Age-dependent treatment effect of vocal fold steroid injection for benign vocal fold lesions.

Objective: Benign vocal fold lesions (BVFLs) cause voice disorders and impair social life. Recently, office-based vocal fold steroid injection (VFSI) has gained attention as a minimally invasive treatment for BVFLs. This study aimed to analyze the age-dependent treatment effect of VFSI and to clarify the indications for treatment. Methods: In this retrospective cohort study, a total of 83 patients with BVFLs were treated with a similar regimen of VFSI. Three or four months after the injection, age-dependent phonological functions were evaluated. The differences between pre- and post-treatment findings were analyzed using the Wilcoxon matched-pair signed-rank test, and the correlation between patient age and improvement rates were determined by Pearson's correlation coefficient. Results: Improvement in voice handicap index (VHI), which was the primary endpoint, was observed. Subjective and objective voice quality measurements also showed significant improvements. Subgroup analyses revealed that there was no age-related difference in the improvement of voice quality and that there was no improvement in aerodynamic effect in patients over 45 years of age. Conclusion: This study clarified the age-dependent treatment effect of VFSI and provided the important suggestion of establishing indication criteria for BVFLs. The study results provided clarity on the indication criteria of VFSI and served as an important indicator for tailoring treatment to patients' needs. Level of Evidence: 4.

Intracordal injection therapy for vocal fold scarring: Steroid versus basic fibroblast growth factor.

Objectives: Vocal fold scarring is caused by replacement of vocal fold mucosa with fibrous tissue due to repeated inflammation or trauma. It can lead to severe dysphonia. It is currently treated conservatively and with phonosurgery and intracordal injections. Intracordal injection of steroid or basic fibroblast growth factor (bFGF) has been recently found to be useful for treating vocal fold scarring that does not respond to voice therapy. Methods: This retrospective study involved the administration of steroid injection and bFGF injection bilaterally under local anesthesia in 16 patients each. Laboratory measurements of voice parameters were performed before and 3-6 months after injection. Results: In the steroid injection group, the Voice Handicap Index (VHI) score significantly improved from 57.1 to 40.5, total Grade, Roughness, Breathiness, Asthenia, Strain (tGRBAS) score significantly improved from 4.2 to 2.6, and mean speech fundamental frequency (SFF) increased from 192.5 to 211.4 dB, but there was no improvement in maximum phonation time (MPT) and mean airflow rate (MFR). In the bFGF injection group, significant improvements in the VHI score (from 53.3 to 35.7), MPT (from 16.9 to 21.8 s) and MFR (from 314.6 to 210.5 ml/s) were seen; however, the tGRBAS score did not improve. In addition, the SFF significantly decreased from 178.1 to 160.5 Hz. Conclusion: These results suggest that both steroid and bFGF injections are effective for treating vocal fold scarring, with steroids improving voice quality and bFGF improving glottic closure, thereby contributing to improvements in VHI scores. Level of Evidence: 4.

Long-term results and safety of fibroblast growth factor injection for unilateral vocal fold paralysis.

Objectives: Treatments for unilateral vocal fold paralysis (UVFP) include conservative voice rehabilitation, vocal fold injection, and laryngeal framework surgery. We proposed basic fibroblast growth factor (bFGF) injection as a potential novel treatment for UVFP and have reported the short-term results. In this study, we present the long-term results and safety of vocal fold bFGF injection as a treatment for UVFP. Methods: This retrospective study included 42 patients (25 males and 17 females) with UVFP who were administered a local injection of bFGF. The injection regimen involved injecting FGF (0.5 µg/ml in 0.5 ml per side) into the bilateral vocal folds using a 23-gauge injection needle. Phonological outcomes were evaluated 6 months and 12 months after the injection. Results: Overall, 26 patients received a single injection of bFGF, six patients received an additional injection, and 10 patients received the additional framework surgery. Maximum phonation time, mean flow rate, pitch range, jitter and shimmer percentages, the total GRBAS (grade, roughness, breathiness, asthenia, strain) score, and voice handicap index scores improved significantly in the long term. In patients who received the additional injection or framework surgery, the effects of bFGF injection were temporary, but did not interfere with the performance of the framework surgery. Conclusion: In total, 42 patients who underwent vocal fold bFGF injections were reviewed. The bFGF injections were effective and safe in the long-term results for UVFP in the selected cases. Some patients with severe symptoms benefited from the additional framework surgery but not the additional bFGF injection.

Azelnidipine treatment reduces the expression of Cav1.2 protein.

AIMS: Azelnidipine, a third-generation dihydropyridine calcium channel blocker (DHP CCB), has a characteristic hypotensive effect that persists even after it has disappeared from the plasma, which is thought to be due to its high hydrophobicity. However, because azelnidipine is unique, it might have other unknown effects on L-type Cav1.2 channels that result in the long-lasting decrease of blood pressure. The aim of this study was to investigate the potential quantitative modification of Cav1.2 by azelnidipine. MAIN METHODS: HEK293 cells were used to express Cav1.2 channels. Immunocytochemical analysis was performed to detect changes in the surface expression of the pore-forming subunit of the Cav1.2 channel, Cav1.2α1c. Western blotting analysis was performed to evaluate changes in expression levels of total Cav1.2α1c and Cavß2c. KEY FINDINGS: The surface expression of Cav1.2α1c was markedly reduced by treatment with azelnidipine, but not with other DHP CCBs (amlodipine and nicardipine). Results obtained with a dynamin inhibitor and an early endosome marker suggested that the reduction of surface Cav1.2α1c was not likely caused by internalization. Azelnidipine reduced the total amount of Cav1.2α1c protein in HEK293 cells and rat pulmonary artery smooth muscle cells. The reduction of Cav1.2α1c was rescued by inhibiting proteasome activity. In contrast, azelnidipine did not affect the amount of auxiliary Cavß2c subunits that function as a chaperone of Cav1.2. SIGNIFICANCE: This study is the first to demonstrate that azelnidipine reduces the expression of Cav1.2α1c, which might partly explain its long-lasting hypotensive effect.

Malignancies in Patients with IgG4-Related Diseases in Head and Neck Regions.

Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized disease, characterized by high serum IgG4 concentrations and IgG4-producing plasma cell expansion with fibrotic or sclerotic changes in affected organs. Recent work has focused on the relationship between IgG4-RD and malignancies, but there is no report of malignancies associated with IgG4-RD in head and neck regions. The aim of this study was to analyze the clinicopathological characteristics of malignancies in patients with IgG4-RD in head and neck regions. We retrospectively analyzed 26 patients with IgG4-RD (12 men and 14 women aged 60.6 ± 11.6 years). The mean follow-up period was 26.6 months (from 12 to 96 months). These patients were divided into single-lesion group (n = 12) with IgG4-RD only in head and neck regions and multiple-lesion group (n = 14) with IgG4-RD in other regions. There was no significant difference in serum IgG4 concentrations between the single-lesion group (459.4 ± 336.4 mg/dL) and the multiple-lesion group (908.0 ± 739.2 mg/dL) (P = 0.07), whereas the IgG4/IgG ratio was significantly lower in the single-lesion group (22.8 ± 11.0%; n = 11) compared with the multiple-lesion group (31.7 ± 15.0%; n = 11, P = 0.02). Among the 26 patients, two patients (7.7%), both in the multiple-lesion group, developed life-threatening malignancies (salivary duct carcinoma in the submandibular gland and lymphoma in the orbital tissue). All physicians need to keep in mind the possible coexistence of malignancies in patients with IgG4-RD with high IgG4/IgG ratio and multiple lesions at the time of diagnosis.

KCNQ1 is internalized by activation of α1 adrenergic receptors.

KCNQ1 (Kv7.1 or KvLQT1) plays important physiological roles in various tissues forming potassium channels with KCNE subunits. Among the channels formed by KCNQ1 and KCNE subunits, the best studied is the slow delayed rectifier potassium channel in the heart, the IKs (KCNQ1/KCNE1) channel, which is critical for repolarization of cardiac action potential. The KCNQ1 channel is internalized by Nedd4/Nedd4-like ligase-dependent ubiquitination. It is also reported that phosphorylation of KCNE1 by PKC results in internalization of the KCNQ1/KCNE1 channel. Because we have observed down-regulation of KCNQ1/KCNE1 currents by activation of the α1-adrenergic receptor (α1AR) that activates PKC, this study investigated whether α1AR causes internalization of the KCNQ1 protein. We fused HaloTag to the extracellular region of KCNQ1 (Halo-KCNQ1) and co-expressed it with α1ARs in HEK293 cells. The KCNQ1 protein on the cell surface was selectively labeled with membrane-impermeable HaloTag ligands, and changes in its localization were monitored by confocal fluorescence microscopy. Activation of α1AAR and α1BAR caused marked internalization of KCNQ1, which was not KCNE1-dependent. Internalization of KCNQ1 by α1AR activation was inhibited by disruption of the PY motif or the YXXΦ motif in the C-terminus. Double staining for the receptor and the channel revealed that KCNQ1 internalization was independent of α1AR internalization. Our results suggest that α1AR-mediated direct internalization of KCNQ1 is AP2/clathrin-dependent and may be triggered by ubiquitination of KCNQ1 via the AMP dependent kinase (AMPK)/Nedd4-2 pathway. When phenylephrine was applied to rat neonatal cardiomyocytes transfected with KCNQ1 and α1AR, the KCNQ1 protein was internalized. The internalization of KCNQ1 by α1AR would affect pathophysiology in a variety of tissues expressing KCNQ1, which merits further in vivo study.

Safety and short-term outcomes of basic fibroblast growth factor injection for sulcus vocalis.

BACKGROUND: Sulcus vocalis (SV) is characterized by the appearance of a groove and fibrotic changes in the vocal fold mucosa and an often irrevocable loss of tissue viscoelasticity and vibratory potential. Although several surgical approaches have been proposed, none are ideal treatments. Basic fibroblast growth factor (bFGF) may stimulate fibroblasts in the superficial layer of the lamina propria (SLP) and increase the vibration of vocal fold mucosa. AIMS/OBJECTIVES: The aim of this study was to evaluate the safety and short-term outcomes of bFGF injection for SV. MATERIALS AND METHODS: This study was registered with the University Hospital Medical Information Network-Clinical Trials Registry (UMIN000019347). Twelve cases of pathological SV were treated using a method involving bFGF injection. The treatment regimen involved the injection of 50 µg of bFGF into the SLP. More than 3 months after the injection, aerodynamic and acoustic outcomes were examined. RESULTS: No adverse events were recorded. Significant improvements were observed in the maximum phonation time (MPT) and Voice Handicap Index (VHI) after treatment. Multiple injections achieved additional effects. CONCLUSIONS AND SIGNIFICANCE: bFGF injection may be a safe and suitable office-based surgery for the alleviation of hoarseness caused by SV based on this preliminary short-term study.

Injection of basic fibroblast growth factor for unilateral vocal cord paralysis.

OBJECTIVE: Unilateral vocal cord paralysis (UVCP) not only induces severe dysphonia, but aspiration as well. Although laryngeal framework surgery is usually performed to treat this condition, the procedure is not tolerated by some patients. In the previous study, basic fibroblast growth factor (bFGF) injections for vocal cord scarring and sulcus have been reported to provide favorable outcomes while being minimally invasive. In this study, the authors retrospectively investigated phonological outcomes after bFGF injection in patients with UVCP. METHODS: This study was registered in University hospital Medical Information Network - Clinical Trials Registry (UMIN000019347). Nineteen patients with unilateral cord paralysis were treated with bFGF injection. The treatment regimen involved a single injection of 50 µg of bFGF into the muscle layer. More than six months after the injection, aerodynamic and acoustic outcomes were examined. RESULTS: The voice handicap index, maximum phonation time, mean airflow rate, and pitch range improved significantly after injection of bFGF. No sex-related differences were observed in any phonological parameter. CONCLUSION: bFGF injection, an easy method and suitable as an office procedure, significantly improved the hoarseness caused by UVCP. It is expected to be widely adopted and effective adjunctive drugs, and procedures are anticipated to be developed.

Epstein-Barr virus in the enlarged salivary tissues of patients with IgG4-related disease.

OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized disease entity characterized by high-serum IgG4 concentration and IgG4-producing plasma cell production with fibrotic or sclerotic changes in affected organs. We aimed to clarify the roles of Epstein-Barr virus (EBV) in patients with IgG4-RDs. STUDY DESIGN AND SETTING: A retrospective clinical study at the Yamagata University School of Medicine, Yamagata, Japan. METHODS: The patient group consisted of four males and four females with an average age of 62 years (range: 48-73). Expression of IgG4, latent member protein 1, EBV nuclear antigens-2, and EBV-encoded RNA in affected salivary glands from patients with IgG4-RD was examined by using immunohistochemistry and in situ hybridization. The copy number of EBV DNA in the salivary glands was also investigated by real-time polymerase chain reaction. RESULTS: All patients had hard masses in the salivary or lacrimal glands, or both, bilaterally. Serum concentrations of IgG4 were elevated in all cases (mean 589.1, range 129-1750), and IgG4-positive plasmacytes were observed in the involved salivary glands. Four patients developed potentially life-threatening systemic involvement after initial salivary gland swelling. EBV-associated molecules (EBNA and EBER) were overexpressed in the affected salivary glands. The copy number of EBV DNA was significantly higher in patients with potentially life-threatening systemic involvement than in patients without systemic involvement (P < 0.05). CONCLUSION: These results suggest that the copy number of EBV DNA could be useful as diagnostic findings in IgG4-RD to predict potentially life-threatening systemic involvement. LEVEL OF EVIDENCE: 4.

Expressions and roles of periostin in otolaryngological diseases.

Periostin is a 90-kDa member of the fasciclin-containing family; it functions as part of matricellular proteins, and its production by airway epithelial cells is induced by IL-4 and IL-13. Periostin is secreted by fibroblasts and upregulated in the airway epithelia of patients with bronchial asthma; it is considered to contribute to remodeling under this pathological condition. However, despite many studies in diverse research areas, our overall understanding of this intriguing molecule is still inadequate. Here, we integrate the available evidence on periostin expression and its roles in otolaryngological diseases, including allergic rhinitis, chronic rhinosinusitis with nasal polyps, aspirin-induced asthma, organized hematoma, eosinophilic otitis media, and IgG4-related disease. Periostin might be involved as an important structural mediator in pathological processes such as insult and injury, Th2-driven inflammation, extracellular matrix restructuring, fibrosclerosis, tumor angiogenesis, and tissue remodeling.

OK-432 treatment of ranula extending to the parapharyngeal space.

CONCLUSIONS: Our results confirmed that OK-432 therapy is simple, easy, safe, and effective and can be used as a substitute for surgery in the treatment of ranula extending to the parapharyngeal space. OBJECTIVE: The aim of this study was to evaluate the outcome and complications of the OK-432 treatment of patients with ranula extending to the parapharyngeal space. METHODS: This was a case series with planned data collection at Yamagata University and Fukase clinic. We tried this therapy in six patients with ranula extending to the parapharyngeal space, between January 2001 and February 2012. We injected OK-432 solution into the lesion with an 18 or 27 gauge needle depending on the patient's condition (location and size of ranula and complications). This treatment was performed on an outpatient basis without hospitalization. RESULTS: Disappearance or marked reduction of the lesion were observed in all patients who had this therapy, and local scarring and deformity of the injection sites did not occur in any patients. As side effects, local pain at the injection site and fever (37-39°C) were observed in 40% of the patients who had this therapy, but such problems resolved within a few days.

Roles of TGF-beta and periostin in fibrosclerosis in patients with IgG4-related diseases.

CONCLUSION: These results suggest that transforming growth factor (TGF)-beta and periostin could be useful as novel biomarkers and therapeutic targets in IgG4-related disease. OBJECTIVES: IgG4-related disease is an uncommon fibrosclerosing and inflammatory mass-forming disease that can be systemic or can affect single organs. To clarify the roles of TGF-beta, periostin, and interleukin (IL)-13 in the pathogenesis of IgG4-related disease, we studied a total of 36 serum and 11 tissue samples from patients with IgG4-related disease. METHODS: This was a retrospective clinical study. The patient group consisted of six females and seven males (average age 60 years, range 38-74 years). Serum IgG4 levels, the tissue density of IgG4-positive plasmacytes, and the expression of TGF-beta and periostin in the affected tissues were examined immunohistochemically. RESULTS: Serum IgG4 levels were elevated in all patients (mean 776.6, range 185-2820 mg/dl), and IgG4-positive plasmacytes were observed in the affected salivary glands. Seven patients with prominent infiltration of the involved glands with IgG4-positive plasmacytes had fatal systemic complications, including pancreatitis, after swelling of the salivary glands. Overexpression of TGF-beta and periostin was observed in affected tissues obtained from these patients.

Aortic aneurysm rupture as a rare complication of granulomatosis with polyangiitis: a case report.

INTRODUCTION: Granulomatosis with polyangiitis is characterized by systemic inflammation of medium and small blood vessels. Aortic involvement in granulomatosis with polyangiitis is extremely rare. As far as we know this is the first reported case of successful treatment in a patient with granulomatosis with polyangiitis complicated with aortic aneurysm rupture. CASE PRESENTATION: We describe a case of granulomatosis with polyangiitis in a 38-year-old Japanese man who developed an aortic aneurysm rupture 22 years after disease onset. The patient was operated on and a J-graft was inserted. He recovered uneventfully. CONCLUSION: Recommendations in regard to, and consideration of, aortic involvement should be kept in mind in the long-term careful follow up of granulomatosis with polyangiitis.

Roles of IL-17, Th1, and Tc1 cells in patients with IgG4-related sclerosing sialadenitis.

OBJECTIVES/HYPOTHESIS: Immunoglobulin G4 (IgG4)-related sclerosing sialadenitis is a recently recognized disease entity characterized by high serum IgG4 concentration and IgG4-producing plasma cell expansion in affected organs, which show fibrotic or sclerotic changes. However, little is known about the roles of CD4+ and CD8+ T cells or interleukin (IL)-17 in this disease. The purpose of this study was to evaluate the characteristics of CD4+ and CD8+ T cells and IL-17 in patients with IgG4-related sclerosing sialadenitis. STUDY DESIGN: A retrospective clinical study at the Yamagata University School of Medicine. METHODS: The patient group consisted of six males and four females with an average age of 57.9 years (range, 38 to 73 years). Subsets of T helper (Th)1, Th2, T cytotoxic type (Tc)1, and Tc2 cells from patients with IgG4-related sclerosing sialadenitis were examined by using intracellular cytokine flow cytometry. Expression of IL-17 in the patients' lesions was also investigated immunohistochemically. RESULTS: Six patients with IgG4-related sclerosing sialadenitis with high ratios of IgG4/IgG and prominent infiltration of IgG4-positive plasmacytes in the involved salivary glands had systemic complications, including pancreatitis, retroperitoneal fibrosis, and/or inflammatory pseudotumor of the lung after the initial swelling of the salivary glands. Populations of Th1 and Tc1 cells were significantly greater in IgG4-related sclerosing sialadenitis than in the controls (P < .05), but Th2 and Tc2 cell populations were not significantly increased. Expression of IL-17 was observed in the lesions of affected patients. CONCLUSIONS: Increases in Th1 and Tc1 cell populations and IL-17 expression might be involved in the mechanism of pathogenesis of IgG4-related sclerosing sialadenitis.

Clinical and pathological characteristics of IgG4-related sclerosing sialadenitis.

OBJECTIVES/HYPOTHESIS: A new concept of IgG4-related sclerosing sialadenitis characterized by high serum IgG4 levels and tissue infiltration of IgG4-expressing plasmacytes has recently been proposed. To determine appropriate serum levels of IgG4 for monitoring disease activity, a total of 36 serum samples and eight tissue samples from patients with IgG4-related sclerosing sialadenitis were studied. STUDY DESIGN: A retrospective clinical study at Yamagata University School of Medicine. METHODS: The patient group consisted of six males and four females with an average age of 60 years (range, 47-74 years). Serum levels of IgG4 and the density of IgG4-positive plasmacytes in affected tissues were studied. RESULTS: All patients had elevated serum IgG4 levels (>135 mg/dL), and IgG4-positive plasmacytes (IgG4+ plasma cells/IgG+ plasma cells >50%) were observed in the involved salivary glands. Six patients with IgG4-related sclerosing sialadenitis with high IgG4/IgG ratios and prominent infiltration of IgG4-positive plasmacytes in the involved salivary glands had systemic complications, including pancreatitis, retroperitoneal fibrosis, and/or inflammatory pseudotumor of the lung after swelling of the salivary glands. All six of these patients were successfully treated with systemic corticosteroids. CONCLUSIONS: In the six patients with systemic complications, treatment with systemic corticosteroids reduced the salivary gland enlargement and lowered serum IgG4 concentrations. These results suggest that IgG4 plays an important role in the pathogenesis of IgG4-related sclerosing sialadenitis, and that IgG4 levels and IgG4/IgG ratios may be used as additional indicators of disease activity and as biomarkers for potential life-threatening complications.