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Functional hearing loss in children.

This report reviewed 39 school-age children diagnosed as having a functional hearing loss utilizing auditory brainstem response (ABR) audiometry during the past 5 years at the Department of Otolaryngology, Kyushu University Hospital in Japan. Twenty-seven cases were females and 12 were males. Seven cases had a hearing loss unilaterally and 32 bilaterally. Although pure-tone audiometry revealed a variety of audiogram shapes, two-thirds of the cases had a flat or saucer-shaped audiogram with a mild to moderately severe hearing loss. ABR audiometry for the frequencies of 1, 2 and 4 kHz indicated a normal hearing threshold in 65 ears of 35 patients, and mild threshold elevations of at least one frequency in the remaining 6 ears of 4 patients. Three illustrative cases were demonstrated, and a discussion was held regarding the features in audiometric tests, and environmental factors surrounding the children with this condition. We emphasized that the physiological hearing measurement such as ABR audiometry should be performed when any discrepancy was noted between the patient's history and results of pure-tone audiometry, because of not infrequent occurrence of functional hearing loss.

Adolescent

Protein kinase C phosphorylation at Thr 654 of the unoccupied EGF receptor and EGF binding regulate functional receptor loss by independent mechanisms.

To test the functional consequence of phosphorylation of the EGF receptor at Thr 654 by protein kinase C, the normal Thr 654 human EGF receptor cDNA or a mutant encoding an Ala 654 were expressed in heterologous cells. In cell lines expressing both the Thr 654 and Ala 654 receptors, functional cell-surface Thr 654 receptors were reduced or were totally lost, but were not degraded, following activation of protein kinase C by phorbol esters (TPA), whereas Ala 654 receptors were unaffected. These data suggest that protein kinase C regulates ligand-independent receptor binding and internalization via phosphorylation of Thr 654 of the EGF holoreceptor. Because EGF induces internalization and degradation of the Ala 654 EGF receptor, at least two independent mechanisms can serve to signal loss of functional EGF receptors.

Alanine

Malocclusion at adolescence related to self-reported tooth loss and functional disorders in adulthood.

It has been argued that malocclusion may predispose to tooth loss and functional disorders of the masticatory system. It was the purpose of this study to examine relationships between untreated malocclusion, recorded at adolescence, and self-reported tooth loss and functional disorders in adulthood. In 1965-66, the occurrence of morphologic traits of malocclusion was recorded in 977 Danish adolescents who did not have access to organized orthodontic care. Fifteen years later, 841 (86%) of these subjects responded to a questionnaire screening for tooth loss, symptoms involving the temporomandibular joints and muscles, and some other symptoms of dysfunction. The occurrence of malocclusion was related to the symptoms of the temporomandibular joints and muscles and other functional symptoms. Only a few significant coefficients of correlation were observed. Extreme maxillary overjet (greater than 9 mm) and frontal open bite showed significant correlations with unsatisfactory biting ability. Crossbite was correlated positively with speech defects but negatively with tenderness or fatigue of the cheeks; unilateral crossbite was associated with locking of the mandible. It was concluded that the untreated morphologic traits of malocclusion did not seem to predispose to tooth loss or functional disorders of the masticatory system as reported at the age of 30 years.

Adolescent

Lung function in relation to silicosis and silica exposure in granite workers.

Lung function tests (forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC %) were related to silica exposure and the extent of radiological opacities in a study of 206 active and 132 previously employed granite workers from two quarries. The investigations included detailed personal interviews, spirometric testing and radiographic examination of the chest. The chest X-ray films were read randomly and independently by three readers, using International Labour Office (ILO) standard films. Cumulative exposure to respirable silica (mg.m-3-yr) and total granite dust (million particles per cubic foot (mppcf-yr)) were estimated for each subject based on his years of employment at various jobs and historical and current measurements of quarry-, period- and job-specific exposures. The results suggest that chronic simple silicosis, especially for profusion category 2 and 3, was associated with significant lung function loss. As expected, mixed dust fibrosis was associated with little or no functional disturbance. Massive fibrosis was associated with significant obstructive and restrictive impairment. No additional effect of exposure to respirable silica on lung function loss was found after allowing for the presence of "silicosis". However, exposure to total dust (mppcf-yr) appeared to be associated with some lung function loss independent of silicosis. Our results indicate that chronic simple silicosis is not a benign disease; silica exposure is the primary cause, but the lung function loss in silicotics is directly attributable to the fibrotic lung disease. However, exposure to total granite dust beyond the respirable size range may separately produce additional lung function loss.

Adult

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

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

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

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

Age-related loss of function of alloactivated interleukin 2-propagated human primed lymphocyte typing clones.

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.

Cell Survival

Extensor indicis proprius transfer for loss of extensor pollicis longus function.

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.

Activities of Daily Living

[Functional hearing loss in speech audiometry (author's transl)].

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.

Adult

Hyperthermia-induced damage to rat sciatic nerve assessed in vivo with functional methods and with electrophysiology.

A 5-mm segment of the rat sciatic nerve was treated in vivo with hyperthermia (43-45 degrees C) for different times using a brass thermode. The effect of this local heat treatment on the nerve was assessed with electrophysiology and using two functional assays. Hyperthermia led to a dose-dependent decrease of motor and sensory function. Electrophysiological examination showed a decrease in amplitude of motor and reflex responses rather than a decrease in conduction velocities. Calculated ED50 values were not significantly different for the two functional and for the electrophysiological methods. Functional recovery from nerve damage took place in all cases. Measured at the same level of damage, i.e., 50% function loss, it took 14 days to recover from complete sensory function loss and 20 days from complete motor function loss. Although both motor and sensory functions were restored, 30 days after hyperthermia no responses could be detected with electrophysiology, this as a result of the thin myelin sheaths that occur upon recovery.

Animals

The role of gsc and BMP-4 in dorsal-ventral patterning of the marginal zone in Xenopus: a loss-of-function study using antisense RNA.

The dorsal-specific homeobox gene goosecoid (gsc) and the bone morphogenetic protein 4 gene (BMP-4) are expressed in complementary regions of the Xenopus gastrula. Injection of gsc mRNA dorsalizes ventral mesodermal tissue and can induce axis formation in normal and UV-ventralized embryos. On the other hand, BMP-4 mRNA injection, which has a strong ventralizing effect on whole embryos, has been implicated in ventralization by UV, and can rescue tail structures in embryos dorsalized by LiCl. The above-mentioned putative roles for BMP-4 and gsc are based on gain-of-function experiments. In order to determine the in vivo role of these two genes in the patterning of the Xenopus mesoderm during gastrulation, partial loss-of-function experiments were performed using antisense RNA injections. Using marker genes that are expressed early in gastrulation, we show that antisense gsc RNA has a ventralizing effect on embryos, whereas antisense BMP-4 RNA dorsalizes mesodermal tissue. These loss-of-function studies also show a requirement for gsc and BMP-4 in the dorsalization induced by LiCl and in the ventralization generated by UV irradiation, respectively. Thus, both gain- and loss-of-function results for gsc and BMP-4 support the view that these two genes are necessary components of the dorsal and ventral patterning pathways in Xenopus embryos.

Animals

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease. METHODS: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. CONCLUSION: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.

Humans

Outcome following radiation treatment for high-risk pigmented villonodular synovitis.

PURPOSE: Pigmented villonodular synovitis (PVNS) is a rare proliferative process involving synovial membranes. It has a variable course, and while usually benign, may be destructive, resulting in major symptoms and loss of function leading to amputation. Optimum treatment is not always clear, and little information exists with respect to the role of radiotherapy. The purpose was to review our experience with radiotherapy in cases at high risk for recurrence with functional loss including instances where amputation was the sole alternative for symptomatic disease. METHODS AND MATERIALS: The records of all patients registered between 1972 and 1992 with a diagnosis of PVNS were identified (21 cases). The records of 14 cases who received radiotherapy after referral were reviewed retrospectively for demographic information, radiotherapy treatment parameters, and tumor outcome. RESULTS: All cases had confirmation of pathologic diagnosis. Six patients had primary and eight had recurrent disease (with a mean of 2.5 prior surgical procedures). All cases had both intra- and extraarticular disease and, without exception, the poorer prognosis diffuse subtype of the disease. The majority had one or more additional risk factors including skin, bone, tendon, neurovascular, or muscle group extension. With a mean follow-up time of 69 months (range 13-250 months), only one patient has shown persistence of disease. With the exception of that single case, all those with measurable disease had obvious disease until at least 12 months and, subsequently, manifested complete responses. The single case was lost from the clinic after 8 months from the initiation of radiotherapy to a dose of 30 Gy in 15 fractions and had a palpable mass at the time. He subsequently was noted to have a persisting mass and an excisional biopsy 9 years later showed PVNS. He remains well 21 years after treatment with good function. Eleven patients enjoyed excellent or good function from the affected limb and three had fair function. All patients had greater use of limb than at the time of treatment. No patient required amputation, and none had evidence of serious radiotherapy complications. CONCLUSIONS: These results demonstrate that moderate dose radiotherapy is an effective modality in the treatment of a subset of cases with this rare condition. Its use has permitted avoidance of amputation in very advanced cases with acceptable function preservation. When treatment is indicated we currently recommend gross total removal of PVNS. This is followed by moderate dose radiotherapy (35 Gy in 15 fractions) for residual disease where salvage of subsequent recurrence may compromise function.

Adolescent

Proteinuria: a risk factor for pregnancy-related renal function decline in primary glomerular disease?

Pregnancy may be followed by a postpartum acceleration of renal function loss in patients with renal disease. We retrospectively analyzed the effects of pregnancy on progressive renal function decline, and the risk factors for an acceleration, in a group of 19 renal disease patients with 30 pregnancies and a group of 31 patients who did not become pregnant after onset of glomerular disease. The rate of renal function loss was calculated for each patient by linear regression on reciprocal serum creatinine values over 11 years' follow-up. Multiple regression analysis showed that both pregnancy (P = 0.03) and initial proteinuria (P = 0.005) were independently related with the rate of renal function loss. Such a relation could not be observed with histologic diagnosis, and initial age, renal function, blood pressure, and serum albumin. Further analysis showed that 10 of 30 pregnancies are followed by a predefined acceleration of renal function loss. These pregnancies were preceded and complicated by a higher proteinuria (4.1 v 1.7 g/d, P < 0.005; and 3.6 v 2.1 g/d, P < 0.05, respectively) compared with the other 20 pregnancies that are not followed by such an acceleration. In conclusion, patients with primary glomerular disease complicated by substantial proteinuria are at risk for acceleration of renal function decline after pregnancy.

Adolescent

Functional visual loss. Follow-up of 42 cases.

Forty-two patients with diagnosed functional visual loss were reexamined an average of four years after their initial visit. Twenty-three patients continued to have constricted or spiral visual fields at follow-up. Despite persistent evidence of functional visual defects, few patients were either socially or economically impaired by them. Patients who had other types of visual field loss or loss of visual acuity were more likely to have these signs resolve than were patients with constricted or spiral fields. Concurrent unrelated organic ocular disease was present in 11 patients. In 20 patients, it was not possible to identify psychiatric symptoms either related to the onset of functional eye signs or at follow-up. Treatment did not substantially alter the course.

Adolescent