Molecular analysis of Duchenne/Becker muscular dystrophy

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GDF15 Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness

Growth differentiation factor 15 (GDF15) is a stress molecule produced in response to mitochondrial, metabolic and inflammatory stress with a number of beneficial effects on metabolism. However, at the level of skeletal muscle it is still unclear whether GDF15 is beneficial or detrimental. The aim of the study was to analyse the levels of circulating GDF15 in people of different age, characterized by different level of physical activity and to seek for correlation with hematological parameters related to inflammation. The plasma concentration of GDF15 was determined in a total of 228 subjects in the age range from 18 to 83 years. These subjects were recruited and divided into three different groups based on the level of physical activity: inactive patients with lower limb mobility impairment, active subjects represented by amateur endurance cyclists, and healthy controls taken from the general population. Cyclists were sampled before and after a strenuous physical bout (long distance cycling race). The plasma levels of GDF15 increase with age and are inversely associated with active lifestyle. In particular, at any age, circulating GDF15 is significantly higher in inactive patients and significantly lower in active people, such as cyclists before the race, with respect to control subjects. However, the strenuous physical exercise causes in cyclists a dramatic increase of GDF15 plasma levels, that after the race are similar to that of patients. Moreover, GDF15 plasma levels significantly correlate with quadriceps torque in patients and with the number of total leukocytes, neutrophils and lymphocytes in both cyclists (before and after race) and patients. Taken together, our data indicate that GDF15 is associated with decreased muscle performance and increased inflammation

Long Covid: where we stand and challenges ahead

Post-acute sequelae of SARS-CoV-2 (PASC), also known as Post-Covid Syndrome, and colloquially as Long Covid, has been defined as a constellation of signs and symptoms which persist for weeks or months after the initial SARS-CoV-2 infection. PASC affects a wide range of diverse organs and systems, with manifestations involving lungs, brain, the cardiovascular system and other organs such as kidney and the neuromuscular system. The pathogenesis of PASC is complex and multifactorial. Evidence suggests that seeding and persistence of SARS-CoV-2 in different organs, reactivation, and response to unrelated viruses such as EBV, autoimmunity, and uncontrolled inflammation are major drivers of PASC. The relative importance of pathogenetic pathways may differ in different tissue and organ contexts. Evidence suggests that vaccination, in addition to protecting against disease, reduces PASC after breakthrough infection although its actual impact remains to be defined. PASC represents a formidable challenge for health care systems and dissecting pathogenetic mechanisms may pave the way to targeted preventive and therapeutic approaches

The cost-effectiveness of naloxone programs for the treatment of heroin overdose in the ‘street’: a 2-years data collection by the Street Unit of the Villa Maraini Foundation

The mortality rate of opioid users is about 5 to 10 times greater than that of the general population, and the overdose represents the most common cause of death. When timely treated with the opioid antagonist naloxone, the opioid overdose is rarely lethal. Unfortunately, many opioid overdoses occur in isolated, hidden, hard to reach location. To circumvent this problem, Villa Maraini Foundation in Rome has created a rescue team, the Street Unit, to provide basic life support and administer naloxone for the treatment of opioid overdose in urban environments. The aim of this paper is to review the cost-effectiveness of our Street Unit. We evaluated the cost of 90 overdose interventions provided by the Street Unit to that provided by the Accident & Emergency departments of the Italian National Health System. The Street Unit not only successfully treated all overdoses but also provided a dramatic reduction in costs, ranging from €123,367.05 (best-case scenario) to €203,377.05 (worst-case scenario). This finding suggests that the treatment of opioid overdose in the street context represents a safe and cost-effective strategy to reduce opioid overdose related mortality

Impact of Age and Heart Rate on Strain-Derived Myocardial Work in a Population of Healthy Subjects

The influence of age and gender on strain-imaging-derived myocardial work (MW) was recently investigated in healthy subjects. No information is available on the impact of heart rate (HR) on MW

Cost minimization analysis of BoNT-As in the treatment of upper limb spasticity and cervical dystonia

Botulinum toxin type A (BoNT-A) injections are recommended for the management of upper limb spasticity (ULS) and cervical dystonia (CD). The main aim of this cost minimization analysis (CMA) was to compare the annual cost per patient for three BoNT-As (Botox®, Dysport® and Xeomin®) in the treatment of ULS or CD in Italy. A budget impact analysis (BIA) was also conducted. Methods The CMA was conducted from the perspective of the Italian National Health Service. Only direct medical costs (BoNT-A and standard therapy) were considered. By using a Delphi panel of twelve Italian Experts in the treatment of ULS and CD, data was collected about BoNT-As (dose, number of administrations and acquisition price) and standard therapy (concomitant medications, visits, Day-Hospital, hospitalizations, etc.). Costs were assessed in Euros 2014. The BIA was conducted to evaluate the pharmaceutical expenditure for the three BoNT-As on a five-year time horizon. A sensitivity analysis was conducted. Results The mean annual cost per patient with ULS was €1,840.20 with Dysport®, €2,067.12 with Botox® and €2,171.05 with Xeomin®. The mean annual cost per patient with CD was €1,353.79 with Dysport®, €1,433.12 with Botox® and €1,503.60 with Xeomin®. In the time horizon considered, the substitution process of Botox® and Xeomin® by Dysport® would result in a total saving of €620,000 when treating ULS and a total saving of €481,000 in the case of CD. Sensitivity and probabilistic analyses showed the robustness of results. Conclusions From the Italian National Health Service's perspective, Dysport® appears to be the cost-saving therapeutic option compared with Botox® and Xeomin® in the treatment of ULS or CD

Silybins inhibit human IAPP amyloid growth and toxicity through stereospecific interactions

Type 2 Diabetes is a major public health threat, and its prevalence is increasing worldwide. The abnormal accumulation of islet amyloid polypeptide (IAPP) in pancreatic β-cells is associated with the onset of the disease. Therefore, the design of small molecules able to inhibit IAPP aggregation represents a promising strategy in the development of new therapies. Here we employ in vitro, biophysical, and computational methods to inspect the ability of Silybin A and Silybin B, two natural diastereoisomers extracted from milk thistle, to interfere with the toxic self-assembly of human IAPP (hIAPP). We show that Silybin B inhibits amyloid aggregation and protects INS-1 cells from hIAPP toxicity more than Silybin A. Molecular dynamics simulations revealed that the higher efficiency of Silybin B is ascribable to its interactions with precise hIAPP regions that are notoriously involved in hIAPP self-assembly i.e., the S20-S29 amyloidogenic core, H18, the N-terminal domain, and N35. These results highlight the importance of stereospecific ligand-peptide interactions in regulating amyloid aggregation and provide a blueprint for future studies aimed at designing Silybin derivatives with enhanced drug-like properties. Keywords: Aggregation; Diabetes; Inhibitors; Molecular dynamics; Peptid