Assessment of Left Lung Remodeling With Magnetic Resonance Imaging in a Murine Model Following Exposure to Douglas Fir Smoke.

Wildland firefighters (WLFFs) experience lung function decline due to occupational exposure to fire smoke. WLFFs typically do not wear respiratory personal protective equipment, and if they do, it is a simple bandana, which is not effective at filtering smoke. To pinpoint the biological underpinnings of abnormal respiratory function following 3-7 years of WLFF service, we exposed mice to Douglas fir smoke (DFS) over 8 weeks. Following exposure, we assessed changes in lung structure through Magnetic Resonance Imaging (MRI) and histological analysis, which was supported by immunohistochemistry staining. With MRI, we found that the signal decay time, T2*, from ultrashort echo time (UTE) images was significantly shorter in mice exposed to DFS compared to air controls. In addition, the variation in T2* was more heterogeneously distributed throughout the left lung in DFS-exposed mice, compared to air controls. As confirmed by histological analysis, shorter T2* was caused by larger parenchyma airspace sizes and not fibrotic remodeling. Destruction of the alveolar spaces was likely due to inflammation, as measured by an influx of CD68+ macrophages and destruction due to enhanced neutrophil elastase. In addition, measurements of airspace dimensions from histology were more heterogeneously distributed throughout the lung, corroborating the enhanced relative dispersion of T2*. Findings from this study suggest that the decline in lung function observed in WLFFs may be due to emphysema-like changes in the lung, which can be quantified with MRI.

Overlapping and Distinct Features of Cardiac Pathology in Inherited Human and Murine Ether Lipid Deficiency.

Inherited deficiency in ether lipids, a subgroup of glycerophospholipids with unique biochemical and biophysical properties, evokes severe symptoms in humans resulting in a multi-organ syndrome. Mouse models with defects in ether lipid biosynthesis have widely been used to understand the pathophysiology of human disease and to study the roles of ether lipids in various cell types and tissues. However, little is known about the function of these lipids in cardiac tissue. Previous studies included case reports of cardiac defects in ether-lipid-deficient patients, but a systematic analysis of the impact of ether lipid deficiency on the mammalian heart is still missing. Here, we utilize a mouse model of complete ether lipid deficiency (Gnpat KO) to accomplish this task. Similar to a subgroup of human patients with rhizomelic chondrodysplasia punctata (RCDP), a fraction of Gnpat KO fetuses present with defects in ventricular septation, presumably evoked by a developmental delay. We did not detect any signs of cardiomyopathy but identified increased left ventricular end-systolic and end-diastolic pressure in middle-aged ether-lipid-deficient mice. By comprehensive electrocardiographic characterization, we consistently found reduced ventricular conduction velocity, as indicated by a prolonged QRS complex, as well as increased QRS and QT dispersion in the Gnpat KO group. Furthermore, a shift of the Wenckebach point to longer cycle lengths indicated depressed atrioventricular nodal function. To complement our findings in mice, we analyzed medical records and performed electrocardiography in ether-lipid-deficient human patients, which, in contrast to the murine phenotype, indicated a trend towards shortened QT intervals. Taken together, our findings demonstrate that the cardiac phenotype upon ether lipid deficiency is highly heterogeneous, and although the manifestations in the mouse model only partially match the abnormalities in human patients, the results add to our understanding of the physiological role of ether lipids and emphasize their importance for proper cardiac development and function.

The Role of Tenascin C in Cardiac Reverse Remodeling Following Banding-Debanding of the Ascending Aorta.

BACKGROUND: Tenascin-C (TN-C) plays a maladaptive role in left ventricular (LV) hypertrophy following pressure overload. However, the role of TN-C in LV regression following mechanical unloading is unknown. METHODS: LV hypertrophy was induced by transverse aortic constriction for 10 weeks followed by debanding for 2 weeks in wild type (Wt) and TN-C knockout (TN-C KO) mice. Cardiac function was assessed by serial magnetic resonance imaging. The expression of fibrotic markers and drivers (angiotensin-converting enzyme-1, ACE-1) was determined in LV tissue as well as human cardiac fibroblasts (HCFs) after TN-C treatment. RESULTS: Chronic pressure overload resulted in a significant decline in cardiac function associated with LV dilation as well as upregulation of TN-C, collagen 1 (Col 1), and ACE-1 in Wt as compared to TN-C KO mice. Reverse remodeling in Wt mice partially improved cardiac function and fibrotic marker expression; however, TN-C protein expression remained unchanged. In HCF, TN-C strongly induced the upregulation of ACE 1 and Col 1. CONCLUSIONS: Pressure overload, when lasting long enough to induce HF, has less potential for reverse remodeling in mice. This may be due to significant upregulation of TN-C expression, which stimulates ACE 1, Col 1, and alpha-smooth muscle actin (α-SMA) upregulation in fibroblasts. Consequently, addressing TN-C in LV hypertrophy might open a new window for future therapeutics.

Naltrexone but Not Ketanserin Antagonizes the Subjective, Cardiovascular, and Neuroendocrine Effects of Salvinorin-A in Humans.

BACKGROUND: Salvinorin-A is a terpene found in the leaves of the plant Salvia divinorum. When administered to humans, salvinorin-A induces an intense but short-lasting modified state of awareness, sharing features with those induced by the classical serotonin-2A receptor agonist psychedelics. However, unlike substances such as psilocybin or mescaline, salvinorin-A shows agonist activity at the kappa-opioid receptor rather than at the serotonin-2A receptor. Here, we assessed the involvement of kappa-opioid receptor and serotonin-2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. METHODS: We conducted a placebo-controlled, randomized, double-blind study with 2 groups of 12 healthy volunteers with experience with psychedelic drugs. There were 4 experimental sessions. In group 1, participants received the following treatment combinations: placebo+placebo, placebo+salvinorin-A, naltrexone+placebo, and naltrexone+salvinorin-A. Naltrexone, a nonspecific opioid receptor antagonist, was administered at a dose of 50mg orally. In group 2, participants received the treatment combinations: placebo+placebo, placebo+salvinorin-A, ketanserin+placebo, and ketanserin+salvinorin-A. Ketanserin, a selective serotonin-2A antagonist, was administered at a dose of 40mg orally. RESULTS: Inhalation of 1mg of vaporized salvinorin-A led to maximum plasma concentrations at 1 and 2 minutes after dosing. When administered alone, salvinorin-A severely reduced external sensory perception and induced intense visual and auditory modifications, increased systolic blood pressure, and cortisol and prolactin release. These effects were effectively blocked by naltrexone, but not by ketanserin. CONCLUSIONS: Results support kappa opioid receptor agonism as the mechanism of action underlying the subjective and physiological effects of salvinorin-A in humans and rule out the involvement of a serotonin-2A-mediated mechanism.

Salvinorin-A Induces Intense Dissociative Effects, Blocking External Sensory Perception and Modulating Interoception and Sense of Body Ownership in Humans.

BACKGROUND: Salvinorin-A is a terpene with agonist properties at the kappa-opioid receptor, the binding site of endogenous dynorphins. Salvinorin-A is found in Salvia divinorum, a psychoactive plant traditionally used by the Mazatec people of Oaxaca, Mexico, for medicinal and spiritual purposes. Previous studies with the plant and salvinorin-A have reported psychedelic-like changes in perception, but also unusual changes in body awareness and detachment from external reality. Here we comprehensively studied the profiles of subjective effects of increasing doses of salvinorin-A in healthy volunteers, with a special emphasis on interoception. METHODS: A placebo and three increasing doses of vaporized salvinorin-A (0.25, 0.50, and 1mg) were administered to eight healthy volunteers with previous experience in the use of psychedelics. Drug effects were assessed using a battery of questionnaires that included, among others, the Hallucinogen Rating Scale, the Altered States of Consciousness, and a new instrument that evaluates different aspects of body awareness: the Multidimensional Assessment for Interoceptive Awareness. RESULTS: Salvinorin-A led to a disconnection from external reality, induced elaborate visions and auditory phenomena, and modified interoception. The lower doses increased somatic sensations, but the highest dose led to a sense of a complete loss of contact with the body. CONCLUSIONS: Salvinorin-A induced intense psychotropic effects characterized by a dose-dependent gating of external audio-visual information and an inverted-U dose-response effect on body awareness. These results suggest a prominent role for the kappa opioid receptor in the regulation of sensory perception, interoception, and the sense of body ownership in humans.

pH-responsive i-motif-conjugated nanoparticles for MRI analysis.

Gadolinium (Gd)-based contrast agents (CAs) are widely used to enhance anatomical details in magnetic resonance imaging (MRI). Significant research has expanded the field of CAs into bioresponsive CAs by modulating the signal to image and monitor biochemical processes, such as pH. In this work, we introduce the modular, dynamic actuation mechanism of DNA-based nanostructures as a new way to modulate the MRI signal based on the rotational correlation time, τR. We combined a pH-responsive oligonucleotide (i-motif) and a clinical standard CA (Gd-DOTA) to develop a pH-responsive MRI CA. The i-motif folds into a quadruplex under acidic conditions and was incorporated onto gold nanoparticles (iM-GNP) to achieve increased relaxivity, r1, compared to the unbound i-motif. In vitro, iM-GNP resulted in a significant increase in r1 over a decreasing pH range (7.5-4.5) with a calculated pKa = 5.88 ± 0.01 and a 16.7% change per 0.1 pH unit. In comparison, a control CA with a non-responsive DNA strand (T33-GNP) did not show a significant change in r1 over the same pH range. The iM-GNP was further evaluated in 20% human serum and demonstrated a 28.14 ± 11.2% increase in signal from neutral pH to acidic pH. This approach paves a path for novel programmable, dynamic DNA-based complexes for τR-modulated bioresponsive MRI CAs.

Edible Fruits from the Ecuadorian Amazon: Ethnobotany, Physicochemical Characteristics, and Bioactive Components.

In the Ecuadorian Amazon region, there are various types of edible fruits that have distinct qualities and benefits. Understanding the uses, properties, and functions of these fruits is important for researching products that are only available in local markets. This review aims to gather and summarize the existing scientific literature on the ethnobotany, physicochemical composition, and bioactive compounds of these native fruits to highlight the potential of the region's underutilized biodiversity. A systematic review was carried out following the PRISMA methodology, utilizing databases such as Web of Science, Scopus, Pubmed, Redalyc, and SciELO up to August 2023. The research identified 55 edible fruits from the Ecuadorian Amazon and reported their ethnobotanical information. The most common uses were fresh fruit consumption, preparation of typical food, and medicine. Additionally, nine native edible fruits were described for their physicochemical characteristics and bioactive components: Aphandra natalia (Balslev and Henderson) Barfod; Eugenia stipitate McVaugh; Gustavia macarenensis Philipson; Mauritia flexuosa L.f; Myrciaria dubia (Kunth) McVaugh; Oenocarpus bataua Mart; Plukenetia volubilis L.; Pouteria caimito (Ruiz and Pav.) Radlk.; and Solanum quitoense Lam. The analyzed Amazonian fruits contained bioactive compounds such as total polyphenols, flavonoids, carotenoids, and anthocyanins. This information highlights their potential as functional foods and the need for further research on underutilized crops.

Prolonged smoldering Douglas fir smoke inhalation augments respiratory resistances, stiffens the aorta, and curbs ejection fraction in hypercholesterolemic mice.

While mounting evidence suggests that wildland fire smoke (WFS) inhalation may increase the burden of cardiopulmonary disease, the occupational risk of repeated exposure during wildland firefighting remains unknown. To address this concern, we evaluated the cardiopulmonary function in mice following a cumulative exposure to lab-scale WFS equivalent to a mid-length wildland firefighter (WLFF) career. Dosimetry analysis indicated that 80 exposure hours at a particulate concentration of 22 mg/m3 yield in mice the same cumulative deposited mass per unit of lung surface area as 3600 h of wildland firefighting. To satisfy this condition, male Apoe-/- mice were whole-body exposed to either air or smoldering Douglas fir smoke (DFS) for 2 h/day, 5 days/week, over 8 consecutive weeks. Particulate size in DFS fell within the respirable range for both mice and humans, with a count median diameter of 110 ± 20 nm. Expiratory breath hold in mice exposed to DFS significantly reduced their minute volume (DFS: 27 ± 4; Air: 122 ± 8 mL/min). By the end of the exposure time frame, mice in the DFS group exhibited a thicker (DFS: 109 ± 3; Air: 98 ± 3 µm) and less distensible (DFS: 23 ± 1; Air: 28 ± 1 MPa-1) aorta with reduced diastolic blood augmentation capacity (DFS: 53 ± 2; Air: 63 ± 2 kPa). Cardiac magnetic resonance imaging further revealed larger end-systolic volume (DFS: 14.6 ± 1.1; Air: 9.9 ± 0.9 µL) and reduced ejection-fraction (DFS: 64.7 ± 1.0; Air: 75.3 ± 0.9 %) in mice exposed to DFS. Consistent with increased airway epithelium thickness (DFS: 10.4 ± 0.8; Air: 7.6 ± 0.3 µm), airway Newtonian resistance was larger following DFS exposure (DFS: 0.23 ± 0.03; Air: 0.20 ± 0.03 cmH2O-s/mL). Furthermore, parenchyma mean linear intercept (DFS: 36.3 ± 0.8; Air: 33.3 ± 0.8 µm) and tissue thickness (DFS: 10.1 ± 0.5; Air: 7.4 ± 0.7 µm) were larger in DFS mice. Collectively, mice exposed to DFS manifested early signs of cardiopulmonary dysfunction aligned with self-reported events in mid-career WLFFs.

Thermal Characterization of Conductive Filaments in Unipolar Resistive Memories.

A methodology to estimate the device temperature in resistive random access memories (RRAMs) is presented. Unipolar devices, which are known to be highly influenced by thermal effects in their resistive switching operation, are employed to develop the technique. A 3D RRAM simulator is used to fit experimental data and obtain the maximum and average temperatures of the conductive filaments (CFs) that are responsible for the switching behavior. It is found that the experimental CFs temperature corresponds to the maximum simulated temperatures obtained at the narrowest sections of the CFs. These temperature values can be used to improve compact models for circuit simulation purposes.

Standards for the Characterization of Endurance in Resistive Switching Devices.

Resistive switching (RS) devices are emerging electronic components that could have applications in multiple types of integrated circuits, including electronic memories, true random number generators, radiofrequency switches, neuromorphic vision sensors, and artificial neural networks. The main factor hindering the massive employment of RS devices in commercial circuits is related to variability and reliability issues, which are usually evaluated through switching endurance tests. However, we note that most studies that claimed high endurances >106 cycles were based on resistance versus cycle plots that contain very few data points (in many cases even <20), and which are collected in only one device. We recommend not to use such a characterization method because it is highly inaccurate and unreliable (i.e., it cannot reliably demonstrate that the device effectively switches in every cycle and it ignores cycle-to-cycle and device-to-device variability). This has created a blurry vision of the real performance of RS devices and in many cases has exaggerated their potential. This article proposes and describes a method for the correct characterization of switching endurance in RS devices; this method aims to construct endurance plots showing one data point per cycle and resistive state and combine data from multiple devices. Adopting this recommended method should result in more reliable literature in the field of RS technologies, which should accelerate their integration in commercial products.

Interarytenoid osseous bridge after prolonged endotracheal intubation.

Posterior glottic stenosis or interarytenoid fibrous adhesion is uncommon and has sometimes been misdiagnosed as cord paralysis. Laryngoscopy and laryngeal electromyography studies are the two main diagnostic aids. We present the case of a 63-year-old man under endotracheal intubation during 10 days after a cardiac procedure who was evaluated in our department for persistent dysphonia. The laryngoscopy showed a granuloma-like lesion in the posterior glottic space. During the microlaryngoscopy procedure, the osseous consistence of the interarytenoid lesion was observed. Laser surgery excision of the lesion was performed with good results. According to our review of the literature, this corresponds to the second case reported.

Towards a TILLING platform for functional genomics in Piel de Sapo melons.

BACKGROUND: The availability of genetic and genomic resources for melon has increased significantly, but functional genomics resources are still limited for this crop. TILLING is a powerful reverse genetics approach that can be utilized to generate novel mutations in candidate genes. A TILLING resource is available for cantalupensis melons, but not for inodorus melons, the other main commercial group. RESULTS: A new ethyl methanesulfonate-mutagenized (EMS) melon population was generated for the first time in an andromonoecious non-climacteric inodorus Piel de Sapo genetic background. Diverse mutant phenotypes in seedlings, vines and fruits were observed, some of which were of possible commercial interest. The population was first screened for mutations in three target genes involved in disease resistance and fruit quality (Cm-PDS, Cm-eIF4E and Cm-eIFI(iso)4E). The same genes were also tilled in the available monoecious and climacteric cantalupensis EMS melon population. The overall mutation density in this first Piel de Sapo TILLING platform was estimated to be 1 mutation/1.5 Mb by screening four additional genes (Cm-ACO1, Cm-NOR, Cm-DET1 and Cm-DHS). Thirty-three point mutations were found for the seven gene targets, six of which were predicted to have an impact on the function of the protein. The genotype/phenotype correlation was demonstrated for a loss-of-function mutation in the Phytoene desaturase gene, which is involved in carotenoid biosynthesis. CONCLUSIONS: The TILLING approach was successful at providing new mutations in the genetic background of Piel de Sapo in most of the analyzed genes, even in genes for which natural variation is extremely low. This new resource will facilitate reverse genetics studies in non-climacteric melons, contributing materially to future genomic and breeding studies.

Decúbito prono: una técnica para mejorar la hipoxemia del síndrome de distrés respiratorio agudo / Prone position: a technique to improve the hypoxemia in acute respiratory distress syndrome

El síndrome de distrés respiratorio agudo (SDRA) representa una complicación respiratoria grave que suelen presentar pacientes ingresados en las Unidades de Cuidados Intensivos (UCI) y se asocia con una alta incidencia y mortalidad, de ahí la importancia del rápido diagnóstico y tratamiento. La posición de decúbito prono (DP) mejora notablemente la oxigenación y la redistribución pulmonar de los pacientes con SDRA. Sin embargo, la utilización del DP en las UCI implica algunos cambios en el tratamiento diario y requiere la protocolización de la actuación antes, durante y después de la maniobra, así como su seguimiento para evitar las posibles complicaciones. En este trabajo, a partir de la revisión bibliografía y teniendo en cuenta la experiencia propia y la forma de trabajar en este hospital, se describe el potencial beneficio de esta técnica, cómo realizarla adecuadamente, las indicaciones y contraindicaciones, las complicaciones potenciales y las intervenciones enfermeras para prevenirlas o detectarlas precozmente

Acute Respiratory Distress Syndrome (ARDS) represents a severe respiratory complication often shown by patients hospitalized in Intensive Care Units (ICUs), and it is associated with high incidence and mortality; hence the importance of its fast diagnosis and treatment. The prone position leads to a noticeable improvement in oxygenation and pulmonary redistribution of patients with ARDS. However, the use of the prone position at ICUs involves certain changes in daily treatment, and requires the protocolization of the action before, during and after the manoeuvre, as well as its follow-up in order to prevent any potential complications. Based on a bibliographic review and taking into account our own experience and the way we work in this hospital, this article describes the potential benefits of this technique, how to perform it adequately, its indications and contraindications, potential complications, and nursing interventions for prevention or early detection

Puente óseo interaritenoideo post-intubación laringotraqueal prolongada / Interarytenoid osseous bridge after prolonged endotracheal intubation

La estenosis glótica posterior por fijación interaritenoidea es muy poco común, y a veces se diagnostica como parálisis de las cuerdas. La laringoscopia y electromiografía laríngea son los métodos diagnósticos principales. Presentamos un paciente varón de 63 años, que estuvo intubado 10 días después de un procedimiento cardíaco. Se valoró en nuestra consulta por disfonía. La endolaringoscopia mostró un granuloma en el espacio glótico posterior. La microcirugía endolaríngea mostró la consistencia ósea de la lesión. Posteriormente se realizó una excisión láser con buenos resultados a largo plazo. Según nuestra revisión este caso sería el segundo reportado en la literatura(AU)

Posterior glottic stenosis or interarytenoid fibrous adhesion is uncommon and has sometimes been misdiagnosed as cord paralysis. Laryngoscopy and laryngeal electromyography studies are the two main diagnostic aids. We present the case of a 63-year-old man under endotracheal intubation during 10 days after a cardiac procedure who was evaluated in our department for persistent dysphonia. The laryngoscopy showed a granuloma-like lesion in the posterior glottic space. During the microlaryngoscopy procedure, the osseous consistence of the interarytenoid lesion was observed. Laser surgery excision of the lesion was performed with good results. According to our review of the literature, this corresponds to the second case reported(AU)