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The applicability of the modified bivariate plotting procedure proposed by Silman, Silverman, Showers, and Gelfand, 1984, was evaluated on a group of functional hearing-loss subjects under age 44 years. The false-positive rate was 17% and the false-negative rate was 0% for both significant and mild or high frequency sensorineural hearing loss.
Many techniques have been described for the detection of functional visual loss. We report four cases in which Ishihara pseudo-isochromatic colour plates gave objective evidence of functional vision loss. In all cases the patients were able to read the first test pattern (No. 12), but could not distinguish any of the following pseudo-isochromatic numbers (plates 2-17). However, they experienced no difficulty in tracing the winding lines (plates 18-24), demonstrating that they in fact had normal colour vision.
We recently demonstrated that autoimmune T cells protect neurons from secondary degeneration after central nervous system (CNS) axotomy in rats. Here we show, using both morphological and electrophysiological analyses, that the neuroprotection is long-lasting and is manifested functionally. After partial crush injury of the rat optic nerve, systemic injection of autoimmune T cells specific to myelin basic protein significantly diminished the loss of retinal ganglion cells and conducting axons, and significantly retarded the loss of the visual response evoked by light stimulation. These results support our challenge to the traditional concept of autoimmunity as always harmful, and suggest that in certain situations T cell autoimmunity may actually be beneficial. It might be possible to employ T cell intervention to slow down functional loss in the injured CNS.
A hypothesis is offered to account for the fact that in functional hearing loss, spondee threshold is frequently significantly lower than the pure-tone average. The hypothesis has three basic components: (1) that patients with functional hearing loss use a loudness criterion in making response decisions to suprathreshold stimuli; (2) that, at suprathreshold levels, pure tones and spondee words appear equally loud at equal sound pressure levels, and (3) that calibration values employed in pure-tone and speech audiometry contribute to the aberrant speech-pure tone relationship. Factors that may confound the speech-pure tone relationship are discussed as are the clinical and research implication of the hypothesis.
Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that involve misfolding of the prion protein. Recent studies have provided evidence that normal prion protein might have a physiological function in neuroprotective signaling, suggesting that loss of prion protein activity might contribute to the pathogenesis of prion disease. However, studies using knockout animals do not support the loss-of-function hypothesis and argue that prion neurodegeneration might be associated with a gain of a toxic activity by the misfolded prion protein. Thus, the mechanism of neurodegeneration in spongiform encephalopathies remains enigmatic.
nautilus (nau), the single Drosophila member of the bHLH-containing myogenic regulatory family of genes, is expressed in a subset of muscle precursors and differentiated fibers. It is capable of inducing muscle-specific transcription as well as myogenic transformation, and plays a role in the differentiation of a subset of muscle precursors into mature muscle fibers. In previous studies, the nau zygotic loss-of-function phenotype was determined using genetic deficiencies in which the gene is deleted. We note that this genetic loss-of-function phenotype differs from the loss-of-function phenotype determined using RNA interference (L. Misquitta and B. M. Paterson, 1999, Proc. Natl. Acad. Sci. USA 96, 1451-1456). The present study re-examines this loss-of-function phenotype using EMS-induced mutations that specifically alter the nau gene, and extends the genetic analysis to include the loss of both maternal and zygotic nau function. In brief, embryos lacking nau both maternally and zygotically are missing a distinct subset of muscle fibers, consistent with its apparent expression in a subset of muscle fibers. The muscle loss is tolerated, however, such that the loss of nau both maternally and zygotically does not result in lethality at any stage of development.
Receptors mediating cell-basement membrane interactions are potent regulators of epithelial architecture and function, and alterations in signals from the basement membrane are implicated in the aberrant behavior of carcinoma cells. In this study, we have investigated the role of the basement membrane receptor dystroglycan (DG) in mammary epithelial cell function, and the significance of loss of DG function in breast tumor cell lines. Nonmalignant mammary epithelial cells express a functional DG. Analysis of multiple breast carcinoma cell lines revealed that DG is expressed in all of the cell lines examined, as evidenced by beta-DG expression, but that alpha-DG is functionally diminished in the majority. High levels of alpha-DG correlated strongly with the ability of cells to polarize in the presence of the basement membrane. Overexpression of the DG cDNA in HMT-3522-T4-2 cells elevated alpha-DG levels and altered responsiveness to the basement membrane; DG overexpression restored the ability of the cells to undergo cytoskeletal changes, to polarize, and to restrict growth in response to basement membrane proteins. Moreover, restoration of DG function to these cells greatly reduced their tumorigenic potential in nude mice. These data point to DG as an important mediator of normal cell responses to the basement membrane, and as a significant variable in carcinoma cells, in which its frequent loss can contribute to aberrant cell behavior.
Biallelic loss-of-function variants in adaptor protein complex 4 (AP-4) disrupt trafficking of transmembrane proteins at the trans-Golgi network, including autophagy-related protein 9A (ATG9A), leading to childhood-onset hereditary spastic paraplegia (AP-4-HSP). AP-4-HSP is characterized by features of both a neurodevelopmental and a degenerative neurological disease. To investigate the molecular mechanisms underlying AP-4-HSP and identify potential therapeutic targets, we conducted an arrayed CRISPR/Cas9 loss-of-function screen of 8,478 genes, targeting the "druggable genome," in a human neuronal model of AP-4 deficiency. Through this phenotypic screen and subsequent experiments, key modulators of ATG9A trafficking were identified, and complementary pathway analyses provided insights into the regulatory landscape of ATG9A transport. Knockdown of ANPEP and NPM1 enhanced ATG9A availability outside the trans-Golgi network, suggesting that they regulate ATG9A localization. These findings deepen our understanding of ATG9A trafficking in the context of AP-4 deficiency and offer a framework for the development of targeted interventions for AP-4-HSP.
Loss of tumor suppressors that restrain important oncoproteins such as c-Myc may contribute to malignant progression. Bin1 is an adapter protein with features of a tumor suppressor that was identified through its interaction with and inhibition of the oncogenic properties of c-Myc. In this study, we analyzed the patterns of Bin1 expression in normal melanocytes and melanoma cells at different stages of tumor progression. Evidence is provided that Bin1 function is abrogated in melanoma cells by a mechanism based on aberrant splicing of a tissue-specific exon. Specifically, most melanoma cells inappropriately expressed exon 12A, which is spliced alternately into Bin1 isoforms found in brain but not into isoforms found in melanocytes and many other nonneuronal cells. Exon 12A sequences abolished the ability of Bin1 to inhibit malignant transformation by c-Myc or adenovirus E1A. Similarly, these sequences abolished the ability of Bin1 to induce programmed cell death in melanoma cells that endogenously expressed exon 12A. Our findings suggest that aberrant splicing of Bin1 may contribute to melanoma progression, and they define a mechanism by which the activity of a tumor suppressor can be eliminated in cells.
Despite the fact that vertigo is the most apparent complaint at the onset of Ménière's disease, standard vestibular examination seldom shows vestibular function loss in the early phase. In this study, three relatively advanced diagnostic tests (passive high frequency head shaking, passive head impulse test and sidewards linear acceleration) were applied to trace vestibular function loss in the early phase in 25 patients with possible Ménière's disease (American Academy of Otolaryngology-Head and Neck Surgery 1995 criteria); one test (passive high frequency head shaking) was also conducted in 20 chronic definite Ménière's disease patients. Head movements were induced by a head shaker and whole-body linear translation by a motor-driven linear slit. Eye movements were detected by electro-oculography (head shaking) and the scleral coil technique (impulse test and linear translation). Standard vestibular examination showed no vestibular function loss in the early phase patient group. In contrast, 17 out of 25 patients (68%) showed a phase lag upon head shaking that was 1-2 degrees larger than the 95% confidence interval in healthy subjects; the remaining 8 patients showed a normal phase lag. Gain was normal in all 25 patients. In the chronic patient group, standard vestibular examination was abnormal (calorics) in 16 out of 20 patients (60%) and 18 out of 20 (90%) showed an abnormal phase on passive head shaking. In 11 of the 25 early phase patients (44%), an increased latency was observed in the response to a passive head impulse to one side. The side to which the abnormal latency occurred did not correspond to the documented or reported side of the hearing loss in 2 out of the 11 patients. The amplitude of ocular counter rolling induced by sidewards sinusoidal translation was reduced in 17 out of the 25 early phase Ménière's disease patients, of whom 6 showed a normal head impulse and head shaking test. Our findings indicate that vestibular function loss occurs in Ménière's disease patients within 9 months of the first vertigo attack. Also, the results support the hypothesis that, at least in some patients, function loss in the statolith system might precede function loss in the horizontal canals.
OBJECTIVE: To determine whether the full Health Assessment Questionnaire (HAQ), the shortened modified HAQ (MHAQ), or the new shortened RA-HAQ, developed on the basis of Rasch item response theory (IRT), performs best in terms of distributional characteristics, detection of functional loss, and identification of change in functional status in patients with active rheumatoid arthritis (RA). METHODS: A total of 2,491 clinic patients with RA with active disease from the practices of 519 US rheumatologists were assessed by questionnaire at the time leflunomide was started and at subsequent followup when there had been sufficient time for response. RESULTS: The HAQ scores were almost normally distributed along the 0-3 scale, but 95% of MHAQ and RA-HAQ values were clustered between 0 and 1.5. Normal or minimally abnormal scores (0 or 0.125) were noted in 6.6% of HAQ but in 21-22% of MHAQ/RA-HAQ. Mild functional loss (< or =0.375) was found in 12.7, 39.1, and 36.1% of patients by the HAQ, MHAQ, and RA-HAQ, respectively. This indicates that the MHAQ and RA-HAQ generally fail to identify appropriately the extent of functional loss in RA. The HAQ was significantly better at detecting changes than the MHAQ or RA-HAQ, with relative efficiencies of 1.28 and 1.37 compared to the MHAQ and RA-HAQ, respectively. This results in roughly a 20-26% reduction in sample size requirements. Two additional HAQ were identified that performed better than the HAQ itself, a 20 item HAQ without the use of aids and devices and an 8 item HAQ composed of the most difficult item in each of the 8 HAQ subscale categories. CONCLUSION: The HAQ is better (more efficient) than the MHAQ or RA-HAQ at detecting treatment change, and identifies the extent of functional disability better than the shortened questionnaires. The 3 questionnaires have different means, sensitivities, and distributional properties and cannot be thought of as simply different versions of the same questionnaire. The benefits of the MHAQ and RA-HAQ are that they are short and easier to score. But these benefits come at the price of loss of sensitivity and loss of sensitivity to change. The 20 item HAQ and the difficult 8 item HAQ are intriguing additional choices that are worthy of further study.
OBJECTIVES: To examine the relationship between urinary incontinence (UI) and psychological distress in older adults. We hypothesized that persons with UI associated with condition-specific functional loss would be most likely to report psychological distress. DESIGN: A population-based longitudinal survey. SETTING: Continuing participants in a study of community-dwelling adults who were initially living in East Baltimore in 1981. PARTICIPANTS: Persons aged 50 and older (n=781) at follow-up interviews conducted between 1993 and 1996 for whom complete data were available. MEASUREMENTS: Participants were classified as incontinent if they reported any uncontrolled urine loss within the 12 months preceding the 13-year follow-up interview. Condition-specific functional loss secondary to UI was further assessed based on a series of questions relating directly to participants' inability to engage in certain activities due to their UI. Psychological distress was assessed using the General Health Questionnaire (GHQ) at interviews in 1981 and at the 13-year follow-up. RESULTS: Persons with UI were more likely to experience psychological distress as measured by the GHQ than were persons without UI (unadjusted odds ratio (OR)=1.74, 95% confidence interval (CI)=1.13-2.68). Persons with condition-specific functional loss secondary to UI were substantially more likely to have psychological distress as measured by the GHQ than were persons without UI (unadjusted OR=4.02, 95% CI=1.86-8.70). In multivariate models that controlled for potentially influential characteristics such as age, gender, ethnicity, and chronic medical conditions the association between condition-specific functional loss secondary to UI and psychological distress remained statistically significant. Among people with UI, persons with persistently elevated GHQ scores were much more likely to report condition-specific functional impairment from UI (adjusted OR=6.55, 95% CI=1.94-22.12). CONCLUSION: Individuals with UI, especially when incontinence was associated with condition-specific functional loss, were more likely to have psychological distress than were other older adults. Our findings support a general conceptual model that condition-specific functional impairment mediates the relationship between a chronic medical condition and psychological distress.
Human lymphocytes alloactivated in vitro were cloned by limiting dilution in the presence of filler cells and interleukin 2 (IL 2)-containing supernatants of phytohaemagglutinin-stimulated lymphocytes. Clones with allospecific proliferative reactivity (PLT clones), measured by tritiated thymidine (3H-TdR) incorporation, were selected for extensive IL 2-dependent expansion. The cloned lines had finite lifespans, ranging from an estimated minimum of 28 to greater than 65 doublings. Function as PLT reagents, however, was retained in all cases for only an estimated 30 cell doublings. This apparent cessation of function was not caused by loss of the ability to metabolize thymidine, since lines continuing to grow for greater than 30 doublings still incorporated 3H-TdR in the presence of IL 2. An altered requirement for stimulating antigen (number of stimulating cells), or altered response kinetics, did not contribute to loss of PLT function. Exogenous IL 2 added during restimulation to responders previously 'rested' overnight without IL 2 did not restore the response. Thus, under present experimental conditions, functional lifespans of cloned PLT reagents appear fixed at approximately 30 cell doublings.
In the period 1969-1991, 46 extensor indicis proprius tendon transfers were performed for functional loss of extensor pollicis longus. The long-term function of the thumb was reviewed in 22 patients with an average follow-up of 7 years. Based on Geldmacher's evaluation scheme for assessment of the results of extensor tendon reconstruction, we report 5 excellent (23%), 4 good (18%), 12 satisfactory (55%) and 1 poor (4%) result. The mean loss of pinch strength was 8% compared with the contralateral, non-operated thumb. Subjectively, the majority of the patients (86%) described no limitations in their daily life activities. It is recommended that the transfer be tight enough to give full thumb extension and that the hand be immobilized with the thumb in this position for 4 weeks.
Gene redundancy in polyploid species complicates genetic analyses by making the generation of recessive, loss-of-function alleles impractical. We show that this problem can be circumvented using RNA interference (RNAi) to achieve dominant loss of function of targeted genes. Arabidopsis suecica is an allotetraploid (amphidiploid) hybrid of A. thaliana and A. arenosa. We demonstrate that A. suecica can be genetically transformed using the floral dip method for Agrobacterium-mediated transformation. Transgenes segregate as in a diploid, indicating that chromosome pairing occurs exclusively (or almost so) among homologs and not among homeologs. Expressing a double-stranded (ds) RNA corresponding to the A. thaliana gene, decrease in DNA methylation 1 (DDM1) caused the elimination of DDM1 mRNAs and the loss of methylation at both A. thaliana- and A. arenosa-derived centromere repeats. These results indicate that a single RNAi-inducing transgene can dominantly repress multiple orthologs.
Neuroimaging with nuclear medicine techniques permits assessment of brain function by measurement of metabolism or blood flow. Such studies complement the anatomic information derived from computed tomography (CT) or magnetic resonance imaging (MRI). We describe two patients with occipital lesions who were initially diagnosed with functional visual loss. Neither CT scan nor MRI adequately demonstrated the source of visual dysfunction; however, single proton emission tomography (SPECT) scanning in a patient with carbon monoxide poisoning and positron emission tomography (PET) scanning in a patient with post-hypoxic delayed encephalopathy were helpful in confirming the organic substrate of their visual impairment. Functional imaging techniques such as SPECT and PET should be considered in patients with suspected cortical visual loss and normal CT or MR scans.
In a group of 238 patients assessed for medico-legal reasons, 26 subjects were found to have functional hearing problems. In detecting the presence of functional hearing loss, the reliability of speech audiometric patterns was shown. Each patient demonstrated at least one suspicious response. The evaluation revealed an irregular configuration of curves ("step-like", 56%) and a better understanding for monosyllabic testwords than for digits (28.8%) as the most important criteria. In the control group of 40 hard-of-hearing patients without functional hearing losses, testing-irregularities were found in only 2.5-3.7% of the patients. Furthermore, discrepancies between speech reception thresholds and pure tone averages (84.6%) as well as poor test-retest reliability in tone audiometry contributed to an identification of functional hearing loss. Békésy-audiometry Type V was obtained in 73% of those patients studied.
The TSH receptor belongs to a subfamily of G protein-coupled receptors that mediates the effect of TSH in thyroid development and hormone synthesis. Similarly to many other G protein--coupled receptors, both gain and loss of function mutations have been found in the TSH receptor. Loss of function mutations in the TSH receptor gene were first described in three siblings with resistance to TSH in 1995. To date, 13 pedigrees with TSH receptor mutations of loss of function type have been reported. The phenotype of the patients varies from euthyroid hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia.