Assessment of pulmonary vascular smooth muscle remodeling in severe equine asthma

Severe equine asthma (SEA) is characterized by reversible airway obstruction and hypoxemia. Pulmonary hypoxic vasoconstriction occurs during SEA exacerbation, inducing pulmonary hypertension (PH). However, PH is only partially reversed by oxygen administration, and other etiological factors are uninvestigated (Dixon 1978). In rodent asthma models, airway inflammation is associated with pulmonary artery (PA) remodeling (Rydell-Tormanen, Uller et al. 2009), that could contribute to PH, as known in human chronic obstructive pulmonary disease (Barbera, Peinado et al. 2003). We investigated the presence of PA remodeling in SEA, the involvement of vascular smooth muscle (VSM) alterations and their reversibility following long-term antigen avoidance or inhaled corticosteroids. Using histomorphometry, the PA wall was measured on sections stained with hematoxylin-eosin saffron, collected post-mortem from different lung regions of 12 asthmatic horses and 6 controls. Pulmonary vascular smooth muscle (VSM) mass was measured on sections stained for α-smooth muscle actin collected with in vivo thoracoscopy or post-mortem peripheral lung biopsy from 5 controls, 6 asthmatic horses in remission, and 11 asthmatic horses while exacerbation and after 1 year of antigen avoidance alone (5 horses) or treatment with fluticasone (6 horses). Data were compared using unpaired t test with Welch correction or paired t test (p<0.05). PA wall surface percentage was increased in apical (p=0.003) and caudo-dorsal (p=0.03) lung regions (respectively 50,66±13,16% and 50,56±15,02) of asthmatic horses, when compared to controls (respectively 35,38±7,06% and 38,13±10,18). Similarly, VSM mass percentage was increased (p=0.03) in asthmatic horses (47,77±3,17%), compared to controls (41,07±6,22%). A tendency for normalization of the VSM mass was observed after treatment with antigen avoidance (p=0.05; 39,64±4,02%), but not with fluticasone (p=0.27; 45,35±14,98%). Remodeling of the PA occurs in SEA and the increase in VSM could lead to lumen narrowing and enhance hypoxic vasoconstriction, contributing to PH during exacerbation. VSM mass normalization is more effectively obtained by antigen avoidance than by corticosteroids

Mining Spatio-Temporal Datasets: Relevance, Challenges and Current Research Directions

Spatio-temporal data usually records the states over time of an object, an event or a position in space. Spatio-temporal data can be found in several application fields, such as traffic management, environment monitoring, weather forerast, etc. In the past, huge effort was devoted to spatial data representation and manipulation with particular focus on its visualisation. More recently, the interest of many users has shifted from static views of geospatial phenomena, which capture its “spatiality” only, to more advanced means of discovering dynamic relationships among the patterns and events contained in the data as well as understanding the changes occurring in spatial data over time

Long‑term Effectiveness and Safety of Upadacitinib for Atopic Dermatitis in a Real‑world Setting: An Interim Analysis Through 48 Weeks of Observation

Background Janus kinase (JAK) inhibitors, including upadacitinib, have been recently approved for the treatment of moderate- severe atopic dermatitis (AD) and real-world data on upadacitinib effectiveness and safety are limited. This interim analysis aimed to assess effectiveness and safety of upadacitinib throughout 48 weeks of observation in a real-world adult AD population. Methods This prospective study collected data on adult patients affected by moderate-to-severe AD and treated with upadacitinib at the dosage of either 15 mg or 30 mg daily based on the physician decision. Upadacitinib was prescribed in the context of a national compassionate use programme. In this interim analysis, within patient comparisons of continuous scores of different scales (namely Eczema Area and Severity Index [EASI], body surface area [BSA], Dermatology Life Quality Index [DLQI], Patient Oriented Eczema Measure [POEM], Numeric Rating Scale [NRS] subtests) were performed. The percentage of patients achieving EASI 75, EASI 90 and EASI 100 at Week 16, 32 and 48 was also evaluated. Results One hundred and forty-six patients were included in the analysis. Upadacitinib 15 mg or 30 mg daily was prescribed as monotherapy in most cases (127/146, 87.0%). Upadacitinib was initially prescribed at the dosage of 30 mg daily in 118 of 146 (80.8%) patients and 15 mg daily in 28/146 (19.2%) patients. A significant improvement in the clinical signs and symptoms of AD was detected by Week 16 and throughout the study period. EASI 75, EASI 90 and EASI 100 responses were achieved by 87.6%, 69.1% and 44.3% at Week 48, associated with a sustained reduction in the mean values of all physicianreported (EASI and BSA) and patient-reported (Itch- Sleep- and Pain-NRS, DLQI, and POEM) disease severity outcomes, up to 48 weeks of treatment. Treatment response observed in 15 mg upadacitinib-treated patients was comparable with that detected in 30 mg upadacitinib-treated patients, revealing no statistical difference between the two patient sub-cohorts. Through the observation period, dose reduction or escalation was observed in 38/146 (26%) of treated cases. Overall, 26 of 146 (17.8%) patients experienced at least one adverse event (AE) during the treatment period. In total, 29 AEs were recorded and most of them were evaluated as mild to moderate, while in 4 cases the occurrence of AE led to drug discontinuation, for a total of 7/146 (4.8%) dropouts. Conclusion This study provides strong evidence of a sustained response obtained by upadacitinib in AD patients, who had failed to respond to conventional or biological systemic agents, through 48 weeks of observation. Upadacitinib was also demonstrated to be advantageous in terms of flexibility in dose reduction or escalation as upadacitinib dose was shaped on clinical needs that, in a real-world setting, might frequently change

Plastic changes in the spinal cord in motor neuron disease.

In the present paper, we analyze the cell number within lamina X at the end stage of disease in a G93A mouse model of ALS; the effects induced by lithium; the stem-cell like phenotype of lamina X cells during ALS; the differentiation of these cells towards either a glial or neuronal phenotype. In summary we found that G93A mouse model of ALS produces an increase in lamina X cells which is further augmented by lithium administration. In the absence of lithium these nestin positive stem-like cells preferentially differentiate into glia (GFAP positive), while in the presence of lithium these cells differentiate towards a neuronlike phenotype (III-tubulin, NeuN, and calbindin-D28K positive). These effects of lithium are observed concomitantly with attenuation in disease progression and are reminiscent of neurogenetic effects induced by lithiumin the subependymal ventricular zone of the hippocampus

High-intensity exercise training induces morphological and biochemical changes in skeletal muscles

IN THE PRESENT STUDY WE INVESTIGATED THE EFFECT OF TWO DIFFERENT EXERCISE PROTOCOLS ON FIBRE COMPOSITION AND METABOLISM OF TWO SPECIFIC MUSCLES OF MICE: the quadriceps and the gastrocnemius. Mice were run daily on a motorized treadmill, at a velocity corresponding to 60% or 90% of the maximal running velocity. Blood lactate and body weight were measured during exercise training. We found that at the end of training the body weight significantly increased in high-intensity exercise mice compared to the control group (P=0.0268), whereas it decreased in low-intensity exercise mice compared to controls (P=0.30). In contrast, the food intake was greater in both trained mice compared to controls (P < 0.0001 and P < 0.0001 for low-intensity and high-intensity exercise mice, respectively). These effects were accompanied by a progressive reduction in blood lactate levels at the end of training in both the exercised mice compared with controls (P=0.03 and P < 0.0001 for low-intensity and high-intensity exercise mice, respectively); in particular, blood lactate levels after high-intensity exercise were significantly lower than those measured in low-intensity exercise mice (P=0.0044). Immunoblotting analysis demonstrated that high-intensity exercise training produced a significant increase in the expression of mitochondrial enzymes contained within gastrocnemius and quadriceps muscles. These changes were associated with an increase in the amount of slow fibres in both these muscles of high-intensity exercise mice, as revealed by the counts of slow fibres stained with specific antibodies (P < 0.0001 for the gastrocnemius; P=0.0002 for the quadriceps). Our results demonstrate that high-intensity exercise, in addition to metabolic changes consisting of a decrease in blood lactate and body weight, induces an increase in the mitochondrial enzymes and slow fibres in different skeletal muscles of mice, which indicates an exercise-induced increase in the aerobic metabolism

The Neuroanatomy of the Reticular Nucleus Locus Coeruleus in Alzheimer's Disease.

Alzheimer's Disease (AD) features the accumulation of β-amyloid and Tau aggregates, which deposit as extracellular plaques and intracellular neurofibrillary tangles (NFTs), respectively. Neuronal Tau aggregates may appear early in life, in the absence of clinical symptoms. This occurs in the brainstem reticular formation and mostly within Locus Coeruleus (LC), which is consistently affected during AD. LC is the main source of forebrain norepinephrine (NE) and it modulates a variety of functions including sleep-waking cycle, alertness, synaptic plasticity, and memory. The iso-dendritic nature of LC neurons allows their axons to spread NE throughout the whole forebrain. Likewise, a prion-like hypothesis suggests that Tau aggregates may travel along LC axons to reach out cortical neurons. Despite this timing is compatible with cross-sectional studies, there is no actual evidence for a causal relationship between these events. In the present mini-review, we dedicate special emphasis to those various mechanisms that may link degeneration of LC neurons to the onset of AD pathology. This includes the hypothesis that a damage to LC neurons contributes to the onset of dementia due to a loss of neuroprotective effects or, even the chance that, LC degenerates independently from cortical pathology. At the same time, since LC neurons are lost in a variety of neuropsychiatric disorders we considered which molecular mechanism may render these brainstem neurons so vulnerable

Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus, the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine beta-hydroxylase; DBH). We found that genetic deletion of DBH (DBH-/- mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioral stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioral, and neurotoxic effects of METH