[Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations].

Objective: To analyze the phenotypic-genotypic characteristics of hereditary deafness caused by OTOA gene variations. Methods: Family histories, clinical phenotypes and gene variations of six pedigrees were analyzed, which were diagnosed with hearing loss caused by OTOA gene variations at the PLA General Hospital from September 2015 to January 2022. The sequence variations were verified by Sanger sequencing and the copy number variations were validated by multiplex ligation-dependent probe amplification (MLPA) in the family members. Results: The hearing loss phenotype caused by OTOA variations ranged from mild to moderate in the low frequencies, and from moderate to severe in the high frequencies in the probands, which came from six sporadic pedigrees, among which a proband was diagnosed as congenital deafness and five were diagnosed as postlingual deafness. One proband carried homozygous variations and five probands carried compound heterozygous variations in OTOA gene. Nine pathogenic variations (six copy number variations, two deletion variations and one missense variation) and two variations with uncertain significance in OTOA were identified in total, including six copy number variations and five single nucleotide variants, and three of the five single nucleotide variants were firstly reported [c.1265G>T(p.Gly422Val),c.1534delG(p.Ala513Leufs*11) and c.3292C>T(p.Gln1098fs*)]. Conclusions: OTOA gene variations can lead to autosomal recessive nonsyndromic hearing loss. In this study, the hearing loss caused by OTOA defects mostly presents as bilateral, symmetrical, and postlingual, and that of a few presents as congenital. The pathogenic variations of OTOA gene are mainly copy number variations followed by deletion variations and missense variations.

Metformin and tuberculosis risk in elderly patients with diabetes mellitus.

SETTING: Tuberculosis (TB) and diabetes mellitus (DM) remain global health concerns. Metformin has recently received attention for its anti-tuberculosis effects.OBJECTIVE: To evaluate the risk of TB development in elderly DM patients treated with metformin compared with sulfonylureas.DESIGN: We performed a retrospective cohort study using the National Health Insurance Service-Senior database. The participants were type-2 DM (T2DM) patients aged ≥60 years between 1 January 2003 and 31 December 2013. We matched each metformin user to a sulfonylurea user using a propensity score. A Cox proportional hazards model was used to compare the risk of TB in metformin and sulfonylurea users.RESULTS: After propensity score matching, 12,582 patients were in each group. The TB incidence was 280.2/100 000 person-years (py) for metformin users and 394.5/100 000 py for sulfonylurea users. Metformin users had a lower risk of TB development than sulfonylurea users (adjusted hazard ratio 0.74, 95%CI 0.58-0.95), and the results were stronger for male participants. A dose-response relationship between metformin use and TB development was found in both sexes.CONCLUSION: Metformin use was associated with a decreased risk of TB development among elderly T2DM patients compared with sulfonylurea use.

[Case report and diagnosis of Noonan syndrome with multiple lentigines with deafness as its main clinical feature].

Summary Noonan syndrome with multiple lentigines（NSML） is a disorder with syndromic hearing loss. Abnormalities of other systems in NSML have received increasing attention, but hearing loss is rarely concerned. And due to the incomplete phenotype, some patients with NSML maybe missed or maybe confused with other syndromic deafness such as Waardenburg syndrome. Our study will familiarize more otolaryngologists with Leopard syndrome. A 5-year-old boy with bilateral sensorineural hearing loss and numerous symmetrically distributed dark brown macules that had good effect of cochlear implantation was collected in this study. And his father had bilateral sensorineural hearing loss and numerous symmetrically distributed dark brown macules. Waardenburg syndrome was initially diagnosed by clinical phenotype and its molecular etiology was confirmed by gene diagnosis. Waardenburg syndrome-related deafness genes and 131 known deafness genes were not identified by second-generation sequencing. Whole-exon sequencing was performed for 4 individuals in the family and the results were confirmed by Sanger sequencing. This study confirmed the diagnosis by identifying a disease-causing mutation in the PTPN11 gene, which was a heterozygous missense mutation at p. Tyr279Cys（c. 836A>G）. The mutation co-segregated with hearing loss in the family. Our results demonstrated that hearing loss in this family was caused by heterozygous mutations in PTPN11. These cases will familiarize more otolaryngologists with NSML, and they emphasize the importance of considering NSML as a possible cause of hearing problems.

Incidence and Risk Factors of Immediate Hypersensitivity Reactions Associated With Low-Osmolar Iodinated Contrast Media: A Longitudinal Study Based on a Real-Time Monitoring System.

OBJECTIVES: We investigated the incidence of immediate hypersensitivity reaction (HSR) caused by different types of low-osmolar contrast media (LOCM) and cumulative exposure to LOCM. METHODS: This cohort study included all consecutive patients who underwent LOCM-enhanced computed tomography from 2012 through 2014. We assessed 5 LOCM (iobitridol, iohexol, iomeprol, iopamidol, and iopromide). All patients were monitored for adverse events, and new symptoms and signs were recorded in real time using the Contrast Safety Monitoring and Management System (CoSM2oS). RESULTS: The overall incidence of immediate HSR to LOCM was 0.97% (2004 events resulting from 205 726 exposures). Incidence differed significantly depending on whether the patient had a previous history of HSR to LOCM (0.80% in patients with no history and 16.99% in patients with a positive history of HSR to LOCM, P=.001). The incidence of HSR to individual LOCM ranged from 0.72% (iohexol) to 1.34% (iomeprol), although there were no significant differences across the 5 LOCM. A longitudinal analysis demonstrated that the incidence of HSR increased gradually with more frequent previous exposure to LOCM (HR=2.006 [95%CI, 1.517-2.653], P<.001). However, this cumulative increase in risk was observed in patients who had experienced HSR to LOCM, but not in those who had not. CONCLUSION: The incidence of HSR did not differ significantly across the 5 LOCM assessed in the study. Repeated exposure to LOCM did not increase the risk of HSR among patients who had never experienced HSR to LOCM.

[Screening for hotspot mutations associated with genetic hearing impairment in pregnant women and subsequent prenatal diagnosis in high risk pregnancies].

Objective: To screen for hotspot gene mutations associated with genetic deafness in Chinese pregnant women, and to perform risk assessment and prenatal diagnosis in high-risk families. Methods: Between November 2012 and October 2017, 26 117 pregnant women were screened by molecular hybridization microarray for 9 hot-spot mutations in 4 hereditary deafness related genes (GJB2 c. 35 del G, c. 176_191 del 16 bp, c. 235 del G, c. 299_300 del AT, GJB3 c. 538 C>T, SLC26A4 c. 2168 A>G, IVS 7-2 A>G, mitochondrial DNA 12S rRNA m. 1494 C>T, m. 1555 A>G). Genotype analysis was carried out in husbands of women carrying mutations, and prenatal diagnosis was carried out in the fetuses with high risk of deafness. Results: Among all women tested, 1 208(4.63%) were carriers of genetic deafness mutations, 7 with hearing impairment were affected by homozygous or compound heterozygous mutations, 51 were mitochondrial gene mutation carriers, 103 were carriers of GJB3 c. 538 C>T heterozygous mutation, 1 026 were carriers of GJB2 or SLC26A4 heterozygous mutations, and 21 carried heterozygous mutations in two genes simultaneously. In 394 families, the husbands accepted gene sequence testing, and 27 in which were determined as carriers of mutations in identical genes as their wives. Among which, 18 families received prenatal diagnosis, and 5 fetuses were diagnosed as hereditary deafness. In 9 families who did not receive prenatal diagnosis, 1 neonate was diagnosed as compound heterozygote after delivery. Conclusion: In order to prevent birth defects with congenital hearing problems, it is effective to provide screening for hotspot mutations in pregnant women and to perform prenatal diagnosis on high risk pregnancies.

Incidence of cephalosporin-induced anaphylaxis and clinical efficacy of screening intradermal tests with cephalosporins: A large multicenter retrospective cohort study.

BACKGROUND: Few studies have investigated the incidence of anaphylaxis induced by individual or structurally similar cephalosporins. The aims of the study were to assess the incidence of cephalosporin-induced anaphylaxis and evaluate the clinical efficacy of screening skin tests. METHODS: In this retrospective cohort study, we obtained information on total cephalosporin use and cephalosporin-induced anaphylaxis in intravenous cephalosporin recipients in 12 general hospitals between 2013 and 2015. Cephalosporins were divided into 4 groups according to similar side-chain structures. The incidence of cephalosporin-induced anaphylaxis was assessed for each cephalosporin, cephalosporin generation, and side-chain group. To verify the efficacy of screening intradermal tests (IDT) with cephalosporin, the 12 hospitals were assigned to the intervention or control group depending on whether they performed screening IDT before the administration of cephalosporins. RESULTS: We identified 76 cases of cephalosporin-induced anaphylaxis with 1 123 345 exposures to intravenous cephalosporins (6.8 per 100 000 exposures), and the incidence of fatal anaphylaxis by cephalosporin was 0.1 cases per 100 000 exposures. The highest incidences of anaphylaxis occurred in the ceftizoxime (13.0 cases per 100 000 exposures) and side-chain group 1 (cefepime, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime; 9.3 per 100 000). There was no case of anaphylaxis induced by cefoxitin, cefmetazole, cefminox, and cefotiam. The clinical effectiveness of routine screening IDT was not significant (P = .06). CONCLUSIONS: The incidence of cephalosporin-induced anaphylaxis differed according to individual drugs and side-chain structure. Screening IDT showed no clinical efficacy at a population level.

Second-harmonic imaging microscopy for identifying colorectal intraepithelial neoplasia.

In this study, second-harmonic imaging microscopy was used to monitor precancerous colorectal lesions at different stages. It was found that the morphology of glands and lamina propria in mucosa changes with the progression of colorectal diseases from normal to low-grade intraepithelial neoplasia to high-grade intraepithelial neoplasia and this microscopy has the ability of direct visualization of these warning symptoms. Furthermore, two morphologic variables were quantified to determine the changes of glands and collagen in lamina propria during the development of colorectal intraepithelial neoplasia. These results suggest that second-harmonic imaging microscopy has the potential in label-freely and effectively distinguishing between normal and precancerous colorectal tissues, and will be helpful for early diagnosis and treatment of colorectal diseases.

Reactive atmospheric pressure plasma for highly efficient removal of structure-directing agents from zeolite thin films.

We present a novel approach to remove the structure-directing agent (SDA) from as-synthesized zeolites using an atmospheric pressure plasma jet (APPJ). This reduces the time required to less than 60 seconds as compared to the existing thermal calcination, whose durations range from hours to days. The highly reactive plasma also results in a pronounced Q(3)-to-Q(4) transformation in the pure-silica zeolite MFI.

A comparative study of two- versus one-lung ventilation for needlescopic bleb resection.

This prospective study was conducted to evaluate the feasibility of two-lung (TL) ventilation with low tidal volume anaesthesia compared with one-lung (OL) ventilation for needlescopic bleb resection. Patients with spontaneous pneumothorax that underwent bleb resection with a 2-mm thoracoscope were enrolled. During the operation, the tidal volume was set at 4.0 mL·kg⁻¹ in the TL group and 8.0 mL·kg⁻¹ in the OL group; the respiration rate was set at 23 and 12 breaths·min⁻¹, respectively, at the same inspiratory oxygen fraction (50%). A total of 108 patients (55 patients in the TL group and 53 in the OL group) were included in this study. Airway pressure was significantly lower in the TL group (mean ± sd 8.0 ± 3.3 versus 24.0 ± 3.9 mmHg in the OL group; p<0.001). The time from endotracheal intubation to the incision was 17.1 ± 4.0 min in the TL group and 35.3 ± 7.6 min in the OL group, which was significantly different (p<0.001). However, the operation time was not different in comparisons between the two groups. Therefore, the total anaesthesia time was significantly longer in the OL group (77.9 ± 21.6 versus 64.9 ± 14.7 min in the TL group; p = 0.002). Needlescopic bleb resection using TL ventilation anaesthesia with low tidal volume was technically feasible, cost-effective and time-saving compared with OL ventilation anaesthesia.

Needlescopy-assisted resection of pulmonary nodule after dual localisation.

The aim of this study was to evaluate the feasibility of dual localisation with hookwire and lipiodol before needlescopy-assisted resection for pulmonary nodule. Computed tomography-guided dual marking was performed on 36 pulmonary nodules of 32 patients and needlescopy-assisted resection was performed monitored by C-arm fluoroscopy. The mean age of the patients was 58 ± 12 (range 12-77) yrs. The mean size of the nodules was 7.5 ± 3.7 (3-17) mm. Their mean distance from the pleural surface was 7.3 ± 7.5 (0-35) mm. There were nine pure ground-glass opacity lesions, five semi-solid lesions and 22 solid lesions. The time of the dual localisation procedure was 13.1 ± 4.8 (7-23) min. Complications of the marking were pneumothorax in nine patients, and intrapulmonary bleeding in three. One hookwire dislodged during the operation. All nodules were successfully resected under needlescopy without conversion to a conventional thoracoscopy (5 mm or 10 mm thoracoscopy) or a minithoracotomy. There was no complication related to needlescopy-assisted resection. Dual marking with hookwire and lipiodol is a safe and none time consuming procedure, and needlescopy-assisted lung resection for small nodules is technically feasible and useful for histological diagnosis and treatment.

Fenofibrate lowers abdominal and skeletal adiposity and improves insulin sensitivity in OLETF rats.

The effect of peroxisome proliferator-activated receptor (PPAR)-alpha activators on the liver is well established, but the other effects on muscle and adipose tissue about lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-alpha activation affects adiposity of skeletal muscle as well as adipose tissue and improves insulin sensitivity in spontaneous type 2 diabetes model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Thirty-three weeks of aged, 20 male OLETF rats were divided into two groups. Control group (n=10) was fed with chow and treatment group (n=10) with chow contained fenofibrate for 7 weeks. At the age of 40 weeks, all rats were examined with MRI, intravenous glucose tolerance test, and then sacrificed for measurement of fat mass and RNA analyses. The total fat (the sum of subcutaneous, mesenteric, epididymal, and retroperitoneal fat pads) measured by dissection was significantly reduced in treatment group. The signal intensity of muscular adiposity was significantly decreased in treatment group. The mRNA levels of FAT/CD36 and mitochondrial carnitine palmitoyltransferase I (M-CPT I) in liver were remarkably increased. Fasting plasma insulin and leptin levels, insulin response after intravenous glucose loading and homeostasis model assessment insulin resistance (HOMA(IR)) index were lowered in treatment group. Fenofibrate increase mitochondrial fatty acid beta-oxidation in liver but not in skeletal muscle and lower the plasma levels of triglyceride and free fatty acid. It might result in reduction of adiposity of truncal adipose tissue and skeletal muscle. We suggest that reduction of adiposity in trunk and skeletal muscle might improve insulin sensitivity.

Heterotopic pancreas in the stomach: CT findings.

PURPOSE: To describe the computed tomographic (CT) findings of heterotopic pancreas in the stomach. MATERIALS AND METHODS: CT findings in 12 patients with heterotopic pancreas in the stomach were reviewed. Surgical resection (n = 11) or endoscopic excision (n = 1) was performed in cases of symptomatic heterotopic pancreas (n = 4), suspected submucosal tumors (n = 7), and gastric carcinoma (n = 1). Seven patients underwent helical CT with water as an oral contrast agent; five underwent nonhelical CT with water-soluble contrast material. RESULTS: Nine heterotopic pancreata were in the antrum and one each was in the body, fundus, and perigastric fat. Seven lesions were on the greater curvature aspect; five, on the lesser curvature aspect. Common CT findings were well-defined oval or round masses with smooth or serrated margins in the gastric antral wall. Four of the seven lesions in which helical CT was performed enhanced similarly to normal pancreas. Preoperatively, CT depicted 11 of the 12 lesions, but CT findings were interpreted correctly as heterotopic pancreas in only two; the remaining 10 were misinterpreted as other lesions. Atypical findings were cystic dilatation of heterotopic pancreatic duct in two, unusual location in the fundus or perigastric fat in two, and malignant transformation in one. CONCLUSION: CT findings of heterotopic pancreas in the stomach appear to be nonspecific for diagnosis, except for location.

Sclerosing Mucoepidermoid carcinoma with eosinophilia of the thyroid glands: a case report with clinical manifestation of recurrent neck mass.

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a recently recognized malignant neoplasm of the thyroid gland. About 14 cases of SMECE have been reported and this is the first reported case in Korea. A 57-year-old woman presented with right neck mass for 20 years. Total thyroidectomy was performed under the impression of thyroid carcinoma. The resected thyroid gland showed a poorly circumscribed hard mass. Histologically, the tumor consisted of solid nests of large atypical cells with dense fibrous stroma. The tumor cells showed squamoid appearance with abundant eosinophilic cytoplasm. There were also rare mucin-containing cells within the nests. Within the hyalinized stroma, numerous eosinophils were found. The surrounding thyroid parenchyma displayed Hashimoto's thyroiditis. There was metastasis in a regional lymph node. Two years after initial surgery, she underwent a modified radical neck dissection due to recurrent neck mass. After the radiation therapy for eight weeks, laryngectomy and esophagectomy were performed due to a recurrent carcinoma in the esophageal wall. We report an additional case of SMECE, with metastasis to regional lymph nodes and esophagus. The tumor appears to be more aggressive than previously reported and a correct diagnosis can be rendered by just examining the metastatic lesions.

Inhibition of expression of P-selectin by antioxidant in cholesterol-fed rats.

Butylated hydroxytoluene (BHT) can inhibit experimental atherosclerosis in animals. Although the agent is an antioxidant, the exact mechanism of the reaction in atherosclerosis is still unknown. To investigate the effects of BHT on expression of P-selectin (PADGEM, GMP-140), intercellular adhesion molecule-1 (ICAM-1) and class II MHC (Ia) antigen, we proposed an experiment on rats. Male rats (n=18 per group) were fed either a normal cholesterol control diet, a normal cholesterol diet containing 0.5% BHT (BD), a high cholesterol diet containing 1.5% cholesterol and 0.1% sodium cholate (CD), or the CD diet containing 0.5% BHT (BCD). Rats were sacrificed after 3 days, and after 1, 2, 4, 10, and 17 weeks of dietary treatment. Although there was no gross or light microscopic atherosclerotic lesions, scanning electron microscopy revealed monocytic adhesion to aortic endothelium and mild endothelial injuries in CD and BCD groups. Immunohistochemically, the addition of BHT to a high cholesterol diet inhibited P-selectin expression but not in ICAM-1 and Ia antigen. These findings suggest that in rats, high cholesterol diets induce expression of ICAM-1, P-selectin and Ia antigen. In addition, the antiatherogenic effect of BHT may play a role in the inhibition of P-selectin.

Proteasome inhibition attenuates nitric oxide synthase expression, VCAM-1 transcription and the development of chronic colitis.

The objectives of this study were to (1) assess the role of the 26S proteasome complex in regulating the expression of the inducible isoform of nitric oxide synthase (iNOS) and vascular cell adhesion molecule-1 (VCAM-1) in a model of chronic granulomatous colitis in vivo and (2) determine the role of the proteasome in regulating the inflammatory response observed in this model of chronic gut inflammation. The selective proteasome inhibitor MG-341 (0.3 mg/kg) was administered by gavage beginning immediately before the induction of colitis and continuing daily thereafter for the entire 14-day experimental period. We found that chronic proteasome inhibition using MG-341 significantly attenuated the peptidoglycan/polysaccharide (PG/PS)-induced up-regulation of iNOS in the colon and spleen and the consequent increase in plasma levels of nitrate and nitrite. Furthermore, we found that the proteasome inhibitor suppressed the up-regulation of the adhesion molecule VCAM-1 in the colon. We also found that MG-341 attenuated PG/PS-induced increases in macroscopic colonic inflammation, bowel wall thickness, colonic dry weight and colonic MPO activity. Treatment with MG-341 also significantly reduced PG/PS-induced increases in macroscopic spleen inflammation, spleen weight and spleen MPO activity. We conclude that the 26S proteasome complex plays an important role in regulating the PG/PS-induced up-regulation of iNOS and VCAM-1 in vivo and appears to be important in regulating colonic and splenic inflammation.