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Τρίτη 4 Οκτωβρίου 2022

Bupivacaine inhibits the TLR4 ‐ and TLR2 ‐ Myd88/NF‐κB pathways in human leukocytes

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Abstract

Background

Local anesthetics have anti-inflammatory effects. Because most previous experiments were performed with supra-therapeutic concentrations, we measured the effects of clinically relevant concentrations of bupivacaine on the TLR4- and TLR2-MyD88-NF-κB pathways.

Methods

We measured TNF-α and PGE2 release, p38 MAP-kinase phosphorylation and translocation of NF-κB in human peripheral blood mononuclear cells (hPBMC) and human monocytes challenged with LPS (lipopolysaccharide) or Pam3CSK4 (tripalmitoylated lipopeptide Pam3CysSerLys4) in the presence or absence of bupivacaine. Similarly, we measured the effect of bupivacaine on HEK293 cells expressing the hTLR4 and the hTLR2 genes and challenged with LPS or Pam3CSK4. Finally, molecular docking simulations of R(+)- and S(-)-bupivacaine binding to the TLR4-MD-2 complex and to the TLR2/TLR1 heterodimer were performed.

Results

In PBMCs, bupivacaine from 0.1 to 100 μM inhibited LPS-induced TNF-α and PGE2 secretion, phosphorylation of p38 and nuclear translocation of NF-κB in monocytes. Bupivacaine similarly inhibited the effects of Pam3CSK4 on TNF-α secretion. Bupivacaine inhibited the effect of LPS on HEK293 cells expressing the human TLR4 receptor and the effect of Pam3CSK4 on HEK293 cells expressing the human TLR2 receptor. Molecular docking showed that bupivacaine binds to the MD-2 co-receptor of TLR4 and to the TLR2 receptor.

Conclusions

Contrary to numerous experiments performed with supratherapeutic doses, our results were obtained with concentrations of bupivacaine as low as 0.1 μM. We conclude that bupivacaine modulates the inflammatory reactions such as those observed after surgery or trauma, at least partly by inhibiting the TLR4- and TLR2-NF-κB pathways.
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Polyethylenglycol – Freund oder Feind?

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Laryngorhinootologie 2022; 101: 784-786
DOI: 10.1055/a-1861-7047

Anaphylaktische Reaktionen nach Impfungen sind selten. Zwei Fälle von Reaktionen nach der Pfizer-BioNTech-Covid-19-Vakzine, BNT162b2, wurden aus dem UK berichtet, weitere 19 aus den USA. Als möglicher Auslöser wurde Polyethylenglycol (PEG) angeschuldigt. Pegylierung ist ein üblicher Vorgang in der Impfstoffherstellung, um die Substanzen vor schnellem immunologischem Abbau zu schützen. PEG ist ein Polyether (Synonyme z. B. Laureth-9, Polidocanol, Thesit, Macrogol) und findet sich in Kosmetika, Körperpflegeprodukten, Nahrungsmitteln, Liposomen und Nanopartikeln als Drug-Delivery-Systeme für Medikamente und als osmotisches Laxans vor Gastro-/Koloskopien. IgM-Antikörper auf PEG werden bei 70% der Bevölkerung nachgewiesen. Bei 2 Fällen von Soforttyp-Reaktionen auf PEG fanden sich IgE-Antiköper, bei anderen Medikamentengaben mit PEG geht man von pseudoallergischen Reaktionen über die Komplement-Aktivierungs-related Pseudoallergie (CARPA) aus. In Relation zum weit verbreiteten Einsatz von PEG sind die Impfreaktionen sehr selten und aktuell kein Grund, Allergiker oder Menschen mit Anaphylaxien bei entsprechenden Vorsichtsmaßnahmen auf bekannte Auslöser auszuschließen. Aufgrund der Meldepflicht (Gesundheitsamt und Arzneimittelkommission der deutschen Ärzteschaft) ist bald mit weiteren Erkenntnissen zu rechnen.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text
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Δευτέρα 3 Οκτωβρίου 2022

Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a Mendelian randomization study

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Abstract
Background
Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight.
Methods
We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH; n = 872) and UK Biobank (UKB; n = 133 187). We conducted two-sample MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs); n = 288 649 European ancestry] on offspring birthweight (n = 406 063 European ancestry; maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-sample MR in UKB women (n = 199 768).
Results
Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: –50, 6); P = 0.13] and UKB [–28 g (95% CI: –31, –25); P = 1.8 × 10–75]. The MR causal effect estimate was directionally consistent, but smaller [–11 g (95% CI: –25, 3); PIVW = 0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1); P = 7.8 × 10–22], consistent with that previously published in women and men.
Conclusion
The marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweigh t. Maternal urate levels are unlikely to be an important contributor to offspring birthweight.
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Κυριακή 2 Οκτωβρίου 2022

Management of Low-Grade Gliomas – Extent of Resection Matters But Not All Tumours Are Amenable to Surgery

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Abstract
AIMS
To present and review our experience in the management of low-grade gliomas.
METHOD
Retrospective case note review of all patients with WHO grade 2 glioma from 2011 to 2018 (based on WHO criteria at time of diagnosis). Data collected on demographics, presentation, location, initial management, histology, treatment, progression free (PFS) and overall survival (OS).
RESULTS
130 eligible patients. Median follow 4.6 years (up to 10.5). Median age 40 years (range: 18-83). There were 70 (53.8%) astrocytomas, 44 (33.8%) oligodenrogliomas, 16 (12.3%) oligoastrocytomas. 66%(n=86) presented with seizures, 10.7%(n=14) with sensory symptoms, 8.5%(n=11) with speech disturbance, 5.3%(n=4) with motor symptoms and 12.3%(n=16) were identified incidentally. 50.1%(n=65) were frontal, 27.7%(n=36) temporal and 9.2%(n=12) parietal. 1st line treatment was resection in 70.7%(n=92), biopsy in 23.8%(n=31) and observation in 4.6%(n=6). 15.4 %(n=20) received adjuvant radiotherapy alone and 6.1%(n=8) received adjuvant radiotherapy followed by chemotherapy . At first recurrence, 31.6%(n=12) received further surgery and 95%(n=38) received radiotherapy and/or chemotherapy . Median PFS from 1st line treatment 66, 44 and 33 months for gross total resection (GRT), subtotal resection (STR), and biopsy respectively. Overall survival was 95.1%, 79.3% and 69.% for GTR, STR and biopsy respectively.
CONCLUSION
Management of low-grade gliomas remains challenging. Extent of resection impacts prognosis but not all patients have gliomas amenable to surgery. The effects of chemoradiotherapy will be presented in future meetings as this is an ongoing project.
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Development of chemiluminescent lab‐on‐fiber immunosensor for rapid point‐of‐care testing of anti‐SARS‐CoV‐2 antibodies and evaluation of longitudinal immune response kinetics following three‐dose inactivation virus vaccination

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Abstract

Developing reliable, rapid, and quantitative point-of-care testing (POCT) technology of SARS-CoV-2 specific antibodies and understanding longitudinal vaccination response kinetics are highly required to restrain the ongoing Coronavirus Disease 2019 (COVID-19) pandemic. We demonstrate a novel portable, sensitive, and rapid chemiluminescent lab-on-fiber detection platform for detection of anti-SARS-CoV-2 antibodies: the c-LOFI. Using SARS-CoV-2 Spike S1 RBD protein functionalized fiber bio-probe, the c-LOFI can detect anti-SARS-CoV-2 IgG and IgM antibodies with high sensitivity based on their respective HRP labeled secondary antibodies. The limits of detection of anti-SARS-CoV-2 IgG and IgM antibodies were 0.6 ng/mL and 0.3 ng/mL, respectively. The c-LOFI was successfully applied for direct detection of anti-SARS-CoV-2 antibodies in whole blood samples with simple dilution, which can serve as a finger prick test to rapidly detect antibodies. Furthermore, the l ongitudinal immune response (>12 months) kinetics following three-dose inactivated virus vaccines was evaluated based on anti-SARS-CoV-2 IgG detection results, which can provide importance significance for understanding the immune mechanism against COVID-19 and identify individuals who may benefit from the vaccination and booster vaccination. The c-LOFI has great potential to become a sensitive, low-cost, rapid, high-frequency POCT tool for the detection of both SARS-CoV-2 specific antibodies and other biomarkers.

This article is protected by copyright. All rights reserved.
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Partial laryngectomy for naïve pT3N0 laryngeal cancer: Systematic review on oncological outcomes

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Abstract

The first aim was to define the oncologic outcomes of open partial laryngectomy (OPL) in naïve pT3 laryngeal cancer. The second aim was to analyze the outcomes after OPL versus total laryngectomy (TL). A literature search was conducted in three databases (MEDLINE, EMBASE, and Cochrane Library) until January 2022. In 805 patients treated with OPL, 5-year OS, DSS, DFS and LFS were 80.5% (95% CI 70.6–87.6), 83.4% (95% CI 75.7–89), 77.4% (95% CI 66.3–85.7) and 77.9% (95% CI 68.7–85), respectively. Three articles compared TL versus OLP: 5-year OS, DSS and DFS risk difference were 0.100 (95% CI −0.092 to 0.291), 0.067 (95% CI −0.085 to 0.220) and 0.018 (95% CI −0.164 to 0.201) respectively. OPL for selected pT3 laryngeal cancer is able to guarantee a high percentage of oncological success. Accurate patient selection is of utmost importance to differentiate advanced disease amenable to conservative surgery.
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Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome

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Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome

The brains of 8-week-old wildtype (WT) mice (left) and mice carrying mutations (D1113H) in the ADAR1 gene (right) probed for expression of Interferon Stimulated Gene 15 (ISG-15) using In situ hybridization (red). WT mice show little to no expression of ISG-15 while ADAR1 mutant mouse brain shows a broad and chaotic distribution of expression throughout the brain (8 of many foci circled).


Abstract

Chronic inflammation is frequently invoked as a mechanism of neurodegeneration and yet inflammatory cell infiltrates are seldom seen in brains of these disorders. Different disciplines utilize different technologies and methodologies to describe what is immunologically defined as the innate immune response (IIR). We examined murine models of the human neurodegenerative disease Aicardi–Gutiérrez Syndrome, where an IIR is initiated by aberrant RNA metabolism secondary to a mutation in adenosine deaminase acting on RNA gene (ADAR1). We previously showed that these mice demonstrated a deficit in RNA editing that lead to MDA-5 mediated RNA sensing pathway activation of the IIR with massive interferon stimulated gene transcription and translation. As early as 2 weeks of age, in situ hybridization demonstrated that different central nervous system (CNS) cell lineages expressed very high levels of distinct interferon stimulated genes (ISGs) in the absence of interferon and absence of immune cell infiltrates. We have expanded these studies to more completely describe the breadth of ISG expression systemically and in CNS using double label in situ hybridization. Within the CNS aberrant ISG expression was mostly limited to neurons, microglia, ependyma, choroid plexus, and endothelial cells with little expression in oligodendroglia and astrocytes except for STAT1. Wild type controls showed a similar pattern of ISG expression but only in aged mice and at levels minimally detectable by in situ hybridization. Despite months of elevated ISG expression in mutant mice, there was essentially no inflammatory infiltrate, no interferon production and minimal glial reaction. Histomorphological neurodegenerative pathology of ventricular dilatation and deep gray matter mineralization were evident in mutant mice 8–13 months of age but this did not show a spatial relationship to ISG expression. This IIR without immune cell infiltration leads to neurodegeneration through non-c anonical pathways that may accentuate normal aging pathways.
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