A novel mutation in COL1A1 causing osteogenesis imperfecta/hearing loss

Abstract Objectives: To screen the COL1A1 and COL1A2 gene mutation sites in a family with type I osteogenesis imperfecta (OI)/hearing loss and analyze the characteristics and recovery of hearing loss in patients with osteogenesis imperfecta. Methods: The basic clinical data of Ol proband and her parents were collected, and the COL1A1 and COL1A2 genes were detected in peripheral blood by PCR amplification and generation Sanger sequencing. Literature of stapedial surgery in patients with osteogenesis imperfecta was collected. Results: The heterozygous mutation of the 26 exon c.1922_1923 ins C in the Ol progenitor COL1A1 gene led to the amino acid frameshift mutation of p.Pro 601FS, which was not detected in the phenotypic parents. The homozygous of exon 28 c.1782>G in COL1A2 was detected in the proband and her parents, resulting in changes in the protein p.Pro 549Ala. Conclusion: The clinical symptoms of the Ol proband is caused by heterozygous mutation of the 26 exon c.1922_1923 ins C in COL1A1 gene. Stapedial surgery can provide short-term and long-term hearing benefits for Ol patients with hearing loss. Level of evidence: Level 4.

A novel mutation in COL1A1 causing osteogenesis imperfecta/hearing loss.

OBJECTIVES: To screen the COL1A1 and COL1A2 gene mutation sites in a family with type I osteogenesis imperfecta (OI)/hearing loss and analyze the characteristics and recovery of hearing loss in patients with osteogenesis imperfecta. METHODS: The basic clinical data of OI proband and her parents were collected, and the COL1A1 and COL1A2 genes were detected in peripheral blood by PCR amplification and generation Sanger sequencing. Literature of stapedial surgery in patients with osteogenesis imperfecta was collected. RESULTS: The heterozygous mutation of the 26 exon c.1922_1923 ins C in the OI progenitor COL1A1 gene led to the amino acid frameshift mutation of p.Pro 601FS, which was not detected in the phenotypic parents. The homozygous of exon 28 c.1782>G in COL1A2 was detected in the proband and her parents, resulting in changes in the protein p.Pro 549Ala. CONCLUSION: The clinical symptoms of the OI proband is caused by heterozygous mutation of the 26 exon c.1922_1923 ins C in COL1A1 gene. Stapedial surgery can provide short-term and long-term hearing benefits for OI patients with hearing loss. LEVEL OF EVIDENCE: Level 4.

Individual treatment strategy of thyroglossal duct cyst carcinoma: a case report.

Background: Neoplasia of ectopic thyroid components is relatively rare in thyroglossal duct cysts. We report a case of histopathologically confirmed papillary thyroid carcinoma in a thyroglossal duct cyst, discuss its clinical characteristics of, and provide reference for diagnosis and treatment. Case Description: We presented a 25-year-old female went to hospital because of "a tumor in her neck". She was preoperatively diagnosed with thyroglossal duct cyst by cervical ultrasound, and enhanced computed tomography (CT). However, the solid component of the mass suggested intracystic neoplasia. She underwent Sistrunk surgical resection, and postoperative histopathology showed thyroglossal duct cyst, and papillary thyroid carcinoma in the cyst wall. The patient had no high-risk factors and had a low risk of recurrence. After full disclosure, the patient chose close follow-up, and to date there has been no recurrence. Conclusions: There are controversies regarding the origin of thyroglossal duct cyst carcinoma and the extent of surgery required, and a lack of unified treatment guidelines. We recommend tailoring individualized treatment based on individual risk stratification. By reporting this case, we hope to inform surgeons of the various abnormalities that may occur in ectopic thyroid tissue.

Effect of treatment modality on the long-term survival of patients with early glottic squamous cancer: a retrospective cohort study based on the SEER database.

Background: The optimal treatment strategy for patients with early glottic (T1-2N0M0) squamous cancer remains unclear. Methods: A retrospective population-based analysis was performed using the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was used to balance treatment arms, and Cox regression analysis was used to determine prognostic factors for survival. Kaplan-Meier analysis, log-rank tests, and competing risk analysis were used to compare survival outcomes between treatment modalities (surgery vs. radiotherapy). Results: Among the 3,994 eligible patients in this study, surgery was associated with improved cancer-specific survival (CSS) and overall survival (OS) compared with radiotherapy (log-rank test, P<0.05). This survival trend favoring surgery was consistent in the T1a, well/moderately differentiated grade, male, and all age subgroups. However, after the baseline characteristics were balanced with PSM, the survival outcomes (CSS and OS) did not differ significantly between the surgery and radiotherapy groups. Interestingly, surgery was associated with a 39% reduced risk of cancer-related death compared with radiotherapy in patients aged ≥70 years (hazard ratio 0.61; 95% CI: 0.43-0.87; P=0.006). However, this survival trend favoring surgery was not observed in younger patients (age <70 years), T stage subgroups, male or female subgroups, or in any of the pathological grade subgroups. Conclusions: In patients with early glottic squamous cell carcinoma undergoing surgery or radiotherapy, there is no sufficient evidence favoring one method over another in terms of survival. However, surgery is recommended in patients aged ≥70 years because, in this group, it was associated with improved survival outcomes compared with radiotherapy.

Sox10 Gene Is Required for the Survival of Saccular and Utricular Hair Cells in a Porcine Model.

Pathological changes of the cochlea and hearing loss have been well addressed in Waardenburg syndrome (WS). However, the vestibular organ malformation in WS is still largely unknown. In this study, the differentiation and development of vestibular sensory epithelium and vestibular function caused by SOX10 mutation, a critical gene induces WS, have been studied in minature pig model. Degeneration of vestibular hair cells was found in this Sox10 mutation porcine model. Inner ear phenotype of the SOX10+/R109W miniature pigs showed cochlear abnormalities as well as saccular hypofunction. In the mutant pigs, no prominent dissimilarity was shown in the bone structure of the semicircular canals. However, the saccular membrane was collapsed, and the infusion of stereocilia of the hair cells was observed. There were no dark cells in the utricles in the mutant pigs. The density of the utricular hair cells was also significantly lower in the mutant pigs compared to the wild type. Our study demonstrated that the SOX10 gene and melanocytes play important roles in the vestibular organ development. Sox10 mutation disrupts the KIT-DCT signaling pathway, affects the development of melanocytes, and leads to vestibule morphogenesis.

The Impact of Electroacupuncture Early Intervention on the Brain Lipidome in a Mouse Model of Post-traumatic Stress Disorder.

The neuroprotective effect of electroacupuncture (EA) treatment has been well studied; growing evidence suggests that changes in lipid composition may be involved in the pathogenesis of post-traumatic stress disorder (PTSD) and may be a target for treatment. However, the influence of early EA intervention on brain lipid composition in patients with PTSD has never been investigated. Using a modified single prolonged stress (mSPS) model in mice, we assessed the anti-PTSD-like effects of early intervention using EA and evaluated changes in lipid composition in the hippocampus and prefrontal cortex (PFC) using a mass spectrometry-based lipidomic approach. mSPS induced changes in lipid composition in the hippocampus, notably in the content of sphingolipids, glycerolipids, and fatty acyls. These lipid changes were more robust than those observed in the PFC. Early intervention with EA after mSPS ameliorated PTSD-like behaviors and partly normalized mSPS-induced lipid changes, notably in the hippocampus. Cumulatively, our data suggest that EA may reverse mSPS-induced PTSD-like behaviors due to region-specific regulation of the brain lipidome, providing new insights into the therapeutic mechanism of EA.

Primary Middle Ear Meningioma with Intact Tympanic Membrane: A Case Report and Literature Review.

Primary ectopic meningioma of the middle ear is relatively rare in clinical practice. It is often difficult to distinguish it from chronic otitis media or otitis media with effusion due to its similar and atypical clinical symptoms. We report a case of epithelial tympanic ectopic meningioma with the main complaints of otalgia, aural fullness, and hearing loss. It was accidentally discovered during tympanotomy due to the symptoms of recurring refractory secretory otitis media. This article briefly reviews the relevant literature in recent years, summarizes the characteristics of primary ectopic tympanic meningioma with intact tympanic membrane, and emphasizes the diagnosis and treatment strategy of the middle ear mass.

Migraine and Cochlear Symptoms.

Migraine is one of the most common and highest burdens of disease. As a primary cerebral dysfunction illness, migraine might exhibit other system-related symptoms, including vestibular and cochlear symptoms. With the publication of the diagnostic criteria of vestibular migraine, the link between migraine and vestibular symptoms became clear. However, the relationship between migraine and cochlear symptoms is far from straightforward. Therefore, we focus on the correlation between migraine and deafness, sudden sensorineural hearing loss, acute tinnitus, and chronic tinnitus to better understand the relationship between migraine and cochlear symptoms.

An Integrated Physical Regulation Theory and Classification of Acute Tinnitus.

Tinnitus, acute or chronic, is one of the most common and refractory disorders. Acute tinnitus is a symptom that is a warning sign when compared with chronic tinnitus. Although hearing loss initiates acute tinnitus, the relationship between hearing loss and tinnitus is far from straightforward. Other factors beyond the auditory system may play important roles in the occurrence of acute tinnitus. To address this issue, we propose an integrated regulation theory of the possible physical causes of acute tinnitus, and summarize a classification system for acute tinnitus based on this regulation theory to help guide clinical treatment.

Properties of a Novel Animal Model of LPR.

BACKGROUND: Few satisfactory animal models of laryngopharyngeal reflux (LPR) is available. Interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) may be associated with the pathogenesis of LPR injuries and laryngeal carcinomas. OBJECTIVES: To establish an animal model of LPR and to explore the related pathological changes and cytokine expression in the vocal cord tissue. METHODS: Twenty rabbits were divided into experimental and control groups. Dilatation of the upper and lower esophageal sphincter were carried out in the experimental group. The pH of the pharynx, pathological, and ultrastructural changes of the laryngeal tissue, and expression of IL-8 and VEGF were compared between the experimental group and controls. RESULTS: pH monitoring results and the dilated intercellular space of the vocal cord mucosa showed that the experimental group developed laryngopharyngeal reflux. There were significant differences in the immunohistochemical staining scores of both IL-8 (P = 0.015) and VEGF (P = 0.007) between the experimental and control groups in the vocal cord tissue. CONCLUSIONS: We successfully established a model of LPR, showing histopathological and ultrastructural changes consistent with the disease. The expression of IL-8 and VEGF may increase during the pathogenesis of LPR.

Whole exome sequencing of multiple meningiomas with varying histopathological presentation in one patient revealed distinctive somatic mutation burden and independent clonal origins.

Background: Although meningiomas are common intracranial tumors, multiple meningiomas (MMs) are rare entities in patients without neurofibromatosis type 2. Previous studies suggest most sporadic MMs are of monoclone in origin. Objective: To elucidate the clonal relationship between two sporadic meningiomas from the same patient by using the next-generation sequencing (NGS) platform. Methods: Two MMs, located frontally and parietally on the right side, were surgically removed from a 52-year-old male. Pathological examinations and whole exome sequencing were performed on tumor samples, followed by Sanger sequencing validation. Results: MMs were diagnosed as secretory and fibrous subtypes, respectively, on histology (WHO grade I) and tumor DNA exhibited distinctive somatic mutation patterns. Specifically, the secretory subtype carried more single nucleotide variant while the fibrous subtype had much higher copy number variation. Besides, the two tumors demonstrated different mutation profiles in predisposing genes and known driver mutations. For example, the secretory subtype had missense mutations in TRAF7 and KLF4, while the fibrous subtype had frameshift deletion of NF2 gene in addition to copy number loss of NF2 and SMARCB1, genetic events that have already been associated with the development of meningiomas. Significantly mutated gene analysis revealed novel mutations of LOC729159 in the secretory subtype and RPGRIP1L and DPP6 in the fibrous subtype. Sanger sequencing validated important point mutations in TRAF7 (c.1678G>A, p.G560S), KLF4 (c.1225A>C, p.K409Q) and CDH11 (c.169T>G, p.W57G). Conclusion: Our data suggest the two meningiomas might develop independently in this patient and molecular subtyping by NGS is a valuable supplement to conventional pathology. Further study is needed to ascertain whether these novel genetic events are tumorigenic or simply passenger mutations, as well as their clinical implications.

The effects of tumor size and postoperative radiotherapy for patients with adult low-grade (WHO grade II) infiltrative supratentorial astrocytoma/oligodendroglioma: A population-based and propensity score matched study.

BACKGROUND: The update of 2018 NCCN guidelines (central nervous system cancers) recommended the risk classification of postoperative patients diagnosed as adult low-grade (WHO grade II) infiltrative supratentorial astrocytoma/oligodendroglioma (ALISA/O) should take tumor size into consideration. Moreover, the guidelines removed postoperative radiotherapy (PORT) for low risk patients. Our study aimed to explore the specific tumor size to divide postoperative patients into relatively low- or high risk subgroups and the effect of PORT for ALISA/O patients. METHODS: We conducted a retrospective study choosing 1277 postoperative ALISA/O patients from the Surveillance, Epidemiology, and End Results database. The X-tile analysis provided the optimal cutoff point based on tumor size. The differences between surgery alone and surgery +RT groups were balanced by propensity score-matched analysis. The multivariable analysis and the nomogram evaluated multiple prognostic factors based on cancer-specific survival (CSS) and overall survival (OS). RESULTS: X-tile plots defined 59 mm (P < 0.001) as the optimal cutoff tumor size value in terms of CSS, which was verified in multivariate analysis (P < 0.001). The Kaplan-Meier analysis showed that the surgery alone had higher CSS and OS than surgery +RT, while the low risk group had no statistical significance after propensity score match. Multivariable analysis showed that surgery +RT was independently associated with diminished OS and CSS for high risk group, which had no statistical significance for low-risk group. CONCLUSIONS: Our study suggested that tumor size of 59 mm was an optimal cutoff point to divide postoperative patients into relatively low- or high risk subgroups. PORT may not benefit patients, while the effects of PORT for low risk patients need further research.

Inhibition of the CyclinD1 promoter in response to sonic hedgehog signaling pathway transduction is mediated by Gli1.

Medulloblastoma (MB) is the most common malignant tumor of the central nervous system in children. Accumulating evidence suggests a major role for the activation of the sonic hedgehog (SHH) signaling pathway in the development of MB cells; however, the mechanisms underlying the effect of this pathway on tumor survival and growth remain poorly understood. The Gli family zinc finger 1 (Gli1) transcription factor is considered as a mediator of the SHH signaling pathway in MB cells. Therefore, the present study investigated whether the SHH signaling pathway promotes the apoptosis of MB cells via downregulation of Gli1. GANT61, a novel Gli1 inhibitor, is known to have an in vitro activity against tumors. In the current study, Daoy cells were treated with different concentrations of GANT61 for 24 h, and the effect on cell proliferation was assayed by cell counting kit-8 assay. In addition, the cell cycle progression and apoptosis were assayed by flow cytometry analysis and hematoxylin-eosin (HE) staining. The effects of GANT61 treatment on SHH signaling pathway at the mRNA level were assayed by polymerase chain reaction (PCR). To further elucidate the inhibitory effects of GANT61 on the expression of Gli1 and CyclinD1, their protein levels were examined by western blot and immunofluorescence. The results indicated that GANT61 significantly inhibited the proliferation of Daoy cells in a dose-dependent manner, compared with the control group (P<0.05). HE staining revealed that cells had increasingly abnormal protuberance with increasing GANT61 concentration. Flow cytometry analysis also demonstrated that GANT61 induced G1/S arrest and apoptosis of Daoy cells in a dose-dependent manner (P<0.05). Gli1 and CyclinD1 mRNA expression levels were downregulated by GANT61 treatment (P<0.05); similarly, their protein levels were downregulated by GANT61 treatment in a dose-dependent manner (P<0.05). In conclusion, Gli1 expression was significantly associated with CyclinD1 expression in MB. These data demonstrated that Gli1 is an important mediator of the SHH pathway activity in MB, and may be a novel agent for use in combined chemotherapeutic regimens.

Suppression of GLI sensitizes medulloblastoma cells to mitochondria-mediated apoptosis.

PURPOSE: The sonic hedgehog (SHH) signalling pathway plays the important role in medulloblastoma (MB). Altered GLI expression plays a key role in these processes, and the inhibition of GLI may be a good cancer-targeted therapy. This study aimed to investigate whether GANT61, a GLI inhibitor, may inhibit the SHH signalling pathway promoting cell mitochondria-mediated apoptosis and enhance cisplatin apoptosis antineoplastic therapy. METHODS: In our study, we determined the effect of GANT61-mediated inhibition of GLI in Daoy MB cells. Cells were treated with different concentrations of GANT61 alone or in combination with cisplatin. Cell proliferation was assessed with CCK-8 assays, and cell invasion and migration were performed using 8-µm transwell inserts. Cell apoptosis was assessed with flow cytometric analysis and rhodamine 123. qPCR was used to complete RNA experiments. Protein expression was assessed with Western blotting. RESULTS: The GANT61 significantly inhibited cell proliferation. GANT61 decreased the cell migration and invasion, impairing these crucial steps in tumour progression. Cell apoptosis was significantly increased in Daoy cells. Rhodamine 123 assay showed that GANT61 could decrease the mitochondrial membrane potential promoting cell mitochondria-mediated apoptosis. GANT61 inhibited the expression of GLI and Bcl-2 at both the mRNA and protein levels and might affect the expression of Bax, caspase-3 and caspase-9 to promote cell intrinsic apoptosis. Furthermore, GANT61 could enhance cisplatin-induced apoptosis to decrease the IC50 value of cisplatin. Finally, data suggest that GANT61 could enhance cisplatin-induced apoptosis through promoting the expression of Bax, caspase-3 and caspase-9 protein levels. CONCLUSION: Our data suggest that the SHH signalling pathway plays an important role in MB. GLI is an oncogenic transcription factor in the SHH pathway, and targeting GLI with GANT61 results in favourable antitumour activity and targeted therapy.

[Development of the mastoid air cells and its relationship to Ménière's disease].

OBJECTIVE: To investigate the fundamental pathological anatomy and possible pathogenetic factors of Ménière's disease(MD), we compared the types of mastoid air cells between the MD group and the control group. METHODS: The MD group had 113 ears and the control group had 100 ears. Temoral bone CT scanning was performed in all the subjects. The types of mastoid air cells were determined by surgical findings and imaging data. All the mastoid air cells were divided into diploetic type, gasified type and sclerosis type. Analysis of the proportion of different types and the statistical analysis were performed between the two groups. RESULTS: 51.4% (57/113) in the MD group and 18.0% (18/100) in the control group were diploetic type mastoid, the difference was significant (χ(2) = 24.476, P < 0.001). The gasified type was 43.4% (49/113) in the MD group and 77.0% (77/100) in the control group, the difference was significant (χ(2) = 24.843, P < 0.001). The sclerosis type was 6.2% in the MD group and 5.0% (5/100) in the control group, and there was no statistical significance (χ(2) = 0.142,P > 0.05). CONCLUSIONS: The mastoid air cells are dysplasia in MD patients, and it may be one of the fundamental pathological anatomy. The long-term ventilation and drainage disorder and recurrent inflammation attack may play an important role in occurrence, development and prognosis of MD.

[Relationship between the tinnitus frequency and the effects of medication and the prognosis in patients with chronic subjective tinnitus].

OBJECTIVE: To investigate the influence of tinnitus frequency on medication and prognosis in patients with chronic subjective tinnitus. METHODS: Seventy-two patients (Ninety-three ears) diagnosed as chronic subjective tinnitus were studied from October 2010 to March 2011. All cases were divided into low frequency(twenty-three ears), medium frequency(fourteen ears) and high frequency (fifty-six ears) according to tinnitus matching test. All cases were treated with microcirculation promotion and steroid therapy (5% glucose 250 ml + ginkgo biloba extract 87.5 mg + dexamethasone 10 mg intravenous drip). Curative effect was evaluated and the factors of prognosis were analyzed after three weeks. RESULTS: After medication, results were acquired as follows: recovery in 0 ear (0%), excellent in 0 ear (0%), effective in 18 ears (19.4%), invalid in 75 ear (80.6%). The effective percentage was 39.1%, 35.7% and 7.1%, respectively. There was significant difference between these groups, but no significant difference between low frequency and medium frequency. Logistic regression analysis showed that the difference of frequency was significant prognostic factors for medication. CONCLUSIONS: Microcirculation promotion and steroid therapy had a poor treatment effect in patients with chronic subjective tinnitus. The prognosis of chronic low-medium frequency tinnitus was better than chronic high frequency tinnitus. The difference of frequency retained significant influence on effects and prognosis of medication.

[Analysis of the effectiveness in patients who were treated with a course of drugs for sudden deafness which was present for at least three weeks].

OBJECTIVE: To investigate and analyze the significance of a course of glucocorticosteroids and other drugs for the treatment of patients with sudden deafness present for at least three weeks. METHODS: A retrospective review was done on 48 patients (58 ears) with sudden deafness present for at least three weeks or more, who were admitted to the Department of Otorhinolaryngology, Peking University People's Hospital from November 2002 to July 2010. The patients were divided into three groups by the type of hearing threshold. The different treatments were used in the three groups. The SPSS 17.0 software was used to analyze the data. RESULTS: In patients with a low tone hearing loss (6 ears), 83.3% improved. For patients with a high tone loss (22 ears) 31.8% improved. For a flat tone hearing loss (30 ears) 36.7% improved. For patients with a hearing loss more than one year (12 ears) there was improvement in 58.3% (7 ears) of the patients. In 9 ears which had a flat tone hearing loss of 90 dB or greater before treatment, 77.8% (7 ears) improved with 33.3% (3 ears) having a significant improvement. In 21 ears which had a hearing threshold was under 90 dB, 14.3% (3 ears) improved. CONCLUSIONS: In the treatment of patients with sudden deafness which was longer than 21 days the treatment was significant, especially for those who had a 90 dB or greater flat-tone type hearing threshold before treatment. Even though the hearing loss was more than a year in some patients there was still a benefit from treatment.