Influence of sleep stages on determining positional dependency in patients with obstructive sleep apnea.

Objective: Supine sleep position and rapid eye movement (REM) stage are widely known to aggravate the severity of obstructive sleep apnea (OSA). In general, position-dependent OSA is defined as an apnea-hypopnea index (AHI) at least twice as high in the supine position as in other sleep positions, but it can be misdiagnosed if a certain sleep stage, REM or NREM, is dominant in a specific sleep position. In this study, we investigated the influences of the sleep stages on positional dependency. Methods: The polysomnographic data from 111 OSA patients aged ≥ 18 years (AHI > five events/hour) who slept in both supine and non-supine positions (each ≥ 5% of the total sleep time) were retrospectively analyzed. The overall ratio of non-supine AHI/supine AHI (NS/S AHI ratio) during the entire sleep was compared between specific sleep stages, i.e., REM or NREM sleep. Additionally, the weighted NS/S AHI ratio reflecting the proportion of each sleep time was created and compared with the original NS/S AHI ratio. Results: The mean value of the NS/S AHI ratio did not differ between the entire sleep and the specific sleep stages. However, those ratios in the individual patients showed poor agreement of the NS/S AHI ratios between the entire sleep and the specific sleep stages. The weighted NS/S AHI ratio also demonstrated poor agreement with the original NS/S AHI ratio, mainly due to the discrepancy in mild to moderate OSA patients. Conclusion: The weighted NS/S AHI ratio might help assess precise positional dependency.

Contralateral Cavernous Sinus Thrombosis Caused by Sphenoid Sinusitis: Case Report and Literature Review.

Cavernous sinus thrombosis (CST) is a rare but life-threatening infectious disease whose diagnosis and treatment are challenging. CST can result in ocular and neurologic morbidities, as well as fatal systemic complications due to systemic thrombus. Occasionally, these clinical symptoms can be a result of contralateral sinusitis. A 75-year-old female presented with severe headache and fever. Magnetic resonance imaging revealed a multifocal filling defect in both cavernous sinuses, with heterogeneous enhancement and thrombosis of the right superior ophthalmic vein. Intravenous antibiotic was administered, and endoscopic sinus surgery was performed. The patient was discharged 40 days after admission and there were no neurologic symptoms and no evidence of sequelae during the 10-month follow-up. Symptoms of CST on the contralateral side are often missed, which delays initiation of appropriate treatment. When CST secondary to paranasal sinusitis is diagnosed, clinicians should consider contralateral as well as ipsilateral infection of the paranasal sinus. Preventing disease progression and complications through early and aggressive antibiotic administration along with sinus surgery is crucial.

Associations Between Chronic Rhinosinusitis and Cancers: A Nationwide Population-Based Cohort Study.

OBJECTIVE: Chronic rhinosinusitis (CRS) is one of the most common chronic inflammatory diseases. The effect of chronic inflammation caused by CRS on the occurrence of various cancers has not been thoroughly evaluated. This study aimed to investigate the increased incidences of 10 types of cancers among CRS patients with/without nasal polyps (NP) using a national population-based database from the Korean Health Insurance Review and Assessment Service. STUDY DESIGN: A case-control cohort study. METHODS: We compared the prevalence of various comorbidities between CRS and control participants from a national cohort dataset of the Korean Health Insurance Review and Assessment Service. METHODS: CRS participants (n = 6,919) and non-CRS (n = 27,676) participants were selected from among the 514,866 participants from 2002 to 2015. A stratified Cox proportional hazards model was utilized to assess the hazard ratio (HR) of CRS for 10 types of cancers. RESULTS: A stratified Cox proportional hazard model demonstrated that the adjusted HR for hematologic malignancy was significantly higher in the CRS patients than in the controls regardless of the presence of NP (2.90 for total CRS; 2.15 for CRS with NP; 4.48 for CRS without NP). The HR for thyroid cancer was significantly higher in the CRS patients without NP but not in those with NP (1.50 for total CRS; 1.78 for CRS without NP). CONCLUSION: This study showed that CRS participants had a significantly higher prevalence of hematologic malignancy and thyroid cancer. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1044-1051, 2023.

Incidence of Asthma, Atopic Dermatitis, and Allergic Rhinitis in Korean Adults before and during the COVID-19 Pandemic Using Data from the Korea National Health and Nutrition Examination Survey.

The prevalence of allergic diseases has been increasing globally prior to COVID-19. The pandemic resulted in changes in lifestyle and personal habits such as universal mask-wearing and social distancing. However, there is insufficient information on the impact of the COVID-19 pandemic on the prevalence of allergic conditions such as asthma, atopic dermatitis, and allergic rhinitis. We analyzed the incidence rate for self-reported and doctor-diagnosed cases of allergic diseases of asthma, atopic dermatitis, and allergic rhinitis. A total of 15,469 subjects were registered from a national cohort dataset of the National Health and Nutrition Examination Survey. Using multiple logistic regression analysis, we calculated the adjusted odds ratio (OR) for each disease in 2020 compared to 2019. Subgroup analyses were performed according to age and sex. There were no statistically significant differences between the incidence of doctor-diagnosed and current allergic diseases in 2019 and 2020 (asthma, p = 0.667 and p = 0.268; atopic dermatitis, p = 0.268 and p = 0.973; allergic rhinitis, p = 0.691 and p = 0.942, respectively), and subgroup analysis showed consistent results. Among the Korean population from 2019 to 2020, the incidence of the allergic diseases asthma, atopic dermatitis, and allergic rhinitis did not decrease as expected.

Neuronal growth regulator 1 promotes adipocyte lipid trafficking via interaction with CD36.

Neuronal growth regulator 1 (NEGR1) is a glycosylphosphatidylinositol-anchored membrane protein associated with several human pathologies, including obesity, depression, and autism. Recently, significantly enlarged white adipose tissue, hepatic lipid accumulation, and decreased muscle capacity were reported in Negr1-deficient mice. However, the mechanism behind these phenotypes was not clear. In the present study, we found NEGR1 to interact with cluster of differentiation 36 (CD36), the major fatty acid translocase in the plasma membrane. Binding assays with a soluble form of NEGR1 and in situ proximal ligation assays indicated that NEGR1-CD36 interaction occurs at the outer leaflet of the cell membrane. Furthermore, we show that NEGR1 overexpression induced CD36 protein destabilization in vitro. Both mRNA and protein levels of CD36 were significantly elevated in the white adipose tissue and liver tissues of Negr1-/- mice. Accordingly, fatty acid uptake rate increased in NEGR1-deficient primary adipocytes. Finally, we demonstrated that Negr1-/- mouse embryonic fibroblasts showed elevated reactive oxygen species levels and decreased adenosine monophosphate-activated protein kinase activation compared with control mouse embryonic fibroblasts. Based on these results, we propose that NEGR1 regulates cellular fat content by controlling the expression of CD36.

Cavernous Hemangioma of the Maxillary Sinus Masquerading Recurrent Hemorrhagic Mass: Histological-Radiological Correlation and a Literature Review.

BACKGROUND: Sinonasal cavernous hemangioma is rare. To date, fewer than 20 cases have been reported in the literature; however, they may be a source of recurrent epistaxis and masquerade of a hemorrhagic mass on CT and MRI. CASE REPORT: A 68-year-old woman was presented with recurrent epistaxis and progressive right malar fullness. On rhinoscopy, a bulge lesion was observed with multifocal hemorrhagic and friable surfaces in the right nasal cavity. CT and MRI demonstrated a well-defined mass in the right maxillary sinus with inhomogenous T2 hyperintensity, hypointense septa, peripheral rim, and multiple papillary enhancement, suggesting a recurrent hemorrhagic mass. The mass was excised endoscopically, and the histologic diagnosis was cavernous hemangioma. CONCLUSION: Imaging studies, such as CT and MRI, are essential in making an accurate diagnosis of cavernous hemangioma of the maxillary sinus. Endoscopic excision of the lesion can be curative.

Epstein-Barr virus-positive diffuse large B-cell lymphoma with human immunodeficiency virus mimicking complicated frontal sinusitis: A case report.

BACKGROUND: Primary non-Hodgkin's lymphoma of the frontal sinus is extremely rare. In addition, Epstein-Barr virus (EBV) has been reported to play a role in the development of human immunodeficiency virus (HIV)-related malignant lymphomas. To the best of our knowledge, there is no report for the HIV-associated, EBV-positive primary diffuse large B-cell lymphoma (DLBCL) in the frontal sinus. CASE SUMMARY: We present a unique case of HIV-associated, EBV-positive DLBCL in the frontal sinus in a 46-year-old man. Computed tomography of paranasal sinuses revealed dense opacification of the right frontal sinus with combined soft tissue swelling. Based on the clinical and radiological findings, the initial diagnosis was complicated frontal sinusitis, presenting Pott's puffy tumor. Unexpectedly, HIV testing was positive on preoperative laboratory test, and the frontal sinus lesion was confirmed as EBV-positive DLBCL on biopsy. CONCLUSION: Through this article, we suggest that EBV-positive DLBCL should be considered as possible diagnosis for patients with nonspecific space-occupying lesion of the paranasal sinuses. We also highlight an importance of clinical suspicion in diagnosing HIV infection because HIV serology is not routinely tested in patients with paranasal sinus problem.

Therapeutic Effects of Intranasal Tofacitinib on Chronic Rhinosinusitis with Nasal Polyps in Mice.

OBJECTIVES: The Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway play a key role in immune modulation, especially in the polarization of T helper cells. JAK inhibitors reduce inflammation by inhibiting the phosphorylation of STAT. We investigated whether a JAK inhibitor, tofacitinib, can reduce inflammation in a mouse model of chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: An eosinophilic CRSwNP model was induced using 4-week-old BALB/c mice. The therapeutic effects of topical tofacitinib were compared with the effects of triamcinolone acetonide (TAC). Polyp formation and eosinophilic infiltration were assessed by histology. Levels of phosphorylated STAT (pSTAT), eosinophil cationic protein, and eotaxin were measured by immunohistochemistry. Gene expression levels of GATA-3 was measured using quantitative PCR. The production of cytokines in sinonasal tissues, including interleukin IL-4, IL-5, IL-12, and interferon-γ, were measured using enzyme-linked immunosorbent assays (ELISA). RESULTS: Topical tofacitinib administration significantly reduced the number of polyp-like lesions and the degree of eosinophilic infiltration, with an efficacy comparable with that of systemic TAC administration. Similarly, the levels of pSTAT6, eosinophil cationic protein, and eotaxin decreased with tofacitinib treatment. Tofacitinib decreased the gene expression level of GATA-3. Lastly, tofacitinib significantly decreased IL-4 and IL-5 production to a similar extent as that by systemic or topical TAC administration. Tofacitinib, but not TAC, significantly increased the production of interferon-γ. CONCLUSION: Topical tofacitinib administration may be an effective treatment for eosinophilic CRSwNP by inhibiting phosphorylation of STATs. LEVEL OF EVIDENCE: N/A. Laryngoscope, 131:E1400-E1407, 2021.

Usefulness of computed tomography in predicting ethmoidal arterial bleeding in refractory epistaxis.

PURPOSE: Epistaxis that is refractory to conservative management can be treated with endoscopic sphenopalatine artery ligation (ESPAL). Although rare, ethmoidal artery (EA) bleeding can be a cause of rebleeding after successful ESPAL. EA bleeding is diagnosed by angiography and can also be identified during surgical exploration. However, since the angiographic embolization of the EA is contraindicated, surgical hemostasis is mandatory. This study investigated whether paranasal sinus (PNS) CT could provide information for predicting EA bleeding without angiography in patients with refractory epistaxis requiring ESPAL. METHODS: Forty-seven patients, who were surgically treated [with ESPAL or EA ligation (EAL)] for refractory epistaxis from March 2010 to June 2019, were retrospectively analyzed. A positive PNS CT finding for EA bleeding was defined as the presence of soft tissue densities having continuity with the EA pathway, accompanied by a partially deficient surrounding bony canal. These findings as well as soft tissue densities in each paranasal sinus were compared between the ESPAL and EAL groups. RESULTS: All patients in the EAL group had positive CT findings of EA bleeding, compared to only 12.2% in the ESPAL group (P < 0.001). The rate of soft tissue densities within the frontal and sphenoid sinuses were noted in 26.8% and 17.1% of patients in the ESPAL group, compared to 83.3% and 83.3% of patients in the EAL group (P = 0.013 and P = 0.003, respectively). CONCLUSION: PNS CT might be useful for predicting EA bleeding in patients with refractory epistaxis requiring surgical hemostasis.

Triangular excision and submucosal rejoining to correct horizontally folded caudal nasal septum.

BACKGROUND: Surgical correction of severe caudal deviation of nasal septum using an endonasal approach is challenging for surgeons. Among cases of severe caudal septal deflection, fracture lines along the horizontal direction are occasionally encountered during the surgery. We devised a simple and efficient technique called "triangular excision and submucosal rejoining" to address this kind of deformity. METHODS: A total of 9 patients with severe caudal septal deflection underwent "triangular excision and submucosal rejoining." After the removal of the deformed posteroinferior portion of the quadrangular cartilage, 2 incision lines were made on the remaining caudal septum, starting from a point at the most anterior portion of the fracture line and diverging posteriorly above and below the fracture line. After removing a triangular cartilaginous piece, the upper and lower remaining cartilage segments were approximated using a single or 2 simple interrupted sutures. Sutures exiting the mucosa were re-entered from the exit point so that all the sutures were buried underneath the mucosa while the mucosal flap was elevated only unilaterally. RESULTS: This technique was effective in all cases. Septal batten grafts were applied in 3 patients, in whom the remaining quadrangular cartilage was weak and thin. One patient showed a mildly recurred septal deviation, but the nasal cavities remained patent with no symptoms. Serious complications such as dorsal saddling or tip ptosis did not occur in any cases. CONCLUSION: "Triangular excision and submucosal rejoining" may be a safe and efficient septoplasty technique to correct a horizontally folded caudal septum.

Neuronal growth regulator 1-deficient mice show increased adiposity and decreased muscle mass.

BACKGROUND: Neuronal growth regulator 1 (NEGR1) is a glycosylphosphatidylinositol-anchored membrane protein that mediates neural cell communication and synapse formation. Multiple genome-wide association studies have reported that variations in NEGR1 are associated with human body weight control. Recently, we found that NEGR1 is involved in intracellular cholesterol trafficking, suggesting that it performs a non-central nervous system (CNS) function associated with human obesity. METHODS: We compared peripheral tissues such as the adipose, liver, and skeletal muscle tissues of Negr1-/- and Negr1+/+ (wild-type [WT]) C57BL/6 mice (n = 5-14). Intracellular lipid content was measured, and lipid accumulation was visualized by staining tissue cross-sections with lipid-specific stains. Muscle capacity of the WT and Negr1-/- mice was determined by performing a treadmill endurance test, and muscle fiber size was examined. Plasma glucose and insulin levels were measured, and glucose and insulin tolerance tests were performed. RESULTS: The Negr1-/- mice showed a significant increase in fat mass (~1.5-fold increase in the epididymal white adipose tissue, p = 0.000002), with abnormally enlarged adipose cells, compared with the WT mice. Primary adipocytes of the Negr1-/- mice contained enlarged cytosolic lipid droplets (p = 0.049). Moreover, these mice showed significant hepatic lipid accumulation (~2.3-fold increase, p = 0.043). Although the Negr1-/- mice did not show a significant change in plasma lipoprotein level, they showed a >1.3-fold increase in a serum glucose (p = 0.0002) and insulin (p = 0.016) levels. Moreover, the Negr1-/- mice showed decreased muscle capacity, as indicated by a decrease in muscle mass (p = 0.000003). CONCLUSION: These results indicate that NEGR1 deficiency induces abnormal fat deposition in various peripheral cells, especially fat and liver tissue cells, and suggest that NEGR1 is a potential molecular target for designing anti-obesity drugs to regulate body weight both centrally and peripherally.

Use of a crossing suture to correct caudal septal deviations.

BACKGROUND: Septoplasty usefully treats patients with nasal obstructions caused by septal deviations. However, correction of a caudal septal deviation remains surgically challenging; no standard procedure is available, although various procedures have been introduced. In this work we propose a simple, safe, and time-saving technique for patients with caudal septal deviations. METHODS: The medical records of 50 patients with caudal septal deviations who underwent septoplasty using a crossing-suture technique from October 2016 to October 2018 were retrospectively reviewed. Postoperative nasal obstruction status and patient satisfaction with their surgical outcomes were subjectively evaluated using the Nasal Obstruction Symptom Evaluation (NOSE) score and telephone interview, respectively. Pre- and postoperative endoscopic findings were evaluated and postoperative complications developing during follow-up were recorded. RESULTS: The NOSE scores of all patients improved after septoplasty. The mean score fell from 13.46 to 3.97, and this change was significant (p < 0.0001). No complication related to use of the crossing suture was encountered. CONCLUSION: The crossing-suture technique is a simple, safe, and useful surgical option for correction of caudal septal deviations.

Establishment and verification of a mouse model of nasal wound healing.

OBJECTIVES: Poor wound healing as reflected by the development of synechia and osteitis after endoscopic sinus surgery may trigger disease recurrence. Animal models provide insights into the pathogenesis of poor wound healing and may aid in the development of new therapeutics. Here, we established a mouse model of nasal wound healing and confirmed its utility. STUDY DESIGN: Animal study. METHODS: Unilateral intranasal wounds were induced using a small interdental brush in 6-week-old C57BL/6 mice. Forty-five mice were divided into three groups (each n = 15): one control and two experimental groups (intranasal vs. intraperitoneal dexamethasone). Mice were sacrificed on days 2, 14, and 28 after injury (each n = 5). Serial changes in nasal wound histopathology were described, and intergroup differences were analyzed. RESULTS: On day 2, mucosal detachment, hemorrhage, and exudate were observed. On day 14, synechiae featuring neo-osteogenesis (bone lacunae, osteoblasts, and multinucleated osteoclasts) between the septum and the maxilloturbinate were prominent, followed by wound maturation on day 28: fewer lacunae and smaller osteoblasts. Macrophages were evident only on day 2, and lymphocytes were predominant on day 28. The amount of exudate on day 2 and the synechial area on day 28 were significantly reduced in mice that received dexamethasone systemically compared with control mice, with similar trends in those treated intranasally. CONCLUSION: Our mouse model of nasal wound healing was characterized by the development of bony synechia and neo-osteogenesis, not soft-tissue synechia. The model may be useful in the assessment of novel therapeutics to prevent those wounds. LEVEL OF EVIDENCE: NA Laryngoscope, 129:E266-E271, 2019.

Negr1 controls adult hippocampal neurogenesis and affective behaviors.

Recent genome-wide association studies on major depressive disorder have implicated neuronal growth regulator 1 (Negr1), a GPI-anchored cell adhesion molecule in the immunoglobulin LON family. Although Negr1 has been shown to regulate neurite outgrowth and synapse formation, the mechanism through which this protein affects mood disorders is still largely unknown. In this research, we characterized Negr1-deficient (negr1-/-) mice to elucidate the function of Negr1 in anxiety and depression. We found that anxiety- and depression-like behaviors increased in negr1-/- mice compared with wild-type mice. In addition, negr1-/- mice had decreased adult hippocampal neurogenesis compared to wild-type mice. Concurrently, both LTP and mEPSC in the dentate gyrus (DG) region were severely compromised in negr1-/- mice. In our effort to elucidate the underlying molecular mechanisms, we found that lipocalin-2 (Lcn2) expression was decreased in the hippocampus of negr1-/- mice compared to wild-type mice. Heterologous Lcn2 expression in the hippocampal DG of negr1-/- mice rescued anxiety- and depression-like behaviors and restored neurogenesis and mEPSC frequency to their normal levels in these mice. Furthermore, we discovered that Negr1 interacts with leukemia inhibitory factor receptor (LIFR) and modulates LIF-induced Lcn2 expression. Taken together, our data uncovered a novel mechanism of mood regulation by Negr1 involving an interaction between Negr1 and LIFR along with Lcn2 expression.

Influence of a medialized middle turbinate on olfactory function: a prospective randomized double-blind study.

BACKGROUND: Medialization of the middle turbinate (MT) is an effective technique to prevent recurrent rhinosinusitis but could, in theory, reduce olfactory function by interfering the odorants to reach the olfactory mucosae. We performed a prospective randomized double-blind trial under the hypothesis that olfactory functions would be affected by the status of olfactory mucosae, not by MT medialization. METHODS: In randomly selected sides, the unilateral MT was medialized in 80 patients undergoing bilateral endoscopic sinus surgery for chronic rhinosinusitis. The status of the bilateral olfactory cleft (OC) was photodocumented intraoperatively and categorized into patent (normal or mucosal swelling with discharge) and congested (hypertrophied mucosae or nasal polyps) groups. The butanol threshold test (BTT) was conducted in each nostril before and 6 months after the surgery. Correlation between the BTT scores and MT medialization or the OC status was assessed. No smell identification test was conducted side by side, which might limit clinical implications. RESULTS: In total, 46 of 80 patients completed the trial. MT medialization was performed on the left and right side of the nose in 19 and 27 cases, respectively. The intraoperative OC status did not differ between the 2 sides. Perioperative changes in the BTT scores were similar between the medialized and intact MT sides, whereas the preoperative and postoperative BTT scores were higher in the patent OC group than in the congested OC group, regardless of side. CONCLUSION: MT medialization does not impair olfactory function, and OC status is closely related to olfactory function.

Association of TRPV1 and TLR4 through the TIR domain potentiates TRPV1 activity by blocking activation-induced desensitization.

BACKGROUND: We have previously reported that histamine-induced pruritus was attenuated in toll-like receptor 4 (TLR4) knockout mice due to decreased transient receptor potential V1 (TRPV1) sensitivity. Our results implied that TLR4 potentiated TRPV1 activation in sensory neurons; however, the molecular mechanism has yet to be elucidated. In this study, we investigated the molecular mechanisms of TLR4-mediated TRPV1 potentiation using TLR4-deficient sensory neurons and a heterologous expression system. METHODS: Primary sensory neurons were obtained from wild-type or TLR4 knockout mice, and HEK293T cells expressing TRPV1 and TLR4 were prepared by transient transfection. TRPV1 activity was analyzed by calcium imaging, fluorophotometry, and patch-clamp recording. Subcellular protein distribution was tested by immunocytochemistry and cell surface biotinylation assay. Protein interaction was assessed by western blot and immunoprecipitation assay. RESULTS: Direct association between TRPV1 and TLR4 was detected in HEK293T cells upon heterologous TRPV1 and TLR4 expression. In an immunoprecipitation assay using TLR4-deletion mutants and soluble toll/interleukin-1 receptor (TIR) protein, the cytoplasmic TIR domain of TLR4 was required for TLR4-TRPV1 association and TRPV1 potentiation. In TLR4-deficient sensory neurons, the activation-induced desensitization of TRPV1 increased, accompanied by enhanced TRPV1 clearance from the cell membrane upon activation compared to wild-type neurons. In addition, heterologous TLR4 expression inhibited activation-induced TRPV1 endocytosis and lysosomal degradation in HEK293T cells. CONCLUSION: Our data show that direct association between TRPV1 and TLR4 through the TIR domain enhances TRPV1 activity by blocking activation-induced TRPV1 desensitization.

Idiopathic benign paroxysmal positional vertigo in the elderly: a long-term follow-up study.

BACKGROUND: Benign paroxysmal positional vertigo (BPPV) is the most common cause of peripheral-type vertigo in the elderly. While some studies have investigated BPPV among the elderly, no study has focused on the isolated idiopathic BPPV (iBPPV) in the elderly. AIMS: To investigate the clinical features and recurrence rate in elderly patients diagnosed with iBPPV. METHODS: The authors prospectively reviewed the medical records of 627 patients diagnosed with BPPV, and a total of 370 patients fulfilled the inclusion criteria. The subjects were divided into two groups by age (experimental group ≥65 years and control group 17-64 years), and the gender, numbers of canalith reposition maneuver (CRM) for successful treatment, time elapsed from onset of symptoms to clinic visit, the affected semicircular canal, and the 1- and 5-year recurrence proportion were analyzed. RESULTS: The gender, numbers of CRM for successful treatment, affected semicircular canal, and the 1- and 5-year recurrence proportion showed no statistically significant difference between two groups (p > 0.05). The only exception was the experimental group which took a longer duration from manifestation of symptoms to hospital visit than control group (student's t test, p = 0.021). DISCUSSION: Several previous studies report that the elderly with iBPPV shows more protracted clinical course and much higher recurrence rate than younger adult. Unlike those reports, our study showed no significant differences about the clinical features and recurrence rate between age groups. CONCLUSION: The elderly with iBPPV could be treated as effective as general population.

Assembly of polymer micelles through the sol-gel transition for effective cancer therapy.

Photo-induced apoptosis-targeted chemotherapy (PIATC) was designed and characterized to propose a new protocol for improved chemotherapy. Intratumoral injection was selected as the mode of administration of the anticancer drug, doxorubicin (DOX). To extend the retention time of DOX at the tumor parenchyma, in-situ gel formation was induced through the sol-gel transition of the Pluronic NPs containing a prodrug of DOX or a photosensitizer. The prodrug (DEVD-S-DOX) was designed to be inactive with a peptide moiety (Aspartic acid-Glutamic acid-Valine-Aspartic acid: DEVD) linked to DOX and to be cleaved into free DOX by caspase-3 expressed with apoptosis. For reactive oxygen species (ROS)-mediated apoptosis, photo-irradiation with methylene blue (MB, photosensitizer) was utilized. The sol-gel transition of the Pluronic NPs containing reactive species, DEVD-S-DOX or MB, was examined by measuring the cloud point and the gel strength in response to temperature change. ROS-mediated apoptosis was observed by measuring the ROS and membrane integrity with induced apoptosis. The in vivo antitumor efficacy of PIATC was measured with a cardiotoxicity assay in tumor-bearing mice.

The multilayer nanoparticles for deep penetration of docetaxel into tumor parenchyma to overcome tumor microenvironment.

Deep penetration of the anticancer drug, docetaxel (DTX), into tumor parenchyma was demonstrated to achieve improved chemotherapy. For this purpose, a multistage nanostructure was designed and characterized using the multilayer nanoparticles (NPs). The multilayer NPs had a core/shell structure. The core was composed of the DTX-loaded Pluronic NPs (diameter: 12nm) that were transferred into the inner side of vesicles to form the vesicle NPs. Förster resonance energy transfer (FRET) in the NPs was observed to verify the incorporation of the DTX-loaded Pluronic NPs into the inner side of the vesicles during the formation of the vesicle NPs. Subsequently, the vesicle NPs were stabilized through Pluronic-lipid bilayer interaction to form the multilayer NPs. To examine the morphology and size distribution of the multilayer NPs, transmittance electron microscopy and dynamic light scattering were used. In vitro release behavior and toxicity were observed to verify the functionality of the multilayer NPs as nanocarriers for cancer therapy. Multistage functionality was evaluated by cellular uptake and tissue distribution behaviors of the multilayer NPs. The biodistribution of the multilayer NPs and their antitumor efficacy were also observed to understand the role of multistage functionality for improved chemotherapy.

Anti-inflammatory effects of intranasal cyclosporine for allergic rhinitis in a mouse model.

BACKGROUND: Although topical corticosteroids are considered a safe and effective drug for allergic rhinitis (AR), some AR patients do not show sufficient symptomatic improvement by use of topical corticosteroids. Topical cyclosporine is a safe and effective drug for patients with allergic conjunctivitis, particularly for those with steroid-resistant allergic conjunctivitis. We investigated the anti-inflammatory effects of intranasal cyclosporine for AR using a mouse model. METHODS: After establishment of allergic inflammation in 5-week-old BALB/c mice, cyclosporine was administered intranasally 3 times per week for 2 weeks. To confirm its anti-inflammatory effects, triamcinolone acetonide (TAC) was utilized as a control drug. Histopathologic changes were evaluated using Sirius red and Giemsa staining for eosinophilic and mast cell infiltration, respectively. The levels of cytokines in sinonasal tissues, including tumor necrosis factor (TNF), interleukin (IL)-4, IL-5, and IL-13, were assessed based on a cytometric bead array. RESULTS: The degree of eosinophilic infiltration was significantly decreased by instillation of cyclosporine, the potency being similar to TAC. However, the number of mast cells was not decreased by cyclosporine or TAC. The levels of TNF, IL-4, IL-5, and IL-13 were significantly decreased after treatment with cyclosporine. CONCLUSION: The anti-inflammatory effects of topical cyclosporine for AR were equivalent to those of topical corticosteroids. Topical cyclosporine may be useful for the treatment of AR, although human studies are required.