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Annals of the American Thoracic Society May 2023Bronchoscopy for research purposes is a valuable tool to understand lung-specific biology in human participants. Despite published reports and active research protocols...
Bronchoscopy for research purposes is a valuable tool to understand lung-specific biology in human participants. Despite published reports and active research protocols using this procedure in critically ill patients, no recent document encapsulates the important safety considerations and downstream applications of this procedure in this setting. The objectives were to identify safe practices for patient selection and protection of hospital staff, provide recommendations for sample procurement to standardize studies, and give guidance on sample preparation for novel research technologies. Seventeen international experts in the management of critically ill patients, bronchoscopy in clinical and research settings, and experience in patient-oriented clinical or translational research convened for a workshop. Review of relevant literature, expert presentations, and discussion generated the findings presented herein. The committee concludes that research bronchoscopy with bronchoalveolar lavage in critically ill patients on mechanical ventilation is valuable and safe in appropriately selected patients. This report includes recommendations on standardization of this procedure and prioritizes the reporting of sample management to produce more reproducible results between laboratories. This document serves as a resource to the community of researchers who endeavor to include bronchoscopy as part of their research protocols and highlights key considerations for the inclusion and safety of research participants.
Topics: Humans; Bronchoscopy; Critical Illness; Bronchoalveolar Lavage; Dimercaprol; Patient Selection
PubMed: 37125997
DOI: 10.1513/AnnalsATS.202302-106ST -
Scientific Reports Sep 2015Autophagy plays a key role in human health and disease, especially in cancer and neurodegeneration. Many autophagy regulators are developed for therapy. Diverse...
Autophagy plays a key role in human health and disease, especially in cancer and neurodegeneration. Many autophagy regulators are developed for therapy. Diverse nanomaterials have been reported to induce autophagy. However, the underlying mechanisms and universal rules remain unclear. Here, for the first time, we show a reliable and general mechanism by which nanoparticles induce autophagy and then successfully modulate autophagy via tuning their dispersity. Various well-designed univariate experiments demonstrate that nanomaterials induce autophagy in a dispersity-dependent manner. Aggregated nanoparticles induce significant autophagic effect in comparison with well-dispersed nanoparticles. As the highly stable nanoparticles may block autophagic degradation in autolysosomes, endocytosis and intracellular accumulation of nanoparticles can be responsible for this interesting phenomenon. Our results suggest dispersity-dependent autophagic effect as a common cellular response to nanoparticles, reveal the relationship between properties of nanoparticles and autophagy, and offer a new alternative way to modulate autophagy.
Topics: Adenine; Autophagy; Carboxylic Acids; Cell Line, Tumor; Citrates; Gold; HeLa Cells; Humans; Lysosomal Membrane Proteins; Metal Nanoparticles; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Silver; Sodium Citrate; Succimer; Surface Properties; Suspensions; Unithiol; Up-Regulation
PubMed: 26394839
DOI: 10.1038/srep14361 -
Biomedicines Aug 2020Animal-derived antivenoms are the only specific therapies currently available for the treatment of snake envenoming, but these products have a number of limitations...
Animal-derived antivenoms are the only specific therapies currently available for the treatment of snake envenoming, but these products have a number of limitations associated with their efficacy, safety and affordability for use in tropical snakebite victims. Small molecule drugs and drug candidates are regarded as promising alternatives for filling the critical therapeutic gap between snake envenoming and effective treatment. In this study, by using an advanced analytical technique that combines chromatography, mass spectrometry and bioassaying, we investigated the effect of several small molecule inhibitors that target phospholipase A (varespladib) and snake venom metalloproteinase (marimastat, dimercaprol and DMPS) toxin families on inhibiting the activities of coagulopathic toxins found in snake venoms. The venoms of , , and , which are known for their potent haemotoxicities, were fractionated in high resolution onto 384-well plates using liquid chromatography followed by coagulopathic bioassaying of the obtained fractions. Bioassay activities were correlated to parallel recorded mass spectrometric and proteomics data to assign the venom toxins responsible for coagulopathic activity and assess which of these toxins could be neutralized by the inhibitors under investigation. Our results showed that the phospholipase A-inhibitor varespladib neutralized the vast majority of anticoagulation activities found across all of the tested snake venoms. Of the snake venom metalloproteinase inhibitors, marimastat demonstrated impressive neutralization of the procoagulation activities detected in all of the tested venoms, whereas dimercaprol and DMPS could only partially neutralize these activities at the doses tested. Our results provide additional support for the concept that combinations of small molecules, particularly the combination of varespladib with marimastat, serve as a drug-repurposing opportunity to develop new broad-spectrum inhibitor-based therapies for snakebite envenoming.
PubMed: 32825484
DOI: 10.3390/biomedicines8090297 -
BMC Pharmacology & Toxicology May 2021There are no reports on the incidence of chronic mercury poisoning in a large population in China. This study investigated the epidemiology, clinical manifestations,...
BACKGROUND
There are no reports on the incidence of chronic mercury poisoning in a large population in China. This study investigated the epidemiology, clinical manifestations, treatment, and follow-up of Chinese patients with chronic mercury poisoning.
METHODS
Data for 288 mercury poisoning patients were collected at our hospital from July 2014 to September 2019, including sex, age, admission time, blood mercury content, urine mercury content, creatinine, urinary mercury/creatinine ratio, 24-h urinary protein levels, electromyography (EMG) findings, renal biopsy, and follow-up. Patient characteristics were evaluated by statistical and correlation analyses.
RESULTS
First, mercury poisoning in China mainly occurred through occupational exposure and the inappropriate use of mercury-containing cosmetics and Chinese folk remedies (CFRs). Second, the most common symptoms were nervous system (50.3 %), kidney (16.4 %) and breathing (8.0 %). Mercury poisoning-induced Nephrotic syndrome (NS) and peripheral neuropathy are common long-term complications. The complications of occupational and cosmetics-induced mercury poisoning are consistent with international belief. However, the NS caused by CFRs is mainly membranous nephropathy and the probability of peripheral neuropathy caused by CFRs is higher than other pathogens. Third, follow-up data shows that 13 patients with EMG-confirmed neurological injury, 10 showed full recovery after 38.50 ± 8.03 months. Furthermore, among 18 patients with NS, 15 had normal urine protein and serum albumin levels after 22.67 ± 10.26 months.
CONCLUSIONS
Regulation of skin-lightening cosmetic products, safety surveillance of CFRs, and prevention and control of occupational exposure must be improved to decrease the incidence of mercury poisoning in China.
Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Chelating Agents; Child; Child, Preschool; China; Chronic Disease; Cosmetics; Drugs, Chinese Herbal; Female; Follow-Up Studies; Humans; Male; Mercury; Mercury Poisoning; Middle Aged; Occupational Diseases; Occupational Exposure; Prednisone; Retrospective Studies; Unithiol; Young Adult
PubMed: 33941274
DOI: 10.1186/s40360-021-00493-y -
Physiological Reports Sep 2023The circadian rhythm system regulates lung function as well as local and systemic inflammations. The alteration of this rhythm might be induced by a change in the eating...
The circadian rhythm system regulates lung function as well as local and systemic inflammations. The alteration of this rhythm might be induced by a change in the eating rhythm. Peroxisome proliferator-activated receptor gamma (PPARG) is a key molecule involved in circadian rhythm regulation, lung functions, and metabolic processes. We described the effect of the PPARG agonist pioglitazone (PZ) on the diurnal mRNA expression profile of core circadian clock genes (Arntl, Clock, Nr1d1, Cry1, Cry2, Per1, and Per2) and metabolism- and inflammation-related genes (Nfe2l2, Pparg, Rela, and Cxcl5) in the male murine lung disrupted by reversed feeding (RF). In mice, RF disrupted the diurnal expression pattern of core clock genes. It decreased Nfe2l2 and Pparg and increased Rela and Cxcl5 expression in lung tissue. There were elevated levels of IL-6, TNF-alpha, total cells, macrophages, and lymphocyte counts in bronchoalveolar lavage (BAL) with a significant increase in vascular congestion and cellular infiltrates in male mouse lung tissue. Administration of PZ regained the diurnal clock gene expression, increased Nfe2l2 and Pparg expression, and reduced Rela, Cxcl5 expression and IL-6, TNF-alpha, and cellularity in BAL. PZ administration at 7 p.m. was more efficient than at 7 a.m.
Topics: Animals; Male; Mice; Dimercaprol; Inflammation; Interleukin-6; Lung; Pioglitazone; PPAR gamma; RNA, Messenger; Tumor Necrosis Factor-alpha
PubMed: 37704580
DOI: 10.14814/phy2.15823 -
Frontiers in Immunology 2021Palearctic vipers are medically significant snakes in the genera , and which occur throughout Europe, Central Asia, Near and Middle East. While the ancestral condition... (Comparative Study)
Comparative Study
Palearctic vipers are medically significant snakes in the genera , and which occur throughout Europe, Central Asia, Near and Middle East. While the ancestral condition is that of a small-bodied, lowland species, extensive diversification has occurred in body size, and niche specialization. Using 27 venom samples and a panel of coagulation assays, we evaluated the relative coagulotoxic potency of Palearctic viper venoms and compared their neutralization by three antivenoms (Insoserp Europe, VIPERFAV and ViperaTAb) and two metalloprotease inhibitors (prinomastat and DMPS). We show that variation in morphology parallels variation in the Factor X activating procoagulant toxicity, with the three convergent evolutions of larger body sizes ( genus, genus, and uniquely within the genus) were each accompanied by a significant increase in procoagulant potency. In contrast, the two convergent evolutions of high altitude specialization (the genus and uniquely within the genus) were each accompanied by a shift away from procoagulant action, with the species being particularly potently anticoagulant. Inoserp Europe and VIPERFAV antivenoms were both effective against a broad range of species, with Inoserp able to neutralize additional species relative to VIPERFAV, reflective of its more complex antivenom immunization mixture. In contrast, ViperaTAb was extremely potent in neutralizing but, reflective of this being a monovalent antivenom, it was not effective against other species. The enzyme inhibitor prinomastat efficiently neutralized the metalloprotease-driven Factor X activation of the procoagulant venoms. In contrast, DMPS (2,3-dimercapto-1-propanesulfonic acid), which as been suggested as another potential treatment option in the absence of antivenom, DMPS failed against all venoms tested. Overall, our results highlight the evolutionary variations within Palearctic vipers and help to inform clinical management of viper envenomation.
Topics: Animals; Antivenins; Blood Coagulation; Blood Coagulation Tests; Evolution, Molecular; Humans; Immunoglobulin Fab Fragments; Matrix Metalloproteinase Inhibitors; Organic Chemicals; Snake Bites; Species Specificity; Time Factors; Unithiol; Viper Venoms; Viperidae
PubMed: 34177943
DOI: 10.3389/fimmu.2021.688802 -
Journal of Medical Toxicology :... Jul 2021
Topics: Antidotes; Brain Diseases; Dimercaprol; Humans; Lead; Pharmaceutical Preparations; United States
PubMed: 33687652
DOI: 10.1007/s13181-021-00830-x -
BMC Pulmonary Medicine Jan 2024Flexible bronchoscopy procedures require detailed anatomical knowledge and advanced technical skills. Simulation-based training offers a patient-safe training...
BACKGROUND
Flexible bronchoscopy procedures require detailed anatomical knowledge and advanced technical skills. Simulation-based training offers a patient-safe training environment that can be more efficient than patient-based training. Physical models are cheaper than virtual reality simulators and allow trainees to be acquainted with the equipment used in the clinic. The choice of a physical model for training depends on the local context. The aim of this study was to compare four different bronchoscopy models for flexible bronchoscopy training.
METHODS
The BronchoBoy manikin, the Koken manikin, a human cadaver, and a preserved porcine lung were included in the study. Seven physicians experienced in bronchoscopy performed a bronchoscopic airway inspection, bronchoalveolar lavage (BAL), and tissue sampling on all four models with performance evaluated by observation and participant evaluation of models by questionnaire.
RESULTS
Nineteen segments were identified in all human anatomy models, and the only significant difference found was that only the Thiel embedded cadaver allowed all participants to enter RB1 with an instrument in the working channel (p = 0.001). The Thiel embedded cadaver and the BronchoBoy manikin had low fluid return on BAL (22 and 52 ml), whereas the Koken manikin and the preserved porcine lung had high return (132 and 134 ml), (p = 0.017). Tissue samplings were only completed in the preserved porcine lung and the Thiel embedded cadaver (p < 0.001).
CONCLUSIONS
An anatomically correct bronchoscopy is best simulated with the Koken manikin or the Thiel embedded cadaver. Bronchoalveolar lavage should be simulated with the Koken manikin or the preserved porcine lung. Tissue sampling procedures are best simulated using the Thiel embedded cadaver or the preserved porcine lung.
Topics: Swine; Animals; Humans; Bronchoscopy; Bronchoalveolar Lavage; Cadaver; Dimercaprol; Manikins
PubMed: 38195463
DOI: 10.1186/s12890-024-02846-9 -
Neurology India 2018
Topics: Adult; Cerebellar Ataxia; Chelating Agents; Dimercaprol; Humans; Male; Medicine, Ayurvedic; Mercury; Mercury Poisoning; Treatment Outcome
PubMed: 30233025
DOI: 10.4103/0028-3886.241403 -
Proteins Jul 2017The molecular details of the association between the human Fyn-SH3 domain, and the fragment of 18.5-kDa myelin basic protein (MBP) spanning residues S38-S107 (denoted as...
Docking and molecular dynamics simulations of the Fyn-SH3 domain with free and phospholipid bilayer-associated 18.5-kDa myelin basic protein (MBP)-Insights into a noncanonical and fuzzy interaction.
The molecular details of the association between the human Fyn-SH3 domain, and the fragment of 18.5-kDa myelin basic protein (MBP) spanning residues S38-S107 (denoted as xα2-peptide, murine sequence numbering), were studied in silico via docking and molecular dynamics over 50-ns trajectories. The results show that interaction between the two proteins is energetically favorable and heavily dependent on the MBP proline-rich region (P93-P98) in both aqueous and membrane environments. In aqueous conditions, the xα2-peptide/Fyn-SH3 complex adopts a "sandwich""-like structure. In the membrane context, the xα2-peptide interacts with the Fyn-SH3 domain via the proline-rich region and the β-sheets of Fyn-SH3, with the latter wrapping around the proline-rich region in a form of a clip. Moreover, the simulations corroborate prior experimental evidence of the importance of upstream segments beyond the canonical SH3-ligand. This study thus provides a more-detailed glimpse into the context-dependent interaction dynamics and importance of the β-sheets in Fyn-SH3 and proline-rich region of MBP. Proteins 2017; 85:1336-1350. © 2017 Wiley Periodicals, Inc.
Topics: Amino Acid Sequence; Animals; Binding Sites; Dimyristoylphosphatidylcholine; Humans; Lipid Bilayers; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; Myelin Basic Protein; Peptides; Phosphorylcholine; Proline; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Structure, Tertiary; Proto-Oncogene Proteins c-fyn; Thermodynamics; Unithiol; Water; src Homology Domains
PubMed: 28380689
DOI: 10.1002/prot.25295