Clinical and molecular features and therapeutic perspectives of spinal muscular atrophy with respiratory distress type 1

Spinal muscular atrophy with respiratory distress (SMARD1) is an autosomal recessive neuromuscular disease caused by mutations in the IGHMBP2 gene, encoding the immunoglobulin μ-binding protein 2, leading to motor neuron degeneration. It is a rare and fatal disease with an early onset in infancy in the majority of the cases. The main clinical features are muscular atrophy and diaphragmatic palsy, which requires prompt and permanent supportive ventilation. The human disease is recapitulated in the neuromuscular degeneration (nmd) mouse. No effective treatment is available yet, but novel therapeutical approaches tested on the nmd mouse, such as the use of neurotrophic factors and stem cell therapy, have shown positive effects. Gene therapy demonstrated effectiveness in SMA, being now at the stage of clinical trial in patients and therefore representing a possible treatment for SMARD1 as well. The significant advancement in understanding of both SMARD1 clinical spectrum and molecular mechanisms makes ground for a rapid translation of pre-clinical therapeutic strategies in humans

Discontinuous Galerkin for the heterodimer model of prion dynamics in Parkinson's disease

Neurodegenerative diseases have a significant global impact affecting millions of individuals worldwide. Some of them, known as proteinopathies, are characterized by the accumulation and propagation of toxic proteins, known as prions. Alzheimer's and Parkinson's diseases are relevant of protheinopathies. Mathematical models of prion dynamics play a crucial role in understanding disease progression and could be of help to potential interventions. This article focuses on the heterodimer model: a system of two partial differential equations that describe the evolution of healthy and misfolded proteins. In particular, we propose a space discretization based on a Discontinuous Galerkin method on polygonal/polyhedral grids, which provides flexibility in handling meshes of complex brain geometries. Concerning the semi-discrete formulation we prove stability and a-priori error estimates. Next, we adopt a $\vartheta$-method scheme for time discretization. Some convergence tests are performed to confirm the theoretical bounds and the ability of the method to approximate travelling wave solutions. The proposed scheme is also tested to simulate the spread of $\alpha$-synuclein in a realistic test case of Parkinson's disease in a two-dimensional sagittal brain section geometry reconstructed from medical images

Discontinuous Galerkin Methods for Fisher-Kolmogorov Equation with Application to α\alpha-Synuclein Spreading in Parkinson's Disease

The spreading of prion proteins is at the basis of brain neurodegeneration. The paper deals with the numerical modelling of the misfolding process of $\alpha$-synuclein in Parkinson's disease. We introduce and analyze a discontinuous Galerkin method for the semi-discrete approximation of the Fisher-Kolmogorov (FK) equation that can be employed to model the process. We employ a discontinuous Galerkin method on polygonal and polyhedral grids (PolyDG) for space discretization, which allows us to accurately simulate the wavefronts typically observed in the prionic spreading. We prove stability and a priori error estimates for the semi-discrete formulation. Next, we use a Crank-Nicolson scheme to advance in time. For the numerical verification of our numerical model, we first consider a manufactured solution, and then we consider a case with wavefront propagation in two-dimensional polygonal grids. Next, we carry out a simulation of $\alpha$-synuclein spreading in a two-dimensional brain slice in the sagittal plane with a polygonal agglomerated grid that takes full advantage of the flexibility of PolyDG approximation. Finally, we present a simulation in a three-dimensional patient-specific brain geometry reconstructed from magnetic resonance images.Comment: arXiv admin note: text overlap with arXiv:2210.0227

Delay of morphine tolerance by palmitoylethanolamide

In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect. The cellular and molecular mechanisms underlying morphine tolerance are complex and still unclear. Recently, the activation of glial cells and the release of glia-derived proinflammatory mediators have been suggested to play a role in the phenomenon. N-Palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation. On this basis, 30 mg kg−1 PEA was subcutaneously daily administered in morphine treated rats (10 mg kg−1 intraperitoneally, daily). PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group. PEA prevented both microglia and astrocyte cell number increase induced by morphine in the dorsal horn; on the contrary, the morphine-dependent increase of spinal TNF-α levels was not modified by PEA. Nevertheless, the immunohistochemical analysis revealed significantly higher TNF-α immunoreactivity in astrocytes of PEA-protected rats suggesting a PEA-mediated decrease of cytokine release from astrocyte. PEA intervenes in the nervous alterations that lead to the lack of morphine antinociceptive effects; a possible application of this endogenous compound in opioid-based therapies is suggested

Role of Nitric Oxide, Nitric Oxide Synthase, Soluble Guanylyl Cyclase, and cGMP-Dependent Protein Kinase I in Mouse Stem Cell Cardiac Development

Introduction and Aim. Nitric oxide (NO) can trigger cardiac differentiation of embryonic stem cells (ESCs), indicating a cardiogenic function of the NO synthetizing enzyme(s) (NOS). However, the involvement of the NO/NOS downstream effectors soluble guanylyl cyclase (sGC) and cGMP activated protein kinase I (PKG-I) is less defined. Therefore, we assess the involvement of the entire NO/NOS/sGC/PKG-I pathway during cardiac differentiation process. Methods. Mouse ESCs were differentiated toward cardiac lineages by hanging drop methodology for 21 days. NOS/sGC/PKG-I pathway was studied quantifying genes, proteins, enzymatic activities, and effects of inhibition during differentiation. Percentages of beating embryoid bodies (mEBs) were evaluated as an index of cardiogenesis. Results and Discussion. Genes and protein expression of enzymes were increased during differentiation with distinctive kinetics and proteins possessed their enzymatic functions. Exogenous administered NO accelerated whereas the blockade of PKG-I strongly slowed cardiogenesis. sGC inhibition was effective only at early stages and NOS blockade ineffective. Of NOS/sGC/PKG-I pathway, PKG-I seems to play the prominent role in cardiac maturation. Conclusion. We concluded that exogenous administered NO and other pharmacological strategies able to increase the activity of PKG-I provide new tools to investigate and promote differentiation of cardiogenic precursors

A Systematic Study on the Degradation Products Generated from Artificially Aged Microplastics

Most of the analytical studies focused on microplastics (MPs) are based on the detection and identification of the polymers constituting the particles. On the other hand, plastic debris in the environment undergoes chemical and physical degradation processes leading not only to mechanical but also to molecular fragmentation quickly resulting in the formation of leachable, soluble and/or volatile degradation products that are released in the environment. We performed the analysis of reference MPs–polymer micropowders obtained by grinding a set of five polymer types down to final size in the 857–509 μm range, namely high‐ and low‐density polyethylene, polystyrene (PS), polypropylene (PP), and polyethylene terephthalate (PET). The reference MPs were artificially aged in a solar‐box to investigate their degradation processes by characterizing the aged (photo‐oxidized) MPs and their low molecular weight and/or highly oxidized fraction. For this purpose, the artificially aged MPs were subjected to extraction in polar organic solvents, targeting selective recovery of the low molecular weight fractions generated during the artificial aging. Analysis of the extractable fractions and of the residues was carried out by a multi‐technique approach combining evolved gas analysis–mass spectrometry (EGA–MS), pyrolysis–gas chromatography–mass spectrometry (Py–GC–MS), and size exclusion chromatography (SEC). The results provided information on the degradation products formed during accelerated aging. Up to 18 wt% of extractable, low molecular weight fraction was recovered from the photo‐aged MPs, depending on the polymer type. The photo‐degradation products of polyolefins (PE and PP) included a wide range of long chain alcohols, aldehydes, ketones, carboxylic acids, and hydroxy acids, as detected in the soluble fractions of aged samples. SEC analyses also showed a marked decrease in the average molecular weight of PP polymer chains, whereas cross‐linking was observed in the case of PS. The most abundant low molecular weight photo‐degradation products of PS were benzoic acid and 1,4‐benzenedicarboxylic acid, while PET had the highest stability towards aging, as indicated by the modest generation of low molecular weight species

Relationship between hospital volume and short-term outcomes: A nationwide population-based study including 75,280 rectal cancer surgical procedures

There is growing interest on the potential relationship between hospital volume (HV) and outcomes as it might justify the centralization of care for rectal cancer surgery. From the National Italian Hospital Discharge Dataset, data on 75,280 rectal cancer patients who underwent elective major surgery between 2002 and 2014 were retrieved and analyzed. HV was grouped into tertiles: low-volume performed 1-12, while high-volume hospitals performed 33+ procedures/year. The impact of HV on in-hospital mortality, abdominoperineal resection (APR), 30-day readmission, and length of stay (LOS) was assessed. Risk factors were calculated using multivariate logistic regression. The proportion of procedures performed in low-volume hospitals decreased by 6.7 percent (p<0.001). The rate of in-hospital mortality, APR and 30-day readmission was 1.3%, 16.3%, and 7.2%, respectively, and the median LOS was 13 days. The adjusted risk of in-hospital mortality (OR = 1.49, 95% CI = 1.25-1.78), APR (OR 1.10, 95%CI 1.02-1.19), 30-day readmission (OR 1.49, 95%CI 1.38-1.61), and prolonged LOS (OR 2.29, 95%CI 2.05-2.55) were greater for low-volume hospitals than for high-volume hospitals. This study shows an independent impact of HV procedures on all short-term outcome measures, justifying a policy of centralization for rectal cancer surgery, a process which is underwa

Co-expression of Myoepithelial and Melanocytic Features in Carcinoma Ex Pleomorphic Adenoma

The presence of melanin pigment and melanocytic markers expression have been rarely reported in salivary gland tumors. Herein, two cases of carcinoma arising in pleomorphic adenoma of the parotid gland and showing diffuse expression of myoepithelial and melanocytic markers are described. The clinical-pathological clues useful in the differential diagnosis with melanoma are discussed. In addition, a review of the pertinent literature is also proposed, discussing the pathologic mechanisms potentially involved in this phenomenon

A case-crossover study of sleep, fatigue, and other transient exposures at workplace and the risk of non-fatal occupational injuries among the employees of an Italian academic hospital

Objectives: Transient exposure with acute effect has been shown to affect the risk of occupational injuries in various industrial settings and at the healthcare workplace. The objective of this study has been to identify transient exposures related to occupational injury risk in an Italian teaching hospital. Material and Methods: A case-crossover study was conducted among the employees of the University Hospital of Udine who reported an occupational injury, commuting accident, or incident involving biological risk in a 15-month period in the years 2013 and 2014. The matched-pair interval approach was used to assess the role of acute sleep deprivation whereas the usual frequency approach was used for other 13 transient exposures. Results: Sleep hours were not associated with the risk of injuries whereas a significant risk increase was associated with fatigue, rush, distraction, emergency situations, teaching to or being taught by someone, non-compliant patients, bloody operative/work field, excess noise, complex procedures, and anger. Conclusions: We identified transient exposures that increased the risk of occupational injuries in an Italian teaching hospital, providing indications for interventions to increase workers' safety at the healthcare workplace. Int J Occup Med Environ Health 2016;29(6):1001–100