Functional Connectivity Alterations and Molecular Characterization of the Anterior Cingulate Cortex in Tinnitus Pathology without Hearing Loss.

Compared with individuals with hearing loss, tinnitus patients without hearing loss have more psychological or emotional problems. Tinnitus is closely associated to abnormal metabolism and function of the limbic system, a key brain region for emotion experience, but the underlying molecular mechanism remains unknown. Using whole-brain microvasculature dynamics imaging, the anterior cingulate cortex (ACC) is identified as a key brain region of limbic system involve in the onset of salicylate-induced tinnitus in mice. In the tinnitus group, there is enhanced purine metabolism, oxidative phosphorylation, and a distinct pattern of phosphorylation in glutamatergic synaptic pathway according to the metabolome profiles, quantitative proteomic, and phosphoproteomic data of mice ACC tissue. Electroencephalogram in tinnitus patients with normal hearing thresholds show that the functional connectivity between pregenual anterior cingulate cortex and the primary auditory cortex is significantly increased for high-gamma frequency band, which is positively correlated with the serum glutamate level. These findings indicate that ACC plays an important role in the pathophysiology of tinnitus by interacting with the primary auditory cortex and provide potential molecular targets in the ACC for tinnitus treatment.

A Novel COCH p.D544Vfs*3 Variant Associated with DFNA9 Sensorineural Hearing Loss Causes Pathological Multimeric Cochlin Formation.

COCH (coagulation factor C homology) is one of the most frequently mutated genes of autosomal dominant non-syndromic hearing loss. Variants in COCH could cause DFNA9, which is characterized by late-onset hearing loss with variable degrees of vestibular dysfunction. In this study, we report a Chinese family with a novel COCH variant (c.1687delA) causing p.D544Vfs*3 in the cochlin. Comprehensive audiometric tests and vestibular function assessments were taken to acquire the phenotypic profile of the subjects. Next-generation sequencing was conducted and segregation analysis was carried out using Sanger sequencing. The proband presented mild vestibular symptoms and normal functional assessment results in almost every test, while the variant co-segregated with hearing impairment in the pedigree. The variant was located beyond the vWFA2 domain, which was predicted to affect the post-translational cleavage of the cochlin via molecular modeling analysis. Notably, in the overexpressing study, by transient transfecting the HEK 293T cells, we found that the p.D544Vfs*3 variant increased the formation of multimeric cochlin. Our result enriched the spectrum of DFNA9-linked pathological COCH variants and suggested that variants, causative of cochlin multimerization, could be related to DFNA9 with sensorineural hearing loss rather than serious vestibular symptoms.

Effect of Electrode Insertion Angle on Cochlear Implantation Outcomes in Adult and Children Patients with Sensorineural Hearing Loss.

Purpose: To determine the role played by electrode insertion angle in cochlear implantation (CI) outcomes in adult and children patients with sensorineural hearing loss (SNHL). Methods: Adults (n = 10) and children (n = 19) with SNHL undergoing CI in a tertiary specialized hospital were retrospectively enrolled. The measurements were evaluated before and after CI surgery using sound field audiometry and speech recognition tests. Questionnaires were used to assess subjective benefits. Electrode insertion angles were determined using postoperative X-rays. Results: Both adult and children patients showed significant improvements in hearing, speech performance, and audiology and speech-related quality of life after CI. The angular insertion depths of adult and children group were 323.70 ± 43.57° and 341.53 ± 57.07°, respectively, showing no significant difference. In the adult group, deeper insertion depths were found to be strongly linked to lower postoperative pure tone thresholds at 12 months and higher postoperative disyllabic Word Recognition and Sentence Recognition Scores at 6 months (all P < 0.05). In the children group, deeper insertion depth had a positive correlation with postoperative monosyllabic Word Recognition Scores 6 and 12 months after CI surgery (both P < 0.05). Multiple linear regression models were constructed to predict disyllabic Word Recognition Scores at 6 and 12 months postoperatively in the children group, in which insertion angle, duration of hearing loss, and preoperative questionnaire result were identified as dependent variables. Conclusions: Greater angular insertion depths resulted in improved hearing and speech performances after CI. The benefits of greater angular insertion depths can be found in both adult and children patients and last for at least 12 months. Clinicians are expected to determine the optimal implantation direction during CI and ensure the insertion depth to improve the speech rehabilitation of patients.

Effect of Sodium Salicylate on Calcium Currents and Exocytosis in Cochlear Inner Hair Cells: Implications for Tinnitus Generation.

Sodium salicylate is an anti-inflammatory medication with a side-effect of tinnitus. Here, we used mouse cochlear cultures to explore the effects of salicylate treatment on cochlear inner hair cells (IHCs). We found that IHCs showed significant damage after exposure to a high concentration of salicylate. Whole-cell patch clamp recordings showed that 1-5 mmol/L salicylate did not affect the exocytosis of IHCs, indicating that IHCs are not involved in tinnitus generation by enhancing their neuronal input. Instead, salicylate induced a larger peak amplitude, a more negative half-activation voltage, and a steeper slope factor of Ca2+ current. Using noise analysis of Ca2+ tail currents and qRT-PCR, we further found that salicylate increased the number of Ca2+ channels along with CaV1.3 expression. All these changes could act synergistically to enhance the Ca2+ influx into IHCs. Inhibition of intracellular Ca2+ overload significantly attenuated IHC death after 10 mmol/L salicylate treatment. These results implicate a cellular mechanism for tinnitus generation in the peripheral auditory system.

Comparative effectiveness of tamoxifen, toremifene, letrozole, anastrozole, and exemestane on lipid profiles in breast cancer patients: A network meta-analysis.

BACKGROUND: Adjuvant endocrine therapy is a vital portion of postoperative comprehensive treatment for breast cancer patients. In recent years, studies have shown that endocrine therapy has a certain impact on the serum lipids of breast cancer patients, and the changes of lipid profiles may bring a series of problems. However, very few studies focus on this issue to date. The results of these studies are inconsistent, and the influence of different adjuvant endocrine modalities on lipid profiles still remains controversial. In order to better explore this issue, we conduct this network meta-analysis. METHOD: The protocol followed preferred reporting items for systematic reviews and meta-analyses protocols. Three main databases (PubMed, Embase, and the Cochrane Library) will be searched systematically for eligible randomized controlled trials without language restriction. In addition, a manual search of the references of relevant published studies will also be considered. Two reviewers will conduct studies selection, data extraction, and risk of bias assessment independently. The primary outcome is the variation of biochemical parameters - the serum lipid profiles (cholesterol, triglyceride, high-density lipoprotein, low low-density lipoprotein). RESULTS: The results will provide useful information about the side effects of different adjuvant endocrine drugs on lipid profiles in postoperative breast cancer patients (estrogen receptor-positive and/or progesterone receptor-positive). CONCLUSION: The findings of this study will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019129850.

Advances on fluid shear stress regulating blood-brain barrier.

The integrity of structure and function of blood-brain barrier (BBB) plays a central role in maintaining the homeostasis of the central nervous system. Patients with severe cerebrovascular stenosis often undergo cerebrovascular bypass surgery. However, the sharply increased fluid shear stress (FSS) after cerebrovascular bypass disrupts the physiological function of brain microvascular endothelial cells (BMECs) at the lesion site, damaging BBB and inducing intracerebral hemorrhage eventually. At present, there are great interests in cerebral vascular flow regulating the structure and function of BBB under physiological and pathological conditions, and most of studies have highlighted the importance of BMECs in BBB. Understanding of how FSS regulating BBB can promote the development of new protective and restorative cerebral vascular interventional therapy.