Nicotiana benthamiana-derived dupilumab-scFv reaches deep into the cultured human nasal epithelial cells and inhibits CCL26 expression.

Plants offer a cost-effective and scalable pharmaceutical platform devoid of host-derived contamination risks. However, their medical application is complicated by the potential for acute allergic reactions to external proteins. Developing plant-based protein therapeutics for localized diseases with non-invasive treatment modalities may capitalize on the benefits of plant proteins while avoiding their inherent risks. Dupilumab, which is effective against a variety of allergic and autoimmune diseases but has systemic responses and injection-related side effects, may be more beneficial if delivered locally using a small biological form. In this study, we engineered a single-chain variable fragment (scFv) of dupilumab, termed Dup-scFv produced by Nicotiana benthamiana, and evaluated its tissue permeability and anti-inflammatory efficacy in air-liquid interface cultured human nasal epithelial cells (HNECs). Despite showing 3.67- and 17-fold lower binding affinity for IL-4Ra in surface plasmon resonance assays and cell binding assays, respectively, Dup-scFv retained most of the affinity of dupilumab, which was originally high, with a dissociation constant (KD) of 4.76 pM. In HNECs cultured at the air-liquid interface, Dup-scFv administered on the air side inhibited the inflammatory marker CCL26 in hard-to-reach basal cells more effectively than dupilumab. In addition, Dup-scFv had an overall permeability of 0.8% across cell layers compared to undetectable levels of dupilumab. These findings suggest that plant-produced Dup-scFv can be delivered non-invasively to cultured HNESc to alleviate inflammatory signaling, providing a practical approach to utilize plant-based proteins for topical therapeutic applications.

Intermittent hypoxia induces Th17/Treg imbalance in a murine model of obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by cyclic normoxic and hypoxic conditions (intermittent hypoxia, IH) induced by the repeated closure of the upper-airway respiratory tract. As a pathomechanism of OSA, IH results in various comorbidities via chronic inflammation and related pathways. However, the role of other inflammatory cells, such as lymphocytes, has not been well-explored. This study aimed to examine the effects of IH on the distribution and balance of T cell subsets and other related cytokines, and mechanisms in the immune system. We modified OSA mouse model (male C57BL/6N male) using our customized chamber that controls specific sleep and oxygenic cycles. To induce hypoxia, the IH group was repeatedly exposed to 5% O2 and 21% O2 lasting for 120 s each for 7 h daily for 4 weeks. Mice were then subjected to a recovery period of 4 weeks, in which IH stimulation was ceased. T cells and related cytokines were analyzed using flow cytometry and immunohistochemistry. Compared with the control group, the IH group had significantly lower levels of CD4+CD25+Foxp3+ regulatory T cells but higher levels of Th 17, IL-4, HIF-1, and inflammatory cytokines. After the recovery period, these altered changes in the immune cells were recovered, and we found no significant difference in their levels between the control and recovery groups. This study revealed that the Th17/Treg ratio is increased by intermittent hypoxia, and this imbalance can explain immune-related diseases, including recently reported allergies, autoimmune, and even cancer diseases, arising from OSA.

Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection.

Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus, thereby compromising the epithelial barrier integrity. Through bacterial adhesion assays and in vitro pull-down assays, we identified fibronectin-binding proteins (FnBP) of S. aureus as a key component that binds to CD47. Furthermore, we found that ciliated cell-specific CD47 deficiency or neutralizing antibody-mediated CD47 inactivation enhanced in vivo survival rates. These findings suggest that interfering with the interaction between airway epithelial CD47 and pathogenic bacterial FnBP holds promise for alleviating the adverse effects of super-infection.

Sinonasal seromucinous hamartoma: a single institution case series combined with a narrative review of the literature.

PURPOSE: This study aimed to investigate the clinical and histopathological characteristics of sinonasal seromucinous hamartomas (SHs). METHODS: Eight patients with sinonasal SH and treated at a tertiary hospital between November 2005 and September 2023 were included. Additionally, a systematic review of published articles was conducted, analyzing 48 cases of SH described in the literature. RESULTS: Among the eight patients treated at our institution, tumors originated from the posterior nasal cavity in four patients and middle turbinate and middle meatus were the primary origin in two patients each. Coexistence of inflammatory nasal polyps (NPs) was observed in four cases. Histopathologically, four patients exhibited focal respiratory epithelial adenomatoid hamartoma (REAH) features, and low-grade dysplasia was found in one patient. A combined analysis with previous literature revealed that 46.3% of all cases originated in the anterior nasal cavity. The proportions of cases accompanied by NPs and those with focal REAH features were 20.5% and 39.1%, respectively. Additionally, the frequencies of cases exhibiting dysplastic features (5.4%) and recurrence (2.1%) were low. Remarkably, tumors originating from the anterior region tended to have a higher frequency of dysplasia than those originating from the posterior region, although this difference was not statistically significant (p = 0.0996). CONCLUSION: Patients with sinonasal SH showed favorable treatment outcomes following surgical resection. Focal REAH features and accompanying NPs were frequently observed. A substantial proportion of cases originate in the anterior nasal cavity, and these tumors may exhibit a high tendency for dysplasia.

Diagnosis of Primary Ciliary Dyskinesia via Whole Exome Sequencing and Histologic Findings.

PURPOSE: To assess the diagnostic potential of whole-exome sequencing (WES) and elucidate the clinical and genetic characteristics of primary ciliary dyskinesia (PCD) in the Korean population. MATERIALS AND METHODS: Forty-seven patients clinically suspected of having PCD were enrolled at a tertiary medical center. WES was performed in all patients, and seven patients received biopsy of cilia and transmission electron microscopy (TEM). RESULTS: Overall, PCD was diagnosed in 10 (21.3%) patients: eight by WES (8/47, 17%), four by TEM. Among patients diagnosed as PCD based on TEM results, two patients showed consistent results with WES and TEM of PCD (2/4, 50%). In addition, five patients, who were not included in the final PCD diagnosis group, had variants of unknown significance in PCD-related genes (5/47, 10.6%). The most frequent pathogenic (P)/likely pathogenic (LP) variants were detected in DNAH11 (n=4, 21.1%), DRC1 (n=4, 21.1%), and DNAH5 (n=4, 21.1%). Among the detected 17 P/LP variants in PCD-related genes in this study, 8 (47.1%) were identified as novel variants. Regarding the genotype-phenotype correlation in this study, the authors experienced severe PCD cases caused by the LP/P variants in MCIDAS, DRC1, and CCDC39. CONCLUSION: Through this study, we were able to confirm the value of WES as one of the diagnostic tools for PCD, which increases with TEM, rather than single gene tests. These results will prove useful to hospitals with limited access to PCD diagnostic testing but with relatively efficient in-house or outsourced access to genetic testing at a pre-symptomatic or early disease stage.

Impact of Non-Pharmaceutical Interventions on the Incidence and Treatment of Chronic Rhinosinusitis during the COVID-19 Pandemic: A Nationwide Retrospective Cohort Study.

Many countries have implemented non-pharmaceutical interventions (NPIs) to prevent the spread of COVID-19. However, the impacts of NPIs on the epidemiology and treatment of chronic rhinosinusitis (CRS) remain unclear. We analyzed 671,216 patients to investigate changes in the incidence rate and treatment frequency of CRS using Korean nationwide health insurance data between 2017 and 2021. The incidence rate (p < 0.001) and the number of outpatients (p < 0.001), patients hospitalized (p < 0.001), and patients prescribed antibiotics (p < 0.001) or steroids (p = 0.024) were significantly lower in the pandemic period than in the pre-pandemic period; however, the number of patients who underwent surgery was not different (p = 0.205). Additionally, the frequency of surgeries per patient was significantly lower in patients during the pandemic period (p < 0.001). In the interrupted time series analysis, the trends in the number of outpatients (p < 0.001), patients hospitalized (p < 0.001), patients who underwent surgery (p < 0.001), and patients prescribed antibiotics (p < 0.001) or steroids (p < 0.001) significantly changed after the onset of the COVID-19 pandemic. In summary, NPI implementation during the COVID-19 pandemic was associated with a reduction in the incidence and treatment of CRS.

Unraveling the Role of Epithelial Cells in the Development of Chronic Rhinosinusitis.

The pathophysiology of CRS is multifactorial and complex yet needs to be completed. Recent evidence emphasizes the crucial part played by epithelial cells in the development of CRS. The epithelial cells act as physical barriers and play crucial roles in host defense, including initiating and shaping innate and adaptive immune responses. This review aims to present a comprehensive understanding of the significance of nasal epithelial cells in CRS. New research suggests that epithelial dysfunction plays a role in developing CRS through multiple mechanisms. This refers to issues with a weakened barrier function, disrupted mucociliary clearance, and irregular immune responses. When the epithelial barrier is compromised, it can lead to the passage of pathogens and allergens, triggering inflammation in the body. Furthermore, impaired mucociliary clearance can accumulate pathogens and secretions of inflammatory mediators, promoting chronic inflammation. Epithelial cells can release cytokines and chemokines, which attract and activate immune cells. This can result in an imbalanced immune response that continues to cause inflammation. The interaction between nasal epithelial cells and various immune cells leads to the production of cytokines and chemokines, which can either increase or decrease inflammation. By comprehending the role of epithelial cells in CRS, we can enhance our understanding of the disease's pathogenesis and explore new therapeutics.

Role of TRPC3 in Right Ventricular Dilatation under Chronic Intermittent Hypoxia in 129/SvEv Mice.

Patients with obstructive sleep apnea (OSA) exhibit a high prevalence of pulmonary hypertension and right ventricular (RV) hypertrophy. However, the exact molecule responsible for the pathogenesis remains unknown. Given the resistance to RV dilation observed in transient receptor potential canonical 3(Trpc3)-/- mice during a pulmonary hypertension model induced by phenylephrine (PE), we hypothesized that TRPC3 also plays a role in chronic intermittent hypoxia (CIH) conditions, which lead to RV dilation and dysfunction. To test this, we established an OSA mouse model using 8- to 12-week-old 129/SvEv wild-type and Trpc3-/- mice in a customized breeding chamber that simulated sleep and oxygen cycles. Functional parameters of the RV were evaluated through analysis of cardiac cine magnetic resonance images, while histopathological examinations were conducted on cardiomyocytes and pulmonary vessels. Following exposure to 4 weeks of CIH, Trpc3-/- mice exhibited significant RV dysfunction, characterized by decreased ejection fraction, increased end-diastole RV wall thickness, and elevated expression of pathological cardiac markers. In addition, reactive oxygen species (ROS) signaling and the endothelin system were markedly increased solely in the hearts of CIH-exposed Trpc3-/- mice. Notably, no significant differences in pulmonary vessel thickness or the endothelin system were observed in the lungs of wild-type (WT) and Trpc3-/- mice subjected to 4 weeks of CIH. In conclusion, our findings suggest that TRPC3 serves as a regulator of RV resistance in response to pressure from the pulmonary vasculature, as evidenced by the high susceptibility to RV dilation in Trpc3-/- mice without notable changes in pulmonary vasculature under CIH conditions.

Visualization of the relationship between electrogustometry and whole mouth test using multidimensional scaling.

Interpreting the relationship between different taste function tests of different stimuli, such as chemical and electrical stimulation, is still poorly understood. This study aims to analyze visually as well as quantitatively how to interpret the relationship of results between taste function tests using different stimuli. Patients who underwent the whole mouth test and Electrogustometry (EGM) at a tertiary medical center between August 2018 and December 2018 were reviewed retrospectively with electronic medical records. Of the 110 patients, a total of 86 adults who self-reported that their taste function was normal through a questionnaire were enrolled. EGM measured the thresholds of the chorda tympani (CT) and glossopharyngeal nerve (GL) area of the tongue. The whole mouth test measured detection and recognition thresholds for sweet, salty, bitter, sour, and umami taste. Statistical analyses of Pearson's, Spearman's rank and polyserial correlation and multidimensional scaling (MDS) was performed. The EGM threshold for the average value of both CT regions and the recognition threshold of the whole mouth test were significantly correlated in sweet, salty, bitter, and sour taste (r = 0.244-0.398, P < 0.05), and the detection threshold was correlated only significant in sweet (r = 0.360, P = 0.007). In the MDS analysis results, the three-dimensional (D) solution was chosen over the 2-D solution because of the lower stress. Detection-, recognition threshold of whole mouth test and EGM thresholds of CT and GL area, those were standardized by Z-score, formed well-distinguished sections in the MDS analyses. The EGM threshold of the CT area was closer to the detection and recognition thresholds than the EGM threshold of the GL area. In general, the EGM threshold was closer to the recognition threshold than the detection threshold for each taste. Overall, visualization of the relationship of whole mouth test and EGM by MDS was in good agreement with quantitative analysis. EGM and whole mouth test seem to reflect different aspects of taste. However, when interpreting the EGM results, the EGM threshold of the CT area will show more similarity to the recognition threshold than the detection threshold for the whole mouth test.

Spatiotemporal dynamics of the development of mouse olfactory system from prenatal to postnatal period.

Introduction: The olfactory epithelium (OE) and olfactory bulb (OB) are the major components of the olfactory system and play critical roles in olfactory perception. However, the embryonic development of OE and OB by using the olfactory specific genes has not been comprehensively investigated yet. Most previous studies were limited to a specific embryonic stage, and very little is known, till date, about the development of OE. Methods: The current study aimed to explore the development of mouse olfactory system by spatiotemporal analysis of the histological features by using the olfactory specific genes of olfactory system from the prenatal to postnatal period. Results: We found that OE is divided into endo-turbinate, ecto-turbinate, and vomeronasal organs, and that putative OB with putative main and accessory OB is formed in the early developmental stage. The OE and OB became multilayered in the later developmental stages, accompanied by the differentiation of olfactory neurons. Remarkably, we found the development of layers of olfactory cilia and differentiation of OE to progress dramatically after birth, suggesting that the exposure to air may facilitate the final development of OE. Discussion: Overall, the present study laid the groundwork for a better understanding of the spatial and temporal developmental events of the olfactory system.

IL-4 drastically decreases deuterosomal and multiciliated cells via alteration in progenitor cell differentiation.

BACKGROUND: Allergic inflammation affects the epithelial cell populations resulting in goblet cell hyperplasia and decreased ciliated cells. Recent advances in single-cell RNA sequencing (scRNAseq) have enabled the identification of new cell subtypes and genomic features of single cells. In this study, we aimed to investigate the effect of allergic inflammation in nasal epithelial cell transcriptomes at the single-cell level. METHODS: We performed scRNAseq in cultured primary human nasal epithelial (HNE) cells and in vivo nasal epithelium. The transcriptomic features and epithelial cell subtypes were determined under IL-4 stimulation, and cell-specific marker genes and proteins were identified. RESULTS: We confirmed that cultured HNE cells were similar to in vivo epithelial cells through scRNAseq. Cell-specific marker genes were utilized to cluster the cell subtypes, and FOXJ1+ -ciliated cells were sub-classified into multiciliated and deuterosomal cells. PLK4 and CDC20B were specific for deuterosomal cells, and SNTN, CPASL, and GSTA2 were specific for multiciliated cells. IL-4 altered the proportions of cell subtypes, resulting in a decrease in multiciliated cells and loss of deuterosomal cells. The trajectory analysis revealed deuterosomal cells as precursor cells of multiciliated cells and deuterosomal cells function as a bridge between club and multiciliated cells. A decrease in deuterosomal cell marker genes was observed in nasal tissue samples with type 2 inflammation. CONCLUSION: The effects of IL-4 appear to be mediated through the loss of the deuterosomal population, resulting in the reduction in multiciliated cells. This study also newly suggests cell-specific markers that might be pivotal for investigating respiratory inflammatory diseases.

Calprotectin in chronic rhinosinusitis eosinophil extracellular traps.

BACKGROUND: Calprotectin is an antimicrobial peptide primarily secreted by neutrophils. Furthermore, calprotectin secretion increases in patients with chronic rhinosinusitis (CRS) with polyps (CRSwNP) and positively correlates with neutrophil markers. However, CRSwNP is known to be associated with type 2 inflammation related to tissue eosinophilia. Therefore, the authors investigated calprotectin expression in eosinophils and eosinophil extracellular traps (EETs) and explored the associations between tissue calprotectin and the clinical findings of patients with CRS. METHODS: A total of 63 patients participated, and patients diagnosed with CRS were classified based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score. The authors performed hematoxylin and eosin staining, immunohistochemistry, immunofluorescence with calprotectin, myeloperoxidase (MPO), major basic protein (MBP), and citrullinated histone H3 with the participant's tissues. Finally, correlations between calprotectin and the clinical data were examined. RESULTS: Calprotectin-positive cells are co-localized not only in MPO-positive cells but also in MBP-positive cells in human tissues. Calprotectin was also involved in EETs and neutrophil extracellular traps. The number of calprotectin-positive cells in the tissue was positively correlated with the number of tissue and blood eosinophils. In addition, calprotectin in the tissue is associated with the olfactory function, Lund-Mackay computed tomography score, and JESREC score. CONCLUSIONS: Calprotectin, known to be secreted by neutrophils, in CRS was also expressed in eosinophils. In addition, calprotectin, which functions as an antimicrobial peptide, may play an important role in the innate immune response based on its EET involvement. Therefore, calprotectin expression could reflect as a disease severity biomarker for CRS.

Clinical Practice Guideline: Clinical Efficacy of Nasal Surgery in the Treatment of Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is a common disorder characterized by upper airway obstruction during sleep. To reduce the morbidity of OSA, sleep specialists have explored various methods of managing the condition, including manifold positive airway pressure (PAP) techniques and surgical procedures. Nasal obstruction can cause significant discomfort during sleep, and it is likely that improving nasal obstruction would enhance the quality of life and PAP compliance of OSA patients. Many reliable studies have offered evidence to support this assumption. However, few comprehensive guidelines for managing OSA through nasal surgery encompass all this evidence. In order to address this gap, the Korean Society of Otorhinolaryngology-Head and Neck Surgery (KORL-HNS) and the Korean Society of Sleep and Breathing designated a guideline development group (GDG) to develop recommendations for nasal surgery in OSA patients. Several databases, including OVID Medline, Embase, the Cochrane Library, and KoreaMed, were searched to identify all relevant papers using a predefined search strategy. The types of nasal surgery included septoplasty, turbinate surgery, nasal valve surgery, septorhinoplasty, and endoscopic sinus surgery. When insufficient evidence was found, the GDG sought expert opinions and attempted to fill the evidence gap. Evidence-based recommendations for practice were ranked according to the American College of Physicians' grading system. The GDG developed 10 key action statements with supporting text to support them. Three statements are ranked as strong recommendations, three are only recommendations, and four can be considered options. The GDG hopes that this clinical practice guideline will help physicians make optimal decisions when caring for OSA patients. Conversely, the statements in this guideline are not intended to limit or restrict physicians' care based on their experience and assessment of individual patients.

Clinical Characteristics and Surgical Outcomes of Obstructive Sleep Apnea Patients With Mixed Apnea Components.

OBJECTIVE: This study was aimed to investigate clinical implications of mixed apnea (MA) in patients with obstructive sleep apnea (OSA), particularly whether surgical outcomes differ between OSA patients with and without MA events. STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary medical center. METHODS: Eighty-eight patients with OSA who underwent multilevel upper airway surgery were included. Patients were divided into 2 groups according to the presence of MA events: "pure group" (n = 30) and "mixed group" (n = 58). The clinical characteristics and surgical outcomes were compared between the 2 groups. RESULTS: The mixed group included more males (P = .020) and hypertensive patients (P = .009) and had a higher apnea-hypopnea index (AHI; P < .001) than the pure group. The surgical success rate was lower in the mixed group (29.3%) than in the pure group (73.3%; P < .001). Furthermore, the postoperative improvements in total AHI (P < .001), supine AHI (P < .001), and oxygen desaturation index (P = .006) were lower in the mixed group than in the pure group. Logistic regression analysis confirmed that the presence of MA (P = .002) was an independent predictor of poor surgical outcomes in patients with OSA. CONCLUSION: OSA patients with MA showed different clinical features and poor surgical outcomes compared to those without MA. These results imply that OSA with MA components may have a distinct pathophysiology, and the presence of MA should be considered in the surgical treatment of OSA.

Comparison of clinical features and surgical outcomes between hypopnea- and apnea-predominant obstructive sleep apnea.

OBJECTIVES: This study is aimed to investigate the differences in the clinical features and surgical outcomes between hypopnea- and apnea-predominant obstructive sleep apnea (OSA). DESIGN: Cohort study. SETTING: Single tertiary care centre. PARTICIPANTS: This study included 190 patients with OSA who underwent multilevel upper airway surgery between September 2012 and September 2021. The patients were divided into two groups according to the proportion of each respiratory event: hypopnea-predominant (n = 102) and apnea-predominant (n = 88). MAIN OUTCOME MEASURES: The primary outcome measure was the percentage improvement in the apnea-hypopnea index (AHI) from baseline AHI after surgery. RESULTS: The apnea-predominant group included more male patients and had higher AHI, respiratory disturbance index (RDI) and oxygen desaturation index (ODI) than the hypopnea-predominant group. Both groups showed significant improvements in AHI, apnea index, RDI, supine AHI, REM AHI, non-REM AHI, ODI, lowest O2 saturation and Epworth Sleepiness Scale scores following the surgery. Notably, hypopnea index increased after surgery in the apnea-predominant OSA group. Although the improvement in the absolute value of AHI by surgery was significantly greater in the apnea-predominant group than in the hypopnea-predominant group, the two groups showed no significant difference in the percentage improvement in AHI from baseline AHI. CONCLUSION: Patients with apnea-predominant OSA had more severe disease than those with hypopnea-predominant OSA; however, surgical outcomes, as evaluated by percentage AHI improvement, were comparable between the two groups. In addition, multilevel upper airway surgery may induce the transition from apnea to hypopnea in patients with apnea-predominant OSA.

Serum high-mobility group box 1 protein level correlates with the lowest SaO2 in patients with sleep apnea: a preliminary study / Nível sérico da proteína de alta mobilidade do grupo Box-1 está associado à SaO2 mais baixa em pacientes com apneia do sono: um estudo preliminar

Abstract Introduction: Serum level of high-mobility group box 1 protein is reportedly correlated with the severity of obstructive sleep apnea. Objective: We tried to evaluate the possibility of using the serum high-mobility group box 1 protein level as a biologic marker in obstructive sleep apnea patients. Methods: We generated a chronic intermittent hypoxia murine model that reflected human obstructive sleep apnea. Obstructive sleep apnea patients who underwent polysomnography were prospectively enrolled. Serum samples were obtained from mice and obstructive sleep apnea patients, and the serum high-mobility group box1 protein level was measured by enzyme-linked immunosorbent assay. Results: Serum high-mobility group box 1 protein level was 56.16 ± 30.33 ng/mL in chronic intermittent hypoxia and 18.63 ± 6.20 ng/mL in control mice (p<0.05). The mean apnea-hypopnea index and respiratory disturbance index values of enrolled obstructive sleep apnea patients were 50.35 ± 27.96 and 51.56 ± 28.53, respectively, and the mean serum high-mobility group box 1 protein level was 30.13 ± 19.97 ng/mL. The apnea-hypopnea index and respiratory disturbance index were not significantly correlated with the serum high-mobility group box 1 protein level (p>0.05). Instead, this protein level was significantly correlated with lowest arterial oxygen concentration (SaO2) (p<0.05). Conclusion: High-mobility group box 1 protein may be involved in the pathogenesis of obstructive sleep apnea, and the possibility of this protein being a useful biologic marker in obstructive sleep apnea should be further evaluated.

Resumo Introdução: O nível sérico da proteína de alta mobilidade do grupo Box-1 está relacionado com a gravidade da apneia obstrutiva do sono. Objetivo: Avaliar o uso do nível sérico da proteína de alta mobilidade do grupo Box-1 como um marcador biológico em pacientes com apneia obstrutiva do sono. Método: Geramos um modelo murino de hipóxia intermitente crônica que imita a apneia obstrutiva do sono em humanos. Pacientes com apneia obstrutiva do sono que fizeram polissonografia foram incluídos prospectivamente. Amostras de soro foram obtidas de camundongos e pacientes com apneia obstrutiva do sono e o nível sérico da proteína de alta mobilidade do grupo Box-1 foi medido por enzyme-linked immunosorbent assay. Resultados: O nível sérico da proteína de alta mobilidade do grupo Box-1 foi 56,16 ± 30,33 ng/mL em hipóxia intermitente crônica e 18,63 ± 6,20 ng/mL em camundongos controle (p < 0,05). Os valores médios do índice de apneia-hipopneia e do índice de distúrbio respiratório nos pacientes com apneia obstrutiva do sono foram 50,35 ± 27,96 e 51,56 ± 28,53, respectivamente, e o nível médio da proteína de alta mobilidade do grupo Box-1 foi 30,13 ± 19,97 ng/mL. O índice de apneia-hipopneia e o índice de distúrbio respiratório não foram significantemente associados com o nível da proteína de alta mobilidade do grupo Box-1 p> 0,05). Em vez disso, esse nível de proteína foi significantemente associado com o valor mais baixo da concentração arterial de oxigênio (SaO2) (p <0,05). Conclusão: A proteína de alta mobilidade do grupo Box-1 pode estar envolvida na patogênese da apneia obstrutiva do sono e a possibilidade de que essa proteína possa ser um marcador biológico útil na apneia obstrutiva do sono deve ser avaliada mais detalhadamente.

Cell-Type-Specific Expression of Hyaluronan Synthases HAS2 and HAS3 Promotes Goblet Cell Hyperplasia in Allergic Airway Inflammation.

Allergic rhinitis (AR) is a multifactorial airway disease characterized by basal and goblet cell hyperplasia. Hyaluronic acid (HA) is a major component of extracellular matrix and a critical contributor to tissue repair and remodeling after injury. We previously demonstrated that the intermediate progenitor cell (IPC) surface marker CD44v3 is upregulated in the basal and suprabasal layers of well-differentiated primary human nasal epithelial (HNE) cells after stimulation with the Th2 (T-helper cell type 2) cytokine IL-4, and an antibody blocking the CD44v3-HA interaction suppressed IL-4-induced goblet cell hyperplasia. We now show that the expression of HA and two HA synthases, HAS2 and HAS3, was upregulated in both the nasal surface epithelium of subjects with AR and IL-4-stimulated HNE cells. Inhibition of HA synthesis by 4-methylumbelliferone suppressed IL-4-induced goblet cell hyperplasia. Moreover, HAS2 and HAS3 were expressed in IPCs depending on the differentiation events, as follows: the rapid, transient upregulation of HAS2 induced basal IPC proliferation and basal-to-suprabasal transition, whereas the delayed upregulation of HAS3 promoted the transition of suprabasal IPCs to a goblet cell fate. 4-methylumbelliferone treatment in a house dust mite-induced murine AR model attenuated goblet cell metaplasia. Last, HA concentrations in nasal epithelial lining fluids from patients with AR positively correlated with the concentrations of mediators causing allergic inflammation. These data suggest that HA produced after the sequential upregulation of HAS2 and HAS3 contributes to goblet cell hyperplasia in allergic airway inflammation and modulates disease progression.

Is obstructive sleep apnea associated with erythrocytosis? A systematic review and meta-analysis.

Objective: The aim of this systematic review and meta-analysis was to investigate the association between obstructive sleep apnea (OSA) and erythrocytosis. Methods: The PubMed, Web of Science, and Cochrane Library databases were searched for articles examining hematocrit values in patients with OSA and control individuals published till September 1, 2021. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated, and subgroup analyses were performed. Results: Eleven eligible studies with a total of 4608 patients with OSA were included in this meta-analysis. Pooled outcomes revealed that hematocrit values were significantly higher in patients with OSA than in controls (SMD, 0.19; 95% CI, 0.08-0.29; p < .01). When studies were stratified by disease severity, the significant differences in hematocrit values between patients and controls were only observed in the severe OSA group (SMD, 0.34; 95% CI, 0.08-0.59; p < .01), but not in the mild and moderate OSA groups. In subgroup analyses according to sex and publication year, significant differences in hematocrit values between patients and controls remained stable in studies with only female patients (SMD, 0.25; 95% CI, 0.12-0.38; p < .01) and in studies published after 2012 (SMD, 0.17; 95% CI, 0.06-0.28, p < .01). Conclusion: Our meta-analysis revealed that the hematocrit value was significantly increased in patients with OSA, particularly in severe patients, compared with that in controls. However, the elevation was modest, and the hematocrit value is expected to be within the normal range in patients with OSA. These data suggest that OSA leads to slight increases in hematocrit but does not cause clinically significant erythrocytosis.

Improvement in obstructive sleep apnea in a child with Down syndrome with rapid palatal expansion.

Children with Down syndrome (DS) have distinct orofacial structures that predispose them to sleep-disordered breathing. The management options for obstructive sleep apnea include continuous positive airway pressure, adenotonsillectomy, mandibular advancement, and maxillary expansion. However, most of these treatment options are less effective or less viable for children with DS. Rapid maxillary expansion with a fixed orthodontic appliance is a viable alternative for DS patients because it separates the midpalatal suture and dilates the airway, regardless of the patient's compliance. We present a case of a 15-year-old boy with DS and severe obstructive sleep apnea, which dramatically improved with rapid maxillary expansion and subsequent orthodontic treatment. Although only the short-term changes have been presented in this report, this case emphasizes the need for further discussions on the viability of rapid maxillary expansion for treating obstructive sleep apnea in children with DS. CITATION: Kim A, Cho HJ, Choi EK, Choi YJ. Improvement in obstructive sleep apnea in a child with Down syndrome with rapid palatal expansion. J Clin Sleep Med. 2022;18(7):1885-1888.