PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Loss of function”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed1991

Linking in accessory pathways. Functional loss of antegrade preexcitation.

BACKGROUND: Concealed retrograde activation has been proposed as a mechanism for antegrade conduction block in the bundle branches and atrioventricular accessory pathways. We studied this hypothesis (linking) in 10 patients with the Wolff-Parkinson-White syndrome in whom antegrade preexcitation could be persistently blocked by overdrive atrial pacing. METHODS AND RESULTS: An atrial pacing protocol, with a decremental ramp followed by an incremental ramp, defined a range of atrial paced cycle lengths (linking window) associated with both persistent conduction and block in the accessory pathway. Within the limits of the linking window, the ability of an atrial impulse to conduct over the accessory pathway was dependent on the preceding state (i.e., conduction or block). The observed linking window ranged from 70 to 290 msec (mean, 185 +/- 68 msec) and closely approximated the measured delay in retrograde activation of the accessory pathway during persistent antegrade block. The mean antegrade effective refractory period of the accessory pathways was long (486 +/- 156 msec), and in each case, it exceeded the antegrade refractory period of the normal atrioventricular pathway. Critically timed premature ventricular extrastimuli, delivered while linking was maintained in the accessory pathway, were able to interrupt the linking and restore antegrade accessory pathway conduction. CONCLUSIONS: These observations suggest that accessory pathway linking is associated with bidirectional block in the accessory pathway. The ability to initiate linking (and the stability of the phenomenon) depends on a critical relation between antegrade accessory pathway refractoriness and the magnitude of retrograde accessory pathway activation delay.

Adult↗
PubMed1991

Functional loss of tumour suppressor genes in multistage chemical carcinogenesis.

Studies of multistage carcinogenesis in mouse skin have provided many of the early concepts of tumour initiation, promotion and progression. Genetic approaches have led to the identification of a number of mutational alterations in proto-oncogenes and tumour suppressor genes which take place at specific stages of carcinogenesis in this particular system. Initiation involves, at least in a proportion of tumours, mutational activation of the cellular H-ras proto-oncogene. Trisomy of chromosome 7, which develops during the premalignant clonal expansion phase, possibly as a consequence of tumour promoter treatment, is followed by further alterations on chromosome 7 which lead to a relative increase in the expression of mutant ras alleles. The p53 tumour suppressor gene undergoes mutational alteration and loss of heterozygosity in a proportion of squamous carcinomas but this particular gene does not appear to be involved in the further transition of squamous carcinomas to highly undifferentiated spindle cell tumours. The latter transition appears to be a recessive event which can be complemented by fusion with cells at earlier stages of malignancy. Mouse skin carcinogenesis therefore continues to provide invaluable information on the nature of the genetic and biological transitions which occur during the step-wise progression of normal cells to malignancy.

Animals↗
PubMed1991

Loss of visual function associated with microalbuminuria in diabetes mellitus: a pilot study.

Visual function loss has been documented in diabetes mellitus in relation to flicker and contrast. However, no direct correlation between the degree of loss in sensitivity and the level of retinopathy has been established. It has been suggested that such non-invasive psychophysical procedures actually reflect metabolic disturbances within the diabetic retina. This study investigates the possibility of whether early nephropathy demonstrated by microalbuminuria, is an indicator of microangiopathy which may be a cause of retinal disturbance leading to a loss of visual function. The visual function of a group of diabetics showing microalbuminuria was studied. Contrast and flicker threshold were measured and the results compared with those obtained with an age-matched control diabetic group. The procedures used effectively separated the two groups and raises the issue of incorporating psychophysics in retinal screening programmes.

Albuminuria↗
PubMed2026

Combined effects of Ret coding and enhancer loss-of-function alleles cause progressive loss of inhibitory motor neurons in the enteric nervous system.

Hirschsprung disease (HSCR) is a congenital enteric neuropathy caused by disrupted development of enteric neural crest-derived cells (ENCDCs). Although pathogenic coding variants in RET account for many cases, the largest genetic contribution to HSCR risk arises from a common noncoding variant (rs2435357) within a SOX10-bound RET enhancer (MCS+9.7) that reduces RET gene expression in vivo and triggers expression changes in other ENS genes in the human fetal gut. However, the ENS cell types affected by this enhancer and the mechanisms by which these transcriptional changes lead to HSCR remain unknown. Here, we investigated the role of this enhancer by generating mice carrying a deletion of the orthologous Ret mcs+9.7 enhancer (Δmcs+9.7). Single-cell RNA sequencing of E14.5 embryonic gut demonstrated that enhancer deletion reduced Ret expression by 8% without altering ENS cell composition. However, reduced Ret expression was restricted to differentiating neurons and inhibitory motor neuron lineages, revealing cell type-specific enhancer activity. To determine the functional consequences of further reducing Ret dosage, we generated compound heterozygous mice carrying both the enhancer deletion and a Ret coding null allele (+/Δmcs+9.7;+/CFP). These mice exhibited additive reductions in Ret expression, altered Sox10 expression, dysregulation of cell-cycle and neuronal differentiation programs, and selective depletion of developing inhibitory motor neuron lineages. These findings establish a cell type-specific role for the mcs+9.7 enhancer in modulating Ret dosage and reveal how subtle enhancer perturbations alter neural subtype specification without overt hypoganglionosis, suggesting that HSCR arises from a cascade of cellular defects triggered by >50% loss of Ret function.

Journal Article↗
PubMed1990

Psychological characteristics of children with functional hearing loss.

The terminology used to describe functional hearing loss (FHL) and some explanations of the phenomenon are discussed briefly. Previous studies of FHL in children are reviewed. Characteristics of 30 children seen for psychological assessment following diagnosis of FHL are described. There were twice as many girls as boys in the sample. A large proportion of the children had experienced middle ear problems. The mean IQ for the sample was below average, but the range of intellectual ability was wide. Nine children showed serious educational retardation. The children were assigned to one of three psychological problem groups depending on whether they had minor, school-based, or deeper, psychological problems. Those with deeper psychological problems tended to show greater hearing losses on pure tone audiometry. FHL seemed to be related to attentional factors in those with only minor or school-based problems but not for those with deeper psychological problems. These findings are discussed with reference to the need for psychological assessment of children with FHL.

Adolescent↗
PubMed1992

Hyperthermic injury versus crush injury in the rat sciatic nerve: a comparative functional, histopathological and morphometrical study.

Functional and morphological changes of the rat sciatic nerve after local hyperthermia (30 min, 45 degrees C) and crush treatment were compared. After hyperthermic injury nerve function loss developed in a time period of about 7 h. Nerve crush led to an immediate loss of nerve function. Nerve function loss was assessed by a motor and a sensory function test. Recovery from function loss took place in both treatment groups and was complete in 4-5 weeks. Early (within 8 h post-treatment) histopathological changes in the nerve after heating included edema, possible blood stasis and changes in the blood vessel wall, like swelling of the media. During this period some axonal changes were observed. Immediate after crushing axons were severely damaged, while many blood vessels remained normal. Within one week after both treatments, degeneration of axons and myelin was observed at the site and distal from the site of the lesion (Wallerian degeneration). Three weeks after treatment a major part of the axons had regenerated and remyelinated. Vascular changes at the site of lesion could still be observed in the heat-treated nerves. Twelve weeks after both treatments, blood vessels appeared to be normal again. Morphometrical analysis of the treated nerves confirmed the histological observations. Three and 12 weeks after treatment average axon diameters were significant smaller and average myelin sheaths were significant thinner compared to untreated nerves. These parameters did not differ significantly when the two treatment groups were compared.

Animals↗
PubMed1989

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↗
PubMed1986

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↗
PubMed1992

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↗
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↗
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↗
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↗