(pollen beetle) gastrointestinal disease experimentally reproduced in sheep.

Intoxication of sheep and cattle by recently occurred in Uruguay and Argentina in association with severe drought. Although the disease was experimentally reproduced in sheep in the 1970s, there is limited information on clinical and pathologic findings of sheep experimentally intoxicated by this beetle. Here, we described the clinical, gross, and microscopic findings in 3 sheep orally dosed with (treatment group, TG) and in 2 control sheep (control group, CG) dosed with distilled water.

Intoxication of dairy cows in Uruguay by ingestion of cocklebur () seeds in sorghum silage.

The ingestion of cotyledons or seeds of cocklebur () causes poisoning as a result of acute liver failure. Here we describe a spontaneous outbreak of toxicity in dairy cows in Uruguay. The outbreak occurred in the winter when the cows were fed sorghum silage contaminated with seeds.

Discovery of CHF-6523, an Inhaled Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.

The design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a topology ensured the desired PI3Kδ selectivity. Achievement of low nanomolar cellular potencies through hinge binder group optimization, reduction of intrinsic permeability through head group optimization to extend lung retention, and screening of crystalline forms suitable for administration as dry powders culminated in the identification of compound .

Discovery and Optimization of Pyridazinones as PI3Kδ Selective Inhibitors for Administration by Inhalation.

A hit-to-lead campaign pursuing the identification of novel inhalant small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of inflammatory respiratory diseases is disclosed. A synthetically versatile pyridazin-3(2)-one scaffold was designed, and three exit vectors on the core moiety were used to explore chemical diversity and optimize pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties. Desired modulation of PI3Kδ selectivity and cellular potency as well as ADME properties in view of administration by inhalation was achieved.

Predicting Response to In-Hospital Pulmonary Rehabilitation in Individuals Recovering From Exacerbations of Chronic Obstructive Pulmonary Disease.

Background: Predicting the response to pulmonary rehabilitation (PR) could be valuable in defining admission priorities. We aimed to investigate whether the response of individuals recovering from a COPD exacerbation (ECOPD) could be forecasted using machine learning approaches.

Method: This multicenter, retrospective study recorded data on anthropometrics, demographics, physiological characteristics, post-PR changes in six-minute walking distance test (6MWT), Medical Research Council scale for dyspnea (MRC), Barthel Index dyspnea (BId), COPD assessment test (CAT) and proportion of participants reaching the minimal clinically important difference (MCID).

Application of an "inhalation by design" approach to the identification and in-vitro evaluation of novel purine based PI3Kδ inhibitors.

PI3Kδ is a lipid kinase which plays a key role in airway inflammatory conditions. Accordingly, the inhibition of PI3Kδ can be considered a valuable strategy for the treatment of chronic respiratory diseases such as Asthma and Chronic obstructive pulmonary disease (COPD). In this work, we describe our efforts to identify new PI3Kδ inhibitors following an "inhalation by design" strategy.

Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA) in IPF is supported by LPA knockdown studies.

The Coronavirus Footprint on Dual-Task Performance in Post-Acute Patients after Severe COVID-19: A Future Challenge for Rehabilitation.

Recent studies suggest that also the non-critical form of COVID-19 infection may be associated with executive function impairments. However, it is not clear if they result from cognitive impairments or by COVID-19 infection per se. We aimed to investigate if patients in the post-acute stage of severe COVID-19 (PwCOVID), without manifest cognitive deficits, reveal impairments in performing dual-task (DT) activities compared to healthy controls (HS).

Balance performance in patients with post-acute COVID-19 compared to patients with an acute exacerbation of chronic obstructive pulmonary disease and healthy subjects.

COVID-19 leaves important sequelae in patients, not only in those who had the experience of a critical illness but also in patients with severe form. Understanding the impairments allows us to target rehabilitation to patients' real needs; balance impairments are an assumed sequela of COVID-19, but no study has specifically evaluated balance performance in these patients. Their performance was compared to that of patients with a pulmonary disease that leads to systemic diseases, such as patients with an acute exacerbation of chronic obstructive pulmonary disease (PwAECOPD), and of healthy subjects.

Pulmonary rehabilitation in patients with interstitial lung diseases: Correlates of success.

Background And Aim: Benefits of pulmonary rehabilitation in Interstitial Lung Diseases (ILD) have been reported. The aim of this large multicenter study was to identify the success predictors of pulmonary rehabilitation in a real-life setting.

Methods: Data of 240 in-patients (110 idiopathic pulmonary fibrosis (IPF), 106 ILD other than IPF and 24 undetermined ILD) undergoing pulmonary rehabilitation in a 10-year period were retrospectively evaluated.

Hypothermia during Surgical Treatment of Type A Aortic Dissection: A 16 Years' Experience.

Acute aortic dissection (AAD) is among the most challenging cases for surgical treatment and requires procedural expertise for its safe conduct. Aortic surgery has undergone several changes over the last years, especially concerning cerebral protection. The brilliant results obtained with the aid of selective anterograde cerebral perfusion led to a progressive increase of circulatory arrest temperature, with the rise of safe time along with a reduction of the extracorporeal circulation time and hypothermia-related side effects.

A Fatal Mediastinitis Due to a Neck Trauma from an Undeclared Assault.

History of neck trauma should be promptly investigated in patients with severe infections of the chest as mediastinitis. We present a forensic case of a death due to a mediastinitis in a patient with an undetected fracture of the superior horn of the thyroid cartilage that was exclusively revealed at autopsy examination. Histological analyses of the neck tissues showed signs of pharyngeal mucosal microperforation caused by the fracture and surrounded by an inflammatory reaction.

Fiber-bundle model with time-dependent healing mechanisms to simulate progressive failure of snow.

Snow is a heterogeneous material with strain- and/or load-rate-dependent strength. In particular, a transition from ductile-to-brittle failure behavior with increasing load rate is observed. The rate-dependent behavior can partly be explained with the existence of a unique healing mechanism in snow that stems from its high homologous temperature (temperature close to melting point).

Developing Product Environmental Footprint Category Rules (PEFCR) for shampoos: The basis for comparable life cycle assessment.

In 2013, the European Commission launched the Environmental Footprint Rules pilot phase. This initiative aims at setting specific rules for life cycle assessment (LCA: raw material sourcing, production, logistics, use, and disposal phase) studies within 1 product category, called product environmental footprint category rules (PEFCR), and for organizations, called organizational environmental footprint sector rules (OEFSR). Such specific rules for measuring environmental performance throughout the life cycle should facilitate the comparability between LCA studies and provide principles for communicating environmental performance, such as transparency, reliability, completeness, and clarity.

Novel Pyrrolidine Derivatives of Budesonide as Long Acting Inhaled Corticosteroids for the Treatment of Pulmonary Inflammatory Diseases.

Inhaled corticosteroids (ICSs) represent the first line therapy for the treatment of asthma and are also extensively utilized in chronic obstructive pulmonary disease. Our goal was to develop a new ICS with a basic group, which can allow solid state feature modulation, achieving at the same time high local anti-inflammatory effect and low systemic exposure. Through a rational drug design approach, a new series of pyrrolidine derivatives of budesonide was identified.

Atropisomerism and Conformational Equilibria: Impact on PI3Kδ Inhibition of 2-((6-Amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one (IC87114) and Its Conformationally Restricted Analogs.

IC87114 [compound 1, (2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one)] is a potent PI3K inhibitor selective for the δ isoform. As predicted by molecular modeling calculations, rotation around the bond connecting the quinazolin-4(3H)-one nucleus to the o-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e.

Metadynamics Simulations Distinguish Short- and Long-Residence-Time Inhibitors of Cyclin-Dependent Kinase 8.

The duration of drug efficacy in vivo is a key aspect primarily addressed during the lead optimization phase of drug discovery. Hence, the availability of robust computational approaches that can predict the residence time of a compound at its target would accelerate candidate selection. Nowadays the theoretical prediction of this parameter is still very challenging.

GLIMPSED: An Improved Docking Protocol for Cognate Docking.

The cognate docking performance of Glide was evaluated using the Astex diverse set. The standard Glide SP protocol obtained a 85.7 % success rate when the shape similarity cutoff was set to 0.

Phospho-p38 MAPK expression in COPD patients and asthmatics and in challenged bronchial epithelium.

Background: The role of mitogen-activated protein kinases (MAPK) in regulating the inflammatory response in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthmatic patients is unclear.

Objectives: To investigate the expression of activated MAPK in lungs of COPD patients and in bronchial biopsies of asthmatic patients and to study MAPK expression in bronchial epithelial cells in response to oxidative and inflammatory stimuli.

Methods: Immunohistochemical expression of phospho (p)-p38 MAPK, p-JNK1 and p-ERK1/2 was measured in bronchial mucosa in patients with mild/moderate (n = 17), severe/very severe (n = 16) stable COPD, control smokers (n = 16), control non-smokers (n = 9), in mild asthma (n = 9) and in peripheral airways from COPD patients (n = 15) and control smokers (n = 15).

Discovery of a novel isoxazoline derivative of prednisolone endowed with a robust anti-inflammatory profile and suitable for topical pulmonary administration.

A novel glucocorticoids series of (GCs), 6α,9α-di-Fluoro 3-substituted C-16,17-isoxazolines was designed, synthesised and their structure-activity relationship was evaluated with glucocorticoid receptor (GR) binding studies together with GR nuclear translocation cell-based assays. This strategy, coupled with in silico modelling analysis, allowed for the identification of Cpd #15, an isoxazoline showing a sub-nanomolar inhibitory potency (IC50=0.84 nM) against TNFα-evoked IL-8 release in primary human airways smooth muscle cells.

Unbinding pathways of VEGFR2 inhibitors revealed by steered molecular dynamics.

A detailed atomistic description of the unbinding process of sorafenib and sunitinib, two known VEGFR2 inhibitors clinically used to treat renal cell carcinoma, was unraveled by using steered molecular dynamics (SMD) simulations. While sunitinib is a fast-dissociating binder, sorafenib exhibits quite a long residence time at this enzyme, which might impact its duration of action in vivo. In order to gain insights into the kinetically different behaviors of the two inhibitors, an SMD study was carried out, which involved a careful optimization of the force and velocity parameters.

Modafinil improves real driving performance in patients with hypersomnia: a randomized double-blind placebo-controlled crossover clinical trial.

Study Objective: Patients with excessive daytime sleepiness (EDS) are at high risk for driving accidents, and physicians are concerned by the effect of alerting drugs on driving skills of sleepy patients. No study has up to now investigated the effect of modafinil (a reference drug to treat EDS in patients with hypersomnia) on on-road driving performance of patients suffering from central hypersomnia. The objective is to evaluate in patients with central hypersomnia the effect of a wake-promoting drug on real driving performance and to assess the relationship between objective sleepiness and driving performance.