Laryngeal mask airway is associated with an increased incidence of adverse respiratory events in children with recent upper respiratory tract infections

BACKGROUND: The laryngeal mask airway (LMA) has been advocated as an alternative technique to tracheal intubation for airway management of children with recent upper respiratory tract infections (URIs). The authors determined the occurrence of adverse respiratory events and identified the associated risk factors to assess the safety of LMA in children. METHODS: During a period of 5 months, parents of children scheduled to undergo general anesthesia with an LMA were asked to fill out a questionnaire regarding their child's medical history and potential symptoms of URI. In addition, all episodes of adverse respiratory events in the perioperative period (laryngospasm, bronchospasm, coughing, airway obstruction, and oxygen desaturation) as well as details of anesthesia management were recorded. RESULTS: Among the 831 children included in the study, 27% presented with a history of a recent URI within the last 2 weeks before anesthesia. The presence of a recent URI doubled the incidence of laryngospasm (odds ratio, 2.6; 95% confidence interval, 1.3-5.0), coughing (odds ratio, 2.7; 95% confidence interval, 1.7-4.3), and oxygen desaturation (odds ratio, 1.9; 95% confidence interval, 1.2-2.8). This incidence was even higher in young children; in those undergoing ear, nose, and throat surgery; and when there were multiple attempts to insert the LMA. CONCLUSION: An LMA used in children with recent URIs was associated with a higher incidence of laryngospasm, cough, and oxygen desaturation compared with healthy children. However, the overall incidence of adverse respiratory events was low, suggesting that if anesthesiologists allow at least a 2-week interval after a URI, they can safely proceed with anesthesia using an LMA.     

Peroxidasin Is Secreted and Incorporated into the Extracellular Matrix of Myofibroblasts and Fibrotic Kidney

Mammalian peroxidases are heme-containing enzymes that serve diverse biological roles, such as host defense and hormone biosynthesis. A mammalian homolog of Drosophila peroxidasin belongs to the peroxidase family; however, its function is currently unknown. In this study, we show that peroxidasin is present in the endoplasmic reticulum of human primary pulmonary and dermal fibroblasts, and the expression of this protein is increased during transforming growth factor-β1-induced myofibroblast differentiation. Myofibroblasts secrete peroxidasin into the extracellular space where it becomes organized into a fibril-like network and colocalizes with fibronectin, thus helping to form the extracellular matrix. We also demonstrate that peroxidasin expression is increased in a murine model of kidney fibrosis and that peroxidasin localizes to the peritubular space in fibrotic kidneys. In addition, we show that this novel pathway of extracellular matrix formation is unlikely mediated by the peroxidase activity of the protein. Our data indicate that peroxidasin secretion represents a previously unknown pathway in extracellular matrix formation with a potentially important role in the physiological and pathological fibrogenic response.Peroxidases are heme-containing enzymes with highly conserved structure, serving diverse functions in the plant and animal kingdom.¹ Peroxidases catalyze the oxidation of various substrates in the presence of H₂O₂. Mammalian peroxidases have an important role in several physiological processes including host defense and hormone biosynthesis. The family of mammalian peroxidases consists of myeloperoxidase, eosinophil peroxidase, lactoperoxidase, thyroid peroxidase, and the mammalian peroxidasin. Myeloperoxidase, eosinophil peroxidase, and lactoperoxidase have antimicrobial activity and serve in the first line of host defense, while thyroid peroxidase has an essential role in the biosynthesis of thyroid hormones.^2,3,4 The function of the mammalian peroxidasin is currently unknown. Peroxidases in plants and in lower animal species frequently participate in extracellular matrix (ECM) formation. In the presence of H₂O₂, peroxidases enzymatically cross-link extracellular proteins through tyrosine residues.⁵ ECM stabilization by dityrosine bridges is well-documented during sea urchin fertilization, where secreted ovoperoxidase is responsible for the formation of cross-links.⁶ Dityrosine formation is also involved in the stabilization of C. elegans cuticle, where dual oxidases, carrying both NADPH oxidase and peroxidase-like domains, provide hydrogen peroxide for the crosslinking reaction.⁷Peroxidasin (PXDN), a unique form of peroxidase was first identified in Drosophila melanogaster.⁸ Beside containing a peroxidase domain, which is highly homologous to other animal peroxidases, peroxidasin also contains protein domains characteristic for proteins of the ECM. Drosophila PXDN was found to be expressed in several stages of development, but the exact function remained unknown.⁸ Little is still known about the mammalian PXDN protein. A human homolog of Drosophila PXDN was originally identified as a p53-responsive gene product from a colon cancer cell line, but it was not characterized in detail.⁹ An independent cloning effort, using subtractive hybridization also led to the identification of the mammalian PXDN gene, which was originally named melanoma gene 50, based on the expression in melanoma samples.¹⁰ This latter study has characterized PXDN as a possible potent melanoma-associated antigen, but it did not examine the possible physiological role of the protein.Here we demonstrate that peroxidasin is expressed by human primary cells, including fibroblasts of different origin, where the protein is localized to the endoplasmic reticulum. On stimulation by transforming growth factor (TGF)-β1, differentiating myofibroblasts show increased expression of peroxidasin. The protein becomes secreted to the extracellular space where it is organized into a fibril-like network. We also show that this pathway of ECM formation is probably not mediated by the peroxidase activity of the protein. Our results suggest that beside the secretion of well-known constituents of the ECM, PXDN secretion by myofibroblasts is a novel way of ECM modification in wound repair and tissue fibrosis.     

Four cases of disseminated Mycobacterium bovis infection following intravesical BCG instillation for treatment of bladder carcinoma

Intravesical BCG (bacillus Calmette-Guérin) instillation is a first-line treatment for superficial transitional cell carcinoma of the bladder. A rare but severe complication of BCG immunotherapy is the development of disseminated BCG disease, which can result in miliary pneumonitis, granulomatous hepatitis, soft tissue infections, bone marrow involvement, and sepsis. Symptoms can present as early as a few hours or as late as several months following the BCG therapy. The key finding in disseminated BCG disease is the formation of caseating granulomas in distant organs; detection of BCG organisms from tissue samples can be difficult. Recommended treatment for disseminated BCG disease includes a combination of antituberculous medications (with the exception of pyrazinamide, to which BCG is typically resistant) and a tapering course of steroids. We present the cases of four patients who developed granulomatous infection consistent with disseminated disease after intravesical BCG treatment and provide a summary of current clinical management recommendations.     

PACAP-Mediated Neuroprotection of Neurochemically Identified Cell Types in MSG-Induced Retinal Degeneration

Pituitary adenylate cyclase-activating polypeptide (PACAP) is neuroprotective in animal models of different brain pathologies and injuries, including cerebral ischemia, Parkinson's disease, and different types of retinal degenerations. We have previously shown that PACAP is protective against monosodium glutamate (MSG)-induced retinal degeneration, where PACAP-treated retinas has more retained structure and PACAP induces anti-apoptotic while it inhibits pro-apoptotic signaling pathways. The aim of the present study was to investigate cell-type specific effects of PACAP in MSG-induced retinal degeneration by means of immunohistochemistry. Rat pups received MSG (2 mg/g b.w.) applied on postnatal days 1, 5, and 9. PACAP (100 pmol in 5 microl saline) was injected into the right vitreous body, while the left eye received only saline. Retinas were processed for immunocytochemistry after 3 weeks. Immunolabeling was determined for vesicular glutamate transporter 1, tyrosine hydroxylase, calretinin, calbindin, parvalbumin, and vesicular gamma-aminobutyric acid (GABA) transporter. In the MSG-treated retinas, the cell bodies and processes in the inner nuclear, inner plexiform, and ganglion cell layers displayed less immunoreactivity for all antisera. Apart from photoreceptors, only one major retinal cell type examined in this study; the calbindin-immunoreactive horizontal cell seemed not to be affected by MSG application. After simultaneous application of MSG and PACAP, staining of retinas was similar to that of normal eyes, with no significant alterations in immunoreactive patterns. These findings further support the neuroprotective function of PACAP in MSG-induced retinal degeneration.     

Liver alterations and detection of SARS-CoV-2 RNA and proteins in COVID-19 autopsies

GeroScience - The most severe alterations in Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection are seen in the lung. However,...     

Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α₂nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1ra_Ast^+/+ mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1ra_Ast^+/+ mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1–parasympathetic–bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.     

Pharmacokinetics of the chemopreventive agent oltipraz and of its metabolite M3 in human subjects after a single oral dose.

The dithiolethione oltipraz (OPZ) has activity as a chemopreventive agent in animal models and is in early clinical trials. OPZ undergoes metabolism by molecular rearrangement to yield a pyrrolopyrazine derivative, M3, which we have previously shown to be inactive in the induction of detoxication genes. M3 is metabolized further: at least 10 possible conjugates have been described in three species. We developed a new high-performance liquid chromatography method to simultaneously measure plasma concentrations of OPZ and of M3. This method was applied to serial plasma samples in a Phase I clinical trial, in which OPZ was administered at single doses varying from 125 to 1000 mg/m2. OPZ and M3 concentration-time profiles were highly variable among individuals, and the occurrence of secondary concentration peaks suggested substantial enterohepatic cycling. Absorption was rapid, and the mean time to peak was 2.2 h. Maximum plasma concentration values were proportional to the dose. Harmonic mean half-lives at these doses ranged from 9.3-22.7 h. There were indications of dose-dependent pharmacokinetic properties because apparent clearance and volume of distribution at steady state increased with dose, although these changes were not statistically significant as a result of high interpatient variability. Accordingly, there were less than proportional increases in the OPZ and M3 area under the curve and maximum plasma values. Interpretation of OPZ and M3 disposition is confounded by the unknown bioavailability factor; however, the most likely inferences are that bioavailability of OPZ decreases with increasing dose and that metabolism to M3 is saturable.     

Plasma carnitine ester profiles in Crohn's disease patients characterized for SLC22A4 C1672T and SLC22A5 G-207C genotypes

Crohn's disease (CD) is a chronic inflammatory bowel disorder caused by environmental and genetic factors. The purpose of this study was to analyse the possible influence of functional variants of genes of OCTN cation transporters on the carnitine ester profile of patients with CD. Genotyping for SLC22A4 1672C --> T, SLC22A5-207G --> C mutations and three common NOD2 variants (R702W, G908R and 1007finsC) were performed in 100 adult CD patients and in ninety-four healthy controls by direct sequencing. The carnitine ester profile was determined using ESI triple quadrupole tandem MS. Contrary to the NOD2/CARD15 mutations, none of the SLC variants showed increased prevalence in the CD group, the prevalence of TC haplotype did not differ between the patients and the controls. In the mixed group of CD patients the fasting propionyl- (0.243 (sem 0.008) v. 0.283 (sem 0.014) micromol/l), butyryl- (0.274 (sem 0.009) v. 0.301 (sem 0.013)) and isovalerylcarnitine (0.147 (sem 0.006) v. 0.185 (sem 0.009)) levels were decreased; while the level of octenoyl- (0.086 (sem 0.006) v. 0.069 (sem 0.005)), myristoleyl- (0.048 (sem 0.003) v. 0.037 (sem 0.003)), palmitoyl- (0.140 (sem 0.005) v. 0.122 (sem 0.004)) and oleylcarnitine (0.172 (sem 0.006) v. 0.156 (sem 0.008); P < 0.05 in all comparisons) were increased. After sorting the patients into SLC22A genotype-specific subgroups, no significant differences could be observed between them. The carnitine ester profile data suggest selective involvement of the carnitine esters in CD patients, probably due to their altered metabolism.