Hereditary spastic paraplegia is a common phenotypic finding in ARG1 deficiency, P5CS deficiency and HHH syndrome: Three inborn errors of metabolism caused by alteration of an interconnected pathway of glutamate and urea cycle metabolism

Hereditary Spastic Paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by a progressive rigidity and weakness of the lower limbs, caused by pyramidal tract lesions. As of today, 80 different forms of HSP have been mapped, 64 genes have been cloned, and new forms are constantly being described. HSPs represent an intensively studied field, and the functional understanding of the biochemical and molecular pathogenetic pathways are starting to be elucidated. Recently, dominant and recessive mutations in the ALDH18A1 gene resulting in the deficiency of the encoded enzyme (delta-1-pyrroline-5-carboxylate synthase, P5CS) have been pathogenetically linked to HSP. P5CS is a critical enzyme in the conversion of glutamate to pyrroline-5-carboxylate, an intermediate that enters in the proline biosynthesis and that is connected with the urea cycle. Interestingly, two urea cycle disorders, Argininemia and Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome, are clinically characterized by highly penetrant spastic paraplegia. These three diseases represent a peculiar group of HSPs caused by Inborn Errors of Metabolism. Here we comment on these forms, on the common features among them and on the hypotheses for possible shared pathogenetic mechanisms causing the HSP phenotype

La tecnologia del Gene Editing nella didattica esperienziale per studenti delle scuole secondarie di secondo grado

Le moderne tecnologie di Gene Editing, come il sistema CRISPR, si sono diffuse in tutti i laboratori del mondo, alimentando al contempo speranze e timori per le sue applicazioni. Poiché queste tecnologie sono destinate ad avere un enorme impatto sulle nostre vite, è fondamentale comunicare e suscitare un dibattito, soprattutto tra i più giovani. Per avvicinare gli studenti delle scuole secondarie di secondo grado ai grandi temi scientifici e far sperimentare loro l’utilizzo di nuove tecnologie per comprenderne le potenzialità, negli ultimi anni abbiamo messo a punto un corso di Gene Editing. La risposta degli studenti a questo tipo di corso dimostra l’efficacia della sperimentazione nell’informare e suscitare una discussione su queste tematiche. In questo articolo riportiamo e commentiamo i risultati dello studio

Transfection of the mutant MYH9 cDNA reproduces the most typical cellular phenotype of MYH9-related disease in different cell lines

ABSTRACT: BACKGROUND: Heterozygous mutations of MYH9, encoding the Non-Muscular Myosin Heavy Chain-IIA (NMMHC-IIA), cause a complex disorder named MYH9-related disease, characterized by a combination of different phenotypic features. At birth, patients present platelet macrocytosis, thrombocytopenia and leukocyte inclusions containing NMMHC-IIA. Moreover, later in life some of them develop the additional features of sensorineural hearing loss, cataracts and/or glomerulonephritis that sometimes leads to end stage renal failure. RESULTS: To clarify the mechanism by which the mutant NMMHC-IIA could cause phenotypic anomalies at the cellular level, we examined the effect of transfection of the full-length mutated D1424H MYH9 cDNAs. We have observed, by confocal microscopy, abnormal distribution of the protein and formation of rod-like aggregates reminiscent of the leukocyte inclusions found in patients. Co-transfection of differently labeled wild-type and mutant full-length cDNAs showed the simultaneous presence of both forms of the protein in the intracellular aggregates. CONCLUSION: These findings suggest that the NMMHC-IIA mutated in position 1424 is able to interact with the WT form in living cells, despite part of the mutant protein precipitates in non-functional aggregates. Transfection of the entire WT or mutant MYH9 in cell lines represents a powerful experimental model to investigate consequences of MYH9 mutations

Hereditary Spastic Paraplegia Is a Common Phenotypic Finding in ARG1 Deficiency, P5CS Deficiency and HHH Syndrome: Three Inborn Errors of Metabolism Caused by Alteration of an Interconnected Pathway of Glutamate and Urea Cycle Metabolism

Hereditary Spastic Paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by a progressive rigidity and weakness of the lower limbs, caused by pyramidal tract lesions. As of today, 80 different forms of HSP have been mapped, 64 genes have been cloned, and new forms are constantly being described. HSPs represent an intensively studied field, and the functional understanding of the biochemical and molecular pathogenetic pathways are starting to be elucidated. Recently, dominant and recessive mutations in the ALDH18A1 gene resulting in the deficiency of the encoded enzyme (delta-1-pyrroline-5-carboxylate synthase, P5CS) have been pathogenetically linked to HSP. P5CS is a critical enzyme in the conversion of glutamate to pyrroline-5-carboxylate, an intermediate that enters in the proline biosynthesis and that is connected with the urea cycle. Interestingly, two urea cycle disorders, Argininemia and Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome, are clinically characterized by highly penetrant spastic paraplegia. These three diseases represent a peculiar group of HSPs caused by Inborn Errors of Metabolism. Here we comment on these forms, on the common features among them and on the hypotheses for possible shared pathogenetic mechanisms causing the HSP phenotype

May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome Are not Distinct Entities but Represent a Variable Expression of a Single Illness

May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Döhle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Döhle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner syndrome and Epstein syndrome but also those referred as May-Hegglin anomaly and Sebastian syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd

Discrete fracture network modeling of background deformation in Apulian carbonates (Altamura Fm., Murge area, Italy)

We present the first results of an ongoing project aimed at better deciphering the role played by background fractures on subsurface fluid flow within Cretaceous Apulian carbonates. Taking advantage of 3D exposures present in the Murge area of southern Italy, which is part of the southern Apennines foreland, we were able to accurately map the fracture network that pervasively crosscut the Cretaceous limestone of the Altamura Fm. (Coniacian – Campanian inf.). There, bed-perpendicular fractures consist of strata-bound joints and sheared joints and no strata-bound, throughoing, small-scale strike-slip faults with cm offsets. Often, the strata-bound joints and sheared joints abut against bed-parallel stylolites present within individual limestone beds. For each fracture/fault set, we assessed its dimensional, spatial and scaling properties from mesoscale structural data (scan line and scan area). Structural data were gathered along artificial walls and pavements of inactive quarries. By computing the mean orientation, size distribution, aspect ratio, aperture, N (number of fractures per sample volume), P32 (fracture area for sample volume) and fractal dimension of each fracture/fault set, we were able to build up a multiple DFN (Discrete Fracture Network) model of a representative rock volume of 10 m-side. In particular we construct different DFN model for each mechanical unit and for strata-bound and non strata-bound fractures. The resulting model was then used to compute the overall 3D permeability (Kx, Ky, Kz) of each individual layer (single limestone beds) and of the representative rock volume comprised of several mechanical units. The results of this work will be key to define, in the next future, an appropriate REV (Elementary Representative Volume) model aimed at simulating the fluid flow properties of such a representative rock volumes at reservoir conditions, which means given values of lithostatic loading under specific tectonic stress states

Multi-scale fracture networks of faulted and fractured Apulian carbonates, Italy

The work is aimed at deciphering the contribution of both background and fault related deformation on the fluid flow properties of tight platform carbonates. Taking advantage of 3D exposures present in the Murge area of southern Italy, we are able to analyze, at different scales, the fracture networks that crosscut the layered Cretaceous limestone of the Altamura Fm (Korneva et al., 2014). The background deformation consists of (i) stratabound fractures, consisting of bed-perpendicular joints and sheared joints and (ii) non-stratabound fractures, represented by incipient strike-slip faults with cm offsets, which crosscut several beds and confined within individual bed-packages. Persistent fracture zones, which are made up of small strike-slip faults that offset several bed-packages and display tens of cm-offset, are also present along the study outcrops. The latter features include thin damage zones and very discontinuous, if not absent, cataclastic fault cores. At larger scales, well-develop faults, characterized by m to tens of m-offset, form a conjugate system of sub-vertical strike-slip faults. These larger faults include 10’s of m-thick fractured and faulted damage zones, which surround up to 1 m-thick cataclastic fault cores. For each fracture/fault set documented along the study outcrops, we assess the dimensional, spatial and scaling properties. Data were gathered in the field by mean of scan line and scan area measurements. By computing the mean orientation, size distribution, aspect ratio, aperture, N (number of fractures per sample volume) and fractal dimension of each fracture/fault set, we build up multi-scale DFN (Discrete Fracture Network) models of representative rock volumes. In particular, concerning the background deformation, different DFN models are constructed based upon the investigated bed thicknesses (stratabound fractures) and bed-packages thicknesses (non-stratabound fractures). One larger model is generated for the persistent facture zones crosscutting several bed-packages, in which both stratabound and non-stratabound fractures are included. Finally, DFN models representing the structural architecture of larger strike-slip faults are also constructed. Outputs of individual models are used to compute, at different scales, the overall P32, porosity and 3D permeability (Kx, Ky, Kz) values of the limestone rocks: from single beds to multiple bed-packages and, finally, to large fault zones. The results enable us to assess the multi-scale properties of the fracture network at different scales and, hence, to discuss the role exerted by brittle deformation on susburface fluid flow within tight layered carbonates