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At least 19 recordsLinked to original sources
PubMed1976

Sexual loss in relation to other functional losses for spinal cord injured males.

To understand more fully the importance of sexual loss for spinal cord injured patients, paraplegic and quadriplegic men were asked to rank order functional losses associated with their respective injuries. In addition, staff members of the rehabilitation team were asked to predict the relative importance of these functional losses to their cord injured patients. The data indicate that relative to actual patient perceptions, staff predictions tended to overemphasize the relative importance of normal genital sexual functioning. Some implications of these findings for comprehensive rehabilitation programs are discussed.

Adolescent↗
PubMed2026

Selectivity Filter KCND3 Variant Causes Spinocerebellar Ataxia 19/22 and KV4.3 Functional Loss.

BACKGROUND: Spinocerebellar ataxia type 19/22 (SCA19/22) is a rare autosomal dominant neurodegenerative disorder caused by KCND3 variants encoding the KV4.3 potassium channel. While most pathogenic variants result in loss-of-function (LOF), no pathogenic variants were previously identified in the channel's selectivity filter, a critical domain for ion selectivity. OBJECTIVES: To elucidate the genetic cause and functional LOF mechanisms underlying severe early-onset cerebellar ataxia and neurodevelopmental impairment in monozygotic twins. METHODS: We evaluated twins presenting with early-onset cerebellar ataxia, developmental delay, and cognitive impairment. Whole-exome sequencing (WES) identified a KCND3 c.1103T>C (p.L368P) variant. Functional impacts were assessed through HEK293T cell protein expression, Xenopus oocyte electrophysiology, and structural homology modeling. RESULTS: WES identified a heterozygous de novo p.L368P variant in the "TLGYG" selectivity filter sequence. Modeling predicted a pore radius reduction, blocking potassium permeation. Biochemical analyses revealed markedly reduced protein expression and impaired trafficking. Electrophysiological recordings confirmed complete potassium current loss and a strong dominant-negative effect on wild-type KV4.3 currents. Clinically, the twins exhibited severe intellectual disability, developmental delay, and cerebellar atrophy with pontine flattening, without epilepsy. CONCLUSIONS: Identifying the first pathogenic variant in the KV4.3 selectivity filter highlights its critical role in channel proteostasis and ion conductance. The p.L368P variant produces a pronounced LOF phenotype and broadens the SCA19/22 clinical spectrum, indicating the filter's structural integrity is a key determinant of disease severity. © 2026 International Parkinson and Movement Disorder Society.

KCND3↗
PubMed1976

Functional hearing loss.

Functional hearing loss is a rather common entity, although it probably is overlooked more often than not. In most instances, the services of an experienced audiologist are necessary if one is to detect these cases. First, one must consider carefully the patient's behavior before and during the otologic and audiologic examination, and note the referral source, if any, since patients with certain backgrounds are more apt to exhibit functional hearing loss than others. Second, careful attention is given to certain aspects of the initial basic audiometric examination. Discrepancies here often stand out and point clearly toward functional loss. A so-called "modified approach" to conventional audiometry has enabled us to detect almost all cases of functional hearing loss without resort to the special audiometric tests designed for that purpose.

Adolescent↗
PubMed1975

Mechanisms of functional loss and recovery in spinal cord damage.

Two main classes of morphological change follow trauma to central nerve fibres: (1) axonal disruption leads to total disintegration of the fibre distal (with respect to the cell body) to the lesion; (2) less severe trauma produces focal demyelination with preservation of axonal continuity. Large experimental demyelinating lesions produce complete conduction block. The histologically normal portions of the fibres, proximal and distal to the lesion, retain the ability to transmit impulses. Smaller lesions allow conduction to continue, but at a reduced velocity, and the ability of the fibres to carry long trains of impulses faithfully is impaired. All three defects of conduction contribute to functional loss. After acute transient compression of the spinal cord of the cat, demyelination increases during the first week. Evidence of remyelination appears in the third week. Inappropriately thin myelin is seen surrounding histologically normal axons. By one month, 90% of the fibres in the lesion have acquired new sheaths. Studies on single fibres have shown that the myelin is organized into segments bounded by nodes. The segments are abnormally thin and short. The myelin increases in thickness with time but thin segments are still present at 18 months. Electron microscopy shows that many of the known ultrastructural prerequisites for conduction are present in the new segments. It is not yet known, however, whether the chains of very short internodes which occur on some fibres allow conduction to be restored.

Demyelinating Diseases↗
PubMed2026

Divergent PXR function in seals: Endocrine adaptation or functional loss?

Seals accumulate xenobiotics through dietary biomagnification and exposure to polluted marine environments, with contaminants concentrating in their blubber. Biotransformation mitigates xenobiotic toxicity by converting lipophilic compounds into excretable hydrophilic metabolites, a process coordinated by nuclear receptors including the Pregnane X Receptor (PXR), whose plastic ligand-binding domain enables broad xenobiotic sensing. By examining PXR in pinnipeds, we investigated the evolutionary conservation and functional characterization of PXR using genomic sequence analysis, protein structural prediction, and transactivation assays, revealing broadly conserved structural features alongside species-specific functional divergence in receptor responsiveness to environmental stressors. Specifically, the obtained results highlight divergent gene and functional landscapes with ORF-disrupting mutations identified in Monachus monachus and Neomonachus schauinslandi that abolish receptor activation toward known PXR ligands. In contrast, Leptonychotes weddelli retained an intact PXR ORF but showed reduced receptor activity, revealing functional divergence in PXR among pinnipeds.

Biotransformation↗
PubMed1992

Sustained renal function loss in psoriasis patients after withdrawal of low-dose cyclosporin therapy.

Eight patients with psoriasis received low-dose cyclosporin (CyA) treatment for an average period of 12 months (range 4-16 months). There was great variability in minimal effective CyA dose. In 50% of the patients long-term treatment was limited by dose reductions necessitated by side-effects. A considerable impairment of renal function during CyA therapy was found. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured with 125I-iothalamate and 131I-hippuran, respectively. Both at the end of the active treatment period (GFR-CyA and ERPF-CyA), and 4 months after withdrawal of CyA (GFR-4mo and ERPF-4mo), there was sustained renal impairment: GFR-BL = 97 (64-117), GFR-CyA reduction 17.8% (2.2-31.9%) [P < 0.02], GFR-4mo reduction = 9.8% (5.5-21.5%) ml/min/1.73 m2 (P < 0.05 vs. BL); ERPF-BL = 401 (232-607), ERPF-CyA reduction = 10.1% (7.4-27.3%) [P < 0.05], ERPF-4mo reduction = 13.5% (3.0-32.9%) ml/min/1.73 m2 (P < 0.02). Further studies of the effects on renal function during, and after, long-term therapy of psoriasis with low-dose CyA are warranted.

Adult↗
PubMed1992

Kinetics of the functional loss of different muscarinic receptor isoforms in Xenopus oocytes.

Native Xenopus oocytes express two isoforms of muscarinic receptors that mediate qualitatively different physiological responses. Oocytes of the majority of donors (common) express M3-like receptors (M3Rs) at comparable densities at both the animal and vegetal hemispheres of the cell. Rare (variant) donors possess oocytes that express mainly M1-like receptors (M1Rs), localized predominantly at the animal hemisphere. We have investigated the apparent degradation of these two isoforms and its relationship to their hemispheric distribution. Cycloheximide (CHX) caused a time-dependent decrease in receptor-mediated responses and [3H]quinuclidinyl benzylate (QNB) binding in oocytes from both types of donors. The t1/2 values ranged between 3 and 7 h. Removal of CHX resulted in rapid recovery of the response. This implied rapid degradation and turnover of both types of receptors. The loss of M1Rs was more than that of M3Rs. Moreover, the decrease was more rapid and more extensive on the animal hemisphere in both types of donors. Injection of oocytes expressing either receptor isoform with specific antisense oligonucleotides complementary to either m1 or m3 muscarinic receptors (from mouse) showed receptor loss at approximately the same rate as that calculated from experiments with CHX. Furthermore, oocytes of variant donors express M1Rs exclusively on the animal hemisphere, while the residual activity found on the vegetal hemisphere of the cell was mediated by M3Rs. Inhibition of putative receptor glycosylation with tunicamycin caused a rapid decrease in receptor-mediated responses and radioligand binding on M1Rs, but had virtually no effect on M3Rs. The expression of cloned m1 muscarinic receptors, however, was not affected by tunicamycin, suggesting that glycosylation is not a general prerequisite for the functional expression of muscarinic receptors.

Animals↗
PubMed1992

Evidence for coincident mutations in human lymphoblast clones selected for functional loss of a thymidine kinase gene.

A mitotic "recombination-competent state" inducible by x-irradiation is thought to exist in yeast. We sought evidence for such a process in mammalian cells by examining the occurrence of mutations at unlinked loci in clones derived from a human lymphoblast cell line. A total of 169 independent clones that arose spontaneously or after exposure to x-rays or ethyl methanesulfonate were selected for new somatic mutations at the thymidine kinase gene on chromosome 17q. They were subsequently screened for coincident mutations by use of variable-number-of-tandem-repeat probes located on different chromosomes. Three coincident mutations were positively identified by Southern analysis on chromosomes 7 and 14; they included one that produced a new allele and two that caused loss of allele heterozygosity. Densitometric analysis of the latter two indicated the presence of two copies of the remaining allele. Several possible coincident genetic events were also observed on chromosome 17. These findings revealed a coincident mutant fraction of about 10(-2)/cell, whereas the expected mutation fraction at these loci is less than 10(-4)/cell. These results may thus provide the first molecular evidence that a "global" mutational process capable of inducing genetic instability exists in mammalian cells.

Blotting, Southern↗
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 (&#x394;mcs+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 (+/&#x394;mcs+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↗
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↗
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↗
PubMed1978

[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↗
PubMed1992

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↗