Mechanistic insight into glioma through spatially multidimensional proteomics.

Characterizing the tumor microenvironment at the molecular level is essential for understanding the mechanisms of tumorigenesis and evolution. However, the specificity of the blood proteome in localized region of the tumor and its linkages with other systems is difficult to investigate. Here, we propose a spatially multidimensional comparative proteomics strategy using glioma as an example. The blood proteome signature of tumor microenvironment was specifically identified by in situ collection of arterial and venous blood from the glioma region of the brain for comparison with peripheral blood. Also, by integrating with different dimensions of tissue and peripheral blood proteomics, the information on the genesis, migration, and exchange of glioma-associated proteins was revealed, which provided a powerful method for tumor mechanism research and biomarker discovery. The study recruited multidimensional clinical cohorts, allowing the proteomic results to corroborate each other, reliably revealing biological processes specific to gliomas, and identifying highly accurate biomarkers.

Impact of environmental noise exposure as an inducing factor on the prognosis of sudden sensorineural hearing loss: a retrospective case-control study.

Objective: The study aimed to evaluate the clinical characteristics and prognostic factors associated with unilateral sudden sensorineural hearing loss (SSNHL) related to environmental noise exposure before its onset. Methods: A total of 50 unilateral SSNHL patients exposed to environmental noise before onset (case group) and 924 unilateral SSNHL patients without any exposure to obvious inducing factors before onset (control group) were enrolled between January 2018 and October 2022. We retrospectively analyzed differences between both groups using the chi-square test, Fisher's exact tests, independent t-tests, and Mann-Whitney U-tests as appropriate before and after propensity score matching (PSM) based on sex, age, and initial pure-tone average (PTA). Prognostic factors for the case group were analyzed using univariate and multivariate logistic analyses between the effective and ineffective groups. Results: Before PSM, significant differences were noted in age, sex, time to treatment, the proportion of combined diabetes mellitus, initial PTA, hearing gain, the incidence of vertigo or aural fulness, the rate of vestibular dysfunction or inner ear MRI abnormalities, the effective rate, the glucose and homocysteine levels, and the proportion of audiogram curve types (P < 0.05) between both groups. After PSM, compared to the control group, a longer time to treatment (Z= -3.02, P < 0.05), higher final PTA (Z= -2.39, P < 0.05), lower hearing gain (Z= -3.46, P < 0.05), lower rate of vestibular dysfunction (χ2 = 55.1, P < 0.001), and lower effective rate (χ2 = 4.87, P < 0.05) were observed in the case group. There was a significant difference between the audiogram curve types in both groups (χ2 = 14.9, P < 0.05). Time to treatment (95% confidence interval: 0.692-0.965, P < 0.05) and final PTA (95% confidence interval: 0.921-0.998, P < 0.05) were associated with the clinical outcomes for the case group. Conclusion: Unilateral SSNHL patients exposed to environmental noise triggers before onset showed a poorer effective rate and a lower rate of vestibular dysfunction than those who were not. The time to treatment and final PTA were associated with the prognosis of these patients.

Characteristics and prognostic analysis of simultaneous bilateral sudden sensorineural hearing loss.

Objective: To evaluate the clinical characteristics of simultaneous bilateral sudden sensorineural hearing loss (Si-BSSNHL) as well as its prognostic factors. Methods: Patients with Si-BSSNHL who were admitted to the Department of Otology Medicine between December 2018 and December 2021 were enrolled in the case group. Propensity score matching (PSM) for sex and age was used to select the control group, which included people who had unilateral sudden sensorineural hearing loss (USSNHL) during the same time period. Hearing recovery, audiological examinations, vestibular function assessments, laboratory tests, and demographic and clinical manifestations were analyzed for intergroup comparisons. Binary logistic regressions were used for both univariate and multivariate analyses of Si-BSSNHL prognostic factors. Results: Before PSM, the Si-BSSNHL and USSNHL groups differed significantly (p < 0.05) in terms of time from onset to treatment, initial pure-tone average (PTA), final PTA, hearing gain, audiogram curve type, proportion of tinnitus, high-density lipoprotein level, homocysteine level, and effective rate. After PSM, significant differences were also observed in time from onset to treatment, initial PTA, final PTA, hearing gain, total and indirect bilirubin levels, homocysteine level, and effective rate between the two groups (p < 0.05). There was a significant difference in the classification of therapeutic effects between the two groups (p < 0.001). For prognostic analysis, the audiogram curve type was significantly different between the effective group and the ineffective groups of Si-BSSNHL (p = 0.01), in which the sloping type was an independent risk factor for the prognosis of the right ear in Si-SSNHL (95% confidence interval, 0.006-0.549, p = 0.013). Conclusion: Patients with Si-BSSNHL had mild deafness, elevated total and indirect bilirubin and homocysteine levels, and poorer prognosis than those with USSNHL. Audiogram curve type was linked to the therapeutic effect of Si-BSSNHL, and the sloping type was an independent risk factor for a poor prognosis in the right ear of Si-SSNHL.

CircLPAR1 Promotes Neuroinflammation and Oxidative Stress in APP/PS1 Mice by Inhibiting SIRT1/Nrf-2/HO-1 Axis Through Destabilizing GDF-15 mRNA.

Circular RNA LPAR1 (circLPAR1) was revealed to be elevated in Alzheimer's disease (AD); nevertheless, its role and mechanisms in AD remain unknown. Memory performance of APP/PS1 mice was assessed by Morris water maze test. Expression of circLPAR1 and indicated messenger RNA (mRNA) in mouse brain tissues or/and SH-SY5Y cells were tested by quantitative real-time PCR (qRT-PCR). Protein expression of indicated gene was examined by western blot. Production of proinflammatory cytokines (tumor necrosis factor-α, TNF-α; interleukin-6, IL-6; interleukin-1ß, IL-1ß; and interleukin-8, IL-8) and oxidative stress-related factors (reactive oxygen species, ROS; malondialdehyde, MDA; superoxide dismutase, SOD; and glutathione, GSH) were assessed by commercial kits. RNA pull down and RNA immunoprecipitation were performed to verify the interplay between up-frameshift protein 1 (UPF1) and circLPAR1 or growth differentiation factor 15 (GDF-15). CircLPAR1 was elevated, while GDF-15 was decreased in both APP/PS1 mice and Aß-treated SH-SY5Y cells. Knockdown of circLPAR1 and overexpression of GDF-15 protected cells against Aß-caused inflammation, oxidative stress, and neuronal apoptosis. CircLPAR1 knockdown was also proved to improve AD-related pathological traits and ameliorate cognitive dysfunctions in vivo. In mechanism, we found that circLPAR1 repressed GDF-15 expression by decreasing GDF-15 mRNA stability through UPF1 recruitment. Rescue assays suggested that sirtuin 1 (SIRT1) knockdown reversed GDF-15 overexpression-induced inhibition on Aß-induced neuronal damage and nuclear factor E2-related factor (Nrf-2)/heme oxygenase-1 (HO-1) pathway inhibition. Moreover, the protective effect of circLPAR1 knockdown against Aß-induced apoptosis was abolished by GDF-15 knockdown, and SIRT1 overexpression could counteract this effect of GDF-15 knockdown. CircLPAR1 knockdown improved AD-related pathological traits in vitro and in vivo by inhibiting SIRT1/Nrf-2/HO-1 axis through GDF-15.

Analysis of Perioperative Nursing Intervention Effect of Cerebrovascular Intervention Patients Based on Intelligent Internet of Things.

The postoperative results of cerebrovascular surgery patients have been successfully used in medical practice using the Internet. The results obtained through data analysis were used in the study. So far, 120 patients who underwent cerebrovascular surgery from February 2018 to December 2018 have been enrolled. The selected class was divided into two groups: 60 psychiatric patients, a control group and an observation group. The former is medical treatment and the latter is postoperative treatment. Results: The results showed that the blood pressure of control group was lower than that of control group, and the incidence of adverse events was lower than that of control group (P < 0.05). Meanwhile, the average hospitalization rate of cerebrovascular disease patients in control group was lower than that in control group (P < 0.05). Conclusion: For patients with cerebrovascular disease, postoperative nursing can reduce the incidence of postoperative complications, reduce the risk of surgery, and improve the effect of surgery. Acute ischemic stroke refers to a kind of clinical syndrome caused by abnormal blood supply in the brain, resulting in ischemia, hypoxic brain tissue necrosis, and focal or comprehensive neurological deficiency. Among them, progressive cerebral infarction accounted for about 20~35%, and most occurred in the early stage of the disease (48~72)h.

Characteristics and prognosis analysis of bilateral sudden sensorineural hearing loss: A retrospective case-control study.

OBJECTIVES: To evaluate the clinical characteristics and prognostic factors of simultaneous and sequential bilateral sudden sensorineural hearing loss (Si-BSSNHL and Se-BSSNHL, respectively). DESIGN: Retrospective case-control study. SETTING: A single tertiary referral centre. PARTICIPANTS: Patients diagnosed with unilateral sudden sensorineural hearing loss (USSNHL), Si-BSSNHL, or Se-BSSNHL between September 2018 and November 2019. MAIN OUTCOME MEASURES: Demographic and clinical characteristics, audiological features, laboratory results and hearing recovery were analysed for intergroup comparisons. Prognostic factors for BSSNHL were analysed using univariate and multivariate logistic analyses between the overall and no-recovery groups. RESULTS: Compared to the USSNHL group, a larger final pure-tone average (PTA) (H = 38.0 and 53.8, respectively, both adjusted p-value (p adj) <.05), lower hearing gain (H = -70.8 and - 74.6, respectively, both p adj <.001) and higher homocysteine levels (H = 46.8, 58.8, respectively, both p adj <.05) were observed in the Si-BSSNHL and Se-BSSNHL groups, while the rate of positive vestibular tests and proportion of tinnitus were lower in the Se-BSSNHL group (χ2  = 8.5 and 38.1, respectively, both p adj <0.05). The USSNHL group showed a significant difference in the degree of deafness and therapeutic outcome in the Se-BSSNHL and Si-BSSNHL groups, respectively (χ2  = 12.4, p adj <.05; χ2  = 13.6; p adj <.05). Hypertension (95% confidence interval, 1.014-28.623, p < .05) and onset days (95% confidence interval, 0.007-0.626, p < .05) were associated with the therapeutic effects of BSSNHL. CONCLUSIONS: Higher homocysteine levels in BSSNHL may implicate microvascular disorders as a causative factor of BSSNHL. Hypertension and onset days were associated with the prognosis of BSSNHL.

Thromboelastography predicting the prognosis of sudden sensorineural hearing loss.

OBJECTIVES: To explore the association between thromboelastography and the clinical features as well as the prognosis of sudden sensorineural hearing loss (SSNHL). DESIGN: Single-centre, retrospective study. SETTING: A hospital in China. PARTICIPANTS: In total, 133 patients presented with SSNHL within 2 weeks before the study, who did not receive treatment. MAIN OUTCOME MEASURES: The patients' medical history was collected. Audiological, imaging and haematological examinations were performed before treatment. Patients with abnormal thromboelastography were re-examined 1 week after treatment, and efficacy was evaluated 1 month after treatment. The chi-squared test and binary logistic regression analysis were used to analyse the association between factors, such as vertigo, degree and type of hearing loss, vestibular function, inner ear MRI results, thromboelastography and efficacy of treatment. RESULTS: Thromboelastography was correlated with prognosis (p = 0.049) and degree (p = 0.030) and type of hearing loss (p = 0.013) in patients with SSNHL. The R (p =  0.002) and angle values (p =  0.010) correlated with prognosis. The MA (p =  0.022) and G values (p =  0.020) correlated with the degree of hearing loss. The R (p =  0.033) value correlated with inner ear MRI results, and the ΔG (p =  0.010) value correlated with fibrinogen levels. ΔThromboelastography (p =  0.032) was correlated with the prognosis of patients with abnormal thromboelastography results. Logistic regression analysis showed that thromboelastography correlated with prognosis (p =  0.013), and Δthromboelastography correlated with the prognosis of patients with abnormal thromboelastography results (p =  0.013) and vertigo (p =  0.016). CONCLUSION: Thromboelastography is an independent risk factor affecting the prognosis of SSNHL with the R and angle values playing a major role.

Analysis of Clinical Effects of Comprehensive Nursing Based on Enhanced Recovery after Surgery in Patients with Embolization for Intracranial Aneurysms.

Objective: This research sets out to elucidate the clinical effect of comprehensive nursing based on the concept of enhanced recovery after surgery (ERAS) in patients with embolization for intracranial aneurysms (IAs). Methods: This study enrolled 119 patients with embolization for IAs in the Zhongnan Hospital of Wuhan University from January 2020 to January 2021 and divided them into two groups according to the perioperative care they received: a control group (n = 39) treated with routine perioperative nursing and an observation group (n = 80) treated with ERAS-based comprehensive nursing. Surgical indicators, neurological function (National Institute of Health Stroke Scale (NIHSS) score; Scandinavian Stroke Scale (SSS) score), anxiety and depression (Self-Rating Anxiety Scale (SAS) score; Self-Rating Depression Scale (SDS) score), incidence of adverse events, and patient satisfaction were compared. Results: The observation group had better surgical indicators and lower scores of NIHSS, SSS, SAS, and SDS than the control group, accompanied by a lower incidence of adverse events and higher patient satisfaction. Conclusions: ERAS-based comprehensive nursing can better promote patients' neurological recovery after embolization for IAs, relieve unhealthy emotions (depression, anxiety, etc.), and reduce the occurrence of adverse reactions, facilitating patient discharge.

Idiopathic Sudden Sensorineural Hearing Loss in Different Ages: Prognosis of Patients With Initial Total Hearing Loss.

Objective: This study aimed to analyze the hearing improvement and prognosis factors of idiopathic sudden sensorineural hearing loss (ISSNHL) in different ages with initial total hearing loss. Methods: We reviewed the medical records of 5,711 hospitalized patients with ISSNHL from 2016 to 2021 in our center. All of the patients had been treated with uniform combination drug therapy. After excluding the patients with initial partial hearing loss and those diagnosed with clear etiology, 188 patients were enrolled in this study and divided into six age groups (18-30, 31-40, 41-50, 51-60, 61-70, ≥ 71 years). In all groups, decreases in pure-tone average (PTA) 1 month posttreatment, effective rate, and clinical characteristics (vertigo, tinnitus, hospital stay, comorbidity, and inner ear magnetic resonance imaging) were analyzed. Results: Among the 188 enrolled patients, 86% had vertigo. Complete recovery was seen in 0.5% of patients, and marked recovery was seen in 43% of patients. The mean 1 month posttreatment PTAs were as follows: 18-30 years: 80 ± 7.5 dB; 31-40 years: 100 ± 9.0 dB; 41-50 years: 99 ± 8.3 dB; 51-60 years: 101 ± 8.6 dB; 61-70 years: 96 ± 9.6 dB; and ≥ 71 years: 88 ± 13.0 dB. Compared with the other groups, the 18-30- years group showed better recovery of hearing threshold in five frequencies (0.25, 0.5, 1, 2, and 4 kHz, respectively, at octave or semioctave frequencies under air conduction), and the recovery of hearing threshold at 0.25 and 0.5 Hz was better than the recovery at 1, 2, and 4 kHz. According to the results of the chi-square test statistical analysis, vertigo and comorbidities were associated with a poor prognosis of ISSNHL. Conclusion: In summary, the treatment outcomes of patients with ISSNHL with initial total hearing loss were poor. There was a significant age-related difference with respect to marked recovery 1 month posttreatment, and the 18-30- years group showed better recovery than the other age groups.

Rs12976445 polymorphism is associated with the risk of post-SAH re-bleeding by modulating the expression of microRNA-125 and ET-1.

This study aimed to study the association between rs12976445 polymorphism and the incidence of IA re-bleeding. Genotype and allele frequency analysis was performed to study the association between rs12976445 polymorphism and the risk of IA re-bleeding. Western blot, ELISA and real-time RT-PCR were conducted to measure the relative expression of miR-125a, ET1 mRNA and ET1 protein. Computational analysis and luciferase assays were utilized to investigate the association between the expression of miR-125a and ET1 mRNA. No significant differences were observed between IA patients with or without symptoms of re-bleeding. Subsequent analyses indicated that the T allele was significantly associated with the reduced risk of IA re-bleeding. In patients carrying the CC genotype, miR-125a level was up-regulated while ET1 mRNA/protein levels were reduced compared with those in patients carrying the CT or TT genotype. And ET1 mRNA was identified as a virtual target gene of miR-125a with a potential miR-125a binding site located on its 3'UTR. Accordingly, the ET mRNA/protein levels could be suppressed by the transfection of miR-125a precursors, but the transfection of ET1 siRNA exhibited no effect on the expression of miR-125a. Therefore, an increased level of miR-125a can lead to the increased risk of IA re-bleeding. Since miR-125a level is higher in CC-genotyped patients, it can be concluded that the presence of T allele in the rs12976445 polymorphism is associated with a lower risk of IA re-bleeding, and miR-125a may be used as a novel diagnostic and therapeutic target for IA rupture.

Flurbiprofen axetil protects against cerebral ischemia/reperfusion injury via regulating miR-30c-5p and SOX9.

The modulatory mechanism of flurbiprofen axetil (FPA) by which it relieves cerebral ischemia/reperfusion (I/R) injury (CIRI) is still obscure. In the present work, adult male Sprague-Dawley (SD) rats were pre-treated with FPA before the construction of a rat model of CIRI. Longa's scoring method and dry-wet method were employed to examine the neurological function and brain water content of the rats. MiR-30c-5p, SOX9, AQP4, SOX9, NF-κB, and p-NF-κB expression levels in the brain tissues of the rats were examined by qRT-PCR or Western blot. ELISA was executed to evaluate the IL-10, IL-6, and TNF-α levels in the serum of rat. SOD and MDA levels in rat brain homogenates were also examined to indicate the oxidative stress. Hematoxylin-eosin (HE) staining was used to examine the pathological changes of the brain tissues. Dual-luciferase reporter gene experiment was implemented to validate the binding relationship between miR-30c-5p and SOX9. In the present work, compared with the rats with CIRI, FPA pre-treatment attenuated neurological injury, cerebral edema, oxidative stress, inflammatory response, and cerebral pathological changes in the rat model with CIRI. FPA up-modulated miR-30c-5p expression. SOX9 was a downstream target of miR-30c-5p. In conclusion, FPA ameliorates CIRI through up-modulating miR-30c-5p expression and reducing SOX9 expression.

proBDNF expression induces apoptosis and inhibits synaptic regeneration by regulating the RhoA-JNK pathway in an in vitro post-stroke depression model.

Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of post-stroke depression (PSD). However, the precise function and potential mechanism of proBDNF, the precursor form of BDNF, are unknown. In our study, a PSD-like model was established by treating neuronal cells with oxygen-glucose deprivation and corticosterone. We found that the protein proBDNF levels were significantly higher in the cortex and hippocampus in the PSD group than in the control group, suggesting that proBDNF plays a role in the pathophysiology of PSD. Furthermore, we re-established the PSD-like cell model using recombinant p75 neurotrophin receptor (p75NTR) or silencing c-Jun N-terminal kinase (JNK), and found that the PSD-induced upregulation of proBDNF was inhibited by recombinant p75NTR and JNK silencing (siJNK), and increased cellular apoptosis. Moreover, the application of recombinant p75NTR and siJNK in the PSD-like cell model significantly reversed the expression of apoptosis-related and depression-related proteins and decreased cellular apoptosis. Our findings suggest that proBDNF is involved in neural plasticity in PSD in vitro. The RhoA-JNK signaling pathway is activated after proBDNF binds to the p75NTR receptor, followed by the expression of apoptosis-related proteins (PSD95, synaptophysin, and P-cofilin), which contribute to PSD progression. The mechanism might involve the promotion of cellular apoptosis and the inhibition of nerve synapses regeneration by proBDNF.

BMSCs-exosomes containing GDF-15 alleviated SH-SY5Y cell injury model of Alzheimer's disease via AKT/GSK-3ß/ß-catenin.

BACKGROUND: Mesenchymal stem cells (MSCs) therapy has great potential for Alzheimer's disease (AD) treatment. Here, we investigated the roles of BMSCs-exosomes containing growth differentiation factor-15 (GDF-15) in regulating SH-SY5Y cell injury in AD. METHODS: The SH-SY5Y cell injury model was constructed by treating SH-SY5Y cells with 10 µM Aß42. GDF-15 expression was assessed using qRT-PCR and western blot. CCK8 assay and flow cytometry assay were employed to elevate cell proliferation and apoptosis, respectively. The expression levels of inflammatory factors (IL-6, IL-1ß, TNFα and IL-8) and Aß42 were detected using ELISA. Besides, the levels of apoptosis-related proteins and AKT pathway-related proteins were determined using western blot. RESULTS: Our results displayed that BMSCs-EVs treatment elevated cell viability, while suppressed cell apoptosis and inflammation in Aß42-treated SH-SY5Y cells. Exosomes secreted by BMSCs after GDF-15 silence lost the ability to restore Aß42-induced SH-SY5Y cell damage. GDF-15 treatment restored Aß42-induced SH-SY5Y cell damage, while it was eliminated by AKT pathway inhibition. BMSCs-exosomes containing GDF-15 upregulated NEP and IDE via activation of AKT/GSK-3ß/ß-catenin pathway, thereby degrading Aß42 protein to relieve SH-SY5Y cell damage. CONCLUSION: BMSCs-exosomes containing GDF-15 alleviated SH-SY5Y cell damage via AKT/GSK-3ß/ß-catenin. Our work confers a promising therapeutic strategy for AD.

Phenotypic Heterogeneity of Post-lingual and/or Milder Hearing Loss for the Patients With the GJB2 c.235delC Homozygous Mutation.

OBJECTIVE: To report the phenotypic heterogeneity of GJB2 c.235delC homozygotes associated with post-lingual and/or milder hearing loss, and explore the possible mechanism of these unconditional phenotypes. METHODS: Mutation screening of GJB2 was performed on all ascertained members from Family 1006983 and three sporadic patients by polymerase chain reaction (PCR) amplification and Sanger sequencing. Next generation sequencing (NGS) was successively performed on some of the affected members and normal controls from Family 1006983 to explore additional possible genetic codes. Reverse transcriptase-quantitative PCR was conducted to test the expression of Connexin30. RESULTS: We identified a Chinese autosomal recessive hearing loss family with the GJB2 c.235delC homozygous mutation, affected members from which had post-lingual moderate to profound hearing impairment, and three sporadic patients with post-lingual moderate hearing impairment, instead of congenital profound hearing loss. NGS showed no other particular variants. Overexpression of Connexin30 in some of these cases was verified. CONCLUSION: Post-lingual and/or moderate hearing impairment phenotypes of GJB2 c.235delC homozygotes are not the most common phenotype, revealing the heterogeneity of GJB2 pathogenic mutations. To determine the possible mechanism that rescues part of the hearing or postpones onset age of these cases, more cases are required to confirm both Connexin30 overexpression and the existence of modifier genes.

Impact of hyperlipidemia as a coexisting factor on the prognosis of idiopathic sudden sensorineural hearing loss: A propensity score matching analysis.

OBJECTIVE: To define the impact of hyperlipidemia as a coexisting factor on the prognosis of Idiopathic Sudden Sensorineural Hearing Loss (ISSHL), we prospectively analysed the Lipid-lowering therapy Group (LLTG) data compared with Control Group (CG) data to determine the effects of Lipid intervention on the prognosis of sudden hearing loss. DESIGN: A prospective, non-randomized study. SETTING: Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China. PARTICIPANTS: A total of 653 in-patient SSHL patients were enrolled between January 2014 to August 2018. MAIN OUTCOME MEASURES: From January 2014 to August 2018, 653 patients with ISSHL who also had hyperlipidemia as coexisting factor were identified. Patients enrolled in LLTG (n = 200) or CG (n = 453) were compared by a propensity score matching analysis (PSM, caliper = 0.01, n = 2) to balance pre-existing clinical characteristics. After matching, the effective rate of different hyperlipidemia types and different types of audiogram in both groups were performed by Cochran-Mantel-Haenszel test (CMH). RESULTS: After PSM, 440 patients were studied (146 in LLTG, 294 in CG), and the influence of interference factors was balanced, meanwhile, the final hearing level was better in LLTG than CG (P = .043), and hearing gain was higher in LLTG than CG (P = .006). Cure rate (32.9%), significant improvement rate (22.6%) and the total effective rate (76.0%) in LLTG were better than that in CG group (26.5%, 15.6% and 63.6%) after the Pearson chi-square test (P < .05). Analysis with the Cochran-Mantel-Haenszel test showed that the total effective rate was better in LLTG than CG respectively (P = .009) in each different hyperlipidemia types, and there were statistically significant differences in TG higher group (TG Group; P = .018). Moreover, the total effective rate was better in LLTG than CG (P = .006) for all patterns of audiogram, and there were statistically significant differences in flat audiogram (P = .043). CONCLUSIONS: Lipid-lowering therapy can improve the curative effect of sudden hearing loss patients combined with hyperlipidemia. There was a significant difference in the total effective rate of TG Group after lipid intervention, suggesting that there might be causal relationship between TG and sudden hearing loss. There was a significant difference in the total effective rate between flat audiogram, which may suggest flat hearing loss was more likely caused by vascular dysfunction.

Intracerebral hemorrhage cadaver model for training in hematoma evacuation under endoscopy.

Neuroendoscopic surgery has been performed as an effective method for intracerebral hemorrhage (ICH). This study describes the know-how of constructing the ICH cadaver model and the training on the main neuroendoscopic procedures for ICH. During the training, operation time of twenty trainees in main stages of craniotomy and corticotomy (stage 2), and hematoma evacuation under endoscopy (stage 3) was recorded. To distinguish factors influencing trainees' surgical proficiency, operation time was calculated according to seniority, experience in neuroendoscopic surgery and training sequence. Questionnaire about validity of model was conducted eventually. Ten ICH cadaver models with bilateral hematoma were constructed. Seven trainees worked with seniority >5 years and eleven had experience in neuroendoscopic surgery. Operation time ranged from 20.6 to 33.4 min in stage 2 and 18.5 to 24.9 min in stage 3. In stage 2, less operation time was needed for trainees with seniority >5 years comparing to trainees with seniority ≦5 years (22.56 ±â€¯1.29 vs 29.25 ±â€¯3.02 min, p < 0.01). In stage 3, significant difference of operation time was found between trainees with experience in neuroendoscopic surgery and trainees without the experience (20.08 ±â€¯1.22 vs 22.02 ±â€¯1.82 min, p = 0.014), and the same between trainees in latter group and in former group (19.75 ±â€¯0.80 vs 22.54 ±â€¯1.45 min, p < 0.01). Questionnaire feedback proved high degree of satisfaction about the training model. Therefore, the ICH cadaver model can assist neurosurgeons with neuroendoscopic treatment learning sessions. Simulation and improvement in neuroendoscopic surgical techniques for ICH treatment were possible with the help of ICH cadaver model.

Further evidence for "gain-of-function" mechanism of DFNA5 related hearing loss.

To report two DFNA5 pathogenic splice-site variations and a novel benign frameshift variation to further support the gain-of-function mechanism of DFNA5 related hearing impairment, targeted genes capture and next generation sequencing were performed on selected members from Family 1007208, 1007081 and a sporadic case with sensorineural hearing loss. Reverse transcriptase polymerase chain reaction was conducted on the proband from Family 1007208 to test how the splice-site variation affects the transcription in RNA level. A novel heterozygous splice-site variation c.991-3 C > A in DFNA5 was found in Family 1007208; a known hotspot heterozygous splice-site variation c.991-15_991_13delTTC was identified in Family 1007081. Both the splice-site variations were segregated with the late onset hearing loss phenotype, leading to the skipping of exon 8 at RNA level. In addition, a novel DFNA5 frameshift variation c.116_119delAAAA was found in the sporadic case, but was not segregated with the hearing impairment phenotype. In conclusion, we identified one novel and one known pathogenic DFNA5 splice-site variation in two Chinese Families, as well as a novel DFNA5 frameshift variation c.116_119delAAAA in a sporadic case, which does not the cause for the hearing loss case. Both the two pathogenic splice-site variations and the nonpathogenic frameshift variation provide further support for the specific gain-of-function mechanism of DFNA5 related hearing loss.

Novel recessive PDZD7 biallelic mutations in two Chinese families with non-syndromic hearing loss.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous genetic condition. PDZD7 has emerged as a new genetic etiology of ARNSHL. Biallelic mutations in the PDZD7 gene have been reported in two German families, four Iranian families, and a Pakistani family with ARNSHL. The effect of PDZD7 on ARNSHL in other population has yet to be elucidated. Two Chinese ARNSHL families, each of which had two affected siblings, were included in this study. The families underwent target region capture and high-throughput sequencing to analyze the exonic, splice-site, and intronic sequences of 128 genes. Furthermore, 1751 normal Chinese individuals served as controls, and 122 Chinese families segregating with apparent ARNSHL, who had been previously excluded for variants in the common deafness genes GJB2 and SLC26A4, were subjected to screening for candidate mutations. We identified a novel homozygous missense mutation (p.Arg66Leu) and novel compound heterozygous frameshift mutations (p.Arg56fsTer24 and p.His403fsTer36) in Chinese families with ARNSHL. This is the first report to identify PDZD7 as an ARNSHL-associated gene in the Chinese population. Our finding could expand the pathogenic spectrum and strengthens the clinical diagnostic role of the PDZD7 gene in ARNSHL patients.

Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome.

BACKGROUND: Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases. METHODS: Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations. Targeted genes capture combining next-generation sequencing was performed within the family. Sanger sequencing was used to confirm the causative mutation. The auditory phenotypes of all reported familial HDR syndrome cases analyzed were provided. RESULTS: In Chinese family 7121, a heterozygous nonsense mutation c.826C>T (p.R276*) was identified in GATA3. All the three affected members suffered from sensorineural deafness and hypocalcemia; however, renal dysplasia only appeared in the youngest patient. Furthermore, an overview of thirty HDR syndrome families with corresponding GATA3 mutations revealed that hearing impairment occurred earlier in the younger generation in at least nine familial cases (30%) and two thirds of them were found to carry premature stop mutations. CONCLUSIONS: This study highlights the phenotypic heterogeneity of HDR and points to a possible genetic anticipation in patients with HDR, which needs to be further investigated.

A novel dominant GJB2 (DFNA3) mutation in a Chinese family.

To decipher the phenotype and genotype of a Chinese family with autosomal dominant non-syndromic hearing loss (ADNSHL) and a novel dominant missense mutation in the GJB2 gene (DFNA3), mutation screening of GJB2 was performed on the propositus from a five-generation ADNSHL family through polymerase chain reaction amplification and Sanger sequencing. The candidate variation and the co-segregation of the phenotype were verified in all ascertained family members. Targeted genes capture and next-generation sequencing (NGS) were performed to explore additional genetic variations. We identified the novel GJB2 mutation c.524C > A (p.P175H), which segregated with high frequency and was involved in progressive sensorineural hearing loss. One subject with an additional c.235delC mutation showed a more severe phenotype than did the other members with single GJB2 dominant variations. Four patients diagnosed with noise-induced hearing loss did not carry this mutation. No other pathogenic variations or modifier genes were identified by NGS. In conclusion, a novel missense mutation in GJB2 (DFNA3), affecting the second extracellular domain of the protein, was identified in a family with ADNSHL.