Glutamine uptake and catabolism is required for myofibroblast formation and persistence.

BACKGROUND: Fibrosis and extracellular matrix remodeling are mediated by resident cardiac fibroblasts (CFs). In response to injury, fibroblasts activate, differentiating into specialized synthetic and contractile myofibroblasts producing copious extracellular matrix proteins (e.g., collagens). Myofibroblast persistence in chronic diseases, such as HF, leads to progressive cardiac dysfunction and maladaptive remodeling. We recently reported that an increase in αKG (alpha-ketoglutarate) bioavailability, which contributes to enhanced αKG-dependent lysine demethylase activity and chromatin remodeling, is required for myofibroblast formation. Therefore, we aimed to determine the substrates and metabolic pathways contributing to αKG biosynthesis and their requirement for myofibroblast formation. METHODS: Stable isotope metabolomics identified glutaminolysis as a key metabolic pathway required for αKG biosynthesis and myofibroblast formation, therefore we tested the effects of pharmacologic inhibition (CB-839) or genetic deletion of glutaminase (Gls1-/-) on myofibroblast formation in both murine and human cardiac fibroblasts. We employed immunofluorescence staining, functional gel contraction, western blotting, and bioenergetic assays to determine the myofibroblast phenotype. RESULTS: Carbon tracing indicated enhanced glutaminolysis mediating increased αKG abundance. Pharmacological and genetic inhibition of glutaminolysis prevented myofibroblast formation indicated by a reduction in αSMA+ cells, collagen gel contraction, collagen abundance, and the bioenergetic response. Inhibition of glutaminolysis also prevented TGFß-mediated histone demethylation and supplementation with cell-permeable αKG rescued the myofibroblast phenotype. Importantly, inhibition of glutaminolysis was sufficient to prevent myofibroblast formation in CFs isolated from the human failing heart. CONCLUSIONS: These results define glutaminolysis as necessary for myofibroblast formation and persistence, providing substantial rationale to evaluate several new therapeutic targets to treat cardiac fibrosis.

Insights into the epidemiology and clinical aspects of post-COVID-19 conditions in adult.

OBJECTIVES: While most individuals infected with COVID-19 recover completely within a few weeks, some continue to experience lingering symptoms. This study was conducted to identify and describe the clinical and subclinical manifestations of adult patients from the long-term effects of COVID-19. METHODS: The study analyzed 205 medical records of inpatients (age ≥ 16 years, ≥ 4 weeks post-COVID-19 recovery, and a negative SARS-CoV-2 status at enrollment) at Thong Nhat Hospital, Vietnam, from 6 September 2021 to 26 August 2022, using R language software. RESULTS: The majority of patients hospitalized with long COVID-19 symptoms (92.68%) had normal consciousness. The most common symptoms on admission were fatigue (59.02%), dyspnea (52.68%), and cough (42.93%). In total, 80% of patients observed respiratory symptoms, primarily dyspnea, while 42.44% reported neurological symptoms, with sleep disturbance being the most common. Noticeably, 42.93% of patients experienced respiratory failure in the post-COVID-19 period, resembling acute respiratory distress syndrome. DISCUSSION: These findings provide crucial insights into the epidemiology, clinical, and subclinical aspects of post-COVID-19 conditions, shedding light on the prevalence of common symptoms and the demographic distribution of affected patients. Understanding these manifestations is vital for patient well-being, improved clinical practice, and targeted healthcare planning, potentially leading to better patient care, management, and future interventions.

Molecular Signature of HFpEF: Systems Biology in a Cardiac-Centric Large Animal Model.

In this study the authors used systems biology to define progressive changes in metabolism and transcription in a large animal model of heart failure with preserved ejection fraction (HFpEF). Transcriptomic analysis of cardiac tissue, 1-month post-banding, revealed loss of electron transport chain components, and this was supported by changes in metabolism and mitochondrial function, altogether signifying alterations in oxidative metabolism. Established HFpEF, 4 months post-banding, resulted in changes in intermediary metabolism with normalized mitochondrial function. Mitochondrial dysfunction and energetic deficiencies were noted in skeletal muscle at early and late phases of disease, suggesting cardiac-derived signaling contributes to peripheral tissue maladaptation in HFpEF. Collectively, these results provide insights into the cellular biology underlying HFpEF progression.

The aborted early history of the translabyrinthine approach: a victim of suppression or technical prematurity?

OBJECTIVE: To ascertain the reasons translabyrinthine (TL) approach to acoustic neuroma, initially attempted in 1911, became relegated to obscurity for nearly half a century. STUDY DESIGN: A scholarly review of more than 40 publications in German and English from the late 19th to the mid-20th century. LITERATURE SUMMARY: Surgeons who first contemplated approaching the cerebellopontine angle recognized that the shortest route from the surface was through the petrous bone. In the late 19th century, otologic surgeons devised numerous procedures to deal with infection in and around the semicircular canals. This familiarity led R. Panse of Dresden to propose (but not actually perform) a TL approach (1904). F.H. Quix of Utrecht performed the first pure TL approach (1911), but others before him had used petrosectomy to augment the suboccipital approach. Subsequent TL attempts by other surgeons met with variable results. Devastating criticism of the method was proffered by leading acoustic neuroma surgeons of the day such as H. Cushing (1921) and W. Dandy (1925). The most important criticisms were that the approach provided only a deep and narrow field of action, was surrounded by major vascular structures, and led to great difficulty with cerebrospinal fluid leakage. HISTORICAL PERSPECTIVE: The literature on this subject is replete with erroneous citations. Panse is often miscited as having performed the first surgery. It has also become traditional to give Quix great credit, even though his procedure failed to remove much of the tumor. Poor outcome and intense criticism led surgeons to abandon the TL approach until W.F. House, armed with operating microscope and high-speed drill, successfully resurrected it in the 1960s. He concisely summarizes the pioneers' efforts: "They had the ideas and desire, but not the technical tools."

Morphological correlates of hearing loss after cochlear implantation and electro-acoustic stimulation in a hearing-impaired Guinea pig model.

Hybrid or electro-acoustic stimulation (EAS) cochlear implants (CIs) are designed to provide high-frequency electric hearing together with residual low-frequency acoustic hearing. However, 30-50% of EAS CI recipients lose residual hearing after implantation. The objective of this study was to determine the mechanisms of EAS-induced hearing loss in an animal model with high-frequency hearing loss. Guinea pigs were exposed to 24 h of noise (12-24 kHz at 116 dB) to induce a high-frequency hearing loss. After recovery, two groups of animals were implanted (n = 6 per group), with one group receiving chronic acoustic and electric stimulation for 10 weeks, and the other group receiving no stimulation during this time frame. A third group (n = 6) was not implanted, but received chronic acoustic stimulation. Auditory brainstem responses were recorded biweekly to monitor changes in hearing. The organ of Corti was immunolabeled with phalloidin, anti-CtBP2, and anti-GluR2 to quantify hair cells, ribbons and post-synaptic receptors. The lateral wall was immunolabeled with phalloidin and lectin to quantify stria vascularis capillary diameters. Bimodal or trimodal diameter distributions were observed; the number and location of peaks were objectively determined using the Aikake Information Criterion and Expectation Maximization algorithm. Noise exposure led to immediate hearing loss at 16-32 kHz for all groups. Cochlear implantation led to additional hearing loss at 4-8 kHz; this hearing loss was negatively and positively correlated with minimum and maximum peaks of the bimodal or trimodal distributions of stria vascularis capillary diameters, respectively. After chronic stimulation, no significant group changes in thresholds were seen; however, elevated thresholds at 1 kHz in implanted, stimulated animals were significantly correlated with decreased presynaptic ribbon and postsynaptic receptor counts. Inner and outer hair cell counts did not differ between groups and were not correlated with threshold shifts at any frequency. As in the previous study in a normal-hearing model, stria vascularis capillary changes were associated with immediate hearing loss after implantation, while little to no hair cell loss was observed even in cochlear regions with threshold shifts as large as 40-50 dB. These findings again support a role of lateral wall blood flow changes, rather than hair cell loss, in hearing loss after surgical trauma, and implicate the endocochlear potential as a factor in implantation-induced hearing loss. Further, the analysis of the hair cell ribbons and post-synaptic receptors suggest that delayed hearing loss may be linked to synapse or peripheral nerve loss due to stimulation excitotoxicity or inflammation. Further research is needed to separate these potential mechanisms of delayed hearing loss.

Association of otosclerosis with Sp1 binding site polymorphism in COL1A1 gene: evidence for a shared genetic etiology with osteoporosis.

HYPOTHESIS: There is an association between otosclerosis and osteoporosis. BACKGROUND: Both osteoporosis and otosclerosis are common bone diseases to which relatively large portions of the population are genetically predisposed. Recently, a strong association has been described between osteoporosis and an Sp1 binding site of putative functional significance in the first intron of the COL1A1 gene. METHODS: We applied polymerase chain reaction-based restriction enzyme analysis to determine the polymorphic distribution of the Sp1 site in 100 patients with otosclerosis and 108 control subjects. RESULTS: This study showed a significant association between otosclerosis and the COL1A1 first intron Sp1 site. The allelic frequency of the Sp1 site is very similar between otosclerosis and osteoporosis. CONCLUSION: Some cases of otosclerosis and osteoporosis could share a functionally significant polymorphism in the Sp1 transcription factor binding site in the first intron of the COL1A1 gene.

Evidence-based practice: management of vertigo.

The article focuses on the evidence basis for the management of benign paroxysmal positional vertigo, the most common diagnosis of vertigo in both primary care and subspecialty settings. An overview is presented, along with evidence-based clinical assessment, diagnosis, and management. Summaries of differential diagnosis of vertigo and outcomes are presented.

Volumetric in vivo imaging of microvascular perfusion within the intact cochlea in mice using ultra-high sensitive optical microangiography.

Studying the inner ear microvascular dynamics is extremely important to understand the cochlear function and to further advance the diagnosis, prevention, and treatment of many otologic disorders. However, there is currently no effective imaging tool available that is able to access the blood flow within the intact cochlea. In this paper, we report the use of an ultrahigh sensitive optical micro-angiography (UHS-OMAG) imaging system to image 3-D microvascular perfusion within the intact cochlea in living mice. The UHS-OMAG image system used in this study is based on spectral domain optical coherence tomography, which uses a broadband light source centered at 1300 nm with an imaging rate of 47[Formula: see text] 000 A-scans/s, capable of acquiring high-resolution B scans at 300 frames/s. The technique is sensitive enough to image very slow blood flow velocities, such as those found in capillary networks. The 3-D imaging acquisition time for a whole cochlea is  âˆ¼ 4.1 s. We demonstrate that volumetric reconstruction of microvascular flow obtained by UHS-OMAG provides a comprehensive perfusion map of several regions of the cochlea, including the otic capsule, the stria vascularis of the apical and middle turns and the radiating arterioles that emanate from the modiolus.

The Otology Data Collection project: report from the CHEER network.

OBJECTIVE: To describe and communicate data collected in the CHEER (Creating Healthcare Excellence through Education and Research) infrastructure proof-of-concept study to facilitate understanding of the potential capabilities of practice-based research networks and to present pilot data for development of future research initiatives. STUDY DESIGN: Prospective observational study of CHEER infrastructure operational capacity using a convenience sample of all patients presenting to the practices with tinnitus, dizziness, or a combination of these symptoms. SETTING: The CHEER network of community and academic practice sites. SUBJECTS AND METHODS: The data collection exercise collected demographic, clinical, treatment, and health-related quality-of-life surveys on tinnitus, dizziness, and migraine disorders. Descriptive analysis of the data is presented. RESULTS: Of the sites in the CHEER network, 73% (16/22) successfully enrolled subjects; a total of 1532 patients were enrolled in 8 months. Tinnitus alone, dizziness alone, and both occurred in 28%, 34%, and 29%, respectively. Patients complaining of tinnitus and dizziness had lower quality of life than those sufferers with 1 disorder. Migraine was associated with 27% of patients. The most frequent diagnoses for patients with tinnitus and dizziness were Ménière disease (34%), vertiginous migraine (18%), and benign paroxysmal positional vertigo (16%). CONCLUSION: Descriptive data on patients with common disorders can be rapidly collected within the framework of a practice-based research network. The data in this study provide valuable pilot information on the targeted disorders, providing a baseline for development of future epidemiological data and clinical trials.

Volumetric in vivo imaging of intracochlear microstructures in mice by high-speed spectral domain optical coherence tomography.

There is considerable interest in developing new methods for in vivo imaging of the complex anatomy of the mammalian cochlea for clinical as well as fundamental studies. In this study, we explored, the feasibility of spectral domain optical coherence tomography (SD-OCT) for 3-D in vivo imaging of the cochlea in mice. The SD-OCT system employed in this study used a broadband light source centered at 1300 nm, and the imaging speed of the system was 47,000 A-scans per second using the InGaAs camera. The system was capable of providing fully processed, high-resolution B-scan images [512 (axial) x 128 (lateral) pixels] at 280 frames per sec. The 3-D imaging acquisition time for a whole cochlea was approximately 0.45 sec. The traditional SD-OCT structural imaging algorithm was used to reconstruct 3-D cochlear morphology. We demonstrated that SD-OCT can be successfully used for in vivo imaging of important morphological features within the mouse cochlea, such as the otic capsule and structures within, including Reissner's membrane, the basilar membrane, tectorial membrane, organ of Corti, and modiolus of the apical and middle turns.