. Key to understanding these diverse pre-earthquake phenomena has been the discovery that, when tectonic stresses build up in the Earth’s crust, highly mobile electronic charge carriers are activated. These charge carriers are defect electrons on the oxygen anion sublattice of silicate minerals, known as positive holes, chemically equivalent to O− in a matrix of O2−. They are remarkable inasmuch as they can flow out of the stressed rock volume and spread into the surrounding unstressed rocks. Travelling fast and far the positive holes cause a range of follow-on reactions when they arrive at the Earth’s surface, where they cause air ionization, injecting massive amounts of primarily positive air ions into the lower atmosphere. When they arrive at the rock-water interface, they act as •O radicals, oxidizing water to hydrogen peroxide. Other reactions at the rock-water interface include the oxidation or partial oxidation of dissolved organic compounds, leading to changes of their fluorescence spectra. Some compounds thus formed may be irritants or toxins to certain species of animals. Common toads, Bufo bufo, were observed to exhibit a highly unusual behavior prior to a M6.3 earthquake that hit L’Aquila, Italy, on April 06, 2009: a few days before the seismic event the toads suddenly disappeared from their breeding site in a small lake about 75 km from the epicenter and did not return until after the aftershock series. In this paper we discuss potential changes in groundwater chemistry prior to seismic events and their possible effects on animals

the effects of climate change on the multifunctional role of basilicata s forests the effects induced on yield and co2 absorption

The first studies on the possible impact of climate change on European forests and the development of adaptation and mitigation strategies began in the 1990s and resulted in the identification of risk assessment models and forest management tools. The prediction of climate change impacts on forests has been based using the evidence theory or Dempster-Shafer (DS)'s theory, appropriately spatialised. The implemented evidence lines refer to the concepts of vulnerability and resilience. The results of the DS model, applied to the Basilicata region, were utilised to assess the loss in biomass production capacity and CO2 absorption ability of different forest-derived biomasses. The loss in stumpage value and in the estimated CO2 absorption shows a reduction over time of forest system's economic value that is basically higher in 2050 than in 2100. The applied methodological approach has shown that the high degree of spatial and information detail may be helpful to produce good predictions to envisage environmental policy strategies for the monitoring and mitigation of the damages caused by the climate change, with a view to ensuring the ecosystems' capacity to produce positive externalities, including air carbon sequestration capacity