Preliminary Investigation of the Mechanics of a Novel Thoracic Cavity Extra Pulmonary Oxygenation Device

2018 ◽  
Author(s):  
Fariba Aghabaglou ◽  
Keely Buesing ◽  
Nathan D. Legband ◽  
Connor Slagle ◽  
Wanchuan Xie ◽  
...  
Keyword(s):  
Distress Syndrome ◽  
Preliminary Investigation ◽  
Clinical Problem ◽  
Large Animal ◽  
Thoracic Cavity ◽  
New Methods ◽  
Injury Model ◽  
Lung Trauma ◽  
Major Clinical Problem

Acute respiratory distress syndrome (ARDS) arising from trauma, sepsis, pneumonia or other diseases has been acknowledged to be a major clinical problem in respiratory medicine. Hypoxia and hypercapnia arising from ARDS are life-threating particularly in children and elderly people. The reported mortality rate for ARDS is high. Current methods for treating patients who have limited or no lung function are ineffective or insufficient and present additional risks to the patients. In this research, we have explored new methods of infusing phospholipid-coated oxygen microbubbles (OMBs) to the thoracic cavity in order to oxygenate patients suffering from ARDS and hypoxemia. In our previous work, OMBs have been shown to be effective in treating hypoxia in models of LPS lung injury and lung trauma in rats and rabbits. In this study, we have developed a novel thoracic cavity extrapulmonary oxygenation devices using OMBs and test this device in a benchtop test and in vivo experiment on a large animal (pig) right pneumothorax injury model.

scholarly journals PI16 is a non-neuronal regulator of neuropathic pain

2019 ◽  
Author(s):  
Pooja Singhmar ◽  
Ronnie The Phong Trinh ◽  
Jiacheng Ma ◽  
XiaoJiao Huo ◽  
Bo Peng ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Clinical Problem ◽  
Endothelial Barrier ◽  
Leukocyte Infiltration ◽  
Spared Nerve Injury ◽  
Protein Levels ◽  
Injury Model ◽  
Major Clinical Problem

AbstractChronic pain is a major clinical problem of which the mechanisms are incompletely understood. Here we describe the concept that PI16, a protein of unknown function mainly produced by fibroblasts, controls neuropathic pain. The spared nerve injury model of neuropathic pain increases PI16 protein levels in fibroblasts in DRG meninges and in the epi/perineurium of the sciatic nerve. We did not detect PI16 expression in neurons or glia in spinal cord, DRG and nerve. Mice deficient in PI16 are protected against neuropathic pain. In vitro, PI16 promotes trans-endothelial leukocyte migration. In vivo, PI16−/− mice show reduced endothelial barrier permeability, lower leukocyte infiltration and reduced activation of the endothelial barrier regulator MLCK and reduced phosphorylation of its substrate MLC2 in response to SNI. In summary, our findings support a model in which PI16 promotes neuropathic pain by mediating a cross talk between fibroblasts and the endothelial barrier leading to barrier opening, cellular influx and increased pain. Its key role in pain and its limited cellular and tissue distribution makes PI16 an attractive target for pain management.Graphical Abstract

scholarly journals The fibroblast-derived protein PI16 controls neuropathic pain

2020 ◽  
Vol 117 (10) ◽  
pp. 5463-5471 ◽  
Author(s):  
Pooja Singhmar ◽  
Ronnie The Phong Trinh ◽  
Jiacheng Ma ◽  
XiaoJiao Huo ◽  
Bo Peng ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root ◽  
Clinical Problem ◽  
Endothelial Barrier ◽  
Leukocyte Infiltration ◽  
Spared Nerve Injury ◽  
Protein Levels ◽  
Major Clinical Problem

Chronic pain is a major clinical problem of which the mechanisms are incompletely understood. Here, we describe the concept that PI16, a protein of unknown function mainly produced by fibroblasts, controls neuropathic pain. The spared nerve injury (SNI) model of neuropathic pain increases PI16 protein levels in fibroblasts in dorsal root ganglia (DRG) meninges and in the epi/perineurium of the sciatic nerve. We did not detect PI16 expression in neurons or glia in spinal cord, DRG, and nerve. Mice deficient in PI16 are protected against neuropathic pain. In vitro, PI16 promotes transendothelial leukocyte migration. In vivo, Pi16−/− mice show reduced endothelial barrier permeability, lower leukocyte infiltration and reduced activation of the endothelial barrier regulator MLCK, and reduced phosphorylation of its substrate MLC2 in response to SNI. In summary, our findings support a model in which PI16 promotes neuropathic pain by mediating a cross-talk between fibroblasts and the endothelial barrier leading to barrier opening, cellular influx, and increased pain. Its key role in neuropathic pain and its limited cellular and tissue distribution makes PI16 an attractive target for pain management.

scholarly journals MicroRNA-93 mediates cabergoline resistance by targeting ATG7 in prolactinoma

2019 ◽  
Vol 240 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Zerui Wu ◽  
Lin Cai ◽  
Jianglong Lu ◽  
Chengde Wang ◽  
Jiaqing Guan ◽  
...  
Keyword(s):  
Cytotoxic Effect ◽  
Clinical Problem ◽  
Inhibitory Effect ◽  
Gh3 Cells ◽  
Promising Therapeutic Target ◽  
Xenograft Models ◽  
Mirna 93 ◽  
Major Clinical Problem

To date, the management of dopamine agonist (DA)-resistant prolactinomas remains a major clinical problem. Previously, we determined that miRNA-93 expression increases in DA-resistant prolactinomas; however, the role of miRNA-93 in the DA resistance remains largely unexplored. Hence, this study aimed to investigate the susceptibility of tumor cells to cabergoline (CAB) and the autophagy changes in MMQ and GH3 cells after miRNA-93 overexpression or inhibition. We used bioinformatics to identify the potential target of miRNA-93. Subsequently, we analyzed the correlation between miRNA-93 and autophagy-related 7 (ATG7) using protein expression analysis and luciferase assays. Furthermore, the change in the effect of miRNA-93 was measured after ATG7 overexpression. miRNA-93 expression was elevated in DA-resistant prolactinomas, whereas the expression of its identified target, ATG7, was downregulated. miRNA-93 overexpression suppressed the cytotoxic effect of CAB in MMQ and GH3 cells. In contrast, miRNA-93 downregulation enhanced CAB efficiency and promoted cell autophagy, eventually resulting in apoptosis. These results were further confirmed in in vivo xenograft models in nude mice. ATG7 overexpression could reverse the inhibitory effect of miRNA-93 on CAB treatment. Taken together, our results suggest that miRNA-93 mediates CAB resistance via autophagy downregulation by targeting ATG7 and serves as a promising therapeutic target for prolactinoma.

scholarly journals Polymerase Theta Inhibition Kills Homologous Recombination Deficient Tumors

2020 ◽  
Author(s):  
Jia Zhou ◽  
Camille Gelot ◽  
Constantia Pantelidou ◽  
Adam Li ◽  
Hatice Yücel ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Tumor Cells ◽  
Clinical Problem ◽  
Parp Inhibitors ◽  
Atpase Domain ◽  
Synthetic Lethal ◽  
Line Of Therapy ◽  
Major Clinical Problem

AbstractPARP inhibitors (PARPi) have become a new line of therapy for Homologous Recombination (HR)-deficient cancers. However, resistance to PARPi has emerged as a major clinical problem. DNA polymerase theta (POLθ) is synthetic lethal with HR and a druggable target in HR-deficient cancers. Here, we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity, and phenocopies POLθ depletion. BRCA-deficient tumor cells and those with acquired PARPi resistance are sensitive to NVB in vitro and in vivo. Increased POLθ expression levels predict NVB sensitivity. The mechanism of NVB-mediated cell death in PARPi resistant cells is the accumulation of toxic RAD51 foci, which also provides a pharmacodynamic biomarker for NVB response. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance.One Sentence SummaryWe identified Novobiocin as a specific POLθ inhibitor that selectively kills naïve and PARPi resistance HR-deficient tumors in vitro and in vivo.

Epidemiology and antimicrobial resistance of Acinetobacter

2018 ◽  
Vol 2 (4) ◽  
pp. 46-59
Author(s):  
A.G. Salmanov ◽  
O.M. Verner ◽  
L.F. Slepova
Keyword(s):  
Antibiotic Resistance ◽  
Laboratory Testing ◽  
Immunocompromised Host ◽  
Clinical Problem ◽  
Healthcare Associated Infections ◽  
Opportunistic Bacteria ◽  
Acinetobacter Spp ◽  
Healthcare Associated ◽  
Major Clinical Problem

Species of the Acinetobacter represent opportunistic bacteria with a growing clinical significance for Healthcare-associated infections (HAIs). In this literature review, we focus on the current role of Acinetobacter in infectious pathology and describe taxonomy, pathogenicity, and antibiotic resistance of these bacteria. Pathogenesis and regulation of virulence factors in Acinetobacter spp. are described in detail. The majority of acinetobacterial infections are associated with A. baumannii and occur predominantly in an immunocompromised host. Usually, acinetobacterial  infections  are characterized by local purulent inflammation; in severe cases, meningitis and sepsis may develop. Antibiotic resistance of Acinetobacter is a major clinical problem; therefore we give special attention to laboratory testing of resistance to antibiotics as well as identification of Acinetobacter.

scholarly journals A novel large animal model of smoke inhalation-induced acute respiratory distress syndrome

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Premila D. Leiphrakpam ◽  
Hannah R. Weber ◽  
Andrea McCain ◽  
Roser Romaguera Matas ◽  
Ernesto Martinez Duarte ◽  
...  
Keyword(s):  
Animal Model ◽  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Distress Syndrome ◽  
Inhalation Injury ◽  
Smoke Inhalation ◽  
Large Animal Model ◽  
Large Animal ◽  
X Ray ◽  
Chest X Ray

Abstract Background Acute respiratory distress syndrome (ARDS) is multifactorial and can result from sepsis, trauma, or pneumonia, amongst other primary pathologies. It is one of the major causes of death in critically ill patients with a reported mortality rate up to 45%. The present study focuses on the development of a large animal model of smoke inhalation-induced ARDS in an effort to provide the scientific community with a reliable, reproducible large animal model of isolated toxic inhalation injury-induced ARDS. Methods Animals (n = 21) were exposed to smoke under general anesthesia for 1 to 2 h (median smoke exposure = 0.5 to 1 L of oak wood smoke) after the ultrasound-guided placement of carotid, pulmonary, and femoral artery catheters. Peripheral oxygen saturation (SpO2), vital signs, and ventilator parameters were monitored throughout the procedure. Chest x-ray, carotid, femoral and pulmonary artery blood samples were collected before, during, and after smoke exposure. Animals were euthanized and lung tissue collected for analysis 48 h after smoke inhalation. Results Animals developed ARDS 48 h after smoke inhalation as reflected by a decrease in SpO2 by approximately 31%, PaO2/FiO2 ratio by approximately 208 (50%), and development of bilateral, diffuse infiltrates on chest x-ray. Study animals also demonstrated a significant increase in IL-6 level, lung tissue injury score and wet/dry ratio, as well as changes in other arterial blood gas (ABG) parameters. Conclusions This study reports, for the first time, a novel large animal model of isolated smoke inhalation-induced ARDS without confounding variables such as cutaneous burn injury. Use of this unique model may be of benefit in studying the pathophysiology of inhalation injury or for development of novel therapeutics.

scholarly journals Superoxide Dismutase 1 Nanoparticles (Nano-SOD1) as a Potential Drug for the Treatment of Inflammatory Eye Diseases

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 396
Author(s):  
Alexander N. Vaneev ◽  
Olga A. Kost ◽  
Nikolay L. Eremeev ◽  
Olga V. Beznos ◽  
Anna V. Alova ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Reproductive Toxicity ◽  
Clinical Problem ◽  
Eye Diseases ◽  
Therapeutic Modality ◽  
Side Reactions ◽  
Copper Zinc Superoxide Dismutase ◽  
Tissue Degeneration ◽  
Endogenous Antioxidant

Inflammatory eye diseases remain the most common clinical problem in ophthalmology. The secondary processes associated with inflammation, such as overproduction of reactive oxygen species (ROS) and exhaustion of the endogenous antioxidant system, frequently lead to tissue degeneration, vision blurring, and even blindness. Antioxidant enzymes, such as copper–zinc superoxide dismutase (SOD1), could serve as potent scavengers of ROS. However, their delivery into the eye compartments represents a major challenge due to the limited ocular penetration. This work presents a new therapeutic modality specifically formulated for the eye on the basis of multilayer polyion complex nanoparticles of SOD1 (Nano-SOD1), which is characterized by appropriate storage stability and pronounced therapeutic effect without side reactions such as eye irritation; acute, chronic, and reproductive toxicity; allergenicity; immunogenicity; mutagenicity even at high doses. The ability of Nano-SOD1 to reduce inflammatory processes in the eye was examined in vivo in rabbits with a model immunogenic uveitis—the inflammation of the inner vascular tract of the eye. It was shown during preclinical studies that topical instillations of Nano-SOD1 were much more effective compared to the free enzyme in decreasing uveitis manifestations. In particular, we noted statistically significant differences in such inflammatory signs in the eye as corneal and conjunctival edema, iris hyperemia, and fibrin clots. Moreover, Nano-SOD1 penetrates into interior eye structures more effectively than SOD itself and retains enzyme activity in the eye for a much longer period of time, decreasing inflammation and restoring antioxidant activity in the eye. Thus, the presented Nano-SOD1 can be considered as a potentially useful therapeutic agent for the treatment of ocular inflammatory disorders.

The Pre-dilatation of vessels: A simple method to recruit small caliber veins for creating distal fistulas

2021 ◽  
pp. 112972982098317
Author(s):  
Marcello Napoli ◽  
Anna Zito ◽  
Maria Luisa Lefons ◽  
Paolo Ria ◽  
Emiliana Ferramosca ◽  
...  
Keyword(s):  
Heart Disease ◽  
Arteriovenous Fistula ◽  
Clinical Problem ◽  
Early Failure ◽  
Simple Method ◽  
Maturation Rate ◽  
Vein Diameter ◽  
Major Clinical Problem

Maturation failure remains a major clinical problem of distal arteriovenous fistula (AVF). Early failure (EF) is associated with the small size of the veins. For about 10 years we have used in more than 1000 fistulas, the Vessels Pre-Dilatation (VPD) to increase the recruitment of small veins for creating distal AVFs. The purpose of this study is to highlight if the VPD can reduce the incidence of EF or failure to mature (FTM) in AVFs created with small veins. Data of all the consecutive patients directly admitted to our Department for their first distal AVF from January to December 2019 were collected. The patients were divided in two groups, one with a vein diameter after the tourniquet ⩽2.0 mm (G1) and one >2 mm (G2). Both in G1 then in G2 the vessels had undergone VPD. Immediate failure (IF), EF, FTM, delayed or arrested maturation rate (DAM), unassisted AVFs and matured AFVs were evaluated. The patients recruited totalled 104, 37 in G1, and 67 in G2. The two groups were homogeneous in age, incidence of diabetes, obesity, heart disease, peripheral vasculopathy, and race. Female were more numerous in G1 (51% vs 12%, p < 0.001). In G1 and G2 occurred respectively 3 IF versus zero ( p < 0.05), 10 EF (29%) versus 6 (9%) ( p < 0.05), 6 DAM (16%) versus 6 (9%), 21 unassisted AVFs (57%) versus 57 (85%) ( p < 0.01). Dividing the patients into groups of unassisted and assisted AVFs, female and low vein diameter are more represented in the assisted group. There were 32 matured AVFs (86%) in G1 and 65 (97%) in G2. In order to increase the incidence of the distal AVF, the PDV allows to include small veins. However, more patients require further interventions to achieve maturation of the fistula.

scholarly journals Hyperspectral Imagery for Assessing Laser-Induced Thermal State Change in Liver

Sensors ◽  
2021 ◽  
Vol 21 (2) ◽  
pp. 643
Author(s):  
Martina De Landro ◽  
Ignacio Espíritu García-Molina ◽  
Manuel Barberio ◽  
Eric Felli ◽  
Vincent Agnus ◽  
...  
Keyword(s):  
Thermal Damage ◽  
Thermal State ◽  
Preliminary Investigation ◽  
Spectral Band ◽  
Spectral Variation ◽  
Ablation Therapy ◽  
Clinical Endpoints ◽  
Breathing Motion ◽  
Living Tissues

This work presents the potential of hyperspectral imaging (HSI) to monitor the thermal outcome of laser ablation therapy used for minimally invasive tumor removal. Our main goal is the establishment of indicators of the thermal damage of living tissues, which can be used to assess the effect of the procedure. These indicators rely on the spectral variation of temperature-dependent tissue chromophores, i.e., oxyhemoglobin, deoxyhemoglobin, methemoglobin, and water. Laser treatment was performed at specific temperature thresholds (from 60 to 110 °C) on in-vivo animal liver and was assessed with a hyperspectral camera (500–995 nm) during and after the treatment. The indicators were extracted from the hyperspectral images after the following processing steps: the breathing motion compensation and the spectral and spatial filtering, the selection of spectral bands corresponding to specific tissue chromophores, and the analysis of the areas under the curves for each spectral band. Results show that properly combining spectral information related to deoxyhemoglobin, methemoglobin, lipids, and water allows for the segmenting of different zones of the laser-induced thermal damage. This preliminary investigation provides indicators for describing the thermal state of the liver, which can be employed in the future as clinical endpoints of the procedure outcome.

scholarly journals A patient-like swine model of gastrointestinal fibrotic strictures for advancing therapeutics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ling Li ◽  
Mohamad I. Itani ◽  
Kevan J. Salimian ◽  
Yue Li ◽  
Olaya Brewer Gutierrez ◽  
...  
Keyword(s):  
Argon Plasma Coagulation ◽  
Argon Plasma ◽  
Large Animal Model ◽  
Swine Model ◽  
Large Animal ◽  
High Grade ◽  
Gi Tract ◽  
Endoscopic Techniques ◽  
Approved Drugs

AbstractGastrointestinal (GI) strictures are difficult to treat in a variety of disease processes. Currently, there are no Food and Drug Administration (FDA) approved drugs for fibrosis in the GI tract. One of the limitations to developing anti-fibrotic drugs has been the lack of a reproducible, relatively inexpensive, large animal model of fibrosis-driven luminal stricture. This study aimed to evaluate the feasibility of creating a model of luminal GI tract strictures. Argon plasma coagulation (APC) was applied circumferentially in porcine esophagi in vivo. Follow-up endoscopy (EGD) was performed at day 14 after the APC procedure. We noted high grade, benign esophageal strictures (n = 8). All 8 strictures resembled luminal GI fibrotic strictures in humans. These strictures were characterized, and then successfully dilated. A repeat EGD was performed at day 28 after the APC procedure and found evidence of recurrent, high grade, fibrotic, strictures at all 8 locations in all pigs. Pigs were sacrificed and gross and histologic analyses performed. Histologic examination showed extensive fibrosis, with significant collagen deposition in the lamina propria and submucosa, as well as extensive inflammatory infiltrates within the strictures. In conclusion, we report a porcine model of luminal GI fibrotic stricture that has the potential to assist with developing novel anti-fibrotic therapies as well as endoscopic techniques to address recurring fibrotic strictures in humans.

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