Comparative study of nasal cavity drug delivery efficiency with different nozzles in a 3D printed model.

Background: Nasal sprays are widely used in treating nasal and sinus diseases; however, there are very few studies on the drug delivery efficiency of nasal sprays. In this study, the drug delivery efficiency of three different nasal spray devices was evaluated in vitro using a 3D printed cast model of nasal cavity. Methods: Three nasal spray devices with different nozzles and angles of administration were used in the 3D model of the nasal cavity and paranasal sinuses. The spraying area (SA), maximal spraying distance (MSD), and spraying distribution scores on the nasal septum and lateral nasal wall were recorded. Results: Different nasal spray devices have their own characteristics, including volume of each spray, SA, and plume angle. The SA of the three nozzles on the nasal septum increased with an increasing angle of administration. When the angle of administration was 50°, each nozzle reached the maximal SA. There was no statistically significant difference in MSD among the three nozzles at the three angles. The total scores for each nozzle using the three different spraying angles were as follows: nozzle A, 40° > 30° > 50°; nozzle B, 30° > 40° > 50°; and nozzle C, 30° > 40° > 50°. The total scores for different nozzles using the same angle were statistically significantly different and the scores for nozzle C were the highest. Nozzle C had the minimum plume angle. None of the three nozzles could effectively delivered drugs into the middle meatus at any angle in this model. Conclusions: The design of the nozzle affects drug delivery efficiency of nasal spray devices. The ideal angle of administration is 50°. The nozzle with smaller plume angle has higher drug delivery efficiency. Current nasal spray devices can easily deliver drugs to most areas of the nasal cavity, such as the turbinate, nasal septum, olfactory fissure, and nasopharynx, but not the middle meatus. These findings are meaningful for nozzle selection and device improvements.

Effect of recombinant human acidic fibroblast growth factor on nasal mucosal healing after endoscopic sinus surgery.

BACKGROUND: Postoperative nasal treatment is an important factor affecting the outcomes of endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS). This study aimed to determine the effect of recombinant human acidic fibroblast growth factor (rh-aFGF) on nasal mucosal healing after ESS. METHODS: This study is a prospective, single-blind, and randomized controlled clinical study. Fifty-eight CRS patients with nasal polyps (CRSwNP) with bilateral ESS were enrolled and randomly given 1 mL of budesonide nasal spray and 2 mL of rh-aFGF solution (rh-aFGF group) or 1 mL of budesonide nasal spray and 2 mL of rh-aFGF solvent (budesonide group)-infiltrated Nasopore nasal packing after ESS. Preoperative and postoperative scores for Sino-Nasal Outcome Test (SNOT-22), Visual Analogue Scale (VAS), and Lund-Kennedy were collected and analyzed. RESULTS: Forty-two patients completed the 12-week follow-up. Postoperative SNOT-22 scores and VAS scores showed no significant differences between the two groups. In terms of the Lund-Kennedy scores, there was a statistically significant difference between the two groups at the 2-, 4-, 8-, and 12-week postoperative visits, but not at the 1-week visit. Twelve weeks after surgery, the nasal mucosa had completely epithelialized in 18 patients in the rh-aFGF group and in 12 patients in the budesonide group (χ2 = 4.200, P = 0.040). CONCLUSION: The combined application of rh-aFGF and budesonide significantly improved postoperative endoscopic appearance in the nasal mucosal healing process.

Plasma oncology: Adjuvant therapy for head and neck cancer using cold atmospheric plasma.

The worldwide incidence of head and neck cancer (HNC) exceeds half a million cases annually, and up to half of the patients with HNC present with advanced disease. Surgical resection remains the mainstay of treatment for many HNCs, although radiation therapy, chemotherapy, targeted therapy, and immunotherapy might contribute to individual patient's treatment plan. Irrespective of which modality is chosen, disease prognosis remains suboptimal, especially for higher staging tumors. Cold atmospheric plasma (CAP) has recently demonstrated a substantial anti-tumor effect. After a thorough literature search, we provide a comprehensive review depicting the oncological potential of CAP in HNC treatment. We discovered that CAP applies to almost all categories of HNC, including upper aerodigestive tract cancers, head and neck glandular cancers and skin cancers. In addition, CAP is truly versatile, as it can be applied not only directly for superficial or luminal tumors but also indirectly for deep solid organ tumors. Most importantly, CAP can work collaboratively with existing clinical oncotherapies with synergistic effect. After our attempts to elaborate the conceivable molecular mechanism of CAP's anti-neoplastic effect for HNC, we provide a brief synopsis of recent clinical and preclinical trials emphasizing CAP's applicability in head and neck oncology. In conclusion, we have enunciated our vision of plasma oncology using CAP for near future HNC treatment.

GWAS-identified variants to allergic disease and early environmental exposure in Chinese schoolchildren with allergic rhinitis induced by house dust mite.

BACKGROUND: There is growing evidence that environmental exposure in early life is associated with the development of childhood allergic rhinitis. OBJECTIVE: To investigate whether polymorphisms in previously published genome wide association studies (GWAS) allergic disease loci are associated with childhood house dust mite-induced allergic rhinitis (HDM-AR) and interaction effects of genetic and environmental factors on it. METHODS: 156 cases diagnosed by HDM-AR and 173 controls were enrolled. Potential confounders were analyzed by using Logistic regression. Twenty-one single nucleotide polymorphisms (SNPs) of GWAS-related allergic diseases including EMSY-LRRC32, IL18R1, IL18RAP, IL13, IL4, HLA region, KIF3A were genopyped and analyzed using the improved multiplex ligation detection reaction (imLDR) technique in all the subjects. RESULTS: Only IL18R1_rs2287037 was associated with HDM-AR in children. After adjusting for several likely confounders, the protective TT genotype of IL18R1_rs2287037 was found in the population analyzed with the fittest recessive model. (adjusted odds ratio [aOR]: 0.44; 95% confidence interval [CI]: 0.21-0.95). The rs2287037_ TT might interact with early-life exclusive breastfeeding in the first 4 months (aOR: 0.33; 95%CI: 014-0.97) or full-term birth (aOR: 0.45; 95%CI: 0.19-0.95) exposure to decrease the risk of HDM-AR. CONCLUSIONS: These data suggest that IL18R1 polymorphism may play a role in controlling risk to HDM-AR and underline the importance of early environmental exposure into studies of genetic risk factors.

Multimodal treatment combining cold atmospheric plasma and acidic fibroblast growth factor for multi-tissue regeneration.

Cold atmospheric plasma (CAP) is an emerging technology for biomedical applications, exemplified by its antimicrobial and antineoplastic potentials. On the contrary, acidic fibroblast growth factor (aFGF) has been a long-standing potent mitogen for cells from various origins. In this study, we are the first to develop a multimodal treatment combining the aforementioned physicochemical and pharmacological treatments and investigated their individual and combined effects on wound healing, angiogenesis, neurogenesis, and osteogenesis. This work was performed at the tissue, cellular, protein, and gene levels, using histochemical staining, flow cytometry, ELISA, and PCR, respectively. Depending on the type of target tissue, various combinations of aforementioned methods were used. The results showed that the enhancement on would healing and angiogenesis by CAP and aFGF were synergistic. The former was manifested by increased murine fibroblast proliferation and reduced cutaneous tissue inflammation, whereas the latter by upregulated proangiogenic markers in vivo, for example, CD31, VEGF, and TGF-ß, and downregulated antiangiogenic proteins in vitro, for example, angiostatin and angiopoietin-2, respectively. In addition, aFGF outperformed CAP during neurogenesis, which was evidenced by superior neurite outgrowth, while CAP exceeded aFGF in osteogenesis which was demonstrated by more substantial bone nodule formation. These novel findings not only support the fact that CAP and aFGF are both multipotent agents during tissue regeneration, but also highlight the potential of our multimodal treatment combining the individual advantages of CAP and aFGF. The versatile administration route, that is, topical and/or systemic, might further broaden its applications.

[Role of gut microbiota in children with allergic rhinitis with high serum total IgE level].

Objective:To study the role of gut microbiota in children with allergic rhinitis with high serum total IgE level. Method:A total of 17 cases of children in Shanghai Children's Medical Center of Shanghai Jiao Tong University School of Medicine, who suffered from perennial allergic rhinitis of grade 5-6, were enrolled in this study. Baseline information were collected from all participants. Peripheral blood was collected to test the level of serum total IgE and specific IgE. Fecal samples were collected for bacterial DNA extraction and sequenced by 16S rDNA high-throughput sequencing. R, Mother and LEfSe softwares were used for diversity analysis, relative abundance calculation and differential species detection. Result:Twenty-three fecal samples were collected in total, including thirteen in attack period（attack group） and ten in control period（control group）. In the attack group, six cases were serum total IgE positive（positive group） and seven were negative（negative group）. Compared with the control group, there was no significant difference in either Alpha diversity or Beta diversity of Weighted Unifrac in the attack group（P>0.05）. The relative abundance of odoribacteraceae and odoribacter were significantly increased in the attack group（LDA score>2）. The relative abundance of Porphyromonadaceae in positive group were significantly lower than that in negative group, while family Dethiosulfovibrionaceae genus Pyramidobacter was definitely higher on the contrast（LDA score>2）. Conclusion:Children with allergic rhinitis have different characteristics of intestinal flora during the attack and control period. Gut microbiota is associated with high serum total IgE level in children with allergic rhinitis. Specific microbial alterations play a potential role in disease pathophysiology.

Efficacy of Chinese Medicine Acupoint Application Combined with Montelukast on Children with Perennial Allergic Rhinitis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy of Chinese medicine acupoint application (CMAA) combined with Western medicine for perennial allergic rhinitis (PAR) in children. METHODS: In this prospective, parallel, randomized, placebo-controlled and single-blind trial from August to September, 2017, 180 children with PAR were randomly assigned to an integrative group (CMAA and Montelukast), CMAA group (CMAA and placebo tablet), or Montelukast group (placebo CMAA and Montelukast). Participants were applied with CMAA for 6 sessions over 2 weeks, and/or Montelukast Chewable Tablet orally once daily for 12 weeks. The changes in severity of symptoms were measured by Visual Analog Scale (VAS) and rhinitis control assessment test (RCAT) at 0, 2, 4 and 12 weeks of treatment. Blood samples were collected for serum interleukin-4, interferon gamma γ and T helper type 1 (Th1)/Th2 flow cytometric analysis at the time points of 0, 4 and 12 weeks. RESULTS: Eight cases dropped out from the trial, 3 in the integrative group, 2 in the CMAA group and 3 in the Montelukast group. The VAS scores decreased significantly while the RCAT scores increased significantly in all three groups at 4 and 12 weeks compared with baseline (P<0.01 or P<0.05). The VAS scores were significantly lower while the RCAT scores were significantly higher in the integrative and CMAA groups than the Montelukast group at 2 and 4 weeks (P<0.01 or P<0.05). At 2, 4 and 12 weeks, the scores of nasal congestion, sneezing, sleep problem, and rhinitis symptom control in the integrative and CMAA groups increased significantly compared with baseline (P<0.01 or P<0.05). The least percentages of Th2 and the most alleviated Th2 shift (highest Th1/Th2) were observed in the integrative group at 12 weeks compared with the other two groups (P<0.05). CONCLUSION: The combination of CMAA with Montelukast might be more effective and appropriate than either option alone for children with PAR. (Registered at Chinese Clinical Trial Register, registration No. ChiCTR-IOR-17012434).

Genetic factors in isolated and syndromic laryngeal cleft.

A laryngotracheoesophageal cleft (LC) is a rare congenital anomaly of the upper aerodigestive tract resulting from the absence of fusion of the posterior cricoid lamina, which affects an abnormal communication between the larynx, trachea and esophagus. The genetic etiology of LC remains elusive. The involvement of genetic factors in the development of LC is suggested by reports of familial occurrence, and the increased prevalence of component features among first-degree relatives of affected individuals and murine knockout models. No consistent pattern of inheritance has been found in nonsyndromic patients, except for cases associated with described syndromes. Once the syndrome related to the laryngeal cleft is considered, an active search for the cleft must be initiated. The genetic evaluation of patients with LCs should be guided by the type and location of the malformation, specific medical history and a detailed physical examination. The application of genetic approaches, such as microarrays and exome sequencing might lead to elucidating the etiology of LCs.

Early-Life Environmental Factors, IFN-γ Methylation Patterns, and Childhood Allergic Rhinitis.

BACKGROUND: While early-life risk factors are known to influence the risk of allergies, the biological mechanisms underlying this observation are unclear. The aim of this study was to examine whether DNA methylation in childhood could underlie the association between early-life risk factors and allergic rhinitis (AR). METHODS: In total, 234 patients, aged 6 years, were recruited, i.e., 114 were patients with AR (AR group) and 120 healthy children without AR (NAR group). The DNA methylation patterns of the IFN-γ promoter regions in CD4+ cells were analyzed using bisulfite sequencing. The percentage of Th1 was investigated by flow cytometry. The relationship among DNA methylation, early-life environment, and AR was examined. RESULTS: After adjusting for several likely confounders, there was a higher likelihood of AR in children who had mothers with allergies than in children who had nonallergic mothers (OR = 5.19; 95% CI 1.18-29.41), in children who were born in autumn or winter than in children who were born in the summer or spring (OR = 2.69; 95% CI 1.34-5.40), and in children who lived with indoor carpet or wallpaper than in children who lived without indoor carpet or wallpaper (OR = 4.14; 95% CI 2.05-8.30). Compared to the NAR group, the AR group had higher mean methylation levels of the promoter region in IFN-γY, and lower numbers of IFN-γ+CD4+ cells were associated with autumn-winter birthdates. The season of birth had an indirect effect on AR at 6 years, which was mediated by the mean IFN-γ promoter methylation level. CONCLUSIONS: This study suggests that early-life environments affect AR, and this is supported by the finding of IFN-γY methylation as a mediator of the effect of an individual's season of birth on AR.

PM2.5 exposure exacerbates allergic rhinitis in mice by increasing DNA methylation in the IFN-γ gene promoter in CD4+T cells via the ERK-DNMT pathway.

Allergic rhinitis (AR) is a common chronic inflammatory disease that has a significant impact on the quality of life of patients. Our previous study suggested that PM2.5 might affect pediatric AR through epigenetic regulation, but the underlying mechanisms remained unclear. In this study, an experimental murine AR model was created, and the nasal symptoms, pathological changes, the DNA methylation level of the IFN-γ gene promoter and activation of the ERK-DNMT pathway were evaluated after treatment with PM2.5. Our results showed that PM2.5 exposure led to more severe symptoms of AR in mice. In addition, PM2.5 exposure significantly decreased the percentage of Th1 T cells in the AR group, and this change was correlated with increased DNA methylation of the IFN-γ gene promoter in CD4 + T cells (r=-0.916, p = 0.029). In addition, PM2.5 exposure increased the activation of the ERK-DNMT pathway in CD4+ T cells, and inhibiting this effect rescued the polarization of the Th1/Th2 balance toward Th2, thereby decreasing the risk of AR. Our findings demonstrate that PM2.5 exposure could exacerbate AR by increasing the DNA methylation of the IFN-γ gene promoter in CD4 + T cells via the ERK-DNMT pathway, and these effects were rescued when the ERK-DNMT pathway was inhibited.

The association between sixteen genome-wide association studies-related allergic diseases loci and childhood allergic rhinitis in a Chinese Han population.

BACKGROUND: Allergic rhinitis (AR) is one of the most common respiratory diseases in children. It is caused by a combination of genetic and environmental factors. Moderate-to-severe AR decreases the quality of life and social performance in children. OBJECTIVE: To investigate whether polymorphisms in previously published genome-wide association studies (GWAS) allergic disease loci are associated with childhood AR and the severity of AR symptoms in a Chinese Han population. METHODS: A case-control study was conducted in 503 pediatric patients with AR and 393 control Chinese school-aged subjects. AR severity was classified as mild or moderate-to-severe according to the AR and its Impact on Asthma (ARIA) guidelines. Overall, 16 tagged single-nucleotide polymorphisms (tSNPs) of published GWAS associations with allergic diseases were selected. All subjects were genotyped and analyzed for the 16 selected tSNPs using the improved multiplex ligation detection reaction (iMLDR) technique. RESULTS: Both rs7130588_AG and rs7927894_CT genotypes in EMSY region were associated with a significantly increased risk of AR (1.75-fold and 1.50-fold) compared to the AA and CC genotypes, respectively, specific to moderate-to-severe AR. The difference of rs7130588 genotypes in cases vs. controls was still statistically significant under the additive model after multiple test correction to adjust the false discovery rate (FDR) with an adjusted odds ratio of 1.818 and 95% confidence interval (CI) of 1.240-2.664 (PFDR = 0.0349). The rs7130588_G allele was only associated with a high risk of moderate-to-severe AR (1.85-fold, Page and gender_adjustment = 0.003). The rs2227284_TG genotype at the IL4 locus was significantly associated with a 0.65-fold decreased risk of AR compared to the TT genotype. The protective effect of the rs2227284_G allele was also found in different severity of AR. Haplotype analysis showed a significantly increased AR risk associated with the haplotype G-T-T (rs7130588-rs2155219-rs7927894) and a protective effect with the haplotype C-G-C (rs2243250-rs2227284-s2243290). CONCLUSIONS: The loci in EMSY and IL4 can be considered as a hereditary marker for childhood AR. The rs7130588_G allele seems to predispose only to moderate-to-severe AR, though other mechanisms are also likely to be involved.

Perioperative levels of total IgE correlate with outcomes of prolonged mechanical ventilation after cardiopulmonary bypass in pediatric patients.

BACKGROUND: Although cardiopulmonary bypass (CPB) has been previously studied as risking infection and inflammatory responses, few studies evaluate the relationship of preoperative high total immunoglobulin E (tIgE) to outcomes in pediatric patients predisposed to atopy undergoing cardiac surgery with CPB. METHODS: Serum tIgE, tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), IL-4, interferon-γ (IFN-γ), and T-helper type 1/2 (Th1/Th2) ratio were quantified in 104 pediatric patients who underwent surgical repair with CPB. Blood samples were obtained: before operation (T1), at the beginning (T2), and before the completion of CPB (T3), after protamine administration (T4), 4 h after CPB (T5), and on postoperative days 1 and 2 (T6, T7). Data on clinical outcomes were collected prospectively. RESULTS: Compared to 50 cases with normal tIgE, 54 cases with high tIgE were found to have higher TNF-α, IL-10, and IL-4 affected by CPB on the specific timepoints (pTNF-α < 0.001; pIL-10 = 0.035; pIL-4 = 0.001). TIgE levels shifted transiently towards Th2, which may be caused by high tIgE specific to T4. This resulted in the correlation between prolonged duration of mechanical ventilation (IL-4: r = 0.426, p = 0.015; Th1/Th2: r = -0.272, p = 0.043) in patients with high tIgE. CONCLUSIONS: A high preoperative tIgE level predisposes patients to an aggravated Th2 shift after protamine administration during CPB in association with increased risk of prolonged mechanical ventilation and medical intervention.