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At least 235 records · Page 13Linked to original sources
PubMed1990

A descending LOT-Bekesy screening test for functional hearing loss.

This study investigated the screening efficiency of a descending version of Hattler's Lengthened Off-time (LOT) Bekesy test. The Descending LOT (DELOT) test was administered to 24 subjects who presented unequivocal audiometric evidence of functional hearing loss during clinical examinations and 30 subjects with no audiometric evidence of functional loss. The DELOT format substantially increased screening sensitivity: 29.2% more functional group subjects and 42.2% more functional group ears were identified correctly relative to LOT test identifications. There was one marginally positive DELOT outcome involving one ear in the nonfunctional group. The high sensitivity of the DELOT test was clearly a function of significantly larger intertrace gaps caused by the DELOT trace. The mean intertrace gap for the DELOT test was more than 10 dB greater than the gap for the LOT test.

Adult↗
PubMed2000

Visual function-specific perimetry for indirect comparison of different ganglion cell populations in glaucoma.

PURPOSE: To compare short-wavelength automated perimetry, frequency-doubling technology perimetry, and motion-automated perimetry, each of which assesses different aspects of visual function, in eyes with glaucomatous optic neuropathy and ocular hypertension. METHODS: One hundred thirty-six eyes from 136 subjects were evaluated with all three tests as well as with standard automated perimetry. Fields were not used in the classification of study groups to prevent bias, because the major purpose of the study was to evaluate each field type relative to the others. Seventy-one of the 136 eyes had glaucomatous optic neuropathy, 37 had ocular hypertension, and 28 served as age-matched normal control eyes. Glaucomatous optic neuropathy was defined by assessment of stereophotographs. Criteria were asymmetrical cupping, the presence of rim thinning, notching, excavation, or nerve fiber layer defect. Ocular hypertensive eyes had intraocular pressure of 23 mm Hg or more on at least two occasions and normal-appearing optic disc stereophotographs. Criteria for abnormality on each visual field test were selected to approximate a specificity of 90% in the normal eyes. Thresholds for each of the four tests were compared, to determine the percentage that were abnormal within each patient group and to assess the agreement among test results for abnormality, location, and extent of visual field deficit. RESULTS: Each test identified a subset of the eyes with glaucomatous optic neuropathy as abnormal: 46% with standard perimetry, 61% with short-wavelength automated perimetry, 70% with frequency-doubling perimetry, and 52% with motion-automated perimetry. In the ocular hypertensive eyes, standard perimetry was abnormal in 5%, short wavelength in 22%, frequency doubling in 46%, and motion in 30%. Fifty-four percent (38/71) of eyes with glaucomatous optic neuropathy were normal on standard fields. However, 90% were identified by at least one of the specific visual function tests. Combining tests improved sensitivity with slight reductions in specificity. The agreement in at least one quadrant, when a defect was present with more than one test, was very high at 92% to 97%. More extensive deficits were shown by frequency-doubling perimetry followed by short-wavelength automated perimetry, then motion-automated perimetry, and last, standard perimetry. However, there were significant individual differences in which test of any given pairing was more extensively affected. Only 30% (11/37) of the ocular hypertensive eyes showed no deficits at all compared with 71% (20/28) of the control eyes (P < 0.001). CONCLUSIONS: For detection of functional loss standard visual field testing is not optimum; a combination of two or more tests may improve detection of functional loss in these eyes; in an individual, the same retinal location is damaged, regardless of visual function under test; glaucomatous optic neuropathy identified on stereophotographs may precede currently measurable function loss in some eyes; conversely, function loss with specific tests may precede detection of abnormality by stereophotograph review; and short-wavelength automated perimetry, frequency-doubling perimetry, and motion-automated perimetry continue to show promise as early indicators of function loss in glaucoma.

Glaucoma↗
PubMed2002

Loss-of-function mutations in the ethylene receptor ETR1 cause enhanced sensitivity and exaggerated response to ethylene in Arabidopsis.

Ethylene signaling in Arabidopsis begins at a family of five ethylene receptors that regulate activity of a downstream mitogen-activated protein kinase kinase kinase, CTR1. Triple and quadruple loss-of-function ethylene receptor mutants display a constitutive ethylene response phenotype, indicating they function as negative regulators in this pathway. No ethylene-related phenotype has been described for single loss-of-function receptor mutants, although it was reported that etr1 loss-of-function mutants display a growth defect limiting plant size. In actuality, this apparent growth defect results from enhanced responsiveness to ethylene; a phenotype manifested in all tissues tested. The phenotype displayed by etr1 loss-of-function mutants was rescued by treatment with an inhibitor of ethylene perception, indicating that it is ethylene dependent. Identification of an ethylene-dependent phenotype for a loss-of-function receptor mutant gave a unique opportunity for genetic and biochemical analysis of upstream events in ethylene signaling, including demonstration that the dominant ethylene-insensitive phenotype of etr2-1 is partially dependent on ETR1. This work demonstrates that mutational loss of the ethylene receptor ETR1 alters responsiveness to ethylene in Arabidopsis and that enhanced ethylene response in Arabidopsis not only results in increased sensitivity but exaggeration of response.

Alkenes↗
PubMed2001

Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function.

Loss of fragile X mental retardation protein (FMRP) function causes the fragile X mental retardation syndrome. FMRP harbors three RNA binding domains, associates with polysomes, and is thought to regulate mRNA translation and/or localization, but the RNAs to which it binds are unknown. We have used RNA selection to demonstrate that the FMRP RGG box binds intramolecular G quartets. This data allowed us to identify mRNAs encoding proteins involved in synaptic or developmental neurobiology that harbor FMRP binding elements. The majority of these mRNAs have an altered polysome association in fragile X patient cells. These data demonstrate that G quartets serve as physiologically relevant targets for FMRP and identify mRNAs whose dysregulation may underlie human mental retardation.

Base Sequence↗
PubMed1993

Loss of function of the Drosophila zfh-1 gene results in abnormal development of mesodermally derived tissues.

The Drosophila zfh-1 gene encodes an unusual protein with nine Cys2His2 type zinc-finger motifs and one homeodomain that shows a complex pattern of expression in the embryonic mesoderm and nervous system. To study the function of zfh-1, we generated loss-of-function zfh-1 mutations. Phenotypic analysis of zfh-1 mutant embryos reveals that the gene is not required for the initial segregation of the mesoderm or for the differentiation of mesodermally derived tissues. Rather, loss of zfh-1 function results in various degrees of local errors in cell fate or positioning.

Alleles↗
PubMed1993

Duchenne-Becker muscular dystrophy and the nondystrophic myotonias. Paradigms for loss of function and change of function of gene products.

Recessively inherited disorders can most often be considered loss of function: the patient has only defective copies of the defective gene (homozygous or hemizygous), with little or no functional protein products produced. Dominantly inherited disorders can most often be considered change of function: the patient has both mutant and normal copies of the gene (heterozygous); however, the mutant gene produces an abnormal protein product that causes dysfunction of the cell. Categorization of inherited disorders simply by their inheritance pattern thus affords some predictions concerning the underlying biochemical defect. To illustrate these generalizations, the molecular data on two important human inherited neurologic disorders will be described. X-linked recessive Duchenne/Becker muscular dystrophy has been shown to caused by loss of function of the dystrophin product. Dominantly inherited hyperkalemic periodic paralysis and paramyotonia congenita have been shown to be the result of single amino acid changes of the skeletal muscle voltage-sensitive sodium channel that alter the channel's function in response to environmental or physiologic stimuli (change of function).

Dystrophin↗
PubMed1996

Titrating for antiproteinuric effect: the clue to renoprotection?

Proteinuria may be involved in the final common pathway of progressive renal function loss. If so, intervention treatment that reduces proteinuria might prevent or retard long-term renal function loss. In renal patients and in experimental renal disease the severity of proteinuria is associated with the rate of long-term renal function loss. Several large trials on the prevention of long-term renal function loss by antihypertensive treatment with ACE inhibitors (ACEi), were recently completed in diabetic and in non-diabetic renal disease. In those studies long-term renal function loss could indeed be retarded by ACEi; these ACEi regimens were associated with a more effective reduction of proteinuria than control regimens. In studies with a single treatment regimen (drug treatment or a protein restricted diet) a more effective reduction of proteinuria is associated with a more favourable long-term course of renal function as well. As reduction of proteinuria is mostly associated with a lower blood pressure (BP) the respective contributions of the fall in BP and in proteinuria are hard to dissect. Remarkably, however, the efficacy of the reduction of proteinuria (but not of BP) at onset of antihypertensive treatment is predictive of long-term renal outcome. Albeit consistent with a causal role of proteinuria reduction in renoprotection these data cannot distinguish between proteinuria as a marker or a mediator of renal damage. In view of the consistent association of antiproteinuric efficacy with long-term renal outcome we suggest that it would be worthwhile to attempt to improve long-term renoprotection by a strategy aimed at enhancing antiproteinuric efficacy. This approach is feasible as antiproteinuric efficacy of ACEi can be enhanced in several ways, ie, by dietary sodium and protein restriction and by adding a diuretic or indomethacin. Such a strategy would require that titration for adequate BP control is followed by titration for a maximal antiproteinuric effect. If this treatment strategy would improve long-term renal outcome, it would not only be a step forward in the clinical treatment of chronic renal failure, but it would also provide compelling evidence for a causal role of proteinuria in the progression of renal disease.

Humans↗
PubMed1994

Detection of functional vision loss using the Ishihara plates.

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.

Adolescent↗
PubMed2000

Autoimmune T cells retard the loss of function in injured rat optic nerves.

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.

Animals↗
PubMed1976

Pure tone-spondee threshold relationships in functional hearing loss: a hypothesis.

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.

Audiometry↗
PubMed2003

Is loss of function of the prion protein the cause of prion disorders?

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.

Animals↗
PubMed2001

Loss-of-function mutations reveal that the Drosophila nautilus gene is not essential for embryonic myogenesis or viability.

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.

Animals↗
PubMed2002

A role for dystroglycan in epithelial polarization: loss of function in breast tumor cells.

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.

Basement Membrane↗
PubMed2026

CRISPR/Cas9 loss-of-function screen in a neuronal model of AP-4 deficiency identifies ATG9A trafficking modulators.

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.

Humans↗
PubMed2004

Computerized kinetic perimetry detects tubular visual fields in patients with functional visual loss.

PURPOSE: To report a novel test that uses computerized kinetic perimetry to detect tubular visual fields in patients with functional visual loss. DESIGN: Observational case series. METHODS: Ten patients who demonstrated generalized visual field constriction on prior examinations underwent testing combining computerized kinetic perimetry with a reversed Galilean telescope, used for optical visual field expansion. RESULTS: Six patients with physiologic visual field constriction demonstrated expansion of their visual fields with the use of the reversed telescope. Four patients with functional visual loss responded to the reversed telescope by demonstrating tubular visual fields, with responses equal to or smaller than their demonstrated visual fields delineated without the telescope. CONCLUSIONS: This test uses a computerized kinetic examination to reduce the subjective nature of tangent screen testing for tubular visual fields and to provide a computerized recording of visual fields. This method is a novel and easy-to-use technique to demonstrate functional visual loss.

Computing Methodologies↗
PubMed1999

Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma.

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.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Vestibular ocular reflexes in Ménière's disease patients evaluated by passive high frequency head rotation (yaw) and sidewards acceleration.

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.

Acceleration↗