Case Report: Keep your eyes open! Nystagmus guides atypical BPPV.

The clinical diagnosis of benign paroxysmal positional vertigo (BPPV) is confirmed from observing the direction, intensity, and duration of nystagmus from unique head positions that advantage gravity to overcome the inertia of otoconia displaced inside the semicircular canals. This case series highlights BPPV with atypical nystagmus presentations relative to the head position. Clinicians should carefully observe symptoms and nystagmus presentations regardless of the testing position and utilize technology and rules of vestibular physiology to enhance their diagnostic acumen.

Unraveling the evolutionary origin of the complex Nuclear Receptor Element (cNRE), a cis-regulatory module required for preferential expression in the atrial chamber.

Cardiac function requires appropriate proteins in each chamber. Atria requires slow myosin to act as reservoirs, while ventricles demand fast myosin for swift pumping. Myosins are thus under chamber-biased cis-regulation, with myosin gene expression imbalances leading to congenital heart dysfunction. To identify regulatory inputs leading to cardiac chamber-biased expression, we computationally and molecularly dissected the quail Slow Myosin Heavy Chain III (SMyHC III) promoter that drives preferential expression to the atria. We show that SMyHC III gene states are orchestrated by a complex Nuclear Receptor Element (cNRE) of 32 base pairs. Using transgenesis in zebrafish and mice, we demonstrate that preferential atrial expression is achieved by a combinatorial regulatory input composed of atrial activation motifs and ventricular repression motifs. Using comparative genomics, we show that the cNRE might have emerged from an endogenous viral element through infection of an ancestral host germline, revealing an evolutionary pathway to cardiac chamber-specific expression.

Utricular Dysfunction and Hearing Impairment Affect Spatial Navigation in Community-dwelling Healthy Adults: Analysis from the Baltimore Longitudinal Study of Aging.

INTRODUCTION: Spatial navigation, the ability to move through one's environment, is a complex skill utilized in everyday life. The effects of specific vestibular end-organ deficits and hearing impairments on spatial navigation have received little to no attention. We hypothesized that hearing impairment adversely affects spatial navigation and that bi-modal impairments (vestibular and hearing) further impair navigation ability. METHODS: Data from 182 participants in the Baltimore Longitudinal Study of Aging who had interpretable results for the video head impulse test (vHIT), cervical (cVEMP) and ocular (oVEMP) vestibular evoked myogenic potentials, audiometric testing, and the triangle completion test (TCT) were retrospectively analyzed. Multiple linear regression, controlling for age, sex, and cognition, was employed to identify predictors of TCT performance in terms of end-point error, angle deviation, and distance walked. RESULTS: oVEMP abnormalities were associated with larger end-point error (p=0.008) and larger angle deviation (p=0.002) but were not associated with distance walked (p=0.392). Abnormalities on cVEMP and vHIT were not associated with distance walked (p=0.835, p=0.300), end-point error (p=0.256, p=0.808), or angle deviation (p=0.192, p=0.966). Compared with normal hearing adults, hearing impaired adults walked a shorter distance during the TCT (p=0.049) but had similar end-point error (p=0.302) and angle deviation (p=0.466). There was no interaction between vestibular and hearing function for predicting spatial navigation ability. CONCLUSION: In this cohort analysis, utricular dysfunction and hearing impairment were associated with poorer spatial navigation performance. We postulate that hearing impairment negatively affects one's ability to use real-time, intrinsic auditory cues and/or prior experience to guide navigation.

Short-lived natural radionuclides as tracers in hydrogeological studies - A review.

Fundamental approaches to the study of groundwater rely on investigating the spatial and temporal distribution of stable and radioactive isotopes and other anthropogenic compounds in natural waterbodies. The most often used tracers for estimating groundwater flow paths and residence times, groundwater/surface water interaction as well as tracing chemical (contamination) sources include stable isotopes of water (δ 18O and δ 2H), radiocarbon (14C; t1/2 = 5730 a), tritium (3H; t1/2 = 12.43 a) as well as unreactive fluorine-containing gases (e.g., chlorofluorocarbons CCl3F or CFC-11; CCl2F3 or CFC-12; C2Cl3F3 or CFC-113; and SF6). While gas tracers are usually referred to as transient tracers and are appropriate for investigating modern flow systems, the isotopic tracers are often used to investigated paleo or regional flow systems. Stable isotopes of water can also be used to investigate groundwater/surface water interactions. Another, thus far been less frequently used group of groundwater tracers, are cosmo- and geo- genic short-lived radioisotopes. These isotopes are uniquely suited for studying a wide range of groundwater problems that have short time scales including high aquifer vulnerability to quantitative and qualitative impacts and groundwater discharge to surface waters. Here, we discuss and compare the applications of radio­sulphur (35S; half-life t1/2 = 87 d), radio­beryllium (7Be; t1/2 = 53 d), radio­phosphorus (32/33P; combined t1/2 = 33 d), natural tritium (3H; t1/2 = 12.43 a), radon (222Rn; t1/2 = 3.8 d) and short-lived radium (224/223Ra; combined t1/2 = 5.2 d). The paper discusses the principles of the individual tracer methods, focusing on the isotopes' input functions or values, on sampling techniques, and on methods of analyses. Case studies that applied a combined use of the tracers are referred to for readers who wish to learn more about the application of the so far underused cosmo- and geo- genic radioisotopes as aquatic tracers.

Effect of vestibular loss on head-on-trunk stability in individuals with vestibular schwannoma.

The vestibulo-collic reflex generates neck motor commands to produce head-on-trunk movements that are essential for stabilizing the head relative to space. Here we examined the effects of vestibular loss on head-on-trunk kinematics during voluntary behavior. Head and trunk movements were measured in individuals with vestibular schwannoma before and then 6 weeks after unilateral vestibular deafferentation via surgical resection of the tumor. Movements were recorded in 6 dimensions (i.e., 3 axes of rotation and 3 axes of translation) using small light-weight inertial measurement units while participants performed balance and gait tasks. Kinematic measures differed between individuals with vestibular schwannoma (at both time points) and healthy controls for the more challenging exercises, namely those performed in tandem position or on an unstable surface without visual input. Quantitative assessment of the vestibulo-ocular reflex (VOR) revealed a reduction in VOR gain for individuals with vestibular schwannoma compared to control subjects, that was further reduced following surgery. These findings indicated that the impairment caused by either the tumor or subsequent surgical tumor resection altered head-on-trunk kinematics in a manner that is not normalized by central compensation. In contrast, we further found that head-on-trunk kinematics in individuals with vestibular schwannoma were actually comparable before and after surgery. Thus, taken together, our results indicate that vestibular loss impacts head-on-trunk kinematics during voluntary balance and gait behaviors, and suggest that the neural mechanisms mediating adaptation alter the motion strategies even before surgery in a manner that may be maladaptive for long-term compensation.

First characterization of the nuclear receptor superfamily in the Mediterranean mussel Mytilus galloprovincialis: developmental expression dynamics and potential susceptibility to environmental chemicals.

Endocrine-disrupting chemicals (EDCs) represent a global threat to human health and the environment. In vertebrates, lipophilic EDCs primarily act by mimicking endogenous hormones, thus interfering with the transcriptional activity of nuclear receptors (NRs). The demonstration of the direct translation of these mechanisms into perturbation of NR-mediated physiological functions in invertebrates, however, has rarely proven successful, as the modes of action of EDCs in vertebrates and invertebrates seem to be distinct. In the present work, we investigated the members of the NR superfamily in a bivalve mollusk, the Mediterranean mussel Mytilus galloprovincialis. In addition to annotating the M. galloprovincialis NR complement, we assessed the potential developmental functions and susceptibility to EDC challenge during early development by gene expression analyses. Our results indicate that a majority of mussel NRs are dynamically expressed during early development, including receptors characterized by a potential susceptibility to EDCs. This study thus indicates that NRs are major regulators of early mussel development and that NR-mediated endocrine disruption in the mussel could be occurring at a larger scale and at earlier stages of the life cycle than previously anticipated. Altogether, these findings will have significant repercussions for our understanding of the stability of natural mussel populations. This article is part of the theme issue 'Endocrine responses to environmental variation: conceptual approaches and recent developments'.

The Mediterranean mussel Mytilus galloprovincialis: a novel model for developmental studies in mollusks.

A model organism in developmental biology is defined by its experimental amenability and by resources created for the model system by the scientific community. For the most powerful invertebrate models, the combination of both has already yielded a thorough understanding of developmental processes. However, the number of developmental model systems is still limited, and their phylogenetic distribution heavily biased. Members of one of the largest animal lineages, the Spiralia, for example, have long been neglected. In order to remedy this shortcoming, we have produced a detailed developmental transcriptome for the bivalve mollusk Mytilus galloprovincialis, and have expanded the list of experimental protocols available for this species. Our high-quality transcriptome allowed us to identify transcriptomic signatures of developmental progression and to perform a first comparison with another bivalve mollusk: the Pacific oyster Crassostrea gigas. To allow co-labelling studies, we optimized and combined protocols for immunohistochemistry and hybridization chain reaction to create high-resolution co-expression maps of developmental genes. The resources and protocols described here represent an enormous boost for the establishment of Mytilus galloprovincialis as an alternative model system in developmental biology.

Risk of Cervical Dizziness in Patients With Cervical Spondylosis.

Importance: The dizziness associated with cervical spondylosis is a controversial topic given that many experts believe that cervical spondylosis is a common cause of dizziness, whereas others do not believe it exists. Objective: To compare the risk of dizziness between patients with cervical spondylosis and matched controls (ie, patients with lumbar spondylosis after propensity score matching [PSM]). Design, Setting, and Participants: This cohort study used medical claims data from the National Health Insurance Research Database of Taiwan for patients 60 years or older with cervical or lumbar spondylosis newly diagnosed in any outpatient department between January 1, 2010, and December 31, 2015. Patients diagnosed with cervical spondylosis were included as the study cohort, and those diagnosed with lumbar spondylosis who were matched to the study cohort via PSM were selected as the control cohort. Both cohorts were followed up for 1 year unless they were diagnosed with dizziness, censored by death, or withdrew from the health insurance program. Data analysis was performed from August 9 to September 20, 2022. Main Outcomes and Measures: The main outcome was the date of outpatient diagnosis of dizziness. The risks of dizziness were compared between groups. The relative risk and incidence rate difference were calculated. Results: A total of 3638 patients with cervical spondylosis (mean [SD] age, 67.9 [7.1] years; 2024 [55.6%] male) and 3638 patients with lumbar spondylosis (mean [SD] age, 68.0 [7.1] years; 2024 [55.6%] male) after PSM were selected as the study and control cohorts, respectively. The patients with cervical spondylosis had higher risk of dizziness than matched controls, with a 1-year relative risk of 1.20 (95% CI, 1.03-1.39). The 1-year incidence of dizziness was 10.2% (95% CI, 9.2%-11.2%) in patients with cervical spondylosis and 8.6% (95% CI, 7.7%-9.5%) in the matched group of lumbar spondylosis. The incidence rate difference between the groups was 1.6% (95% CI, 0.3%-3.0%). Conclusions and Relevance: These data support the association between dizziness and cervical spondylosis, but the small difference between groups reveals that dizziness associated with cervical spondylosis is uncommon. Clinicians should be wary of diagnosing a cervical cause for dizziness based on an actual history of cervical spondylosis.

Head movement kinematics are differentially altered for extended versus short duration gait exercises in individuals with vestibular loss.

Head kinematics are altered in individuals with vestibular schwannoma (VS) during short duration gait tasks [i.e., Functional Gait Assessment (FGA)], both before and after surgery, yet whether these differences extend to longer duration gait exercises is currently unknown. Here we examined the effects of vestibular loss and subsequent compensation on head kinematics in individuals with VS during gait exercises of relatively extended versus short duration (< 10 versus 30 s), compared to age-matched controls. Six-dimensional head movements were recorded during extended and short duration gait exercises before and then 6 weeks after sectioning of the involved vestibular nerve (vestibular neurectomy). Standard functional, physiological, and subjective clinical assessments were also performed at each time point. Kinematics were differentially altered in individuals with vestibular loss at both time points during extended versus short duration exercises. Range of motion was significantly reduced in extended tasks. In contrast, movement variability predominately differed for the short duration exercises. Overall, our results indicate that quantifying head kinematics during longer duration gait tasks can provide novel information about how VS individuals compensate for vestibular loss, and suggest that measurements of range of motion versus variability can provide information regarding the different strategies deployed to maintain functional locomotion.

epiAneufinder identifies copy number alterations from single-cell ATAC-seq data.

Single-cell open chromatin profiling via scATAC-seq has become a mainstream measurement of open chromatin in single-cells. Here we present epiAneufinder, an algorithm that exploits the read count information from scATAC-seq data to extract genome-wide copy number alterations (CNAs) for individual cells, allowing the study of CNA heterogeneity present in a sample at the single-cell level. Using different cancer scATAC-seq datasets, we show that epiAneufinder can identify intratumor clonal heterogeneity in populations of single cells based on their CNA profiles. We demonstrate that these profiles are concordant with the ones inferred from single-cell whole genome sequencing data for the same samples. EpiAneufinder allows the inference of single-cell CNA information from scATAC-seq data, without the need of additional experiments, unlocking a layer of genomic variation which is otherwise unexplored.

226Ra measurement via gamma-ray spectrometry of 222Rn progeny - quantification of radon losses from sample capsules.

Radium-226 detection in sediment samples is generally executed by means of gamma-ray spectrometry. Data evaluation relies (besides the 186.2 keV 226Ra gamma peak) on the combined analysis of major gamma peaks that are produced by the short-lived radon (222Rn) daughters 214Pb and 214Bi. Precondition for this detection approach is equilibrium decay of all members of the decay chain between 226Ra and 214Bi. In closed systems, this equilibrium is reached after about five half-lives of 222Rn (19 days). However, a closed system can only be guaranteed if the capsule which contains the sample prevents diffusive escape of radon. Such radon-tightness cannot be guaranteed for a wide range of plastic materials. Due to its polymer structure, plastic material generally tends to allow radon diffusion and hence radon loss from the sample resulting in a disturbance of the required decay equilibrium. The paper introduces an approach that allows quantifying radon loss from sample capsules by direct radon measurements using mobile radon detection equipment. The experimental findings are supported by theoretical considerations. An examined alternative approach based on the offset of the 186.2 keV data point from an efficiency function that is calculated exclusively from short-lived radon progeny peaks in the gamma-ray spectrum did not prove to be applicable due to a lack of supporting peaks in the low-energy section of the spectrum.

Quantitative vestibular assessment: The development and validation of a novel, remote video head impulse test against in-clinic measurements.

Objectives: To develop a novel remote head impulse test (rHIT), and to provide preliminary data validating the rHIT vestibular-ocular reflex (VOR) gains against the in-clinic vHIT. Methods: A convenience sample of 10 patients referred for vestibular assessment at our institution was recruited. In-clinic vHIT was used to quantify lateral VOR gains. Patients subsequently underwent an rHIT protocol, whereby patients performed active, lateral head rotations while their eyes and heads were recorded using a laptop camera and video-conferencing software. The vHIT and rHIT VOR gains were compared using paired t-tests, and a Pearson correlation coefficient between the gains was calculated. Absolute accuracy, sensitivity, and specificity of the rHIT were additionally calculated. Results: Of the 10 patients recruited, 4 were male, and the average ± standard deviation (SD) age was 61.4 ± 15.3 years. As determined by the vHIT, 2 patients had normal bilateral VOR gains, 6 with unilateral vestibular hypofunction, and 2 with bilateral vestibular hypofunction. The correlation between the rHIT and vHIT gains was 0.73 (p < .001). The rHIT exhibited an absolute accuracy of 75.0%, sensitivity of 70.0%, and specificity of 80.0%. When ears had a vHIT VOR gain less than 0.40, the rHIT exhibited 100.0% accuracy. Conversely, 60.0% of deficient ears with vHIT VOR gains greater than 0.40 were incorrectly categorized by the rHIT. Conclusion: The rHIT may be better suited for detecting more severe vestibular deficiencies. Future iterations of the rHIT should aim to increase the video frame-rate capabilities to detect subtler VOR impairments. Level of Evidence: 4.

MND1 enables homologous recombination in somatic cells primarily outside the context of replication.

Faithful and timely repair of DNA double-strand breaks (DSBs) is fundamental for the maintenance of genomic integrity. Here, we demonstrate that the meiotic recombination co-factor MND1 facilitates the repair of DSBs in somatic cells. We show that MND1 localizes to DSBs, where it stimulates DNA repair through homologous recombination (HR). Importantly, MND1 is not involved in the response to replication-associated DSBs, implying that it is dispensable for HR-mediated repair of one-ended DSBs. Instead, we find that MND1 specifically plays a role in the response to two-ended DSBs that are induced by irradiation (IR) or various chemotherapeutic drugs. Surprisingly, we find that MND1 is specifically active in G2 phase, whereas it only marginally affects repair during S phase. MND1 localization to DSBs is dependent on resection of the DNA ends and seemingly occurs through direct binding of MND1 to RAD51-coated ssDNA. Importantly, the lack of MND1-driven HR repair directly potentiates the toxicity of IR-induced damage, which could open new possibilities for therapeutic intervention, specifically in HR-proficient tumors.

Resolution of atypical posterior semicircular canal BPPV: evidence for putative short-arm location.

This case demonstrates the successful identification and treatment of atypical posterior semicircular canal benign paroxysmal positional vertigo (BPPV) based on a unique presentation of positional nystagmus, the resultant nystagmus from repositioning manoeuvers, and restored function of the affected semicircular canal. This case illustrates the importance of completing a comprehensive clinical examination and the value for incorporating the video head impulse test as well as adjusting treatment based on testing and patient response when managing variant cases of BPPV.

Quantification of groundwater discharge into a shallow coastal lagoon applying a multi-tracer approach.

In many cases, shallow coastal lagoons are, on the one hand, vulnerable habitats for birds and marine ecosystems and, on the other hand, threatened by discharging nutrient-laden surface waters and groundwater. In particular, the localization and quantification of submarine groundwater discharge (SGD) is of key concern in this regard. The presented study aimed at investigating SGD into a vulnerable coastal lagoon that is strongly impacted by evaporation applying a multi-tracer approach. The joint application of radionuclides (222Rn, 223Ra, 224Ra), stable water isotopes (δ18O, δ2H) and the water salinity as environmental water tracers allowed evaluating the suitability of the individual parameters in this specific type of environment. Whilst stable isotope and salinity data were difficult to construe in terms of SGD occurrence due to the intense impact of evaporation, a radon mass balance allowed localising SGD areas within the lagoon and quantifying the related SGD flux rates. In addition, a 224Ra/223Ra ratio analysis revealed information on the apparent age of the discharged groundwater, and hence on the flushing intensity of the lagoon. Besides these site-specific results, the study allowed the following general conclusions regarding the suitability of the applied tracers: (i) we verified the suitability of a radon mass balance approach for proving/disproving SGD occurrence and quantifying SGD fluxes in shallow coastal lagoons strongly impacted by evaporation; (ii) we showed that the impact of evaporation may impede the use of water stable isotope and salinity data as SGD indicators in such specific environments; (iii) we demonstrated that the tidal impact on a lagoon water body during a sampling campaign can be compensated by adapting sampling schedule and cruise track to the tidal cycle.

Short-term molecular consequences of chromosome mis-segregation for genome stability.

Chromosome instability (CIN) is the most common form of genome instability and is a hallmark of cancer. CIN invariably leads to aneuploidy, a state of karyotype imbalance. Here, we show that aneuploidy can also trigger CIN. We found that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN. This generates a repertoire of genetically diverse cells with structural chromosomal abnormalities that can either continue proliferating or stop dividing. Cycling aneuploid cells display lower karyotype complexity compared to the arrested ones and increased expression of DNA repair signatures. Interestingly, the same signatures are upregulated in highly-proliferative cancer cells, which might enable them to proliferate despite the disadvantage conferred by aneuploidy-induced CIN. Altogether, our study reveals the short-term origins of CIN following aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for aneuploidy occurrence in tumors.

Video Ocular Counter-Roll (vOCR): Otolith-Ocular Function and Compensatory Effect of the Neck Following Vestibular Loss.

OBJECTIVE: Assessment of recovery following vestibular loss has been limited by the lack of bedside measures in clinical settings. Here, we used the video ocular counter-roll (vOCR) test to study otolith-ocular function and compensatory effect of neck proprioception in patients at different stages of vestibular loss. STUDY DESIGN: Case-control study. SETTING: Tertiary care center. METHODS: Fifty-six subjects were recruited including patients with acute (9 ± 2 days [mean ± standard error of mean]), subacute (61 ± 11 days), and chronic (1009 ± 266 days) unilateral loss of vestibular function, as well as a group of healthy controls. We used a video-oculography method based on tracking the iris for vOCR measurement. To examine the effect of neck inputs, vOCR was recorded during two simple tilt maneuvers in all subjects while seated: 30° head-on-body tilt and 30° head-and-body tilt. RESULTS: The vOCR responses evolved at different stages following vestibular loss with improvement of the gains in the chronic stage. The deficit was more pronounced when the whole body was tilted (acute: 0.08 ± 0.01, subacute: 0.11 ± 0.01, chronic: 0.13 ± 0.02, healthy control: 0.18 ± 0.01), and the gain of vOCR improved when the head was tilted on the body (acute: 0.11 ± 0.01, subacute: 0.14 ± 0.01, chronic: 0.13 ± 0.02, healthy control: 0.17 ± 0.01). The time course of vOCR response was affected as well with reduced amplitude and slower response in the acute stage of vestibular loss. CONCLUSION: The vOCR test can be valuable as a clinical marker to measure vestibular recovery and compensatory effect of neck proprioception in patients at different stages following loss of vestibular function.

Retinoic Acid and Retinoid X Receptors.

One of the most fundamental discoveries in human biology was that of the existence of essential micronutrients that the body cannot synthesize but nonetheless requires for proper functioning [...].

Retinoic Acid and POU Genes in Developing Amphioxus: A Focus on Neural Development.

POU genes are a family of evolutionarily conserved transcription factors with key functions in cell type specification and neurogenesis. In vitro experiments have indicated that the expression of some POU genes is controlled by the intercellular signaling molecule retinoic acid (RA). In this work, we aimed to characterize the roles of RA signaling in the regulation of POU genes in vivo. To do so, we studied POU genes during the development of the cephalochordate amphioxus, an animal model crucial for understanding the evolutionary origins of vertebrates. The expression patterns of amphioxus POU genes were assessed at different developmental stages by chromogenic in situ hybridization and hybridization chain reaction. Expression was further assessed in embryos subjected to pharmacological manipulation of endogenous RA signaling activity. In addition to a detailed description of the effects of these treatments on amphioxus POU gene expression, our survey included the first description of Pou2 and Pou6 expression in amphioxus embryos. We found that Pit-1, Pou2, Pou3l, and Pou6 expression are not affected by alterations of endogenous RA signaling levels. In contrast, our experiments indicated that Brn1/2/4 and Pou4 expression are regulated by RA signaling in the endoderm and the nerve cord, respectively. The effects of the treatments on Pou4 expression in the nerve cord revealed that, in developing amphioxus, RA signaling plays a dual role by (1) providing anteroposterior patterning information to neural cells and (2) specifying neural cell types. This finding is coherent with a terminal selector function of Pou4 for GABAergic neurons in amphioxus and represents the first description of RA-induced changes in POU gene expression in vivo.

The minimal clinically important difference for gait speed in significant unilateral vestibular hypofunction after vestibular rehabilitation.

Gait speed is a valid measure of both physical function and vestibular health. Vestibular rehabilitation is useful to improve gait speed for patients with vestibular hypofunction, yet there is little data to indicate how changes in gait speed reflect changes in patient-reported health outcomes. We determined the minimal clinically important difference in the gait speed of patients with unilateral vestibular hypofunction, mostly due to deafferentation surgery, as anchored to the Dizziness Handicap Index and the Activities Balance Confidence scale, validated using regression analysis, change difference, receiver-operator characteristic curve, and average change methods. After six weeks of vestibular rehabilitation, a change in gait speed from 0.20 to 0.34 m/s with 95% confidence was required for the patients to perceive a significant reduction in perception of dizziness and improved balance confidence.