Crotoxin-Induced Mice Lung Impairment: Role of Nicotinic Acetylcholine Receptors and COX-Derived Prostanoids

Respiratory compromise in Crotalus durissus terrificus (C.d.t.) snakebite is an important pathological condition. Considering that crotoxin (CTX), a phospholipase A2 from C.d.t. venom, is the main component of the venom, the present work investigated the toxin effects on respiratory failure. Lung mechanics, morphology and soluble markers were evaluated from Swiss male mice, and mechanism determined using drugs/inhibitors of eicosanoids biosynthesis pathway and autonomic nervous system. Acute respiratory failure was observed, with an early phase (within 2 h) characterized by enhanced presence of eicosanoids, including prostaglandin E2, that accounted for the increased vascular permeability in the lung. The alterations of early phase were inhibited by indomethacin. The late phase (peaked 12 h) was marked by neutrophil infiltration, presence of pro-inflammatory cytokines/chemokines, and morphological alterations characterized by alveolar septal thickening and bronchoconstriction. In addition, lung mechanical function was impaired, with decreased lung compliance and inspiratory capacity. Hexamethonium, a nicotinic acetylcholine receptor antagonist, hampered late phase damages indicating that CTX-induced lung impairment could be associated with cholinergic transmission. The findings reported herein highlight the impact of CTX on respiratory compromise, and introduce the use of nicotinic blockers and prostanoids biosynthesis inhibitors as possible symptomatic therapy to Crotalus durissus terrificus snakebite.

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Noninvasive Ventilation in the Critically Ill Patient With Obesity Hypoventilation Syndrome: A Review

Journal of Intensive Care Medicine ◽

10.1177/0885066616663179 ◽

2016 ◽

Vol 32 (7) ◽

pp. 421-428 ◽

Cited By ~ 11

Author(s):

Telma C. A. Sequeira ◽

Ahmed S. BaHammam ◽

Antonio M. Esquinas

Keyword(s):

Respiratory Failure ◽

Critically Ill ◽

Noninvasive Ventilation ◽

Hospital Admissions ◽

Lung Mechanics ◽

Critically Ill Patient ◽

Obesity Hypoventilation Syndrome ◽

Hypoventilation Syndrome ◽

The Impact ◽

Obesity Hypoventilation

Obesity is a global epidemic that adversely affects respiratory physiology. Sleep-disordered breathing and obesity hypoventilation syndrome (OHS) are among the most common pulmonary complications related to obesity class III. Patients with OHS may present with acute hypercapnic respiratory failure (AHRF) that necessitates immediate noninvasive ventilation (NIV) or invasive ventilation and intensive care unit (ICU) monitoring. The OHS is underrecognized as a cause of AHRF. The management of mechanical ventilation in obese ICU patients is one of the most challenging problems facing respirologists, intensivists, and anesthesiologists. The treatment of AHRF in patients with OHS should aim to improve alveolar ventilation with better alveolar gas exchange, as well as maintaining a patent upper airway, which is ideally achieved through NIV. Treatment with NIV is associated with improvement in blood gases and lung mechanics and may reduce hospital admissions and morbidity. In this review, we will address 3 main issues: (1) NIV of critically ill patients with acute respiratory failure and OHS; (2) the indications for postoperative application of NIV in patients with OHS; and (3) the impact of OHS on weaning and postextubation respiratory failure. Additionally, the authors propose an algorithm for the management of obese patients with AHRF.

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Rationale for Polyclonal Intravenous Immunoglobulin Adjunctive Therapy in COVID-19 Patients: Report of a Structured Multidisciplinary Consensus

Journal of Clinical Medicine ◽

10.3390/jcm10163500 ◽

2021 ◽

Vol 10 (16) ◽

pp. 3500

Author(s):

Irene Coloretti ◽

Giorgio Berlot ◽

Stefano Busani ◽

Francesco Giuseppe De Rosa ◽

Abele Donati ◽

...

Keyword(s):

Respiratory Failure ◽

Adjunctive Therapy ◽

Early Phase ◽

Potential Role ◽

Late Phase ◽

Ivig Therapy ◽

Target Population ◽

Severe Respiratory Failure ◽

Hospital Acquired ◽

Bacterial Superinfection

Introduction: Adjunctive therapy with polyclonal intravenous immunoglobins (IVIg) is currently used for preventing or managing infections and sepsis, especially in immunocompromised patients. The pathobiology of COVID-19 and the mechanisms of action of Ig led to the consideration of this adjunctive therapy, including in patients with respiratory failure due to the SARS-CoV-2 infection. This manuscript reports the rationale, the available data and the results of a structured consensus on intravenous Ig therapy in patients with severe COVID-19. Methods: A panel of multidisciplinary experts defined the clinical phenotypes of COVID-19 patients with severe respiratory failure and, after literature review, voted for the agreement on the rationale and the potential role of IVIg therapy for each phenotype. Due to the scarce evidence available, a modified RAND/UCLA appropriateness method was used. Results: Three different phenotypes of COVID-19 patients with severe respiratory failure were identified: patients with an abrupt and dysregulated hyperinflammatory response (early phase), patients with suspected immune paralysis (late phase) and patients with sepsis due to a hospital-acquired superinfection (sepsis by bacterial superinfection). The rationale for intravenous Ig therapy in the early phase was considered uncertain whereas the panelists considered its use in the late phase and patients with sepsis/septic shock by bacterial superinfection appropriate. Conclusion: As with other immunotherapies, IVIg adjunctive therapy may have a potential role in the management of COVID-19 patients. The ongoing trials will clarify the appropriate target population and the true effectiveness.

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Crotalus durissus terrificus (viperidae; crotalinae) envenomation: Respiratory failure and treatment with antivipmyn TRI® antivenom

Toxicon ◽

10.1016/j.toxicon.2019.03.009 ◽

2019 ◽

Vol 163 ◽

pp. 32-35 ◽

Cited By ~ 5

Author(s):

R.A. Baum ◽

J. Bronner ◽

P.D.S. Akpunonu ◽

J. Plott ◽

A.M. Bailey ◽

...

Keyword(s):

Respiratory Failure ◽

Crotalus Durissus Terrificus ◽

Crotalus Durissus

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Strong Early Phase Parasympathetic Inhibition Followed by Sympathetic Withdrawal During Propofol Induction: Temporal Response Assessed by Wavelet-Based Spectral Analysis and Photoplethysmography

Frontiers in Physiology ◽

10.3389/fphys.2021.705153 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hsin-Yi Wang ◽

Men-Tzung Lo ◽

Kun-Hui Chen ◽

Susan Mandell ◽

Wen-Kuei Chang ◽

...

Keyword(s):

High Frequency ◽

Repeated Measures ◽

Early Phase ◽

Late Phase ◽

Low Frequency ◽

Clinical Trial Registration ◽

Cardiac Autonomic Nervous System ◽

Institutional Review ◽

Post Hoc ◽

The Impact

Background: Induction of anesthesia with propofol is associated with a disturbance in hemodynamics, in part due to its effects on parasympathetic and sympathetic tone. The impact of propofol on autonomic function is unclear. In this study, we investigated in detail the changes in the cardiac autonomic nervous system (ANS) and peripheral sympathetic outflow that occur during the induction of anesthesia.Methods: Electrocardiography and pulse photoplethysmography (PPG) signals were recorded and analyzed from 30 s before to 120 s after propofol induction. The spectrogram was derived by continuous wavelet transform with the power of instantaneous high-frequency (HFi) and low-frequency (LFi) bands extracted at 1-s intervals. The wavelet-based parameters were then divided into the following segments: (1) baseline (30 s before administration of propofol), (2) early phase (first minute after administration of propofol), and (3) late phase (second minute after administration of propofol) and compared with the same time intervals of the Fourier-based spectrum [high-frequency (HF) and low-frequency (LF) bands]. Time-dependent effects were explored using fractional polynomials and repeated-measures analysis of variance.Results: Administration of propofol resulted in reductions in HFi and LFi and increases in the LFi/HFi ratio and PPG amplitude, which had a significant non-linear relationship. Significant between-group differences were found in the HFi, LFi, and LFi/HFi ratio and Fourier-based HF and LF after dividing the segments into baseline and early/late phases. On post hoc analysis, changes in HFi, LFi, and the LFi/HFi ratio were significant starting from the early phase. The corresponding effect size (partial eta squared) was > 0.3, achieving power over 90%; however, significant decreases in HF and LF were observed only in the late phase. The PPG amplitude was increased significantly in both the early and late phases.Conclusion: Propofol induction results in significant immediate changes in ANS activity that include temporally relative elevation of cardiac sympathovagal balance and reduced sympathetic activity.Clinical Trial Registration: The study was approved by the Institutional Review Board of Taipei Veterans General Hospital (No. 2017-07-009CC) and is registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03613961).

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Rationale for Polyclonal Intravenous Immunoglobulin Adjunctive Therapy in Covid19 Patients: Report of a Structured Multidisciplinary Consensus

10.20944/preprints202105.0345.v1 ◽

2021 ◽

Author(s):

Irene Coloretti ◽

Giorgio Berlot ◽

Stefano Busani ◽

Giuseppe De Rosa ◽

Abele Donati ◽

...

Keyword(s):

Respiratory Failure ◽

Adjunctive Therapy ◽

Early Phase ◽

Potential Role ◽

Late Phase ◽

Ivig Therapy ◽

Target Population ◽

Severe Respiratory Failure ◽

Hospital Acquired ◽

Bacterial Superinfection

Adjunctive therapy with polyclonal intravenous immunoglobins (IVIg) is currently used for preventing or managing infections and sepsis, especially in immunocompromised patients. The pathobiology of COVID19 and the mechanisms of action of Ig led to consider this adjunctive therapy also in patients with respiratory failure by SARS-CoV2 infection. This manuscript report the rationale, the available data and the results of a structured consensus on intravenous Ig therapy in patients with severe COVID19. METHODS A panel of multidisciplinary experts defined the clinical phenotypes of COVID19 patients with severe respiratory failure and, after literature review, voted for the agreement on the rationale and the potential role of IVIg therapy for each phenotype. Due to the scarce evidence available, a modified RAND/UCLA appropriateness method was used. RESULTS Three different phenotypes of COVID19 patients with severe respiratory failure were identified: patients with an abrupt and dysregulated hyperinflammatory response (early phase), patients with suspected immune-paralysis (late phase), and patients with sepsis by hospital-acquired superinfection (sepsis by bacterial superinfection). The rationale for intravenous Ig therapy in the early phase was considered uncertain whereas the panellists considered appropriate its use in the late phase and patients with sepsis/septic shock by bacterial superinfection. CONCLUSION As with other immunotherapies, IVIg adjunctive therapy may a potential role in the managing of COVID19 patients. The ongoing trials will clarify the appropriate target population and the true effectiveness.

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Impact of timing of atrial fibrillation, CHA2DS2-VASc score and cancer therapeutics on mortality in oncology patients

Open Heart ◽

10.1136/openhrt-2020-001412 ◽

2020 ◽

Vol 7 (2) ◽

pp. e001412

Author(s):

Muzna Hussain ◽

Rabel Misbah ◽

Eoin Donnellan ◽

Saqer Alkharabsheh ◽

Yuan Hou ◽

...

Keyword(s):

Atrial Fibrillation ◽

Cancer Diagnosis ◽

Early Phase ◽

Late Phase ◽

Cancer Therapeutics ◽

Older Age ◽

Oncology Patients ◽

After Cancer ◽

The Impact ◽

First Diagnosis

ObjectivesTo investigate timing and age distribution of atrial fibrillation (AF) in selected oncology patients, and the impact of AF timing, CHA2DS2-VASc score and cancer therapeutics on mortality.MethodsThis is a retrospective cohort study of oncology patients referred to the cardio-oncology service from 2011 to 2018 for echocardiographic cardiosurveillance and/or pre-existing cardiovascular risk factor/disease management. Rates of first AF diagnosis was assessed using a parametric multiphase hazard model (predictive modelling) and non-parametrically by Kaplan-Meier with transformations tested using a bootstrap methodology.ResultsAmong 6754 patients identified, 174 patients had their first AF diagnosis before cancer while 609 patients had their first diagnosis of AF after cancer. Most first AF diagnosis occurred at/early after cancer diagnosis. Increasing AF prevalence at time of cancer diagnosis was seen across older age groups ranges. Diagnosis of cancer at an older age and exposure to cardiotoxic treatment (anthracyclines, HER2-neu inhibitors, tyrosine kinase inhibitors including ibrutinib and radiation) were associated with an increased risk of AF.Modelling of the hazard function of AF identified a high left-skewed peak within 3 years after cancer diagnosis (‘early phase’), followed by a gradual late slight rise 3 years after cancer diagnosis (‘late phase’). AF diagnosis was only associated with death in the early phase (p<0.001), while CHA2DS2-VASc score was only associated with death in the late phase (p<0.001).ConclusionsThis study reports a nuanced/complex relationship between AF and cancer. First diagnosis of AF in patients with cancer was more common at/early after cancer diagnosis, especially in older patients and those exposed to cardiotoxic treatment. Pre-existing AF or a diagnosis of AF within 3 years after cancer diagnosis carried a negative prognosis. CHA2DS2-VASc score did not relate to mortality in those that developed AF within 3 years of cancer diagnosis.

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Improved Stage Categorization of PTZ-Induced Kindling and Late Enhanced Neurogenesis in PTZ Kindled Mice

10.31661/gmj.v8i0.1511 ◽

2019 ◽

Vol 8 ◽

pp. 1511

Author(s):

Marzieh Shahpari ◽

Hadi Aligholi ◽

Mohammad Reza Namavar ◽

Farzaneh Vafaee ◽

Masoumeh Emamghoreishi

Keyword(s):

Subventricular Zone ◽

Early Phase ◽

Hind Limb ◽

Late Phase ◽

The Other ◽

Myoclonic Jerk ◽

Ptz Kindling ◽

First Occurrence ◽

Tonic Extension ◽

Behavioral Index

Background: There is no universally accepted behavioral scoring to define the early development of phenothiazine (PTZ) kindling. Therefore, studies investigating alterations of neurogenesis in the PTZ model were mainly focused on full kindled animals rather than early stages of kindling. This study aimed to determine an appropriate behavioral index for categorizing stages of PTZ kindling progress and to evaluate neurogenesis during PTZ kindling. Materials and Methods: Twenty-four mice were intraperitoneally injected with a sub convulsive dose of PTZ (40mg/kg) every other day until they became full kindled. The first occurrence of different seizure behaviors and their durations were recorded during kindling development, and the different stages of kindling were categorized. Neurogenesis was evaluated in the lateral subventricular zone (SVZ) at each stage of kindling by immunofluorescence staining. Results: First occurrence of restlessness, motionless staring, hind limb tonic extension, Straub’s tail, myoclonic jerk, and tonic-clonic were sequentially observed in more than 80% of animals with increasing PTZ injections. The duration of the myoclonic jerk was significantly longer than the other seizure behaviors. The significantly higher percentage of BrdU-positive cells was found in SVZ of mice showing tonic-clonic in comparison to other seizure behaviors. Conclusion: A hierarchy behavior was observed during the kindling process when considering the first occurrence of seizure behaviors. We defined the first occurrence of restlessness, motionless, hind limb tonic extension and Straub’s tail behaviors as an early phase, myoclonic jerk as a borderline phase and tonic-clonic as a late phase of PTZ-induced kindling. Our results indicated an enhanced SVZ neurogenesis at the late phase of kindling. [GMJ.2019;8:e1511]

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The impact of non-pharmaceutical interventions on COVID-19 epidemic growth in the 37 OECD member states

European Journal of Epidemiology ◽

10.1007/s10654-021-00766-0 ◽

2021 ◽

Author(s):

Francisco Pozo-Martin ◽

Heide Weishaar ◽

Florin Cristea ◽

Johanna Hanefeld ◽

Thurid Bahr ◽

...

Keyword(s):

Growth Rate ◽

Early Phase ◽

Policy Decision ◽

Multilevel Modelling ◽

Daily Growth ◽

Public Places ◽

Member States ◽

Unit Increase ◽

Policy Decision Making ◽

The Impact

AbstractWe estimated the impact of a comprehensive set of non-pharmeceutical interventions on the COVID-19 epidemic growth rate across the 37 member states of the Organisation for Economic Co-operation and Development during the early phase of the COVID-19 pandemic and between October and December 2020. For this task, we conducted a data-driven, longitudinal analysis using a multilevel modelling approach with both maximum likelihood and Bayesian estimation. We found that during the early phase of the epidemic: implementing restrictions on gatherings of more than 100 people, between 11 and 100 people, and 10 people or less was associated with a respective average reduction of 2.58%, 2.78% and 2.81% in the daily growth rate in weekly confirmed cases; requiring closing for some sectors or for all but essential workplaces with an average reduction of 1.51% and 1.78%; requiring closing of some school levels or all school levels with an average reduction of 1.12% or 1.65%; recommending mask wearing with an average reduction of 0.45%, requiring mask wearing country-wide in specific public spaces or in specific geographical areas within the country with an average reduction of 0.44%, requiring mask-wearing country-wide in all public places or all public places where social distancing is not possible with an average reduction of 0.96%; and number of tests per thousand population with an average reduction of 0.02% per unit increase. Between October and December 2020 work closing requirements and testing policy were significant predictors of the epidemic growth rate. These findings provide evidence to support policy decision-making regarding which NPIs to implement to control the spread of the COVID-19 pandemic.

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Nucleolin Improves Heart Function During Recovery From Myocardial Infarction by Modulating Macrophage Polarization

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248421989570 ◽

2021 ◽

pp. 107424842198957

Author(s):

Yuting Tang ◽

Xiaofang Lin ◽

Cheng Chen ◽

Zhongyi Tong ◽

Hui Sun ◽

...

Keyword(s):

Myocardial Infarction ◽

Early Phase ◽

Heart Function ◽

Macrophage Polarization ◽

Late Phase ◽

Macrophage Infiltration ◽

Enzyme Linked Immunosorbent Assay ◽

M2 Macrophage ◽

M2 Macrophage Polarization ◽

Nucleolin Expression

Background: Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism. Methods: Male BALB/c mice aged 6–8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay. Results: Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages. Conclusions: Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.

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COVID-19 in liver transplant candidates: pretransplant and post-transplant outcomes - an ELITA/ELTR multicentre cohort study

Gut ◽

10.1136/gutjnl-2021-324879 ◽

2021 ◽

pp. gutjnl-2021-324879

Author(s):

Luca Saverio Belli ◽

Christophe Duvoux ◽

Paolo Angelo Cortesi ◽

Rita Facchetti ◽

Speranta Iacob ◽

...

Keyword(s):

Liver Disease ◽

Respiratory Failure ◽

Meld Score ◽

Decompensated Cirrhosis ◽

Cox Regression Analysis ◽

Post Transplant ◽

End Stage Liver Disease ◽

Significant Difference ◽

End Stage ◽

The Impact

ObjectiveExplore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course.DesignData from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed.ResultsFrom 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10–30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15–19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44–102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31–170).ConclusionsIncreased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%).

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