Standards for X-Ray Microanalysis of Calcified Structures

The ability of electron probe X-ray microanalysis (EPMA) to solve biological problems often depends on the use of a quantitative approach. EPMA allows the quantitative determination of chemical elements of biological materials by using reference standards which resemble the specimen in the mode of interaction with the electron beam. Although there is a large experience in the quantification of elements in biological thin specimens, experience with standards for X-ray microanalysis of bulk specimens is limited, especially for calcified structures where the density of the specimen is difficult to estimate. The quality of the results in EPMA depends on obtaining accurate calibration curves which allow the establishment of the relationship between the signal measured and the concentration of the element of interest. The different methods for specimen preparation and the thickness of the specimen will also determine the precise nature of the standardization technique to be adopted. The physics of the electron beam-specimen interactions impose limitations upon the accuracy of calibration, and the choice of an unstable standard can result in large errors in the quantification of elements. We have reviewed the different types of compounds that have been used as standards for biological EPMA of thin and bulk specimens and discuss their potential use for quantitative analysis of mineralized tissues, with special reference to otoconia, the calcified structures of the vestibular system

Genetics of Tinnitus:An Emerging Area for Molecular Diagnosis and Drug Development

Subjective tinnitus is the perception of sound in the absence of external or bodily-generated sounds. Chronic tinnitus is a highly prevalent condition affecting over 70 million people in Europe. A wide variety of comorbidities, including hearing loss, psychiatric disorders, neurodegenerative disorders and temporomandibular joint dysfunction, have been suggested to contribute to the onset or progression of tinnitus, however the precise molecular mechanisms of tinnitus are not well understood and the contribution of genetic and epigenetic factors remains unknown. Human genetic studies could enable the identification of novel molecular therapeutic targets, possibly leading to the development of novel pharmaceutical therapeutics. In this article, we briefly discuss the available evidence for a role of genetics in tinnitus and consider potential hurdles in designing genetic studies for tinnitus. Since multiple diseases have tinnitus as a symptom and the supporting genetic evidence is sparse, we propose various strategies to investigate the genetic underpinnings of tinnitus, first by showing evidence of heritability using concordance studies in twins, and second by improving patient selection according to phenotype and/or etiology in order to control potential biases and optimize genetic data output. The increased knowledge resulting from this endeavor could ultimately improve the drug development process and lead to the preventive or curative treatment of tinnitus

Motion sickness diagnostic criteria: Consensus document of the classification committee of the Bárány society

We present diagnostic criteria for motion sickness, visually induced motion sickness (VIMS), motion sickness disorder (MSD), and VIMS disorder (VIMSD) to be included in the International Classification of Vestibular Disorders. Motion sickness and VIMS are normal physiological responses that can be elicited in almost all people, but susceptibility and severity can be high enough for the response to be considered a disorder in some cases. This report provides guidelines for evaluating signs and symptoms caused by physical motion or visual motion and for diagnosing an individual as having a response that is severe enough to constitute a disorder. The diagnostic criteria for motion sickness and VIMS include adverse reactions elicited during exposure to physical motion or visual motion leading to observable signs or symptoms of greater than minimal severity in the following domains: nausea and/or gastrointestinal disturbance, thermoregulatory disruption, alterations in arousal, dizziness and/or vertigo, headache and/or ocular strain. These signs/symptoms occur during the motion exposure, build as the exposure is prolonged, and eventually stop after the motion ends. Motion sickness disorder and VIMSD are diagnosed when recurrent episodes of motion sickness or VIMS are reliably triggered by the same or similar stimuli, severity does not significantly decrease after repeated exposure, and signs/symptoms lead to activity modification, avoidance behavior, or aversive emotional responses. Motion sickness/MSD and VIMS/VIMSD can occur separately or together. Severity of symptoms in reaction to physical motion or visual motion stimuli varies widely and can change within an individual due to aging, adaptation, and comorbid disorders. We discuss the main methods for measuring motion sickness symptoms, the situations conducive to motion sickness and VIMS, and the individual traits associated with increased susceptibility. These additional considerations will improve diagnosis by fostering accurate measurement and understanding of the situational and personal factors associated with MSD and VIMSD

Generation and characterization of the human iPSC line PBMC1-iPS4F1 from adult peripheral blood mononuclear cells

AbstractHere we describe the generation and characterization of the human induced pluripotent stem cell (iPSC) line PBMC1-iPS4F1 from peripheral blood mononuclear cells from a healthy female with Spanish background. We used heat sensitive, non-integrative Sendai viruses containing the reprogramming factors Oct3/4, Sox2, Klf4 and c-Myc, whose expression was silenced in the established iPSC line. Characterization of the PBMC1-iPS4F1 cell line included analysis of typical pluripotency-associated factors at mRNA and protein level, alkaline phosphatase enzymatic activity, and in vivo and in vitro differentiation studies

Association between Hyperacusis and Tinnitus

The following are available online at http://www.mdpi.com/2077-0383/9/8/2412/ s1We gratefully acknowledge the support and generosity of Nancy Pedersen, head of LifeGene.Many individuals with tinnitus report experiencing hyperacusis (enhanced sensitivity to sounds). However, estimates of the association between hyperacusis and tinnitus is lacking. Here, we investigate this relationship in a Swedish study. A total of 3645 participants (1984 with tinnitus and 1661 without tinnitus) were enrolled via LifeGene, a study from the general Swedish population, aged 18–90 years, and provided information on socio-demographic characteristics, as well as presence of hyperacusis and its severity. Tinnitus presence and severity were self-reported or assessed using the Tinnitus Handicap Inventory (THI). Phenotypes of tinnitus with (n = 1388) or without (n = 1044) hyperacusis were also compared. Of 1661 participants without tinnitus, 1098 (66.1%) were women and 563 were men (33.9%), and the mean (SD) age was 45.1 (12.9). Of 1984 participants with tinnitus, 1034 (52.1%) were women and 950 (47.9%) were men, and the mean (SD) age was 47.7 (14.0) years. Hyperacusis was associated with any tinnitus [Odds ratio (OR) 3.51, 95% confidence interval (CI) 2.99–4.13], self-reported severe tinnitus (OR 7.43, 95% CI 5.06–10.9), and THI ≥ 58 (OR 12.1, 95% CI 7.06–20.6). The association with THI ≥ 58 was greater with increasing severity of hyperacusis, the ORs being 8.15 (95% CI 4.68–14.2) for moderate and 77.4 (95% CI 35.0–171.3) for severe hyperacusis. No difference between sexes was observed in the association between hyperacusis and tinnitus. The occurrence of hyperacusis in severe tinnitus is as high as 80%, showing a very tight relationship. Discriminating the pathophysiological mechanisms between the two conditions in cases of severe tinnitus will be challenging, and optimized study designs are necessary to better understand the mechanisms behind the strong relationship between hyperacusis and tinnitus.GENDER-NET Co-Plus Fund GNP-182Decibel Therapeutics, Inc.Svenska Lakaresallskapet SLS-779681Tysta SkolanHorselforskningsfonden 503European Union (EU) 72204655 848261NIHR Nottingham Biomedical Research CentreSwedish Medical Research Council (SMRC) K2014-99X-22478-01-3Karolinska InstitutetNational Institute for Health Research (NIHR

Polymorphisms of CD16A and CD32 Fcγ receptors and circulating immune complexes in Ménière's disease: a case-control study

<p>Abstract</p> <p>Background</p> <p>Autoimmune diseases with elevated circulating autoantibodies drive tissue damage and the onset of disease. The Fcγ receptors bind IgG subtypes modulating the clearance of circulating immune complexes (CIC). The inner ear damage in Ménière's disease (MD) could be mediated by an immune response driven by CIC. We examined single-nucleotide polymorphism (SNPs) in the CD16A and CD32 genes in patients with MD which may determine a Fcγ receptor with lower binding to CIC.</p> <p>Methods</p> <p>The functional CD16A (FcγRIIIa*559A > C, rs396991) and CD32A (FcγRIIa*519A > G, rs1801274) SNPs were analyzed using PCR-based TaqMan Genotyping Assay in two cohorts of 156 mediterranean and 112 Galicia patients in a case-control study. Data were analyzed by χ²with Fisher's exact test and Cochran-Armitage trend test (CATT). CIC were measured by ELISA for C1q-binding CIC.</p> <p>Results</p> <p>Elevated CIC were found in 7% of patients with MD during the intercrisis period. No differences were found in the allelic frequency for rs396991 or rs1801274 in controls subjects when they were compared with patients with MD from the same geographic area. However, the frequency of AA and AC genotypes of CD16A (rs396991) differed among mediterranean and Galicia controls (Fisher's test, corrected p = 6.9 × 10^-4for AA; corrected p = 0.02 for AC). Although genotype AC of the CD16A receptor was significantly more frequent in mediterranean controls than in patients, [Fisher's test corrected p = 0.02; OR = 0.63 (0.44-0.91)], a genetic additive effect for the allele C was not observed (CATT, p = 0.23). Moreover, no differences were found in genotype frequencies for rs396991 between patients with MD and controls from Galicia (CATT, p = 0.14). The allelic frequency of CD32 (rs1801274) was not different between patients and controls either in mediterranean (p = 0.51) or Galicia population (p = 0.11).</p> <p>Conclusions</p> <p>Elevated CIC are not found in most of patients with MD. Functional polymorphisms of CD16A and CD32 genes are not associated with onset of MD.</p

Clinical subgroups in bilateral meniere disease

Meniere disease (MD) is a heterogeneous clinical condition characterized by sensorineural hearing loss, episodic vestibular symptoms, and tinnitus associated with several comorbidities, such as migraine or autoimmune disorders (AD). The frequency of bilateral involvement may range from 5 to 50%, and it depends on the duration of the disease. We have performed a two-step cluster analysis in 398 patients with bilateral MD (BMD) to identify the best predictors to define clinical subgroups with a potential different etiology to improve the phenotyping of BMD and to develop new treatments. We have defined five clinical variants in BMD. Group 1 is the most frequently found, includes 46% of patients, and is defined by metachronic hearing loss without migraine and without AD. Group 2 is found in 17% of patients, and it is defined by synchronic hearing loss without migraine or AD. Group 3, with 13% of patients, is characterized by familial MD, while group 4, that includes 12% of patients, is associated by the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by AD. This approach can be helpful in selecting patients for genetic and clinical research. However, further studies will be required to improve the phenotyping in these clinical variants for a better understanding of the diverse etiological factors contributing to BMD

Standardised profiling for tinnitus research: The European School for Interdisciplinary Tinnitus Research Screening Questionnaire (ESIT-SQ)

Background: The heterogeneity of tinnitus is substantial. Its numerous pathophysiological mechanisms and clinical manifestations have hampered fundamental and treatment research significantly. A decade ago, the Tinnitus Research Initiative introduced the Tinnitus Sample Case History Questionnaire, a case history instrument for standardised collection of information about the characteristics of the tinnitus patient. Since then, a number of studies have been published which characterise individuals and groups using data collected with this questionnaire. However, its use has been restricted to a clinical setting and to the evaluation of people with tinnitus only. In addition, it is limited in the ability to capture relevant comorbidities and evaluate their temporal relationship with tinnitus. Method: Here we present a new case history instrument which is comprehensive in scope and can be answered by people with and without tinnitus alike. This ‘European School for Interdisciplinary Tinnitus Research Screening Questionnaire’ (ESIT-SQ) was developed with specific attention to questions about potential risk factors for tinnitus (including demographics, lifestyle, general medical and otological histories), and tinnitus characteristics (including perceptual characteristics, modulating factors, and associations with co-existing conditions). It was first developed in English, then translated into Dutch, German, Italian, Polish, Spanish, and Swedish, thus having broad applicability and supporting international collaboration. Conclusions: With respect to better understanding tinnitus profiles, we anticipate the ESIT-SQ to be a starting point for comprehensive multi-variate analyses of tinnitus. Data collected with the ESIT-SQ can allow establishment of patterns that distinguish tinnitus from non-tinnitus, and definition of common sets of tinnitus characteristics which might be indicated by the presence of otological or comorbid systemic diseases for which tinnitus is a known symptom

Long-term symptoms in dizzy patients examined in a university clinic

Background: The long-term course of dizziness was investigated combining medical chart and survey data. The survey was undertaken median (interquartile range (IQR)) 4.6 (4.3) years after the initial medical examination. Methods: Chart data comprised sex, age, diagnosis, symptom duration, postural sway and neck pain. Survey data comprised symptom severity assessed by the Vertigo Symptom Scale – Short Form (VSS-SF), and data regarding current state of dizziness, medication, neck pain and other chronic conditions. Results: The sample consisted of 503 patients, the mean (standard deviation (SD)) age was 50.0 (11.6) years, women being slightly overrepresented (60%). Severe problems with dizziness (VSS-SF mean (SD) 13.9, (10.8)) were indicated in the total group and in 5 of 6 diagnostic sub-groups. Vertigo/balance- and autonomic/anxiety-related symptoms were present in all groups. Current dizziness was confirmed by 73% who had significantly more severe problems than the non-dizzy (VSS-SF mean (SD): 17.2 (10.1) versus 5.0 (7.3)). Symptoms were related to vertigo/balance more than to autonomic/anxiety (test of interaction p < 0.001). Based on simple logistic regression analysis, sex, symptom duration, neck pain, sway and diagnoses predicted dizziness. Symptom duration and neck pain remained predictors in the adjusted analysis. Age, symptom duration, neck pain, sway and diagnoses predicted vertigo/balance-related dizziness in both regression analyses. Sex, neck pain and sway predicted development of autonomic/anxiety-related dizziness according to simple regression analysis, while only neck pain remained a significant predictor in the adjusted analysis. With respect to diagnosis, simple regression analysis showed significant reduced likelihood for development of dizziness in all vestibular sub-groups when compared to the non-otogenic dizziness group. With respect to vertigo/balance- and autonomic/anxiety-related symptoms, the implication of diagnostic belonging varied. No effect of diagnoses was seen in adjusted analyses. Conclusion: The majority of patients had persistent and severe problems with dizziness. The wait-and-see attitude before referral to specialist institutions may be questioned. Early, active movements seem necessary, and attention should be paid to the presence of neck pain. Diagnoses had limited prognostic value. Questionnaire-based evaluations could assist in classification and identification of type of dizziness and thereby provide a better basis for specific rehabilitation

Genome sequencing and population genomic analyses provide insights into the adaptive landscape of silver birch

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