Preclinical Optimization of Treatment with Inhaled Argon to Improve Neurological Outcome and Survival After Cardiac Arrest

Introduction. Treatment of post cardiac arrest (CA) syndrome represents a clinical priority. Inhalation of the noble gas Argon may represent an attractive option. The purpose of the current thesis is to determine the efficacy, safety and mechanisms of action of Argon in different experimental models. Methods. In order to assess the efficacy of argon treatment on post CA syndrome, a pig model of CA with underlying acute myocardial infarction and cardiopulmonary resuscitation (CPR) was used. Following resuscitation, animals were randomly assigned to receive ventilation with 70% Argon (Ar 70%) or 70% Nitrogen (N270%) in oxygen. Argon effects were studied in models of CA with different level of severity (i.e. short or long duration of untreated ventricular fibrillation). Furthermore, administration of low Argon concentration (i.e. 50%) was evaluated in a subset of animals. Hemodynamics, myocardial function, neurologic recovery, brain and cardiac histological injury and biomarkers together with survival were evaluated. The safety of Argon treatment was assessed in healthy pigs. In parallel, mechanisms of action were explored. Specifically, brain protection was investigated in a rat model of CA followed by CPR. After resuscitation, animals were randomized to receive Ar 70% or N270%. Brain glutamate, gamma-amino butyric acid, pyruvate and lactate were measured by in vivo micro-dialysis. In addition, myocardial protection by argon was explored in rats subjected to coronary artery occlusion followed by reperfusion and receiving Ar 70% or N270% during reperfusion. Six and 24 h after reperfusion, myocardial injury, plasma troponin T concentration and myocardial neutrophil infiltration were evaluated. Results. Efficacy of argon on preventing post CA brain injury has been demonstrated in swine. Indeed, a faster and complete neurologic recovery following CA and CPR was achieved in Argon-treated animals compared to controls, without detrimental effects on hemodynamics and respiratory gas exchanges. Beneficial effects of Argon tended to be higher at a concentration of 70% than of 50%. Results obtained in small rodents suggest that ventilation with Argon reduces brain lactate/ pyruvate level and troponin T release. However, further studies are needed in order explain the mechanism underpining Argon protective effects. Conclusion. The consistency of the results is highly suggestive to consider ventilation with Argon as a promising therapeutic approach after CA and CPR

Strategies to improve Critical Infrastructures Robustness against the IEMI threat : a Review of relevant Standards and Guidelines on the topic

This paper aims to provide a brief overview of relevant standards, procedures and guidelines to standard bodies to manage the impact of the Intentional ElectroMagnetic Interference (IEMI) threat. It also provides guidelines for CI operators on how to reduce their exposure on IEMI hazards

miRNA expression is increased in serum from patients with semantic variant primary progressive aphasia

Primary progressive aphasia (PPA) damages the parts of the brain that control speech and language. There are three clinical PPA variants: nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). The pathophysiology underlying PPA variants is not fully understood, including the role of micro (mi)RNAs which were previously shown to play a role in several neurodegenerative diseases. Using a two-step analysis (array and validation through real-time PCR), we investigated the miRNA expression pattern in serum from 54 PPA patients and 18 controls. In the svPPA cohort, we observed a generalized upregulation of miRNAs with miR-106b-5p and miR-133a-3p reaching statistical significance (miR-106b-5p: 2.69 ± 0.89 mean ± SD vs. 1.18 ± 0.28

Lectin Pathway of Complement Activation Is Associated with Vulnerability of Atherosclerotic Plaques

Inflammatory mechanisms may be involved in atherosclerotic plaque rupture. By using a novel histology-based method to quantify plaque instability here, we assess whether lectin pathway (LP) of complement activation, a major inflammation arm, could represent an index of plaque instability. Plaques from 42 consecutive patients undergoing carotid endarterectomy were stained with hematoxylin-eosin and the lipid core, cholesterol clefts, hemorrhagic content, thickness of tunica media, and intima, including or not infiltration of cellular debris and cholesterol, were determined. The presence of ficolin-1, -2, and -3 and mannose-binding lectin (MBL), LP initiators, was assessed in the plaques by immunofluorescence and in plasma by ELISA. LP activation was assessed in plasma by functional in vitro assays. Patients presenting low stenosis (≤75%) had higher hemorrhagic content than those with high stenosis (>75%), indicating increased erosion. Increased hemorrhagic content and tunica media thickness, as well as decreased lipid core and infiltrated content were associated with vulnerable plaques and therefore used to establish a plaque vulnerability score that allowed to classify patients according to plaque vulnerability. Ficolins and MBL were found both in plaques’ necrotic core and tunica media. Patients with vulnerable plaques showed decreased plasma levels and intraplaque deposition of ficolin-2. Symptomatic patients experiencing a transient ischemic attack had lower plasma levels of ficolin-1. We show that the LP initiators are present within the plaques and their circulating levels change in atherosclerotic patients. In particular, we show that decreased ficolin-2 levels are associated with rupture-prone vulnerable plaques, indicating its potential use as marker for cardiovascular risk assessment in atherosclerotic patients

Critical issues for the proper diagnosis of Metachromatic Leukodystrophy

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Frailty, psychological well-being, and social isolation in older adults with cognitive impairment during the SARS-CoV-2 pandemic: data from the GeroCovid initiative

Background: The containment measures linked to the COVID-19 pandemic negatively affected the phyco-physical well-being of the population, especially older adults with neurocognitive disorders (NCDs). This study aims to evaluate whether the frailty of NCD patients was associated with different changes in multiple health domains, in particular in relation to loneliness and social isolation, pre- and post-lockdown. Materials and methods: Patients were recruited from 10 Italian Centers for Cognitive Disorders and Dementia. Data were collected in the pre-pandemic period (T0), during the pandemic lockdown (T1), and 6-9 months post-lockdown (T2). The UCLA Loneliness Scale-3, Activities of Daily Living (ADL), Instrumental ADL (IADL), Mini-Mental State Examination, and Neuropsychiatric Inventory (NPI) were administered. Caregivers' burden was also tested. Patients were categorized as non-frail, pre-frail, and frail according to the Fatigue, Resistance, Ambulation, Illness, and Loss of Weight scale. Results: The sample included 165 subjects (61.9% women, mean age 79.5 ± 4.9 years). In the whole sample, the ADL, IADL, and NPI scores significantly declined between T0 and T2. There were no significative variations in functional and cognitive domains between the frail groups. During lockdown we recorded higher Depression Anxiety Stress Scales and Perceived Stress Scale scores in frail people. In multivariable logistic regression, frailty was associated with an increase in social isolation, and a loss of IADL. Conclusions: We observed a global deterioration in functional and neuro-psychiatric domains irrespective of the degree of frailty. Frailty was associated with the worsening of social isolation during lockdown. Frail patients and their caregivers seemed to experience more anxiety and stress disorders during SARS-CoV-2 pandemic

Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

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