Models for gain-of-function and loss-of-function of MMPs. Transgenic and gene targeted mice.
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Animals↗
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Results for “Loss of function”
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Functional visual loss.
Patients with functional loss of visual acuity or visual fields range from the "deliberate malingerer" to the "suggestible innocent." Between these extremes are patients with varying mixtures of fraud and suggestibility. These patients do not, as a rule, have psychiatric disease and do not need to see a psychiatrist. The ophthalmologist must be able to control frustration with these patients to prove that the patient has better visual fields and visual acuity than admitted to, and so that he can perform a careful, dispassionate examination to establish that no organic disease is present. This examination makes it possible to offer believable reassurance to the patient. Simple reassurance seems to be effective therapy.
Evoked Potentials, Visual↗
Tumor and growth suppression of breast cancer cells by chromosome 17-associated functions.
Losses of functions from chromosome 17 are the most frequent genetic abnormalities in human breast cancer. To assess the biological role of chromosome 17 in the development of breast cancer, we transferred a normal human chromosome 17 to two breast cancer cell lines. No viable clone maintaining an intact chromosome was obtained in either MDA-MB-231 or MCF-7. Only one MDA-231/H17 clone contained the long arm of the transferred chromosome 17. Interestingly, this clone lost the ability to induce tumors in nude mice, indicating that at least one gene mapping to the long arm of chromosome 17 could suppress the tumorigenic phenotype. The p53 protein most likely was responsible for the selective loss of the short arm of the chromosome. Both cell lines have no wild-type p53 activity. MDA-MB-231 carries a single mutant TP53 allele, while MCF-7 carries two wild-type alleles, but p53 protein is excluded from the nucleus. Transfection in both cell lines of vectors expressing wild-type p53 produced only clones with rearrangements of the transfected TP53 complementary DNA. Thus, nonregulated expression of the p53 protein driven by the strong cytomegalovirus promoter may have triggered a rapid process of cell death. Stable expression of a mutant p53 in MCF-7 cells proved that nuclear localization of the protein was possible; however, no progression toward an estrogen-independent tumorigenic phenotype was induced. This work indicates that functional inactivation of the wild-type p53 protein and of the product of a gene located on 17q are essential to the development of breast neoplasms.
Amino Acid Sequence↗
Predicting loss of pulmonary function after pulmonary resection for bronchogenic carcinoma.
Studies of regional pulmonary function using radioactive 133xenon gas and spirometric tests (forced vital capacity and forced expiratory volume in the first second) were performed before and after unilateral pulmonary resection for cancer of the lung. Ninety-one patients were evaluated; 47 underwent total pneumonectomy, and 44 underwent lobectomy. The postoperative serial evaluations were classified into short-term and long-term studies (less than or more than three months, respectively). The preoperative and postoperative data were utilized to derive formulas for predicting an estimate of the overall functional loss after pulmonary resection based on the number of segments removed. The correlation between the predicted and measured postoperative values was good for resections involving more than three segments (r = 0.83). Prediction for smaller resections was unreliable. While both regional and overall pulmonary functions were relatively stable after pneumonectomy, there was a disproportionate early loss, followed by significant functional improvement with time following lobectomy. The anticipation of and preparation for this early loss of function may be crucial in the treatment of these patients.
Carcinoma, Bronchogenic↗
Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3.
Two types of photoreceptors, rods and cones, coexist in the vertebrate retina. An in-depth analysis of the retinal circuitry that transmits rod and cone signals has been hampered by the presence of intimate physical and functional connections between rod and cone pathways. By deleting the cyclic nucleotide-gated channel CNG3 we have generated a mouse lacking any cone-mediated photoresponse. In contrast, the rod pathway is completely intact in CNG3-deficient mice. The functional loss of cone function correlates with a progressive degeneration of cone photoreceptors but not of other retinal cell types. CNG3-deficient mice provide an animal model to dissect unequivocally the contribution of rod and cone pathways for normal retinal function.
Animals↗
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↗
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↗
Structure-function relationships of two loss-of-function mutations of the thyrotropin receptor gene.
The functional and structural characteristics of two previously described "loss-of-function" mutants of the thyrotropin receptor (TSHR) gene were analyzed by transient transfection in COS cells. Both mutations (Pro162Ala, Ile167Asn) are located in the putative extracellular hormone-binding domain of the receptor. The following parameters were analyzed: expression of native receptor on the cell surface (as measured by binding of labeled thyrotropin [TSH] to intact cells, or flow cytometry of intact cells); total TSHR expression (measured by flow cytometry of permeabilized cells); response to TSH measured as cyclic adenosine monophosphate (cAMP) accumulation. The total cellular expression of both mutant receptors was similar. Cell surface expression of Pro162A1a mutant was reduced about twofold and the EC50 for TSH stimulation was increased twofold. In contrast, the Ile167Asn mutant did not reach the cell surface and the intracellularly expressed mutant protein did not react with a monoclonal antibody (BA8) recognizing only the native TSHR. Based on the current model of the three-dimensional structure of the TSHR, the Pro162Ala substitution maps at the surface of the molecule, while the Ile167Asn mutation affects a residue whose side chain contributes to the hydrophobic core characteristic of proteins harboring leucine repeat motifs. These results are consistent with Ile167Asn causing a gross destabilization of receptor structure incompatible with its normal routing through the intracellular membrane system of the cell.
Amino Acid Sequence↗
Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP12 loss-of-function mutant mice.
KARAP/DAP12 is a transmembrane polypeptide with an intracytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). KARAP/DAP12 is associated with several activating cell surface receptors in hematopoietic cells. Here, we report that knockin mice bearing a nonfunctional KARAP/DAP12 ITAM present altered innate immune responses. Although in these mice NK cells are present and their repertoire of inhibitory MHC class I receptors is intact, the NK cell spectrum of natural cytotoxicity toward tumor cell targets is restricted. KARAP/DAP12 loss-of-function mutant mice also exhibit a dramatic accumulation of dendritic cells in muco-cutaneous epithelia, associated with an impaired hapten-specific contact sensitivity. Thus, despite its homology with CD3zeta and FcRgamma, KARAP/DAP12 plays a specific role in innate immunity, emphasizing the nonredundancy of these ITAM-bearing polypeptides in hematopoietic cells.
Adaptor Proteins, Signal Transducing↗
Analyses of neuro-otological complications after radiosurgery for acoustic neurinomas.
PURPOSE: To find out the optimum treatment parameters and the proper indications for treatment of acoustic neurinomas, univariate and multivariate actuarial analyses of neuro-otological complications after stereotactic radiosurgery for acoustic neurinomas were performed. METHODS AND MATERIALS: The subjects were 46 patients with acoustic neurinomas who underwent unilateral radiosurgery between June 1990 and June 1994 and were followed up at the University of Tokyo. Age ranged from 13 to 77 years (median, 54 years). Tumor diameter ranged from 0 to 25 mm (mean, 12 mm) at the cerebellopontine angle and from 2 to 15 mm (mean, 8.3 mm) in the internal auditory meatus. Maximum tumor doses ranged from 20 to 40 Gy (mean, 31.4 Gy), and peripheral doses from 12 to 25 Gy (mean, 16.8 Gy). One to eight isocenters were used (mean, 3.2). Median follow-up was 39 months. Eight events concerning neuro-otological complications were chosen, and the potential risk factors for them were analyzed by the actuarial analyses (univariate and multivariate). The events examined include hearing loss, vestibular function loss, facial palsy, and trigeminal nerve dysfunction. In order to point out potential risk factors for neuro-otological complications, univariate analyses were performed using both the Wilcoxon test and the log rank test, and multivariate analyses were performed with the Cox proportional hazards model. Variables nominated as potential risk factors were 1) demographic variables such as patient age and sex, 2) tumor dimensions, 3) treatment variables such as tumor doses and number of isocenters, and 4) pretreatment hearing levels. A variable with significant p-values (p < 0.05) in two or more of the three actuarial analyses (two univariate and one multivariate) was considered a possible risk factor. RESULTS: The possible variables that increase the risk for each event analyzed were: neurofibromatosis type II (NF2) and the number of isocenters for total hearing loss; experience of prior operation, the tumor diameter in the internal auditory meatus, and NF2 for hearing threshold elevation; peripheral tumor dose for vestibular function loss; patient age or midporus transverse tumor diameter (the two variables were correlated), and the number of isocenters for facial palsy; and the number of isocenters for trigeminal neuropathy. CONCLUSION: NF2 and the tumor diameter were the common risk factors for hearing loss in previous studies and ours. For the 5th/7th nerve dysfunction, the tumor diameter was the common risk factor. The risk of using more isocenters remains controversial. The difference in risk factors for hearing impairment and vestibular function loss suggests different mechanisms for the two. Further studies with larger populations and longer follow-up periods are required in order to draw conclusions on the risk factors in radiosurgery.
Adolescent↗
[Prevention of loss of functional independence and institutionalization].
LOSS OF FUNCTIONAL INDEPENDENCE: This is a serious problem in the management of older subjects. Prevention is necessary in order to assure better quality of life and avoid definitive institutionalization in a medical or social center. RELATED FACTORS: An analysis of the literature on the risk of loss of functional independence points out several medical (comorbidity, falls, cognitive capacity, sensorial deficiencies, nutrition, drugs), psychological (depression), and physical activity and social factors related to functional independence. RISK OF INSTITUTIONALIZATION: The risk is related to functional limitations and especially declining cognition, as well as social factors and the role of the primary care giver. PREVENTION: Systematic screening for risk factors is needed. The impact of measures to remedy certain medical risk factors has been clearly demonstrated. Specific programs can improve functional status, avoid institutionalization, and perhaps prolong survival.
Activities of Daily Living↗
Role of laminin in maintenance of type II pneumocyte morphology and function.
Loss of differentiated function by type II pneumocytes plated on plastic surfaces was demonstrated by decreased lamellar body content, increased cellular protein, and rapid cellular flattening, changes that were retarded modestly by plating cells on laminin-coated surfaces. Laminin surfaces also inhibited [3H]thymidine (THM) incorporation into cellular DNA by 40% compared with plastic at 40 h, but did not alter an additional mitogenic effect of rat serum over fetal calf serum. In contrast, cells plated on the laminin-rich basement membrane-like gel formed from an extract of EHS mouse sarcoma, matrix gel (MG), maintained a high content of intracellular lipids in lamellar inclusions and retained a rounded morphology for at least 3 days. MG markedly inhibited THM incorporation and morphological changes when cells were cultured on this surface or when MG was formed over cells initially plated on plastic for various intervals. The importance of the laminin component of MG was demonstrated when these surfaces were pretreated with a highly specific antilaminin serum. Type II cells commenced flattening on the treated MG surface, and THM incorporation increased with the same time course as did control cells on plastic. The data suggest that short-term culture and study of differentiated type II pneumocytes may require a laminin-rich substratum. THM incorporation into type II cell DNA provides an important early and sensitive index of cell-basement membrane interaction and subsequent maintenance of function.
Animals↗
The conceptual problem of 'functional hearing loss'.
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Hearing Loss↗
[Functional hearing loss in children].
The cases of children diagnosed with pseudohypacusis in the Department of Pediatric Otolaryngology were presented. Probable mechanism of its pathogenesis was described. The main stress was put on its correct diagnosis particularly in children with co-existing organic changes. Diagnosis of pseudohypacusis in children is not problematic provided that the occurence of this disease is taken into consideration during diagnostic procedures.
Adolescent↗
Personality and functional hearing loss in children.
Thirty children with functional hearing loss were seen for psychological assessment. The sample included twice as many girls as boys. Most had experienced middle-ear problems and scored outside normal limits on the Junior Eysenck Personality Inventory. Introversion alone or combined with neuroticism was the most important personality dimension, especially for girls. The relationship between introverted behaviour, hearing impairment and previous experience of hearing problems is discussed.
Audiometry, Pure-Tone↗
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↗
The use of decision-theoretic approach in regulating toxicity.
This paper presents a general decision model for quantitative risk analysis to help in solving the problem of setting the optimal exposure level of a potential carcinogen in regulatory decision-making. This model consists of a probability function and two loss functions. The probability function describes the dose-response relationship for a potential carcinogen at various exposure levels. The two loss functions include the cost of using a potential carcinogen, e.g., health loss, and the cost of not using the compound, e.g., economic loss. Using the principle of minimum expected loss, a fundamental formula for setting the optimal beneficial dose level is derived. The formula equates the probability function to a ratio of loss functions. The general form of loss functions is described in the paper. Under certain conditions, the current approach for quantitative risk assessment is a special situation of this general model.
Carcinogens↗
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↗