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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 -
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 -
Environmental Research Jul 2023Propyl-propane-thiosulfonate (PTSO) is an organosulfur compound found inAllium spp. Due to its antioxidant and antimicrobial activities, PTSO has been proposed for...
Propyl-propane-thiosulfonate (PTSO) is an organosulfur compound found inAllium spp. Due to its antioxidant and antimicrobial activities, PTSO has been proposed for applications in the agri-food sector, such as feed additive. However, its use with commercial purposes depends on its toxicity evaluation. The present work aimed to perform a pilot-study of toxicokinetic profile of PTSO combining in silico and in vitro techniques, important steps in the risk assessment process. In silico ecotoxicity studies were also performed considering the importance of the environmental impact of the compound before its commercial use. First, an analytical method has been developed and validated to determine the original compound and its metabolites by ultra-performance liquid chromatography-tandem mass spectrometry. The phase I and II metabolism of PTSO was predicted using Meta-Pred Web Server. For the phase I metabolism, rat (male and female) and human liver microsomes were incubated with PTSO and NADPH regeneration system. Furthermore, in the phase II, microsomes were incubated with PTSO and glutathione or uridine 5'- diphosphoglucuronic acid. The analysis revealed the presence of propylpropane thiosulfinate (PTS) originated by redox reaction in phase I, and two conjugates from the phase II: S-propylmercaptoglutathione (GSSP) and S-propylmercaptocysteine (CSSP). Additionally, considering the environmental fate of PTSO and its metabolites, the ADME parameters and the potential ecotoxicity were also predicted using in silico softwares. The results of the ecotoxicity in silico study evidenced that the metabolism induced the formation of detoxified metabolites from the parent compound, except for dimercaprol and 3-mercaptopropane1,2-diol. Further in vivo assays are needed to confirm this prediction.
Topics: Male; Rats; Humans; Female; Animals; Allium; Pilot Projects; Antioxidants; Microsomes, Liver; Chromatography, High Pressure Liquid
PubMed: 37116679
DOI: 10.1016/j.envres.2023.116001 -
Journal of Applied Biomaterials &... 2024To evaluate the antitumor and antimicrobial properties of an alginate-based membrane (ABM) loaded with bismuth lipophilic nanoparticles (BisBAL NPs) and cetylpyridinium...
OBJECTIVE
To evaluate the antitumor and antimicrobial properties of an alginate-based membrane (ABM) loaded with bismuth lipophilic nanoparticles (BisBAL NPs) and cetylpyridinium chloride (CPC) on clinically isolated bacteria and a pancreatic cancer cell line.
MATERIAL AND METHODS
The BisBAL NP-CPC ABM was characterized using optical and scanning electron microscopy (SEM). The antimicrobial potential was measured using the disk-diffusion assay, and antibiofilm activity was determined through the live/dead assay and fluorescence microscopy. The antitumor activity was analyzed on the pancreatic cell line (Panc 03.27) using the MTT assay and live/dead assay with fluorescence microscopy.
RESULTS
After a 24-h exposure (37°C, aerobic conditions), 5 µM BisBAL NP reduced the growth of by 77.9%, while 2.5 µM BisBAL NP inhibited the growth of , and by 82.9%, 82.6%, and 78%, respectively (). The BisBAL NPs-CPC ABM (at a ratio of 10:1; 500 and 50 µM, respectively) inhibited the growth of all isolated bacteria, producing inhibition halos of 9.5, 11.2, 7, and 10.3 mm for , and , respectively, in contrast to the 6.5, 9.5, 8.5, and 9.8 mm obtained with 100 µM ceftriaxone (). The BisBAL NPs-CPC ABM also reduced bacterial biofilms, with 81.4%, 74.5%, 97.1%, and 79.5% inhibition for , and , respectively. Furthermore, the BisBAL NPs-CPC ABM decreased Panc 03.27 cell growth by 76%, compared to 18% for drug-free ABM. GEM-ABM reduced tumoral growth by 73%. The live/dead assay confirmed that BisBAL NPs-CPC-ABM and GEM-ABM were cytotoxic for the turmoral Panc 03.27 cells.
CONCLUSION
An alginate-based membrane loaded with BisBAL NP and CPC exhibits dual antimicrobial and antitumoral efficacy. Therefore, it could be applied in cancer treatment and to diminish the occurrence of surgical site infections.
Topics: Bismuth; Cetylpyridinium; Anti-Infective Agents; Alginates; Klebsiella pneumoniae; Dimercaprol; Organometallic Compounds
PubMed: 38444166
DOI: 10.1177/22808000241236590 -
The Journal of Infectious Diseases Jan 2024The impact of metagenomic next-generation sequencing (mNGS) on antimicrobial stewardship in patients with lower respiratory tract infections (LRTIs) is still unknown.
Impact of Metagenomic Next-Generation Sequencing of Bronchoalveolar Lavage Fluid on Antimicrobial Stewardship in Patients With Lower Respiratory Tract Infections: A Retrospective Cohort Study.
BACKGROUND
The impact of metagenomic next-generation sequencing (mNGS) on antimicrobial stewardship in patients with lower respiratory tract infections (LRTIs) is still unknown.
METHODS
This retrospective cohort study included patients who had LRTIs diagnosed and underwent bronchoalveolar lavage between September 2019 and December 2020. Patients who underwent both mNGS and conventional microbiologic tests were classified as the mNGS group, while those with conventional tests only were included as a control group. A 1:1 propensity score match for baseline variables was conducted, after which changes in antimicrobial stewardship between the 2 groups were assessed.
RESULTS
A total of 681 patients who had an initial diagnosis of LRTIs and underwent bronchoalveolar lavage were evaluated; 306 patients were finally included, with 153 in each group. mNGS was associated with lower rates of antibiotic escalation than in the control group (adjusted odds ratio, 0.466 [95% confidence interval, .237-.919]; P = .02), but there was no association with antibiotic de-escalation. Compared with the control group, more patients discontinued the use of antivirals in the mNGS group.
CONCLUSIONS
The use of mNGS was associated with lower rates of antibiotic escalation and may facilitate the cessation of antivirals, but not contribute to antibiotic de-escalation in patients with LRTIs.
Topics: Humans; Bronchoalveolar Lavage Fluid; Antimicrobial Stewardship; Retrospective Studies; High-Throughput Nucleotide Sequencing; Respiratory Tract Infections; Anti-Bacterial Agents; Dimercaprol; Metagenomics; Antiviral Agents; Sensitivity and Specificity
PubMed: 37506257
DOI: 10.1093/infdis/jiad296 -
Proceedings of the National Academy of... Nov 2023Cobalt-containing alloys are useful for orthopedic applications due to their low volumetric wear rates, corrosion resistance, high mechanical strength, hardness, and...
Cobalt-containing alloys are useful for orthopedic applications due to their low volumetric wear rates, corrosion resistance, high mechanical strength, hardness, and fatigue resistance. Unfortunately, these prosthetics release significant levels of cobalt ions, which was only discovered after their widespread implantation into patients requiring hip replacements. These cobalt ions can result in local toxic effects-including peri-implant toxicity, aseptic loosening, and pseudotumor-as well as systemic toxic effects-including neurological, cardiovascular, and endocrine disorders. Failing metal-on-metal (MoM) implants usually necessitate painful, risky, and costly revision surgeries. To treat metallosis arising from failing MoM implants, a synovial fluid-mimicking chelator was designed to remove these metal ions. Hyaluronic acid (HA), the major chemical component of synovial fluid, was functionalized with British anti-Lewisite (BAL) to create a chelator (BAL-HA). BAL-HA effectively binds cobalt and rescues in vitro cell vitality (up to 370% of cells exposed to IC levels of cobalt) and enhances the rate of clearance of cobalt in vivo ( from 48 h to 6 h). A metallosis model was also created to investigate our therapy. Results demonstrate that BAL-HA chelator system is biocompatible and capable of capturing significant amounts of cobalt ions from the hip joint within 30 min, with no risk of kidney failure. This chelation therapy has the potential to mitigate cobalt toxicity from failing MoM implants through noninvasive injections into the joint.
Topics: Humans; Hip Prosthesis; Hyaluronic Acid; Dimercaprol; Chelation Therapy; Prosthesis Failure; Arthroplasty, Replacement, Hip; Metals; Cobalt; Chelating Agents; Ions
PubMed: 37903261
DOI: 10.1073/pnas.2309156120 -
The American Journal of Emergency... Jun 2024A 53-year-old male patient presented to a regional hospital Emergency Department approximately 2 h post an intentional ingestion of Coopers Instant Wetting Powder Sheep...
A 53-year-old male patient presented to a regional hospital Emergency Department approximately 2 h post an intentional ingestion of Coopers Instant Wetting Powder Sheep Dip (66% arsenic trioxide, 23% sulphur and 0.42% rotenone), mixed in 600 mL water, as a suicide attempt. On arrival to the Emergency Department, the patient had nausea, vomiting and diarrhoea. Seven hours post ingestion, hypotension developed (BP 90/60 mmHg) and intravenous fluids were commenced. He later developed QTc prolongation. He was treated with 2,3-Dimercapto-1-propanesulfonic acid (DMPS) and N-acetylcysteine and improved without development of neurology. Further investigation of NAC efficacy in humans in the setting of acute arsenic poisoning is required and the optimal duration of treatment and dosing needs to be established. This case highlights an uncommon poisoning which presented to the Emergency Department, the acute symptoms of arsenic toxicity and considerations for management.
Topics: Male; Humans; Middle Aged; Suicide, Attempted; Arsenic Poisoning; Acetylcysteine; Arsenicals; Arsenic Trioxide; Oxides; Antidotes; Unithiol
PubMed: 38702220
DOI: 10.1016/j.ajem.2024.04.050 -
Redox Biology Jul 2024Glutathione (GSH) is a major endogenous antioxidant, and its depletion has been observed in several brain diseases including epilepsy. Previous studies in our laboratory...
Glutathione (GSH) is a major endogenous antioxidant, and its depletion has been observed in several brain diseases including epilepsy. Previous studies in our laboratory have shown that dimercaprol (DMP) can elevate GSH via post-translational activation of glutamate cysteine ligase (GCL), the rate limiting GSH biosynthetic enzyme and inhibit neuroinflammation in vitro. Here we determined 1) the role of cysteamine as a new mechanism by which DMP increases GSH biosynthesis and 2) its ability to inhibit neuroinflammation and neuronal injury in the rat kainate model of epilepsy. DMP depleted cysteamine in a time- and concentration-dependent manner in a cell free system. To guide the in vivo administration of DMP, its pharmacokinetic profile was determined in the plasma, liver, and brain. The results confirmed DMP's ability to cross the blood-brain-barrier. Treatment of rats with DMP (30 mg/kg) depleted cysteamine in the liver and hippocampus that was associated with increased GCL activity in these tissues. GSH levels were significantly increased (20 %) in the hippocampus 1 h after 30 mg/kg DMP administration. Following DMP (30 mg/kg) administration once daily, a marked attenuation of GSH depletion was seen in the SE model. SE-induced inflammatory markers including cytokine release, microglial activation, and neuronal death were significantly attenuated in the hippocampus with DMP treatment. Taken together, these results highlight the importance of restoring redox status with rescue of GSH depletion by DMP in post epileptogenic insults.
Topics: Animals; Rats; Glutathione; Status Epilepticus; Oxidative Stress; Neuroinflammatory Diseases; Male; Disease Models, Animal; Hippocampus; Cysteamine; Antioxidants; Glutamate-Cysteine Ligase; Liver
PubMed: 38714094
DOI: 10.1016/j.redox.2024.103168 -
Advances in Respiratory Medicine Dec 2023Hospitalized patients with a high suspicion of pulmonary tuberculosis (HS-PTB) are isolated until a definite diagnosis can be determined. If doubt remains after negative...
Hospitalized patients with a high suspicion of pulmonary tuberculosis (HS-PTB) are isolated until a definite diagnosis can be determined. If doubt remains after negative sputum samples, bronchoscopy with bronchoalveolar lavage (BAL) is often sought. Still, evidence of the added value of BAL in this patient population is scarce. To address this issue, we included consecutive HS-PTB patients with negative sputum samples who underwent BAL between 2017 and 2018. Chest X-rays (CXR) and CT scans were evaluated by a chest radiologist blind to the final diagnosis. Independent predictors for PTB were assessed by multivariate regression, using all positive PTB patients between 2017 and 2019 (by sputum or BAL) as a control group ( = 41). Overall, 42 HS-PTB patients were included (mean age 51 ± 9, 36% female). BAL was a viable diagnostic for PTB in three (7%) cases and for other clinically relevant pathogens in six (14%). Independent predictors for PTB were ≥2 sub-acute symptoms (adjusted OR 3.18, 95% CI 1.04-9.8), CXR upper-lobe consolidation (AOR 8.70, 95% CI 2.5-29), and centrilobular nodules in chest CT (AOR 3.96, 95% CI 1.20-13.0, = 0.02). In conclusion, bronchoscopy with BAL in hospitalized patients with HS-PTB had a 7% added diagnostic value after negative sputum samples. Our findings highlight specific predictors for PTB diagnosis that could be used in future controlled studies to personalize the diagnostic evaluation.
Topics: Humans; Female; Adult; Middle Aged; Male; Mycobacterium tuberculosis; Sputum; Bronchoalveolar Lavage Fluid; Sensitivity and Specificity; Tuberculosis, Pulmonary; Bronchoalveolar Lavage; Dimercaprol
PubMed: 38392033
DOI: 10.3390/arm92010003 -
Frontiers in Pharmacology 2023Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have...
Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration in a clinical setting. Next-generation snakebite therapies are being widely investigated with the aim to improve cost, efficacy, and safety. In recent years several small molecule drugs have shown considerable promise for snakebite indication, with oral bioavailability particularly promising for community delivery rapidly after a snakebite. However, only two such drugs have entered clinical development for snakebite. To offset the risk of attrition during clinical trials and to better explore the chemical space for small molecule venom toxin inhibitors, here we describe the first high throughput drug screen against snake venom metalloproteinases (SVMPs)-a pathogenic toxin family responsible for causing haemorrhage and coagulopathy. Following validation of a 384-well fluorescent enzymatic assay, we screened a repurposed drug library of 3,547 compounds against five geographically distinct and toxin variable snake venoms. Our drug screen resulted in the identification of 14 compounds with pan-species inhibitory activity. Following secondary potency testing, four SVMP inhibitors were identified with nanomolar ECs comparable to the previously identified matrix metalloproteinase inhibitor marimastat and superior to the metal chelator dimercaprol, doubling the current global portfolio of SVMP inhibitors. Following analysis of their chemical structure and ADME properties, two hit-to-lead compounds were identified. These clear starting points for the initiation of medicinal chemistry campaigns provide the basis for the first ever designer snakebite specific small molecules.
PubMed: 38273820
DOI: 10.3389/fphar.2023.1328950