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PubMed1987

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↗
PubMed2000

[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↗
PubMed1986

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↗
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↗
PubMed1986

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↗
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↗
PubMed1984

Functional hearing loss presenting as sudden hearing loss: a case report.

A case of functional hearing loss presenting as sudden sensorineural hearing loss in the only hearing ear of a musician is presented. Pure-tone audiometric evaluation showed good intratest and intertest consistency. The pitfalls of diagnosis, ultimately made by brain stem evoked response audiometry, are discussed in light of the literature on sudden and functional hearing loss. Psychiatric evaluation revealed features consistent with hysterical conversion. It is argued that it is important to establish the exact etiologic agent of functional hearing loss despite the difficulty of diagnosis so that the patient may receive appropriate treatment.

Adult↗
PubMed2000

MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X).

Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes characterized by early onset of pancreatic dysfunction. MODY type 3 is caused by mutations in the hepatocyte nuclear factor (HNF)-1alpha. During a screening of Norwegian patients with suspected MODY we identified two novel HNF-1alpha mutations, P112L and Q466X. The molecular mechanisms underlying the disease were studied by analyzing the DNA binding properties, transcriptional activation, and subcellular localization of HNF-1alpha P112L and Q466X compared to wild type HNF-1alpha. P112L had reduced ability to bind an HNF1 consensus sequence and to activate transcription. Q466X did not differ from wild type HNF-1alpha in DNA binding activity. Transactivation, however, was markedly reduced. When both mutants were coexpressed with wild type HNF-1alpha in HeLa cells, transcriptional activity appeared unaffected, suggesting that a dominant-negative mechanism was not present. Immunolocalization experiments showed that P112L HNF-1alpha was correctly targeted to nuclei in HeLa cells. In contrast, some Q466X HNF-1alpha protein was retained in the cytoplasm, which indicated that the mechanism for nuclear localization was disturbed. Thus, the HNF-1alpha mutations P112L and Q466X both seem to impair pancreatic beta-cell function by loss-of-function mechanisms; P112L by reduced DNA binding and reduced ability to transactivate, and Q466X by reduced transactivation and incomplete nuclear targeting.

DNA↗
PubMed1999

Loss-of-function and dominant-negative mechanisms associated with hepatocyte nuclear factor-1beta mutations in familial type 2 diabetes mellitus.

Hepatocyte nuclear factor (HNF)-1beta, a homeodomain-containing transcription factor, regulates gene expression in a dimerized form in pancreas, liver, and some other tissues. Recent genetic studies have identified two HNF-1beta mutations, R177X and A263fsinsGG, in subjects with a monogenic form of type 2 diabetes. Despite the defects being in the same gene, diverse severities of disease are observed in the affected subjects. To investigate the molecular mechanism by which mutations might cause various phenotypic features, wild type and mutant proteins were transiently expressed in insulin-producing (MIN6) and hepatic (HepG2) cells. Luciferase reporter assay showed that both mutations resulted in a marked reduction of transactivation activity. Because their dimerization activity was found to be intact by the yeast two-hybrid system, it was possible that they were dominant-negative to wild type activity. When co-expressed with wild type, both of the mutants significantly decreased wild type activity in HepG2 cells. In contrast, although A263fsinsGG functioned similarly in MIN6 cells, R177X failed to affect wild type activity in this cell line. Immunohistochemical analysis of the mutants suggests that this functional divergence might be generated by the modification of nuclear localization. These results suggest that HNF-1beta mutations may impair pancreatic beta-cell function by loss-of-function and dominant-negative mechanisms.

Base Sequence↗
PubMed2000

The consequences of growth of a mutator strain of Escherichia coli as measured by loss of function among multiple gene targets and loss of fitness.

We have examined the composition of members of mutator populations of Escherichia coli by employing an extensive set of phenotypic screens that allow us to monitor the function of >700 genes, constituting approximately 15% of the genome. We looked at mismatch repair deficient cells after repeated cycles of single colony isolation on rich medium to generate lineages that are forced through severe bottlenecks, and compared the results to those for wild-type strains. The mutator lineages continued to accumulate mutations rapidly with each increasing cycle of colony isolation. By the end of the 40th cycle, after approximately 1000 generations, most of the lineages had reduced colony size, 4% had died out, 55% had auxotrophic requirements (increasing to 80% after 60 cycles), and 70% had defects in at least one sugar or catabolic pathway. In addition, 33% had a defect in cell motility, and 26% were either temperature-sensitive or cold-sensitive lethals. On the other hand, only 3% of the wild-type lineages had detectable mutations of any type after 40 cycles. By the 60th cycle, the typical mutator cell carried 4-5 inactive genes among the 15% of the genome being monitored, indicating that the average cell carried at least 24-30 inactivated genes distributed throughout the genome. Remarkably, 30% of the lineages had lost the ability to utilize xylose as a carbon source. DNA sequencing revealed that most of the Xyl(-) mutants had a frameshift in a run of eight G's (GGGGGGGG) in the xylB gene, either adding or deleting one -G-. Further analysis indicated that rendering E. coli deficient in mismatch repair unmasks hypermutable sites in certain genes or intergenic regions. Growth curves and competition tests on lineages that passed through 90 cycles of single colony isolation showed that all lineages suffered reduced fitness. We discuss these results in terms of the value of mutators in cellular evolution.

Adaptation, Biological↗
PubMed1994

DPhK-gamma, a putative Drosophila kinase with homology to vertebrate phosphorylase kinase gamma subunits: molecular characterisation of the gene and phenotypic analysis of loss of function mutants.

Partial and total loss of function mutant alleles of a putative Drosophila homologue (DPhK-gamma) of the vertebrate phosphorylase kinase gamma-subunit gene have been isolated. DPhK-gamma is required in early embryonic processes, such as gastrulation and mesoderm formation; however, defects in these processes are seen only when both the maternal and zygotic components of DPhK-gamma expression are eliminated. Loss of zygotic expression alone does not appear to affect normal embryonic and larval development; some pupal lethality is observed but the majority of mutant animals eclose as adults. Many of these adults show defects in their leg musculature (e.g. missing and degenerating muscles), in addition to exhibiting melanised "tumours" on their leg joints. Loss of only the maternal component has no obvious phenotypic consequences. The DPhK-gamma gene has been cloned and sequenced. It has an open reading frame (ORF) of 1680 bp encoding a 560 amino acid protein. The predicted amino acid sequence of DPhK-gamma has two conserved domains, the catalytic kinase and calmodulin-binding domains, separated by a linker sequence. The amino acid sequence of DPhK-gamma is homologous to that of mammalian PhK-gamma proteins but differs in the length and amino acid composition of its linker sequence. The expression of DPhK-gamma mRNA is developmentally regulated. We discuss the implications of these observations.

Amino Acid Sequence↗
PubMed1997

Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis.

It is not known whether mutations in the PKD1 gene cause autosomal dominant polycystic kidney disease (PKD) by an activating (gain-of-function) or an inactivating (loss-of-function) model. We analyzed DNA from cyst epithelial cells for loss of heterozygosity (LOH) in the PKD1 region of chromosome 16p13 using microsatellite markers. 29 cysts from four patients were studied. Five cysts from three patients had chromosome 16p13 LOH. Four of the cysts had loss of two chromosome 16p13 markers that flank the PKD1 gene. In two patients, microsatellite analysis of family members was consistent with loss of the wild-type copy of PKD1 in the cysts. In the third patient, 16p13 LOH was detected in three separate cysts, all of which showed loss of the same alleles. Chromosome 3p21 LOH was detected in one cyst. No LOH was detected in four other genomic regions. These results demonstrate that some renal cyst epithelial cells exhibit clonal chromosomal abnormalities with loss of the wild-type copy of PKD1. This supports a loss-of-function model for autosomal dominant PKD, with a germline mutation inactivating one copy of PKD1 and somatic mutation or deletion inactivating the remaining wild-type copy.

Chromosome Deletion↗
PubMedDate not supplied

Functional hearing loss and its relationship to resolved hearing levels.

The nature of functional hearing loss was retrospectively studied with respect to hearing sensitivity after resolution of the nonorganic components in 63 adults with bilateral exaggerated losses (126 ears). The configuration of the functional components (difference between the functional and resolved thresholds) was found to be related to that of the resolved hearing levels. The size of the functional overlay was essentially the same across the audiometric frequency range when the hearing was actually normal or if there was only mild loss. In cases of precipitously sloping high-frequency losses, the magnitude of the functional overlay became dramatically smaller for the impaired frequencies than for lower frequencies where hearing was normal or only mildly impaired. Moderate and severe losses represented a transitional situation, in which the functional components became gradually smaller with increasing frequency. Subjects with different resolved hearing in each ear (e.g., mild loss in one ear and a precipitous loss in the other) demonstrated nonorganic overlays that were consistent with the actual hearing levels for each respective ear. The findings suggest the use of an internalized, loudness level-based anchor by subjects with functional losses: the test signal must sound as loud as the anchor at each frequency in order for an exaggerated threshold response to be volunteered at that respective frequency. The pure-tone audiometric configuration and amount of functional loss at least in bilateral cases is thus consistently accounted for on the basis of known and explainable auditory factors.

Adult↗
PubMed1993

Perception of horizontal head and trunk rotation: modification of neck input following loss of vestibular function.

Chronic loss of vestibular function modifies the role of neck afferents in human perception of self-motion. We characterized this change by comparing the self-motion perception of patients with chronic vestibular loss (Ps) to that of normal subjects (Ns). Stimuli consisted of sinusoidal horizontal rotations (0.025-0.4 Hz) of the trunk relative to the head (neck stimulation) and/or of the head in space (vestibular stimulation). Perception of head rotation relative to the trunk, of trunk rotation in space, or of head rotation in space was assessed in terms of gain and phase (veridical perception, G = 1 and phi = 0 degree) as well as detection threshold using a pointing procedure. (1) Perception of head rotation relative to the trunk (neck proprioception). Ps' detection threshold of head-to-trunk rotation was normal (i.e. similar to that of Ns) across all frequencies tested. Also, with peak angular velocities above 5 degrees/s, the gain of their perception was approximately normal. When peak velocity was decreased below this value, however, either by lowering stimulus frequency with peak displacement kept constant (+/- 8 degrees) or by decreasing peak displacement at constant frequency (0.05 Hz), the gain increased above unity, unlike in Ns. In contrast, the phase remained normal (approximately 0 degree). (2) Perception of trunk rotation in space. Ps perceived their trunks as stationary during neck stimulation and all vestibular-neck combinations at medium to low frequencies. At 0.4 Hz, however, Ps consistently perceived the trunk rotation, conceivably due to somatosensory self-motion cues arising from high body acceleration. In contrast, Ns perceive a trunk-in-space rotation with the neck stimulation and most of the stimulus combinations across the whole frequency range tested. Ns perceived their trunks as stationary only during head rotation on the stationary trunk (presumed to reflect a mutual cancellation of neck and vestibular signals). (3) Perception of head rotation in space. In Ps, unlike Ns, this perception always resembled that of head rotation relative to the trunk. (4) When Ps were presented with a visual or somatosensory space reference (not motion cues), their perception of trunk and head rotation in space became approximately normal. (5) We suggest that there are basically two changes in the neck-induced self-motion perception associated with chronic vestibular loss. First, neck proprioception shows a non-linear gain that overemphasizes low stimulus velocities, for unknown reasons.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1999

Effect of internal thoracic artery preparation on blood loss, lung function, and pain.

BACKGROUND: Postoperative blood loss, respiratory distress, and pain after coronary artery operation were assessed in a prospective, randomized, clinical study comparing two techniques of internal thoracic artery preparation. METHODS: In group A (n = 57) the internal thoracic artery was dissected with the entire surrounding connective tissue after opening the pleura, using routine lateral pleural drainage. In group B (n = 55) a venoarterial pedicle was prepared without surrounding muscle leaving the pleura intact. We assessed blood loss, clinical outcome, lung function, location, intensity, and quality of pain 6 days and 3 months after the operation. RESULTS: Significantly higher blood loss was observed in group A (A, 608+/-58 mL; B, 470+/-48 mL; p = 0.027). Forced expiratory volume in 1 second was significantly decreased in group A 6 days after surgery (A, 76.0%+/-1.6%; B, 83.2%+/-1.6%; p = 0.020). The forced expiratory volume in 1 second correlated to inspiratory vital capacity, which confirmed the advantage of the venoarterial technique (A, 0.771+/-0.021; B, 0.832+/-0.020; p = 0.003). Vital capacity was significantly higher in the venoarterial group at 3 months (A, 85.2%+/-2.1%; B, 98.5%+/-1.2%; p = 0.009), but not on postoperative day 6. The incidence of pleural effusion and atelectasis was significantly higher in group A (effusion: A, 52.6%; B, 23.6%; p = 0.002; atelectasis: A, 42.1%; B, 20.0%, p = 0.015). Sternal pain (A, 36.8%; B, 9.1%; p = 0.001) and suspenders pain (A, 33.3%; B, 7.3%; p = 0.001) occurred more often in group A. When using a multidimensional pain score, patients in group A experienced significantly sharper (6 days: A, 6.7+/-0.3; B, 3.3+/-0.2; p = 0.018; 3 months: A, 3.5+/-0.3; B, 1.4+/-0.3; p = 0.046) and more annoying pain (6 days: A, 7.6+/-0.2; B, 2.7+/-0.1; p = 0.036; 3 months: A, 6.6+/-0.3; B, 2.3+/-0.2; p = 0.040). CONCLUSIONS: These results demonstrate that the venoarterial preparation technique is superior to conventional internal thoracic artery preparation regarding postoperative blood loss, lung function, and pain.

Female↗
PubMed2001

Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease.

CMTX, the X-linked form of Charcot-Marie-Tooth disease, is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding the gap junction protein connexin 32 (Cx32). In this communication, we describe the expression levels and biophysical parameters of seven mutant forms of Cx32 associated with CMTX, when expressed in paired Xenopus oocytes. Paired oocytes expressing the R15Q and H94Q mutants show junctional conductances not statistically different from that determined for Cx32WT, though both show a trend toward reduced levels. The S85C and G12S mutants induce reduced levels of junctional conductance. Three other mutants (R15W, H94Y and V139M) induce no conductance above baseline when expressed in paired oocytes. Analysis of the conductance voltage relations for these mutants shows that the reduced levels of conductance are entirely (H94Y and V139M) or partly (S85C and R15W) explicable by a reduced open probability of the mutant hemichannels. The R15Q and H94Q mutations also show alterations in the conductance voltage relations that would be expected to minimally (H94Q) or moderately (R15Q) reduce the available gap junction communication pathway. The reduction in G12S induced conductance cannot be explained by alterations in hemichannel open probability and are more likely due to reduced junction formation. These results demonstrate that many CMTX mutations lead to loss of function of Cx32. For these mutations, the loss of function model is likely to explain the pathogenesis of CMTX.

Amino Acid Substitution↗
PubMed2001

Phosphate-binding loop and Rab GTPase function: mutations at Ser29 and Ala30 of Rab5 lead to loss-of-function as well as gain-of-function phenotype.

Ras-like GTPases contain a structurally conserved GTP-binding domain. An important element of the GTP-binding domain is the phosphate-binding loop, which contains two Gly residues (Gly(12) and Gly(13)) in Ras. Because the two Gly residues are crucial for normal Ras function, it is intriguing that they are not conserved in other Ras-like GTPases, including the Rab GTPases; for example, the equivalent residues in Rab5 are Ser(29) and Ala(30). The present study builds on earlier biochemical characterizations of the Rab5 mutants containing substitutions at Ala(30) and provides a comprehensive analysis of the structure-function relationship of the Rab5 phosphate-binding loop. We have generated 19 new mutants containing amino acid substitutions at Ser(29) and determined whether these Ser(29) mutants, as well as the Ala(30) mutants, remain able to stimulate the endocytosis of horseradish peroxidase in baby hamster kidney cells. A total of 11 mutants lose the activity of stimulating endocytosis. Of these 11 mutants, 9 are defective in membrane association. In contrast, 27 mutants remain able to stimulate endocytosis. Five of them induce a novel cellular phenotype: cell rounding and detachment from culture dishes. They also induce super-large early endosomes such as the constitutively activated Rab5:Q79L mutant. Biochemical results suggest that the constitutive activation of Rab5 requires an increased nucleotide exchange rate and/or decreased GTPase activity. This study establishes functional significance for the phosphate-binding loop of Rab5 and shows that mutations in this region lead to either a loss-of-function or a gain-of-function phenotype, indicating a structure-function relationship distinct from that of Ras.

Alanine↗