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1.
Article in Chinese | MEDLINE | ID: mdl-38973049

ABSTRACT

Large vestibular aqueduct syndrome(LVAS) is a common recessive hereditary hearing loss disease, and some patients may also experience vestibular dysfunction. With the wide application of cochlear implant(CI) and the development of vestibular medicine, the pathophysiological mechanism of LVAS and the influence mechanism of CI on vestibular function are gradually elucidated. Consequently, the evaluation and rehabilitation of vestibular dysfunction function have also become research hotspots. This article reviews studies on vestibular function and related rehabilitation in patients with large vestibular aqueduct syndrome.


Subject(s)
Vestibular Aqueduct , Humans , Vestibular Aqueduct/abnormalities , Cochlear Implants , Vestibular Diseases/rehabilitation , Vestibular Diseases/physiopathology , Cochlear Implantation , Hearing Loss, Sensorineural/rehabilitation , Hearing Loss, Sensorineural/physiopathology , Vestibule, Labyrinth/physiopathology
2.
BMJ Open ; 14(7): e078017, 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38977364

ABSTRACT

OBJECTIVE: To explore the experiences, current approaches, opinions and awareness of healthcare professionals (HCPs) caring for adults with traumatic brain injury (TBI) regarding the audio-vestibular consequences. DESIGN/SETTING: Cross-sectional online survey study. PARTICIPANTS: HCPs with experience of caring for adults with TBI, who were not ENT (ear nose throat) specialists or audiologists. METHODS: The study was conducted from May 2022 to December 2022. The online survey consisted of 16 closed and open-text questions in English and Turkish about clinical experience, current approaches and awareness of audio-vestibular consequences following TBI. Frequencies of responses to closed questions and associations between variables were analysed using SPSS V.28. Open-text responses were summarised in Microsoft Excel. RESULTS: Seventy HCPs participated from 17 professions and 14 countries, with the majority from the UK (42.9%). HCPs stated that 'some' to 'all' of their patients had auditory problems such as 'inability to understand speech-in-noise' (66%), 'tinnitus' (64%), 'hyperacusis' (57%) and balance problems such as 'dizziness' (79%) and 'vertigo' (67%). Usually, HCPs asked about the balance status of patients at appointments and when they observed dizziness and/or balance disorder they used screening tests, most commonly finger-to-nose (53%). For auditory impairments, HCPs preferred referring patients with TBI to audiology/ENT services. However, 6% of HCPs felt that audio-vestibular conditions could be ignored on referral because patients with TBI struggled with many impairments. Additionally, 44% would suggest hearing aids to patients with TBI with hearing loss 'if they would like to use' rather than 'definitely'. CONCLUSIONS: Many audio-vestibular impairments are observed by HCPs caring for patients with TBI. The assessment and intervention opinions and awareness of HCPs for these impairments vary. However, non-expert HCPs may not be aware of negative consequences of untreated audio-vestibular impairments following TBI. Therefore, developing a simple framework for screening and indications of audio-vestibular impairments for referral may be helpful for non-audiological specialists regularly seeing these patients.


Subject(s)
Brain Injuries, Traumatic , Humans , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/psychology , Cross-Sectional Studies , Adult , Male , Female , Health Personnel/psychology , Surveys and Questionnaires , Attitude of Health Personnel , Health Knowledge, Attitudes, Practice , Middle Aged , Vestibular Diseases/etiology
3.
Otol Neurotol ; 45(6): 608-618, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38865717

ABSTRACT

BACKGROUND: People with vestibular dysfunction encounter many obstacles when seeking vestibular rehabilitation treatment. Remote delivery of vestibular rehabilitation may offer a promising avenue for overcoming these barriers, ensuring uninterrupted and cost-effective care. OBJECTIVE: To evaluate clinical trials studying telerehabilitation and virtual reality devices as therapeutic interventions for individuals with vestibular dysfunction. METHODS: A PRISMA systematic review of PubMed, EMBASE, Cochrane, Web of Science, and SCOPUS was conducted for randomized controlled trials describing the use of remote care delivery for vestibular rehabilitation. Bias of studies was assessed with the revised Cochrane risk-of-bias tool (RoB2). RESULTS: The search identified 1,358 unique articles and 14 articles matched the search criteria. Study samples size ranged from 20 to 337, with mean ages ranging from 29.3 to 77.7 years. Interventions included telephone and online communication, exergaming devices, web-based applications, and head-mounted devices to deliver vestibular rehabilitation. Outcomes included validated questionnaires, objective clinical tests, and physical examinations. CONCLUSIONS: The studies reviewed in this article reported greater or equivalent outcomes when incorporating remote care options as supplements or alternatives to standard care for patients with vestibular dysfunction. Further research is required to address limitations in these studies such as heterogeneity of control groups and cost-effectiveness of these interventions.


Subject(s)
Telerehabilitation , Vestibular Diseases , Humans , Vestibular Diseases/rehabilitation , Virtual Reality
4.
Adv Exp Med Biol ; 1441: 761-775, 2024.
Article in English | MEDLINE | ID: mdl-38884747

ABSTRACT

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.


Subject(s)
Aorta, Thoracic , Aortic Valve , Humans , Aorta, Thoracic/abnormalities , Aorta, Thoracic/pathology , Aortic Valve/abnormalities , Aortic Valve/pathology , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Bicuspid Aortic Valve Disease/genetics , Pulmonary Valve Stenosis/genetics , Mutation , Receptor, Notch1/genetics , Aortic Valve Disease/genetics , Heart Valve Diseases/genetics , Heart Valve Diseases/pathology , Calcinosis/genetics , Calcinosis/pathology , Hematologic Diseases/genetics , Hematologic Diseases/pathology , Vestibular Diseases/genetics , Vestibular Diseases/pathology
5.
Sensors (Basel) ; 24(12)2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38931672

ABSTRACT

BACKGROUND: Sensory information obtained from the visual, somatosensory, and vestibular systems is responsible for regulating postural control, and if damage occurs in one or more of these sensory systems, postural control may be altered. OBJECTIVE: To evaluate and compare the postural sway velocity between children with normal hearing and with sensorineural hearing loss (SNHL), matched by sex and age group, and to compare the postural sway velocity between children with normal hearing and with SNHL, with and without vestibular dysfunction. METHODS: Cross-sectional study that evaluated 130 children (65 with normal hearing and 65 with SNHL), of both sexes and aged between 7 and 11 years, from public schools of the city of Caruaru, Pernambuco state, Brazil. The postural sway velocity of the center of pressure (COP) was assessed by a force platform, in two directions, anteroposterior (AP) and mediolateral (ML)), in three positions, namely bipedal support with feet together and parallel (parallel feet (PF)), bipedal support with one foot in front of the other (tandem foot (TF)), and single-leg support (one foot (OF)), evaluated with the eyes open and closed. RESULTS: Children with SNHL demonstrated greater postural sway velocity compared to children with normal hearing in all the positions evaluated, with significant differences in the AP direction, with the eyes open (PF: p = 0.001; TF: p = 0.000; OF: p = 0.003) and closed (PF: p = 0.050; TF: p = 0.005). The same occurred in the ML direction, with the eyes open (PF: p = 0.001; TF: p = 0.000; OF: p = 0.001) and closed (PF: p = 0.002; TF: p = 0.000). The same occurred in relation to vestibular function, where the children with SNHL with an associated vestibular dysfunction demonstrated greater postural sway velocity compared to children with normal hearing in all the positions evaluated, demonstrating significant differences in the AP direction, with the eyes open (TF: p = 0.001; OF: p = 0.029) and eyes closed (PF: p = 0.036; TF: p = 0.033). The same occurred in the ML direction, with the eyes open (TF: p = 0.000) and with the eyes closed (PF: p = 0.008; TF: p = 0.009). CONCLUSIONS: Children with SNHL demonstrated greater instability of postural control than children with normal hearing in all the directions assessed. Children with SNHL and an associated vestibular dysfunction demonstrated the greatest instability of postural control in this study.


Subject(s)
Postural Balance , Vestibular Diseases , Humans , Child , Postural Balance/physiology , Male , Female , Cross-Sectional Studies , Vestibular Diseases/physiopathology , Hearing Loss, Sensorineural/physiopathology , Deafness/physiopathology
6.
Cephalalgia ; 44(6): 3331024241262488, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38887813

ABSTRACT

OBJECTIVE: This study aimed to identify the potential subgroups of migraines based on the patterns of migraine associated symptoms, vestibular and auditory symptoms using latent class analysis and to explore their characteristics. METHOD: A total of 555 patients with migraine participated in the study. Symptoms such as nausea, vomiting, photophobia, phonophobia, osmophobia, visual symptoms, vestibular symptoms (dizziness, vertigo), and auditory symptoms (tinnitus, hearing loss, aural fullness) were assessed. Latent class analysis was performed to identify subgroups of migraines. Covariates such as gender, age of migraine onset, frequency of migraine attacks per month, and family history were also considered. RESULTS: The analysis revealed four latent classes: the Prominent Vestibular; Prominent Nausea; Presenting Symptoms but not prominent or dominant; and Sensory Hypersensitivity groups. Various covariates, such as gender, age of migraine onset, and frequency of migraine attacks, demonstrated significant differences among the four groups. The Sensory Hypersensitivity group showed the presence of multiple sensory symptoms, earlier age of migraine onset, and higher proportion of females. The Prominent Vestibular group had the highest probability of dizziness or vertigo but lacked the presence of auditory symptoms. The Prominent Nausea group exhibited prominent nausea. The Presenting Symptoms but not prominent or dominant group comprised individuals with the highest migraine attacks per month and proportion of chronic migraine. CONCLUSION: This study identifies four subgroups of migraines based on the patterns of symptoms. The findings suggest potential different but overlapped mechanisms behind the vestibular and auditory symptoms of migraine. Considering the different patterns of migraine-related symptoms may provide deeper insights for patients' prognosis and clinical decision-making.


Subject(s)
Latent Class Analysis , Migraine Disorders , Humans , Migraine Disorders/diagnosis , Migraine Disorders/epidemiology , Female , Male , Adult , Middle Aged , Vertigo/diagnosis , Vertigo/epidemiology , Young Adult , Nausea/epidemiology , Nausea/etiology , Nausea/diagnosis , Dizziness/epidemiology , Dizziness/diagnosis , Aged , Adolescent , Vestibular Diseases/diagnosis , Vestibular Diseases/epidemiology , Vestibular Diseases/complications
7.
J Otolaryngol Head Neck Surg ; 53: 19160216241250354, 2024.
Article in English | MEDLINE | ID: mdl-38888938

ABSTRACT

OBJECTIVES: This study aims to provide an overview of dizziness post head injury in those with prominent features for central vestibular dysfunction (CVD) in comparison to those with a post-traumatic peripheral vestibular etiology. STUDY DESIGN: Retrospective. SETTING: University Health Network (UHN) Workplace Safety and Insurance Board (WSIB) database from 1988 to 2018 were evaluated for post-traumatic dizziness. METHODS: The UHN WSIB neurotology database (n = 4291) between 1998 and 2018 was retrospectively studied for head-injured workers presenting with features for CVD associated with trauma. All patients had a detailed neurotological history and examination, audiovestibular testing that included video nystagmography (VNG) and cervical vestibular-evoked myogenic potentials (cVEMPs). Imaging studies including routine brain and high-resolution temporal bone computed tomography (CT) scans and/or intracranial magnetic resonance imaging (MRI) were available for the majority of injured workers. RESULTS: Among 4291 head-injured workers with dizziness, 23 were diagnosed with features/findings denoting CVD. Complaints of imbalance were significantly more common in those with CVD compared to vertigo and headache in those with peripheral vestibular dysfunction. Atypical positional nystagmus, oculomotor abnormalities and facial paralysis were more common in those with CVD. CONCLUSION: Symptomatic post-traumatic central vestibular injury is uncommon. It occurred primarily following high-impact trauma and was reflective for a more severe head injury where shearing effects on the brain often resulted in diffuse axonal injury. Complaints of persistent imbalance and ataxia were more common than complaints of vertigo. Eye movement abnormalities were highly indicative for central nervous system injury even in those with minimal change on CT/MRI.


Subject(s)
Craniocerebral Trauma , Dizziness , Vestibular Diseases , Humans , Retrospective Studies , Male , Craniocerebral Trauma/complications , Craniocerebral Trauma/physiopathology , Female , Adult , Dizziness/etiology , Dizziness/physiopathology , Middle Aged , Vestibular Diseases/etiology , Vestibular Diseases/physiopathology , Vestibular Diseases/diagnosis , Vestibular Evoked Myogenic Potentials , Vestibular Function Tests , Magnetic Resonance Imaging , Tomography, X-Ray Computed
8.
PLoS Genet ; 20(6): e1011310, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38857303

ABSTRACT

Growth deficiency is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth deficiency in a mouse model of KS1 and further established that a Kmt2d-/- chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth deficiency in a mouse model of KS2, Kdm6atm1d/+. We show that Kdm6atm1d/+ mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure. Kdm6atm1d/+ growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a-/- chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found that Kdm6a-/- cells undergo premature, enhanced differentiation towards chondrocytes compared to Kdm6a+/+ controls. RNA-seq showed that Kdm6a-/- cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously on Kmt2d-/-, Kdm6a-/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression between Kmt2d-/- and Kdm6a-/- at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.


Subject(s)
Abnormalities, Multiple , Chondrocytes , Disease Models, Animal , Face , Hematologic Diseases , Histone Demethylases , Vestibular Diseases , Animals , Vestibular Diseases/genetics , Vestibular Diseases/pathology , Mice , Face/abnormalities , Histone Demethylases/genetics , Histone Demethylases/metabolism , Hematologic Diseases/genetics , Hematologic Diseases/pathology , Chondrocytes/metabolism , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Cell Differentiation/genetics , Chondrogenesis/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/deficiency , Humans , Mice, Knockout , Phenotype , Histone-Lysine N-Methyltransferase , Myeloid-Lymphoid Leukemia Protein
9.
Brain Behav ; 14(6): e3591, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38849984

ABSTRACT

PURPOSE: Vestibular migraine (VM) is a disorder with prominent vestibular symptoms that are causally correlated with migraine and is the most prevalent neurological cause of episodic vertigo. Nevertheless, the functional underpinnings of VM remain largely unclear. This study aimed to reveal concordant alteration patterns of functional connectivity (FC) in VM patients. METHODS: We searched literature measuring resting-state FC abnormalities of VM patients in PubMed, Embase, Cochrane, and Scopus databases before May 2023. Furthermore, we applied the anisotropic effect size-signed differential mapping (AES-SDM) to conduct a whole-brain voxel-wise meta-analysis to identify the convergence of FC alterations in VM patients. RESULTS: Nine studies containing 251 VM patients and 257 healthy controls (HCs) were included. Relative to HCs, VM patients showed reduced activity in the left superior temporal gyrus and left midcingulate/paracingulate gyri, and increased activity in the precuneus, right superior parietal gyrus, and right middle frontal gyrus. Jackknife's analysis and subgroup analysis further supported the generalization and robustness of the main results. Furthermore, meta-regression analyses indicated that the Dizziness Handicap Inventory (DHI) ratings were positively correlated with the activity in the precuneus, while higher Headache Impact Test-6 and DHI scores were associated with lower activity within the left midcingulate/paracingulate gyri. CONCLUSIONS: The study indicates that VM is associated with specific functional deficits of VM patients in crucial regions involved in the vestibular and pain networks and provides further information on the pathophysiological mechanisms of VM.


Subject(s)
Migraine Disorders , Humans , Migraine Disorders/physiopathology , Migraine Disorders/diagnostic imaging , Magnetic Resonance Imaging , Vestibular Diseases/physiopathology , Functional Status , Connectome/methods , Vertigo/physiopathology , Brain/physiopathology , Brain/diagnostic imaging
10.
J Bodyw Mov Ther ; 39: 132-141, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38876618

ABSTRACT

OBJECTIVES: To examine the effects of Cawthorne-Cooksey exercises on individuals with vestibular dysfunction symptoms. METHODS: Systematic search was conducted using PubMed, EBSCO SCOPUS, Web of Science, and Google Scholar from inception to March 2023. The Physiotherapy Evidence Database (PEDro) scale was employed to evaluate the risk of bias in the included studies. RESULTS: Ten randomized controlled trials met the eligibility criteria. In total, 610 participants, 41.31 % of whom were men were included in this review. The PEDro scale scores ranged from 6 to 8 with a median of 6.5/10. Our findings revealed improvements in patients' vestibular dysfunction symptoms after Cawthorne-Cooksey exercises and other conventional interventions. CONCLUSIONS: The initial findings showed that Cawthorne-Cooksey exercises are not superior to other concurrent vestibular rehabilitation interventions in improving vestibular dysfunction symptoms. Additional trials with long-term follow-ups are strongly recommended to understand the impacts of Cawthorne-Cooksey exercises on vestibular dysfunction symptoms.


Subject(s)
Exercise Therapy , Randomized Controlled Trials as Topic , Vestibular Diseases , Humans , Vestibular Diseases/rehabilitation , Exercise Therapy/methods , Postural Balance/physiology
11.
Otol Neurotol ; 45(7): 818-823, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38896787

ABSTRACT

AIM: To characterize vestibular recovery in a mouse model of unilateral labyrinthotomy under local AAT and dexamethasone treatment. BACKGROUND: Alpha1-antitrypsin (AAT) is a circulating tissue-protective molecule that rises during inflammatory conditions and promotes inflammatory resolution. Its local concentration in human perilymph inversely correlates with the severity of inner ear dysfunction; concomitantly, mice that overexpress AAT and undergo inner ear trauma rapidly restore vestibular function. Locally applied AAT has yet to be examined in this context, nor has it been directly compared with anti-inflammatory corticosteroid treatment. METHODS: Wild-type mice C57BL/6 underwent a unilateral inner ear injury. Nine microliters of saline, clinical-grade AAT (180 µg/site), dexamethasone (4 mg/site), or both were applied locally on Days 0, 1, and 2 (n = 5/group). Vestibular function was assessed for 7 days. An in vitro human epithelial gap closure assay was performed using A549 cells in the presence of AAT and/or dexamethasone. RESULTS: Upon labyrinthotomy, all groups displayed severe vestibular dysfunction. Saline-treated mice showed the longest impairment. That group and the dexamethasone group displayed partial to no recovery, while AAT-treated mice exhibited complete recovery within 7 days; at this time point, dexamethasone-treated mice exhibited 50% recovery. Objective vestibular testing showed similar outcomes. In vitro, cotreatment with AAT and dexamethasone resulted in a gap closure dynamic that was superior to AAT alone at 6 h and superior to DEX alone at 48 h. CONCLUSION: Locally applied AAT treatment is superior to locally applied dexamethasone in promoting vestibular recovery in vivo. Ongoing studies are exploring the potential advantages of AAT combined with early low-dose dexamethasone therapy.


Subject(s)
Dexamethasone , Mice, Inbred C57BL , alpha 1-Antitrypsin , Animals , Mice , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , alpha 1-Antitrypsin/administration & dosage , Vestibular Diseases/drug therapy , Vestibular Diseases/etiology , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacology , Ear, Inner/drug effects , Disease Models, Animal , Recovery of Function/drug effects , Vestibule, Labyrinth/drug effects , Vestibule, Labyrinth/injuries , Humans , Male
12.
NeuroRehabilitation ; 54(4): 691-698, 2024.
Article in English | MEDLINE | ID: mdl-38875051

ABSTRACT

BACKGROUND: Cerebellar ataxia, neuropathy and bilateral vestibular areflexia (CANVAS) is a rare neurodegenerative disease affecting the cerebellum, the peripheral nervous system and the vestibular system. Due to the lack of approved drugs, therapy comprises physiotherapy and speech therapy. Transcranial magnetic stimulation is a promising non-invasive therapeutic option to complement classical symptomatic therapies. OBJECTIVE: To test feasibility of the combination of transcranial magnetic stimulation using an accelerated protocol and standard symptomatic therapy in patients with CANVAS. METHODS: Eight patients with genetically confirmed CANVAS were assigned to either verum or sham cerebellar transcranial magnetic stimulation using an accelerated protocol. Treatment duration was limited to 5 days. Additionally, patients in both groups received symptomatic therapy (speech and physiotherapy) for the duration of the study. RESULTS: All patients completed the stimulation protocol. Adverse events were rare. Ataxia severity improved in the verum group only. CONCLUSION: The combination of transcranial magnetic stimulation and classic symptomatic therapy is feasible in a neuro-rehabilitation setting and potentially ameliorates ataxia severity.


Subject(s)
Feasibility Studies , Physical Therapy Modalities , Transcranial Magnetic Stimulation , Humans , Transcranial Magnetic Stimulation/methods , Pilot Projects , Male , Middle Aged , Female , Combined Modality Therapy , Adult , Cerebellum , Aged , Cerebellar Ataxia/rehabilitation , Cerebellar Ataxia/therapy , Treatment Outcome , Vestibular Diseases/rehabilitation , Vestibular Diseases/therapy
13.
EBioMedicine ; 104: 105156, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38768529

ABSTRACT

BACKGROUND: Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can 'open' chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. METHODS: Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n = 4) versus controls (n = 4). FINDINGS: Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. A 12-year-old boy with KS, suffering from recurrent episodes of cognitive decline, exhibited improved cognitive function and neuropsychological assessment performance after 12 months on the ketogenic diet, with concomitant improvement in transcriptomic ribosomal protein dysregulation. INTERPRETATION: Our data reveals that lysine methyltransferase deficiency is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders. FUNDING: This study was supported by the Dale NHMRC Investigator Grant (APP1193648) (R.D), Petre Foundation (R.D), and The Sydney Children's Hospital Foundation/Kids Research Early and Mid-Career Researcher Grant (E.T).


Subject(s)
DNA-Binding Proteins , Diet, Ketogenic , Face , Hematologic Diseases , Proteomics , Ribosomal Proteins , Vestibular Diseases , Vestibular Diseases/genetics , Vestibular Diseases/metabolism , Vestibular Diseases/diet therapy , Humans , Face/abnormalities , Male , Hematologic Diseases/metabolism , Hematologic Diseases/genetics , Hematologic Diseases/etiology , Hematologic Diseases/diet therapy , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism , Child , Proteomics/methods , Female , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Gene Expression Regulation , Mutation , Transcriptome , Abnormalities, Multiple
14.
15.
Prim Care ; 51(2): 195-209, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38692770

ABSTRACT

Dizziness is a prevalent symptom in the general population and is among the most common reasons patients present for medical evaluations. This article focuses on high yield information to support primary clinicians in the efficient and effective evaluation and management of dizziness. Key points are as follows: do not anchor on the type of dizziness symptom, do use symptom timing and prior medical history to inform diagnostics probabilities, do evaluate for hallmark examination findings of vestibular disorders, and seek out opportunities to deliver evidence-based interventions particularly the canalith repositioning maneuver and gaze stabilization exercises.


Subject(s)
Dizziness , Primary Health Care , Humans , Dizziness/diagnosis , Dizziness/therapy , Vestibular Diseases/diagnosis , Vestibular Diseases/therapy
16.
Genome Res ; 34(5): 696-710, 2024 06 25.
Article in English | MEDLINE | ID: mdl-38702196

ABSTRACT

Many Mendelian developmental disorders caused by coding variants in epigenetic regulators have now been discovered. Epigenetic regulators are broadly expressed, and each of these disorders typically shows phenotypic manifestations from many different organ systems. An open question is whether the chromatin disruption-the root of the pathogenesis-is similar in the different disease-relevant cell types. This is possible in principle, because all these cell types are subject to effects from the same causative gene, which has the same kind of function (e.g., methylates histones) and is disrupted by the same germline variant. We focus on mouse models for Kabuki syndrome types 1 and 2 and find that the chromatin accessibility changes in neurons are mostly distinct from changes in B or T cells. This is not because the neuronal accessibility changes occur at regulatory elements that are only active in neurons. Neurons, but not B or T cells, show preferential chromatin disruption at CpG islands and at regulatory elements linked to aging. A sensitive analysis reveals that regulatory elements disrupted in B/T cells do show chromatin accessibility changes in neurons, but these are very subtle and of uncertain functional significance. Finally, we are able to identify a small set of regulatory elements disrupted in all three cell types. Our findings reveal the cellular-context-specific effect of variants in epigenetic regulators and suggest that blood-derived episignatures, although useful diagnostically, may not be well suited for understanding the mechanistic basis of neurodevelopment in Mendelian disorders of the epigenetic machinery.


Subject(s)
Abnormalities, Multiple , Aging , Chromatin , CpG Islands , Face , Hematologic Diseases , Neurons , Vestibular Diseases , Animals , Hematologic Diseases/genetics , Hematologic Diseases/metabolism , Mice , Face/abnormalities , Chromatin/metabolism , Chromatin/genetics , Vestibular Diseases/genetics , Neurons/metabolism , Aging/genetics , Abnormalities, Multiple/genetics , Disease Models, Animal , Epigenesis, Genetic , T-Lymphocytes/metabolism , B-Lymphocytes/metabolism
17.
Front Immunol ; 15: 1341745, 2024.
Article in English | MEDLINE | ID: mdl-38765012

ABSTRACT

Individuals with Kabuki syndrome present with immunodeficiency; however, how pathogenic variants in the gene encoding the histone-modifying enzyme lysine methyltransferase 2D (KMT2D) lead to immune alterations remain poorly understood. Following up on our prior report of KMT2D-altered integrin expression in B-cells, we performed targeted analyses of KMT2D's influence on integrin expression in T-cells throughout development (thymocytes through peripheral T-cells) in murine cells with constitutive- and conditional-targeted Kmt2d deletion. Using high-throughput RNA-sequencing and flow cytometry, we reveal decreased expression (both at the transcriptional and translational levels) of a cluster of leukocyte-specific integrins, which perturb aspects of T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR suggests that these evolutionary similar integrins are under direct control of KMT2D. KMT2D loss also alters multiple downstream programming/signaling pathways, including integrin-based localization, which can influence T-cell populations. We further demonstrated that KMT2D deficiency is associated with the accumulation of murine CD8+ single-positive (SP) thymocytes and shifts in both human and murine peripheral T-cell populations, including the reduction of the CD4+ recent thymic emigrant (RTE) population. Together, these data show that the targeted loss of Kmt2d in the T-cell lineage recapitulates several distinct features of Kabuki syndrome-associated immune deficiency and implicates epigenetic mechanisms in the regulation of integrin signaling.


Subject(s)
Integrins , Lymphocyte Activation , Animals , Mice , Integrins/metabolism , Integrins/genetics , Lymphocyte Activation/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Mice, Knockout , Vestibular Diseases/genetics , Vestibular Diseases/immunology , Vestibular Diseases/metabolism , Face/abnormalities , Humans , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Mice, Inbred C57BL , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Neoplasm Proteins/metabolism , Signal Transduction , Gene Expression Regulation , Abnormalities, Multiple , Hematologic Diseases , Myeloid-Lymphoid Leukemia Protein
18.
PeerJ ; 12: e17287, 2024.
Article in English | MEDLINE | ID: mdl-38766481

ABSTRACT

Background: The performance of balance is an important factor to perform activities. The complications of type 2 diabetes mellitus (T2DM), especially vestibular dysfunction (VD), could decrease balance performance and falls-efficacy (FE) which consequently impacts social participation and quality of life (QoL). Purpose: This study aimed to compare balance performance, FE, social participation and QoL between individuals with T2DM with and without VD. Methods: The participants comprised 161 T2DM with VD and 161 without VD. Three clinical tests used for confirming VD included the Head Impulse Test (HIT), the Dix Hallpike Test (DHT) and the Supine Roll Test (SRT). The scores of static and dynamic balances, FE, social participation and QoL were compared between groups. Results: The balance performance, FE, social participation and QoL were lower in the group with VD. The number of patients who had severe social restriction was higher in T2DM with VD than without VD (58.4% vs 48.4%). Moreover, all domains of QoL (physical, psychological, social relationships and environmental) were lower in T2DM with VD than without VD. Conclusion: The presence of VD in T2DM patients was associated with decreased physical balance performances and increased social and QoL disengagement. Comprehensive management related to balance and FE, as well as the monitoring to support social participation and QoL, should be emphasized in patients with T2DM with VD.


Subject(s)
Accidental Falls , Diabetes Mellitus, Type 2 , Postural Balance , Quality of Life , Social Participation , Vestibular Diseases , Humans , Diabetes Mellitus, Type 2/psychology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/physiopathology , Postural Balance/physiology , Male , Female , Quality of Life/psychology , Accidental Falls/prevention & control , Middle Aged , Vestibular Diseases/physiopathology , Vestibular Diseases/psychology , Aged
19.
Otol Neurotol ; 45(5): 572-579, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38728561

ABSTRACT

INTRODUCTION: Studies on incidence and prevalence of vestibular disorders tend to focus on small pockets of patients recruited from specialized clinics and often exclude measures of vestibular function. The objectives of the study were to characterize patients with common vestibular disorders, estimate the prevalence of common vestibular disorders, and ascertain whether patients with vestibular disorders experience increased risks of falls and morbidity. MATERIALS AND METHODS: This retrospective cohort study includes both inpatient and outpatient routine clinical care data culled from a nationally representative, population-based sample. Patients were included if their record in the TriNetX Diamond Cohort comprised at least one vestibular function test or vestibular diagnosis. The main outcome measures were diagnosis with a vestibular disorder, a fall, or a common medical comorbidity (e.g., diabetes, cerebrovascular disease). RESULTS: The cohort includes n = 4,575,724 patients, of which 55% (n = 2,497,136) had a minimum of one vestibular diagnosis. Patients with vestibular diagnoses were 61.3 ± 16.6 years old (mean ± standard deviation), 67% women, 28% White race (69% unknown race), and 30% of non-Hispanic or Latino ethnicity (66% unknown ethnicity). The prevalence of vestibular disorders was estimated at 2.98% (95% confidence interval [CI]: 2.98-2.98%). Patients with vestibular diagnoses experienced a significantly greater odds of falls (odds ratio [OR] = 1.04; 95% CI: 1.02-1.05), cerebrovascular disease (OR = 1.42; 95% CI: 1.40-1.43), ischemic heart disease (OR = 1.17; 95% CI: 1.16-1.19), and diabetes (OR = 1.14; 95% CI: 1.13-1.15), among others. DISCUSSION: Vestibular disorders affect an estimated 3% of the U.S. population, after weighting. Patients with these disorders are at greater risk for many common, consequential medical conditions.


Subject(s)
Accidental Falls , Comorbidity , Vestibular Diseases , Humans , Vestibular Diseases/epidemiology , Female , Middle Aged , Male , Aged , Retrospective Studies , Prevalence , Adult , Accidental Falls/statistics & numerical data , Cerebrovascular Disorders/epidemiology , Cerebrovascular Disorders/complications , Cohort Studies , Diabetes Mellitus/epidemiology , Aged, 80 and over
20.
Otol Neurotol ; 45(5): e443-e449, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38728562

ABSTRACT

OBJECTIVE: To investigate the clinical manifestations and complete auditory function in primary tinnitus patients with and without migraine or vestibular migraine. DESIGN: Retrospective case-control study. SETTING: A tertiary referral center. PARTICIPANTS: This study enrolled 298 patients from the Kaohsiung Veterans General Hospital. All patients were diagnosed with primary tinnitus by a neurotologist between April 2020 and August 2021. Patients were excluded if they had histories of chronic otitis media, idiopathic sudden sensorineural hearing loss, Ménière's disease, skull base neoplasm, or temporal bone trauma. INTERVENTIONS: Twenty-five-item Tinnitus Handicap Inventory (THI), speech audiometry including speech recognition threshold, most comfortable level, uncomfortable loudness levels, dynamic range, and pure-tone audiometry. MAIN OUTCOMES MEASURES: Objective hearing loss is defined as a mean threshold greater than 25 dB. Extremely elevated THI is defined as a score greater than 1 standard deviation above the mean THI. RESULTS: Among the 298 patients with tinnitus, 149 were women and 149 were men, with a mean age of 57.06 (range, 19.22-94.58) years.A total of 125 patients completed the THI questionnaire during their initial visit. The median THI score was 32 (95% confidence interval: 13.98-56.00), and the mean score was 34.99 with a standard deviation of 21.01. The sole contributing factor significantly associated with higher total THI score was the diagnosis of migraine or vestibular migraine (p < 0.001, odds ratio = 19.41).Tinnitus patients with migraine or vestibular migraine exhibited significantly lower mean pure-tone auditory thresholds (right 22.2 versus 29.5, p = 0.002; left 22.5 versus 30.4, p < 0.001), speech recognition threshold (right 20.0 versus 25.2, p = 0.016; left 20.2 versus 25.5, p = 0.019), and most comfortable levels values (right 46.1 versus 51.4, p = 0.007; left 46.9 versus 51.4, p = 0.021) compared with the tinnitus patients without migraine. CONCLUSIONS: In this population-based study, patients with primary tinnitus experienced significantly higher THI scores and exhibited concurrent symptoms, including dizziness/vertigo, cervicalgia, and migraine or vestibular migraine. Among these parameters, the diagnosis of migraine or vestibular migraine was the sole contributor to significant higher THI score.


Subject(s)
Audiometry, Pure-Tone , Migraine Disorders , Quality of Life , Tinnitus , Humans , Tinnitus/complications , Tinnitus/diagnosis , Tinnitus/physiopathology , Female , Male , Migraine Disorders/complications , Middle Aged , Retrospective Studies , Case-Control Studies , Aged , Adult , Vestibular Diseases/complications , Vestibular Diseases/diagnosis
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