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PubMed1984

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↗
PubMed1998

A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor.

A single natural loss of function mutation of the follicle stimulating hormone receptor (FSHR) has been described to date. Present in the Finnish population it markedly impairs receptor function, blocking follicle development at the primary stage and presenting as primary amenorrhea with atrophic ovaries. When Western European women with this phenotype were examined for FSHR mutations the result was negative, suggesting that other etiologies corresponding to this clinical pattern are markedly more frequent. We now describe a novel phenotype related to mutations provoking a partial loss of function of the FSHR. A woman with secondary amenorrhea had very high plasma gonadotropin concentrations (especially FSH), contrasting with normal sized ovaries and antral follicles up to 5 mm at ultrasonography. Histological and immunohistochemical examination of the ovaries showed normal follicular development up to the small antral stage and a disruption at further stages. The patient was found to carry compound heterozygotic mutations of the FSHR gene: Ile160Thr and Arg573Cys substitutions located, respectively, in the extracellular domain and in the third intracellular loop of the receptor. The mutated receptors, when expressed in COS-7 cells, showed partial functional impairment, consistent with the clinical and histological observations: the first mutation impaired cell surface expression and the second altered signal transduction of the receptor. This observation suggests that a limited FSH effect is sufficient to promote follicular growth up to the small antral stage. Further development necessitates strong FSH stimulation. The contrast between very high FSH levels and normal sized ovaries with antral follicles may thus be characteristic of such patients.

Adult↗
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↗
PubMed2000

A clinical prediction rule for nerve-function impairment in leprosy patients.

BACKGROUND: Nerve-function impairment (NFI) commonly occurs during or after chemotherapy in leprosy and is the key pathological process leading to disability and handicap. We describe the development of a simple clinical prediction rule for estimating the risk of NFI occurrence. METHODS: New leprosy cases who presented to a centre in Bangladesh were recruited and followed up for 2 years in a field setting. We used multivariable regression analysis by Cox's proportional hazards model to identify predictive variables for NFI. Discriminative ability was measured by a concordance statistic. Internal validity was assessed with bootstrap resampling techniques. FINDINGS: 2510 patients were followed up for 2 years, 166 developed NFI. A simple model was developed with leprosy group (either paucibacillary leprosy [PB] or multibacillary leprosy [MB]) and the presence of any nerve-function loss at registration as predictive variables. Patients with PB leprosy and no nerve-function loss had a 1.3% (95% CI 0.8-1.8%) risk of developing NFI within 2 years of registration; patients with PB leprosy and nerve-function loss, or patients with MB leprosy and no nerve-function loss had a 16.0% (12-20%) risk; and patients with MB leprosy with nerve-function loss had a 65% (56-73%) risk. INTERPRETATION: Our prediction rule can be used to plan surveillance of new leprosy patients. Patients at low risk of NFI may need no follow-up beyond their course of chemotherapy (6 months); patients with intermediate risk need a minimum of 1 year of surveillance; and patients with high risk should have at least 2 years of surveillance for new NFI. Current recommendations for surveillance of patients with leprosy (for the duration of chemotherapy only) exclude an important group of patients who are at risk of developing NFI after completion of treatment.

Adolescent↗
PubMed2001

Pattern visual evoked potential in the diagnosis of functional visual loss.

OBJECTIVE: To study the pattern visual evoked potential (P-VEP) in the diagnosis of functional visual loss. STUDY DESIGN: Retrospective study of observational case series. PARTICIPANTS: Seventy-two subjects whose best corrected visual acuity (VA) was 20/50 or worse, with or without visual field defect, and whose visual abnormalities could not be explained by the findings of ophthalmologic and neurologic examination were included in this study. MAIN OUTCOME MEASURES: To compare the P-VEP estimated acuity to the initial subjective VA and to the best-performed VA. RESULTS: Seventy-two subjects with functional visual loss had normal P-VEPs. The initial subjective VA was 20/50 in 9 subjects and < or =20/200 in 42 subjects. After clinical examination and reassurance, the best-performed VA was > or =20/50 in 53 subjects and < or =20/200 in 8 subjects. The discrepancy between the P-VEP estimated acuity and the best-performed VA was less than 3 lines of Snellen acuity in 63 of 72 (87.5%) subjects and more than 4 lines in 6 subjects. These six subjects were three women with loss of vision of unknown origin and three men with injury-related visual loss. CONCLUSIONS: P-VEP has the advantage of objectively predicting VA and is a useful test in the diagnosis of functional visual loss.

Adolescent↗
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↗