Characterization of pathogenic genetic variants in Russian patients with primary ciliary dyskinesia using gene panel sequencing and transcript analysis.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a group of rare genetically heterogeneous disorders caused by defective cilia and flagella motility. The clinical phenotype of PCD patients commonly includes chronic oto-sino-pulmonary disease, infertility, and, in about half of cases, laterality defects due to randomization of left-right body asymmetry. To date, pathogenic variants in more than 50 genes responsible for motile cilia structure and assembly have been reported in such patients. While multiple population-specific mutations have been described in PCD cohorts from different countries, the data on genetic spectrum of PCD in Russian population are still extremely limited. RESULTS: The present study provides a comprehensive clinical and genetic characterization of 21 Russian families with PCD living in various country regions. Anomalies of ciliary beating in patients` respiratory epithelial cells were confirmed by high-speed video microscopy. In the most cases, custom-designed panel sequencing allowed to uncover causative variants in well-known or rarely mentioned PCD-related genes, including DNAH5, DNAH11, CFAP300, LRRC6, ZMYND10, CCDC103, HYDIN, ODAD4, DNAL1, and OFD1. The variations comprised common mutations, as well as novel genetic variants, some of which probably specific for Russian patients. Additional targeted analysis of mRNA transcripts from ciliated cells enabled us to specify functional effects of newly identified genetic variants in DNAH5 (c.2052+3G>T, c.3599-2A>G), HYDIN (c.10949-2A>G, c.1797C>G), and ZMYND10 (c.510+1G>C) on splicing process. In particular, the splice site variant c.2052+3G>T, detected in four unrelated families, resulted in skipping of exon 14 in DNAH5 transcripts and, according to haplotype analysis of affected probands, was proposed as an ancestral founder mutation in Udmurt population. CONCLUSIONS: The reported data provide a vital insight into genetic background of primary ciliary dyskinesia in the Russian population. The findings clearly illustrate the utility of gene panel sequencing coupled with transcriptional analysis in identification and clinical interpretation of novel genetic variants.

Prevalence and Clinical Impact of Viral and Bacterial Coinfections in Hospitalized Children and Adolescents Aged under 18 Years with COVID-19 during the Omicron Wave in Russia.

The COVID-19 pandemic has altered respiratory infection patterns in pediatric populations. The emergence of the SARS-CoV-2 Omicron variant and relaxation of public health measures have increased the likelihood of coinfections. Previous studies show conflicting results regarding the impact of viral and bacterial coinfections with SARS-CoV-2 on severity of pediatric disease. This study investigated the prevalence and clinical impact of coinfections among children hospitalized with COVID-19 during the Omicron wave. A retrospective analysis was conducted on 574 hospitalized patients aged under 18 years in Russia, from January 2022 to March 2023. Samples from patients were tested for SARS-CoV-2 and other respiratory pathogens using qRT-PCR, bacterial culture tests and mass spectrometry, and ELISA. Approximately one-third of COVID-19 cases had coinfections, with viral and bacterial coinfections occurring at similar rates. Adenovirus and Staphylococcus aureus were the most common viral and bacterial coinfections, respectively. Viral coinfections were associated with higher fevers and increased bronchitis, while bacterial coinfections correlated with longer duration of illness and higher pneumonia rates. Non-SARS-CoV-2 respiratory viruses were linked to more severe lower respiratory tract complications than SARS-CoV-2 monoinfection. These findings suggest that during the Omicron wave, seasonal respiratory viruses may have posed a greater threat to children's health than SARS-CoV-2.

Gut Microbiota as a Mediator of Essential and Toxic Effects of Zinc in the Intestines and Other Tissues.

The objective of the present study was to review the existing data on the association between Zn status and characteristics of gut microbiota in various organisms and the potential role of Zn-induced microbiota in modulating systemic effects. The existing data demonstrate a tight relationship between Zn metabolism and gut microbiota as demonstrated in Zn deficiency, supplementation, and toxicity studies. Generally, Zn was found to be a significant factor for gut bacteria biodiversity. The effects of physiological and nutritional Zn doses also result in improved gut wall integrity, thus contributing to reduced translocation of bacteria and gut microbiome metabolites into the systemic circulation. In contrast, Zn overexposure induced substantial alterations in gut microbiota. In parallel with intestinal effects, systemic effects of Zn-induced gut microbiota modulation may include systemic inflammation and acute pancreatitis, autism spectrum disorder and attention deficit hyperactivity disorder, as well as fetal alcohol syndrome and obesity. In view of both Zn and gut microbiota, as well as their interaction in the regulation of the physiological functions of the host organism, addressing these targets through the use of Zn-enriched probiotics may be considered an effective strategy for health management.

A follow-up study of mucociliary clearance and trace element and mineral status in children with chronic rhinosinusitis before and three months after endoscopic sinus surgery.

BACKGROUND: The existing data demonstrate the potential role of trace elements in nasal mucociliary clearance, although the association between trace element and mineral status and ciliary function in children with chronic rhinosinusitis is insufficiently studied. Therefore, the objective of the present study is evaluation of trace element and mineral status and mucociliary function in pediatric CRS patients before and after functional endoscopic sinus surgery. METHODS: The present study involved 30 children with chronic rhinosinusitis without nasal polyps. During this follow-up the patients were examined preoperatively (point 0), underwent functional endoscopic sinus surgery, and were repeatedly examined at three months postoperatively (point 1). At both points the patients were subjected to quality-of-life assessment using SNOT-20 questionnaire; endoscopic and computer tomography examination of the nasal sinuses; evaluation of ciliary function and mucosal cytology using high-speed videomicroscopy; assessment of blood count and inflammatory markers; as well as analysis of trace element and mineral levels in whole blood, serum, and hair using inductively-coupled plasma mass-spectrometry. RESULTS: The obtained data demonstrate that endoscopic sinus surgery significantly improved sinonasal pathology in children with chronic rhinosinusitis, as evidenced by significantly reduced Lund-Mackay, Lund-Kennedy, and SNOT-20 scores. At the same time, no significant improvement of ciliary functions or mucosal cytology was observed postoperatively. Trace element status assessment demonstrated that postoperative serum Zn, whole blood Mg and Cu were significantly lower as compared to preoperative values. In contrast, serum Mn and Cr, as well as whole blood Cr and hair Se were characterized by a significant increase at three months postoperatively. Multiple linear regression analysis demonstrated that serum Zn is significantly associated with the number of ciliated cells and cell viability, whereas serum Mn and whole blood Cu concentrations are inversely associated with cell viability and ciliary length, respectively. Hair Se was found to be associated with the number of neutrophils in the mucosa biopsy. CONCLUSION: Redistribution of trace elements and minerals may at least partially mediate prolonged recovery of mucosal ciliary function in children with chronic rhinosinusitis in three months after functional sinus surgery, although the particular mechanisms of these alterations in trace element levels are to be discovered.

Comparative Analysis of Mucociliary Clearance and Mucosal Morphology Using High-Speed Videomicroscopy in Children With Acute and Chronic Rhinosinusitis.

OBJECTIVE: evaluation of mucociliary clearance and mucosal morphology using high-speed videomicroscopy, and their association with markers of disease severity in children with acute (ARS) and chronic rhinosinusitis (CRS). METHODS: A total of 67 children aged from 6 to 17 years including 15 healthy children, 20 pediatric patients with acute rhinosinusitis, and 32 cases with chronic rhinosinusitis were enrolled in the present study. SNOT20, Lund-Kennedy, and Lund-Mackay scores were also evaluated. RESULTS: Children with rhinosinusitis were characterized by significantly lower number of cells with motile cilia, ciliary beat frequency, cilia length, and cell viability, as well as ciliary beat asynchrony, epithelia dystrophy and reduced epithelial cell height, being more severe in ARS group. Neutrophil infiltration of sinonasal mucosa was more profound in children with ARS, whereas the number of lymphocytes was significantly reduced. Markers of ciliary function were characterized by a significant correlation with epithelia dystrophia and neutrophil infiltration. Discriminant analysis demonstrated significant group separation based on the parameters of mucociliary clearance and mucosal morphology. In regression models mucociliary function was also associated with SNOT20, Lund-Kennedy, and Lund-Mackay scores. CONCLUSION: The results of the present study demonstrate significant alteration of mucociliary clearance and mucosal morphology and its association with sinonasal inflammation and disease severity in patients with rhinosinusitis. Given a tight association between altered mucociliary clearance and severity of the disease, modulation of inflammation and ciliary function both in acute and chronic rhinosinusitis may be considered as the potential tool in therapeutic and surgical management of the disease.

Serum, Whole Blood, Hair, and Mucosal Essential Trace Element and Mineral Levels in Children with Verified Chronic Rhinosinusitis Undergoing Functional Endoscopic Sinus Surgery.

The objective of the present study was to assess hair, serum, whole blood, and excised tissue essential element content in children with chronic rhinosinusitis (CRS). Eighty-eight children with chronic rhinosinusitis and 66 healthy controls were enrolled in the present study. Evaluation of endoscopic Lund-Kennedy and computed tomography Lund-Mackay scores, as well as tissue sampling, was performed only in children with chronic rhinosinusitis. Assessment of Sino-Nasal Outcome Test-20 (SNOT-20) scores was performed in both cases and controls. Hair, whole blood, blood serum, and excised mucosal tissue (only in patients) analysis was performed using inductively coupled argon plasma mass-spectrometry. The obtained data demonstrate that whole blood Ca, Mg, Se, and Zn, as well as hair Ca, Cu, Mg, and Zn levels in the examined patients were significantly lower as compared with the control values. Only serum Zn concentration in children with CRS exceeded the respective control values, whereas serum Cu levels only tended to decrease in CRS. In turn, hair Fe content in children with CRS exceeded that in healthy controls. Regression analysis demonstrate that hair Ca levels, as well as whole blood Ca, Se, and Zn concentrations, were considered as negative predictors, whereas increased hair iron level was significantly directly associated with CRS. Significant associations between hair, serum, whole blood, and tissue element levels and Lund-Kennedy and Lund-Mackay scores were also revealed. Generally, the obtained data demonstrate that chronic rhinosinusitis is associated with impaired essential metal levels in pediatric patients with chronic rhinosinusitis. The observed alterations may contribute to CRS pathogenesis through modulation of mucociliary clearance, immunity, inflammatory response, and redox environment.

Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases.

Multiple medical, lifestyle, and environmental conditions, including smoking and particulate pollution, have been considered as risk factors for COronaVIrus Disease 2019 (COVID-19) susceptibility and severity. Taking into account the high level of toxic metals in both particulate matter (PM2.5) and tobacco smoke, the objective of this review is to discuss recent data on the role of heavy metal exposure in development of respiratory dysfunction, immunotoxicity, and severity of viral diseases in epidemiological and experimental studies, as to demonstrate the potential crossroads between heavy metal exposure and COVID-19 severity risk. The existing data demonstrate that As, Cd, Hg, and Pb exposure is associated with respiratory dysfunction and respiratory diseases (COPD, bronchitis). These observations corroborate laboratory findings on the role of heavy metal exposure in impaired mucociliary clearance, reduced barrier function, airway inflammation, oxidative stress, and apoptosis. The association between heavy metal exposure and severity of viral diseases, including influenza and respiratory syncytial virus has been also demonstrated. The latter may be considered a consequence of adverse effects of metal exposure on adaptive immunity. Therefore, reduction of toxic metal exposure may be considered as a potential tool for reducing susceptibility and severity of viral diseases affecting the respiratory system, including COVID-19.

Zinc and respiratory tract infections: Perspectives for COVID­19 (Review).

In view of the emerging COVID­19 pandemic caused by SARS­CoV­2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID­19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS­CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn2+ may decrease the activity of angiotensin­converting enzyme 2 (ACE2), known to be the receptor for SARS­CoV­2. Improved antiviral immunity by zinc may also occur through up­regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti­inflammatory activity by inhibiting NF­κB signaling and modulation of regulatory T­cell functions that may limit the cytokine storm in COVID­19. Improved Zn status may also reduce the risk of bacterial co­infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID­19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID­19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator­induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.

Comparative analysis of the outcome of external and endoscopic frontal sinus surgery in children.

Background: Both open and functional endoscopic sinus surgery (FESS) are performed in the case of pediatric frontal rhinosinusitis. However, data from comparative analysis of these surgery types are insufficient.Objective: Prospective randomized trial for comparison of open and endoscopic surgery outcome in pediatric chronic rhinosinusitis.Material and methods: The cohort included 30 pediatric patients (7-17 years) with open frontal sinus surgery and 34 patients who underwent FESS using DrafIIa. Lund-Kennedy and Lund-Mackay scores, as well as Sino-Nasal Outcome Test-20 (SNOT-20)questionnaire was used for pre- and postoperative assessment.Results: Open surgery and FESS resulted in a significant improvement in total Lund-Kennedy, Lund-Mackay, and SNOT-20 scores, being more profound in FESS group. Using FESS significantly reduced surgery duration by 15% as compared to open surgery. In addition, open surgery was associated with a higher rate of scar formation, reduced local sensitivity, as well as local soreness, lacrimation, and psychological discomfort. In regression models FESS was negatively associated with postoperative total Lund-Kennedy, Lund-Mackay, and SNOT-20 scores.Conclusion and significance: Generally, FESS resulted in better surgery outcome as compared to open surgery, although both approaches resulted in a significant improvement in chronic rhinosinusitis.

Comparison of the efficiency and safety of endonasal and open rhinosurgery in children.

OBJECTIVES/HYPOTHESIS: The objective of this study was to compare the efficiency and safety of endonasal endoscopic maxillary surgery and the Caldwell-Luc approach in children. STUDY DESIGN: Case series. METHODS: A total of 121 children aged 9 to 17 years with chronic rhinosinusitis were included in the study. The patients were operated on using Caldwell-Luc (n = 36) and endoscopic maxillary surgery (n = 85) procedures. Efficiency and safety of the surgeries were assessed using pre- and postoperative endoscopic evaluation of the mucosa of the nasal cavity, 20-item Sino-Nasal Outcome Test (SNOT-20), and subjective (both children's and parents') evaluation of the outcomes. RESULTS: Endoscopic investigation of the mucosa of the nasal cavity demonstrated a significant improvement after both Caldwell-Luc and endoscopic surgery, although the Caldwell-Luc procedure did not result in significant improvement in mucosal color. However, no significant group difference was observed. Both techniques resulted in a significant improvement of mucosal edema and fluid characteristics. Based on the results of the SNOT-20, endoscopic maxillary surgery was characterized by a significant improvement in headache frequency, waking up at night, reduced concentration, ear pain, and emotional suppression as compared to Caldwell-Luc surgery. Although no significant group difference in efficiency between the Caldwell-Luc approach and endoscopic surgery was observed, the latter was characterized by a lower rate of scar formation, and reduced sensitivity, local painfulness, lacrimation, and psychologic discomfort. CONCLUSIONS: The obtained data demonstrate the higher efficiency and safety of endoscopic sinus surgery as compared to the Caldwell-Luc approach in children. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1056-1063, 2020.

Mucociliary transport as a link between chronic rhinosinusitis and trace element dysbalance.

Chronis rhinosinusitis is considered as a widespread public health issue with a prevalence of 10%. The disease significantly reduces quality of life and increases the risk of cardiovascular diseases as well as certain forms of cancer. Alteration of mucociliary clearance frequently observed in the patients and plays a significant role in disease pathogenesis. Certain studies have demonstrated that patients with chronic rhinosinusitis are characterized by significant reduction of essential trace elements and toxic metal overload. However, the particular mechanisms of the role of trace element dysbalance in chronic rhinosinusitis are unclear. We hypothesize that exposure to toxic trace elements (arsenic, nickel, cadmium) damages ciliary mucosal epithelium thus affecting mucociliary transport. In turn, altered mucociliary transport results in reduced removal of the inhaled metal-containing particles from nasal mucosa leading to their absorption and further aggravation of toxicity. Essential trace elements (zinc, selenium) play a significant role in regulation of mucociliary transport and immunity, thus their deficiency (either dietary or due to antagonism with toxic metals) may be associated with impaired functions and increased toxic metal toxicity. Therefore, a vicious circle involving metal accumulation and toxicity, essential element deficiency, impairment of mucociliary transport and metal particle removal, resulting in further accumulation of metals and aggravation of toxic effects is formed. The present hypothesis is supported by the findings on the impact of trace elements especially zinc and arsenic on mucociliary clearance, the role of mucociliary transport in heavy metal particles elimination from the airways, trace element dysbalance in chronic rhinosinusitis, as well as toxic and essential metal antagonism. The data from hypothesis testing and its verification may be used for development of therapeutic approach for management of chronic rhinosinusitis. Particularly, the use of essential elements (zinc, selenium) may reduce toxic metal toxicity thus destroying the vicious circle of heavy metal exposure, toxicity, alteration of mucociliary clearance, and aggravation of chronic rhinosinusitis. Essential element supplementation may be considered as a tool for management of chronic refractory rhinosinusitis. In addition, analysis of essential and toxic trace element status may provide an additional diagnostic approach to risk assessment of chronic rhinosinusitis in highly polluted environments.

Neuronal Representation of 3-D Space in the Primary Visual Cortex and Control of Eye Movements.

The aim of this article is to consider the correlations between the structure of the primary visual cortical area V1 and control of coordinated movements of the two eyes. Using the anatomical data available, a schematic map of 3-D space representation in the layer IV of area V1 containing only monocular cells has been constructed. The analysis of this map revealed that binocular neurons of V1, which are formed by convergence of monocular cells, should encode the absolute disparity. Participation of monocular and binocular neurons of V1 in the control of convergence, divergence, and version eye movements is discussed. It is proposed that synchronous contraction of corresponding extraocular muscles of both eyes for vergence might be ensured by duplicated transmission of information from the central part of retina to visual cortex of both hemispheres.