Numerical and experimental evaluation of nasopharyngeal aerosol administration methods in children with adenoid hypertrophy.

Administering aerosol drugs through the nasal pathway is a common early treatment for children with adenoid hypertrophy (AH). To enhance therapeutic efficacy, a deeper understanding of nasal drug delivery in the nasopharynx is essential. This study uses an integrated experimental, numerical modelling approach to investigate the delivery process of both the aerosol mask delivery system (MDS) and the bi-directional delivery system (BDS) in the pediatric nasal airway with AH. The combined effect of respiratory flow rates and particle size on delivery efficiency was systematically analyzed. The results showed that the nasopharyngeal peak deposition efficiency (DE) for BDS was approximately 2.25-3.73 times higher than that for MDS under low-flow, resting and high-flow respiratory conditions. Overall nasopharyngeal DEs for MDS were at a low level of below 16 %. For each respiratory flow rate, the BDS tended to achieve higher peak DEs (36.36 % vs 9.74 %, 37.80 % vs 14.01 %, 34.58 % vs 15.35 %) at smaller particle sizes (15 µm vs 17 µm, 10 µm vs 14 µm, 6 µm vs 9 µm). An optimal particle size exists for each respiratory flow rate, maximizing the drug delivery efficiency to the nasopharynx. The BDS is more effective in delivering drug aerosols to the nasal cavity and nasopharynx, which is crucial for early intervention in children with AH.

Numerical investigation of nanoparticle deposition in the olfactory region among pediatric nasal airways with adenoid hypertrophy.

To understand inhaled nanoparticle transport and deposition characteristics in pediatric nasal airways with adenoid hypertrophy (AH), with a specific emphasis on the olfactory region, virtual nanoparticle inhalation studies were conducted on anatomically accurate child nasal airway models. The computational fluid-particle dynamics (CFPD) method was employed, and numerical simulations were performed to compare the airflow and nanoparticle deposition patterns between nasal airways with nasopharyngeal obstruction before adenoidectomy and healthy nasal airways after virtual adenoidectomy. The influence of different inhalation rates and exhalation phase on olfactory regional nanoparticle deposition features was systematically analyzed. We found that nasopharyngeal obstruction resulted in significant uneven airflow distribution in the nasal cavity. The deposited nanoparticles were concentrated in the middle meatus, septum, inferior meatus and nasal vestibule. The deposition efficiency (DE) in the olfactory region decreases with increasing nanoparticle size (1-10 nm) during inhalation. After adenoidectomy, the pediatric olfactory region DE increased significantly while nasopharynx DE dramatically decreased. When the inhalation rate decreased, the deposition pattern in the olfactory region significantly altered, exhibiting an initial rise followed by a subsequent decline, reaching peak deposition at 2 nm. During exhalation, the pediatric olfactory region DE was substantially lower than during inhalation, and the olfactory region DE in the pre-operative models were found to be significantly higher than that of the post-operative models. In conclusions, ventilation and particle deposition in the olfactory region were significantly improved in post-operative models. Inhalation rate and exhalation process can significantly affect nanoparticle deposition in the olfactory region.

[Effect of nasal swell body on nasal airflow and Artemisia pollen deposition].

Objective:The nasal swell body（NSB） consists of the nasal septal cartilage, nasal bone, and swollen soft tissue, all of which are visible during endoscopic and imaging examinations. Although the function of the NSB remains uncertain, there is evidence to suggest that it plays a vital role in regulating nasal airflow and filtering inhaled air. Based on anatomical and histological evidence, it is hypothesized that the NSB is indispensable in these processes. This study aims to investigate the impact of NSB on nasal aerodynamics and the deposition of allergen particles under physiological conditions. Methods:The three-dimensional （3D） nasal models were reconstructed from computed tomography （CT） scans of the paranasal sinus and nasal cavity in 30 healthy adult volunteers from Northwest China, providing basis for the construction of models without NSB following virtual NSB-removal surgery. To analyze the distribution of airflow in the nasal cavity, nasal resistance, heating and humidification efficiency, and pollen particle deposition rate at various anatomical sites, we employed the computed fluid dynamics（CFD） method for numerical simulation and quantitative analysis. In addition, we created fully transparent segmented nasal cavity models through 3D printing, which were used to conduct bionic experiments to measure nasal resistance and allergen particle deposition. Results:①The average width and length of the NSB in healthy adults in Northwest China were （12.85±1.74） mm and （28.30±1.92） mm, respectively. ②After NSB removal, there was no significant change in total nasal resistance, and cross-sectional airflow velocity remained essentially unaltered except for a decrease in topical airflow velocity in the NSB plane. ③There was no discernible difference in the nasal heating and humidification function following the removal of the NSB; ④After NSB removal, the deposition fraction（DF） of Artemisia pollen in the nasal septum decreased, and the DFs post-and pre-NSB removal were（22.79±6.61）% vs （30.70±12.27）%, respectively; the DF in the lower airway increased, and the DFs post-and pre-NSB removal were（24.12±6.59）% vs （17.00±5.57）%, respectively. Conclusion:This study is the first to explore the effects of NSB on nasal airflow, heating and humidification, and allergen particle deposition in a healthy population. After NSB removal from the healthy nasal cavities: ①nasal airflow distribution was mildly altered while nasal resistance showed no significantly changed; ②nasal heating and humidification were not significantly changed; ③the nasal septum's ability to filter out Artemisia pollen was diminished, which could lead to increased deposition of Artemisia pollen in the lower airway.

Effect of different degrees of adenoid hypertrophy on pediatric upper airway aerodynamics: a computational fluid dynamics study.

To improve the diagnostic accuracy of adenoid hypertrophy (AH) in children and prevent further complications in time, it is important to study and quantify the effects of different degrees of AH on pediatric upper airway (UA) aerodynamics. In this study, based on computed tomography (CT) scans of a child with AH, UA models with different degrees of obstruction (adenoidal-nasopharyngeal (AN) ratio of 0.9, 0.8, 0.7, and 0.6) and no obstruction (AN ratio of 0.5) were constructed through virtual surgery to quantitatively analyze the aerodynamic characteristics of UA with different degrees of obstruction in terms of the peak velocity, pressure drop (△P), and maximum wall shear stress (WSS). We found that two obvious whirlpools are formed in the anterior upper part of the pediatric nasal cavity and in the oropharynx, which is caused by the sudden increase in the nasal cross-section area, resulting in local flow separation and counterflow. In addition, when the AN ratio was ≥ 0.7, the airflow velocity peaked at the protruding area in the nasopharynx, with an increase 1.1-2.7 times greater than that in the nasal valve area; the △P in the nasopharynx was significantly increased, with an increase 1.1-6.8 times greater than that in the nasal cavity; and the maximum WSS of the posterior wall of the nasopharynx was 1.1-4.4 times larger than that of the nasal cavity. The results showed that the size of the adenoid plays an important role in the patency of the pediatric UA.

Melatonin reduces IL-33 and TSLP expression in human nasal epithelial cells by scavenging ROS directly.

BACKGROUND: Chronic rhinosinusitis (CRS) is a chronic mucosal inflammation of the nasal cavity and sinuses. It is classified into CRS without nasal polyps and CRS with nasal polyps (CRSwNP). CRSwNP has high recurrence, especially CRSwNP with massive eosinophil infiltration which is mediated by type 2 inflammatory response. Melatonin is a hormone secreted by the pineal gland, it has powerful antioxidant and anti-inflammatory effects in addition to regulating biological rhythms. There are no studies on melatonin for the treatment of CRS, so we aimed to explore whether melatonin could be used for the treatment of CRS. MATERIALS AND METHODS: In this study, we used melatonin to treat a cell model of CRS. Subsequently, MTT assay was performed to examine the cell viability of human nasal epithelial cells (HNEpCs), a reactive oxygen species (ROS) kit to detect ROS production, a malondialdehyde (MDA) kit to detect the MDA content in the cell culture supernatant, and an apoptosis kit and Western blot analysis to detect apoptosis. The expressions of Nrf2, HO-1, IL-33, TSLP, and IL-25 were detected by Western blot analysis. RESULTS: Melatonin improved the viability of HNEpCs, reduced lipopolysaccharide-induced ROS, reduced the MDA content, and inhibited their apoptosis. More importantly, melatonin reduced the expression of IL-33 and TSLP, an important phenomenon for the treatment of CRSwNP. CONCLUSION: Melatonin protects HNEpCs from damage in inflammation and reduces IL-33 and TSLP expression of HNEpCs.

HO-1: a new marker for predicting postoperative recurrence of CRSwNP.

BACKGROUND: Chronic rhinosinusitis with polyps (CRSwNP) is a subtype of chronic rhinosinusitis and is highly prone to recurrence; therefore, it is urgent to find appropriate markers to predict recurrence of CRSwNP after surgery. PURPOSE: We aim to investigate the expression of HO-1 in CRSwNP and assess its value of predicting postoperative recurrence of CRSwNP. METHODS: We recruited 77 participants and collected clinical data of all. We use Immunohistochemical staining to determine the expression of HO-1 in tissues. We use Spearman correlation test to analyze the correlation between HO-1 positive cell count and clinical score, and ROC curve to assess the value of HO-1 positive cell count in predicting recurrence of CRSwNP. RESULTS: HO-1 positive cells were macrophages and significantly increased in CRSwNP; HO-1 positive cell count was negatively correlated with preoperative SNOT-22 score; HO-1 can predict postoperative recurrence of CRSwNP, AUC = 0.80, p = 0.004. CONCLUSION: HO-1 is a biochemical marker of CRSwNP and can predict postoperative recurrence of CRSwNP.

Transplantation of olfactory ensheathing cells decreases local and serological monocyte chemoattractant protein 1 level during the acute phase of rat spinal cord injury.

OBJECTIVES: Monocyte chemoattractant protein 1 (MCP1) is one of the most upregulated cytokines in the spinal cord and serum throughout acute spinal cord injury (SCI). Olfactory ensheathing cells (OECs) transplantation improves SCI through multiple mechanisms, including immunomodulation. Our study aimed to investigate whether OECs ameliorate acute inflammation after SCI by modulating MCP1 expression. METHODS: We established a standardized clinically relevant contusion model using the NYU impactor. OECs were administered to the injured spinal cord via microinjection 30 minutes after injury. Rat locomotor functions were assessed by the Basso-Beattie-Bresnahan scale score. Time-course histopathological (H&E and IHC) analyses were performed to record rapid changes in acute inflammation at lesion epicenters. Serum MCP1 level was detected by ELISA assay. RESULTS: BBB scores showed improved locomotor functional recoveries in the OECs transplantation group after SCI ( P < 0.05). Staining of H&E and CD68 illustrated that OECs transplantation attenuated inflammatory response by reducing lesion areas and infiltrating myeloid cell numbers. We further revealed significantly decreased MCP1 levels in the spinal cord and serum after OECs transplantation ( P < 0.05). Noteworthily, distinct expression levels of MCP1 were found in rats undergoing a mild injury (cord impacted from a 10-mm height) compared to the moderate injury (25-mm) group. CONCLUSION: Our study reports that transplantation of OECs promotes locomotor functional recovery after SCI and alleviates acute inflammation by decreasing local and serological MCP1 levels. We provide preliminary evidence that MCP1 might serve as a potential biomarker to reflect the severity of SCI, which is of great interest in future studies.

C-reactive protein inhibits C3a/C3aR-dependent podocyte autophagy in favor of diabetic kidney disease.

Numerous studies have reported the pathogenic roles of C-reactive protein (CRP) and complement activation in diabetic kidney disease (DKD) individually. However, considering the potent regulatory effect of CRP on complement activation, it remains unclear whether CRP participates in DKD pathogenesis by regulating complement activation. Moreover, this work focuses on complement activation in rats, which aims at settling the dispute that whether rat CRP can activate the complement system. To address this question, the complement effectors C3a, C5a, and C5b-9 were examined in human patients with diabetic nephropathy (DN) and wt, Crp-/- , and huCRPtg rats with STZ-diabetic DKD. The Crp-/- rats showed more C3a accumulation in blood and glomeruli than wt and huCRPtg rats. The balance between autophagy and apoptosis was evaluated in DKD rats, and Crp-/- rats showed increased podocyte autophagy compared with wt and huCRPtg rats. Meanwhile, stable CRP-overexpression and CRP-knockout cell lines were established and used to demonstrate that CRP suppresses C3a-induced podocyte autophagy under high-glucose conditions. We further verified that the inhibition of C3a-induced podocyte autophagy by CRP was dependent on C3aR expression and that this effect could be reversed with a C3aR antagonist and agonist. Therefore, our findings provide evidence that CRP suppresses podocyte autophagy to accelerate the development of DKD by inhibiting C3a/C3aR axis signaling, which may help in the development of a new therapeutic strategy for the management of podocyte autophagy and DKD. In addition, rat CRP has been shown to be identical to human CRP in the activation of autologous complement and interspecific complement.

Timing of Splenectomy after Acute Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating condition. Splenectomy may play a protective role in the development of SCI. However, little is known about whether the timing of splenectomy affects the outcome after SCI. Investigation into splenectomy after SCI would provide insight into how the timing can be selected following SCI to improve neurologic outcomes. Rats were randomized into a sham group, a nonsplenectomized group (NonSPX), four splenectomized groups with the surgery performed immediately, 6 h, 12 h, and 24 h after SCI (SPX0, SPX6, SPX12, and SPX24, respectively). Rats were subjected to severe contusive SCI at the level of the third thoracic vertebra. At different time points following SCI, Basso, Beattie, and Bresnahan (BBB) score was used to assess the recovery of injury. The animals in each group were randomly selected for tissue collection at days 3, 14, and 28 after surgery. Then, immunohistochemistry of immunologic cells was performed and inflammatory mediators were determined. Our study showed that splenectomy within 6 h after SCI improved BBB scores as compared with splenectomy more than 12 h after SCI, and decrease the immune cell responses to SCI. Protein levels of interleukin (IL)-1ß and tumor necrosis factor (TNF)-α were significantly elevated in nonsplenectomized group compared with sham group. No difference was observed in IL-10 at the lesion site between splenectomized and nonsplenectomized groups at 3 d post-SCI. The study demonstrates that splenectomy within 6 h after SCI would lessen the development of SCI and improve outcome.

Evaluation of nasal function after endoscopic endonasal surgery for pituitary adenoma: a computational fluid dynamics study.

OBJECTIVE: To analyze the effect of different endoscopic endonasal approaches (EEAs) on nasal airflow and heating and humidification in patients with pituitary adenoma (PA) by computational fluid dynamics (CFD). METHODS: A three-dimensional pre-surgical model (Pre) of the nasal cavity and 6 that were post-EEA surgery were created from computed tomography scans as follows: small posterior septectomy (0.5 cm, sPS), middle posterior septectomy (1.5 cm, mPS), large posterior septectomy (2.5 cm, lPS), and sPS with middle turbinate resection (sPS-MTR), mPS-MTR, and lPS-MTR. Simulations were performed by CFD to compare the changes in different models. RESULTS: The temperature in the nasal vestibule rose more rapidly than in other parts of the nasal cavities in all models. There were no apparent differences in temperature and humidity among the models in sections anterior to the middle turbinate head (C6 section). MTR significantly influenced airflow distribution between the bilateral nasal cavities and the different parts of the nasal cavity, while changes in temperature and humidity in each section were mainly affected by MTR. The temperature and humidity of the choana and nasopharynx of each postoperative model were significantly different from those of the preoperative model and the change in values significantly correlated with the surface-to-volume ratio (SVR) of the airway. CONCLUSIONS: Changes due to the different nasal structures caused different effects on nasal function following the use of EEA surgery for the treatment of PA. CFD provided a new approach to assess nasal function, promising to provide patients with individualized preoperative functional assessment and surgical planning.

Schizandrin A induces the apoptosis and suppresses the proliferation, invasion and migration of gastric cancer cells by activating endoplasmic reticulum stress.

Apart from its basic antioxidant and anti­inflammatory properties, schizandrin A (SchA), which is isolated from Fructus schisandra, can exert anticancer effects on multiple cancer types. However, to the best of our knowledge, there has been no study identifying the impacts of SchA on gastric cancer (GC). Therefore, the aim of the present study was to identify how SchA functioned to affect the progression of GC. To investigate the role of SchA in GC development, Cell Counting Kit­8, colony formation, wound healing and Transwell assays were conducted to assess the viability, proliferation, migration and invasion of AGS cells, respectively. Then, the apoptosis rate and apoptosis­ and endoplasmic reticulum (ER) stress­related protein expression levels in AGS cells exposed to SchA were detected via TUNEL assays and western blotting, respectively. Subsequently, the aforementioned functional assays were performed again in AGS cells exposed to both SchA and the ER stress inhibitor 4­phenylbutyric acid (4­PBA) for the confirmation of the effect of SchA on ER stress in GC. It was found that SchA markedly decreased the viability, proliferation, migration and invasion, while it induced the apoptosis of AGS cells. Moreover, the markers of ER stress were elevated by SchA treatment in AGS cells. Nevertheless, 4­PBA reversed the effects of SchA on the viability, proliferation, migration, invasion and apoptosis of AGS cells, accompanied by decreased expression of ER stress markers. In conclusion, the present study demonstrated that SchA induced the apoptosis and suppressed the proliferation, invasion and migration of GC cells by activating ER stress, which provides a theoretical basis for the use of SchA in the treatment of GC.

Numerical Simulation of Nasal Airflow Aerodynamics, and Warming and Humidification in Models of Clival Chordoma Pre and Post-Endoscopic Endonasal Surgery.

OBJECTIVES: To study the effect of endoscopic endonasal surgery on nasal function for the treatment of clival chordoma. METHODS: Pre and post-operative computed tomography (CT) scans of a case of chordoma treated with an endoscopic endonasal approach (EEA) were collected retrospectively, and models of the nasal cavity were reconstructed so that a subsequent numerical simulation of nasal airflow characteristics, warming, and humidification could be conducted. RESULTS: Middle turbinectomy resulted in redistribution of airflow within the nasal cavity, and the most significant changes occurred in the middle section. Consistent with the results of airflow evaluation, it was found that the change in nasal anatomical structure significantly reduced warming and humidification. Nasal humidification decreased substantially when postoperative loss of mucosa was taken into consideration. The H2O mass fraction of pharynx in inspiration phase were significantly correlated with airway surface-to-volume ratio (SVR). CONCLUSIONS: The EEA for chordoma significantly affected nasal function. Attention should be paid to the protection of nasal structure and the associated mucosa.

C-Reactive Protein Suppresses the Th17 Response Indirectly by Attenuating the Antigen Presentation Ability of Monocyte Derived Dendritic Cells in Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a classical murine model for Multiple Sclerosis (MS), a human autoimmune disease characterized by Th1 and Th17 responses. Numerous studies have reported that C-reactive protein (CRP) mitigates EAE severity, but studies on the relevant pathologic mechanisms are insufficient. Our previous study found that CRP suppresses Th1 response directly by receptor binding on naïve T cells; however, we did not observe the effect on Th17 response at that time; thus it remains unclear whether CRP could regulate Th17 response. In this study, we verified the downregulation of Th17 response by a single-dose CRP injection in MOG-immunized EAE mice in vivo while the direct and indirect effects of CRP on Th17 response were differentiated by comparing its actions on isolated CD4+ T cells and splenocytes in vitro, respectively. Moreover, the immune cell composition was examined in the blood and CNS (Central Nervous System), and a blood (monocytes) to CNS (dendritic cells) infiltration pathway is established in the course of EAE development. The infiltrated monocyte derived DCs (moDCs) were proved to be the only candidate antigen presenting cells to execute CRP's function. Conversely, the decrease of Th17 responses caused by CRP disappeared in the above in vivo and in vitro studies with FcγR2B-/- mice, indicating that FcγR2B expressed on moDCs mediates CRP function. Furthermore, peripheral blood monocytes were isolated and induced to establish moDCs, which were used to demonstrate that the antigen presenting ability of moDCs was attenuated by CRP through FcγR2B, and then NF-κB and ERK signaling pathways were manifested to be involved in this regulation. Ultimately, we perfected and enriched the mechanism studies of CRP in EAE remission, so we are more convinced that CRP plays a key role in protecting against EAE development, which may be a potential therapeutic target for the treatment of MS in human.

Safety and efficacy of remote ischemic postconditioning after thrombolysis in patients with stroke.

OBJECTIVE: To determine the effect of remote ischemic postconditioning (RIPC) on patients with acute ischemic stroke (AIS) undergoing IV thrombolysis (IVT). METHODS: A single-center randomized controlled trial was performed with patients with AIS receiving IVT. Patients in the RIPC group were administered RIPC treatment (after IVT) during hospitalization. The primary endpoint was a score of 0 or 1 on the modified Rankin scale (mRS) at day 90. The safety, tolerability, and neuroprotection biomarkers associated with RIPC were also evaluated. RESULTS: We collected data from both the RIPC group (n = 34) and the control group (n = 34). The average duration of hospitalization was 11.2 days. There was no significant difference between 2 groups at admission for the NIH Stroke Scale score (p = 0.364) or occur-to-treatment time (p = 0.889). Favorable recovery (mRS score 0-1) at 3 months was obtained in 71.9% of patients in the RIPC group vs 50.0% in the control group (adjusted odds ratio 9.85, 95% confidence interval 1.54-63.16; p = 0.016). We further found significantly lower plasma S100-ß (p = 0.007) and higher vascular endothelial growth factor (p = 0.003) levels in the RIPC group than in the control group. CONCLUSIONS: Repeated RIPC combined with IVT can significantly facilitate recovery of nerve function and improve clinical prognosis of patients with AIS. CLINICALTRIALSGOV IDENTIFIER: NCT03218293. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that RIPC after tissue plasminogen activator treatment of AIS significantly increases the proportion of patients with an MRS score of 0 or 1 at 90 days.

Correlation between elevated inflammatory cytokines of spleen and spleen index in acute spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a devastating disorder. After SCI, it initiates a robust immune response. Considering the spleen is one of the most important immune organs, the present study further characterizes the inflammatory cytokine profile of spleen in acute SCI. METHODS: Adult rats were divided into sham and SCI groups (n = 36). SCI was produced at the T3 vertebral level. The whole blood and spleen was collected at 6, 24, 48, 72, 120, and 168 h after SCI. The levels of the inflammatory factors (IL-1ß, IL-6, IL-10, TNF-α, and TGF-ß) in spleen and serum were measured with an ELISA kit. RESULTS: The results showed significantly elevated levels of IL-1ß, IL-6, IL-10 and TNF-α in spleen compared with control group levels. Inflammatory cytokine levels of spleen correlated negatively with spleen index. CONCLUSION: It was found that inflammatory cytokines in spleen showed dynamic responses to SCI, which suggest their specificity change of spleen caused by SCI. These results suggest that a possible involvement of spleen in the initiation of the inflammatory response after SCI.

Cellular Inflammatory Response of the Spleen After Acute Spinal Cord Injury in Rat.

Spinal cord injury (SCI) involves both primary and secondary damages. After the phase of primary injury, a series of inflammatory responses initiate, which belong to the secondary injury. There has been little investigation into the cellular inflammatory response of the spleen to SCI. To disclose the impact of SCI on the spleen, we examined the inflammatory reactions of the spleen during the acute phase of SCI in rat. Adult rats were used as experimental animals and divided into un-injured, sham, and SCI groups (n = 36). Contusion injuries were produced at the T3 vertebral level. Spinal cords were harvested 6 h, 24 h, 48 h, 72 h, 120 h, and 168 h after surgery and were prepared for immunohistochemistry. Spleen wet weight was measured. Blood and spleens were prepared for quantitative analyses. The spleen index was significantly decreased in the SCI groups. Immunohistochemical results showed an increase of the infiltrating cells in the spinal cord tissues from SCI rats at all time points, peaking in 72 h post injury. In the blood, T and B lymphocytes significantly decreased in the SCI group as compared with the sham group, while monocyte increased. Surprisingly, in the SCI group, neutrophil initially decreased and subsequently tended to return toward baseline levels, then remained elevated until the end of the study. Spleen analyses revealed a significant increase in monocyte and neutrophil but a minor (not statistically significant) reduction in T and B lymphocytes. Our data show that the four most prevalent inflammatory cells infiltrate the spinal cord after injury. Increased levels of inflammatory cells (monocyte and neutrophil) in the blood and spleen appear to be very sensitive to SCI. The spleen plays a critical role in the acute phase of SCI.