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The organizational properties of the self-concept and instability of affect.

Affect instability, a core symptom of several major mental illnesses, contributes to high levels of subjective distress and impaired self-care abilities. The findings of previous studies have shown that, in asymptomatic samples, the organizational properties of the self-concept impact short-term affect regulation. In this study, that work is extended to examine the association between the organizational properties of the self-concept and instability of affect in adults with a major mental illness. Subjects were 19 adults with a major mental illness (clinical) and 10 asymptomatic adults. Zajonc's card-sorting task was used to measure two organizational properties: (a) differentiation--the number of attributes included in the self-concept, and (b) unity--the degree of interdependence among the attributes. An experience sampling procedure was used to obtain 50 measures of affect across a 10-day period. The clinical group experienced more instability of negative affects than the asymptomatic group. Furthermore, the clinical group had lower differentiation and higher unity of the self-concept than the asymptomatic controls, although both organizational properties were related to education. In the total sample, differentiation was not related to instability of affect. Unity accounted for 21% of the variance in instability of negative affect.

Adult↗

Mutations of the transforming growth factor-beta type II receptor gene and genomic instability in hereditary nonpolyposis colorectal cancer.

To determine the relation between the mutation of the TGF-beta type II receptor gene and genomic instability in the tumorigenesis of hereditary nonpolyposis colorectal cancer (HNPCC), we screened genomic DNA of 38 tumors from 25 HNPCC patients, 15 colorectal cancers from familial adenomatous polyposis patients, and 8 sporadic endometrial cancers, in two areas containing a (A)10 repeat or a (GT)3 repeat of the gene. Seventeen of the 24 (71%) genomic instability-positive HNPCC tumors carried one or two A deletions in the (A)10 repeat, while none of the 14 genomic instability-negative tumors did. These deletions inactivate the receptor through a frameshift mutation and the resultant protein truncation. No mutation was detected in the (GT)3 repeat sequence, but we found a missense mutation of codon 537 in the same area in one tumor. One A deletion was also detected in a genomic instability-positive sporadic endometrial cancer, but none in familial adenomatous polyposis tumors. No mutations were detected in the corresponding normal cells of these cases, indicating a somatic mutation. These data suggest that the TGF-beta type II receptor gene is a major target of genomic instability in HNPCC tumorigenesis.

Base Sequence↗

Chromosome instability in mutagen sensitive mutants of Neurospora.

Four mutagen sensitive mutants of Neurospora (mus-7, mus-9, mus-11, and mei-2) are shown to increase mitotic chromosome instability in the duplication test developed by Newmeyer. Three other mutagen-sensitive mutants (upr-1, mus-8, and mus-10) do not increase chromosome instability. Previously three mutagen-sensitive mutants (uvs-3, uvs-6, and mei-3) were also shown to increase chromosome instability. The growth of all seven mutants that increase chromosome instability, is shown here to be more sensitive to hydroxyurea than that of wild type. Hydroxyurea, a compound which inhibits the enzyme ribonucleotide diphosphate reductase, is also shown to increase chromosome instability in the absence of any mutagen-sensitive mutation. These seven mutations are known to represent seven different genes in two epistasis groups. They have been shown previously to have four other properties in common: meiotic defects and sensitivity to gamma-rays, methyl methane sulfonate and the amino acid histidine. Their shared properties lead to the prediction here that all have reduced or altered deoxyribonucleotide pools.

Cell Division↗

Influence of cellular sequences on instability of plasmid integration sites in human cells.

To learn more about mechanisms of genome instability in human cells, I investigated DNA sequences that promote high rates of recombination by analyzing rare unstable plasmid integration sites in simian virus 40-transformed human fibroblasts. Previous studies had hypothesized that rearrangement or loss of integrated sequences could be attributed to adjacent cellular DNA. Consistent with this interpretation, a cloned fragment containing both the integrated plasmid and 2.0 kb of adjacent cell DNA from one such unstable integration site in the cell line LM205 demonstrated a much higher incidence of rearrangements when integrated into other chromosome locations than did the original plasmid. To further test this hypothesis, portions of cellular DNA from this region were integrated in duplicate in other locations to determine their ability to promote restriction-fragment-length polymorphism, an indicator of high rates of homologous recombination. Although two types of instability were observed, neither could be attributed solely to the cell sequences being tested in the plasmid. The first type of instability was a transient deletion or amplification of the plasmid DNA soon after integration, which appeared to be a general phenomenon often associated with any type of newly integrated sequence. A second type of instability continued indefinitely for many cell generations, as did that observed in cell line LM205. Because this was rare (one of 78 clones tested), it could not be attributed solely to cell sequences contained within the plasmid. However, the rearrangements in this cell clone occurred exclusively within the cell DNA adjacent to the integration site, again suggesting a role for cis-acting cell sequences in this process. The inability to identify specific cell sequences responsible for instability may therefore indicate that a complex combination of sequences is involved, possibly within both the plasmid and cell DNA.

Base Sequence↗

Assessment of microsatellite instability in a cell line from a patient with xeroderma pigmentosum variant.

Cells from patients with xeroderma pigmentosum (XP) variant are thought to be defective in postreplication repair. This DNA repair pathway is not well defined in human cells and the exact genetic defect of XP variant is unknown. In another cancer-prone hereditary disorder, hereditary nonpolyposis colon cancer, tumors are characterized by a DNA mismatch repair defect with microsatellite instability. Since there are some similarities between postreplication repair and mismatch repair, we investigated microsatellite instability, the hallmark of a DNA mismatch repair defect, in a lymphoblastoid cell line from a patient with XP variant. Two normal lines and one nucleotide excision repair-defective XP group A line were used as controls. In a host cell microsatellite instability assay, the recently developed shuttle vector pZCA29 was transfected into these cells and replicated plasmid recovered after 3 days. The plasmid contains two CA repeat tracts that interrupt the reading frame of the lacZ gene. Reversion to active beta-galactosidase, detectable by a color reaction of bacterial transformants, represents the frequency of frameshift mutations in the CA repeat tracts during replication of the plasmid, and thereby the host cells' microsatellite instability. We did not find any significant differences in the mutation frequencies of the plasmids after passage through either cell line. This indicates that there is no microsatellite instability in the examined XP variant cell line.

Cell Line↗

Herbivore effects on developmental instability and fecundity of holm oaks.

Plants are able to compensate for loss of tissue due to herbivores at a variety of spatial and temporal scales, masking detrimental effects of herbivory on plant fitness at these scales. The stressing effect of herbivory could also produce instability in the development of plant modules, and measures of such instability may reflect the fitness consequences of herbivory if instability is related to components of plant fitness. We analyse the relationships between herbivory, developmental instability and production of female flowers and fruits of holm oak Quercus ilex trees by means of herbivore removal experiments. Removal of leaf herbivores reduced herbivory rates at the tree level, but had no effect on mean production of female flowers or mature fruits, whereas herbivory tended to enhance flower production and had no effect on fruit abortion at the shoot level. Differences in herbivory levels between shoots of the same branch did not affect the size and fluctuating asymmetry of intact leaves. These results indicate compensation for herbivory at the tree level and over-compensation at the shoot level in terms of allocation of resources to female flower production. Removal of insect herbivores produced an increase in the mean developmental instability of leaves at the tree level in the year following the insecticide treatment, and there was a direct relationship between herbivory rates in the current year and leaf fluctuating asymmetry the following year irrespective of herbivore removal treatment. Finally, the production of pistillate flowers and fruits by trees was inversely related to the mean fluctuating asymmetry of leaves growing the same year. Leaf fluctuating asymmetry was thus an estimator of the stressing effects of herbivory on adult trees, an effect that was delayed to the following year. As leaf fluctuating asymmetry was also related to tree fecundity, asymmetry levels provided a sensitive measure of plant performance under conditions of compensatory responses to herbivory.

Animals↗

Quantitative measurement of electrical instability as a function of myocardial infarct size in the dog.

To investigate the relation between electrical instability and myocardial infarct size, 20 foxhounds were studied in the awake state 3 to 5 days after closed chest coronary occlusion. Programmed right ventricular stimulation was performed with use of an epicardial electrode. After six paced beats at 10 percent greater than control rate, single and then double extrastimuli were introduced, scanning from late diastole to ventricular refractoriness in steps of 10 to 20 ms. Abnormal responses observed after this provocation were repetitive ventricular response, unsustained ventricular tachycardia, sustained ventricular tachycardia and ventricular fibrillation. Scores for electrical instability were determined for each dog, with higher scores assigned for more hazardous tachyarrhythmias (ventricular fibrillation greater than sustained ventricular tachycardia greater than unsustained ventricular tachycardia greater than repetitive ventricular response) and for those provokable later in diastole. An electrical instability index derived from these scores correlated well with infarct size measured with tetrazolium staining (r = 0.94). When scores were given only for the type of abnormal response elicited, excluding the effect of diastolic timing and the number of extrastimuli or vice versa, there was no significant difference in correlation with infarct size (r = 0.85 versus 0.92). Thus the results demonstrate that inducible electrical instability early after infarction is directly related to infarct size. Further, these data demonstrate the usefulness of an electrical instability index derived from the results of programmed right ventricular stimulation in assessing the severity of ischemic damage to the heart.

Animals↗

Infrequent microsatellite instability during the evolution of myelodysplastic syndrome to acute myelocytic leukemia.

Microsatellites are highly polymorphic, short-tandem repeat sequences dispersed throughout the genome. Instability of these repeat sequences at multiple gentic loci may result from mismatch repair errors and occur in hereditary nonpolyposis colorectal cancer and several other sporadic cancers, including chronic myelocytic leukemia as it progresses to blastic crisis. We investigated whether genetic instability occurred as myelodysplasia progressed to acute myelocytic leukemia. To this end, we studied microsatellite instability in 20 patients with myelodysplastic syndrome (MDS). These included five patients with refractory anemia (RA), three with refractory anemia with ringed sideroblast (RARS), nine with refractory anemia with excess blasts (RAEB) and three with chronic myelomonocytic leukemia (CMML). All of these patients transformed to acute myelocytic leukemia (AML) of various subtypes: three patients with M1, 11 with M2 and six patients with M4 (according to FAB classification). The DNA from both the MDS and AML phases of their disease was analyzed at 16 loci, and only four microsatellite instabilities were found in the 240 paired samples (1.6%) analyzed. These results indicate that mismatch repair errors such as microsatellite instability are not important in the evolution of MDS to AML.

Adult↗

Microsatellite instability in gastric carcinoma with special references to histopathology and cancer stages.

To study the molecular mechanism of gastric carcinogenesis, the frequencies of microsatellite instability were evaluated with seven dinucleotide repeat loci in 59 patients with gastric carcinoma. Microsatellite instability at two or more loci was found in 41.5% (17/41) of advanced gastric carcinoma, 21.4% (3/14) of early gastric carcinoma, but not in remnant gastric carcinoma (0/4), with an overall frequency of 33.9% (20/59). Diffuse gastric carcinoma had a similar prevalence (32.1%, 9/28) to intestinal gastric carcinoma (40.7%, 11/27). The frequency of microsatellite instability in gastric carcinoma was not significantly different with respect to age, sex and Helicobacter pylori infection. Microsatellite instability tended to occur more frequently in cancers of the cardia (62.5%, 5/8) compared with cancers of other stomach regions (31.9%, 15/47), but the difference was not statistically significant. These data suggest that microsatellite instability occurs in early gastric carcinoma and its occurrence increases during tumour progression. Furthermore, its frequency was independent of age, gender, histological types and Helicobacter pylori infection.

Adenocarcinoma↗

High-level microsatellite instability is not involved in gallbladder carcinogenesis.

The molecular alterations involved in the pathogenesis of gallbladder cancer are not yet well defined. Our aim was to determine the microsatellite status of gallbladder carcinomas and its possible correlation with alterations in K-ras and p53 genes as well as the clinicopathological characteristics of these tumors. A group of 37 gallbladder carcinomas was analyzed for alterations in a proposed panel of mononucleotide and dinucleotide markers of microsatellite instability. Somatic frameshift mutations at repeated sequences in the coding regions of TGF-betaRII, Bax, hMSH3, hMSH6 were also examined. The findings were correlated with the presence of K-ras and p53 alterations, and tumors' clinicopathological features. Microsatellite instability and/or LOH was observed in 9 gallbladder carcinomas. Cases showing microsatellite instability displayed alterations only in dinucleotide markers and were classified as MSI-L carcinomas. A subset of gallbladder carcinomas is characterized by low-level instability, based on the analysis of the above mentioned panel of markers. The pathway of microsatellite instability seems to play a minor role in the pathogenesis of gallbladder cancer.

Adult↗

Loss of fragile histidine triad (FHIT) expression and microsatellite instability in periocular sebaceous gland carcinoma in patients with Muir-Torre syndrome.

PURPOSE: To report fragile histidine triad expression and microsatellite instability in periocular sebaceous gland carcinoma. DESIGN: Interventional case series. METHODS: Biopsy specimens of periocular sebaceous gland carcinoma obtained from six patients (mean age, 60 +/- 17 years; range, 38 to 83 years, 5 male, 1 female) with Muir-Torre syndrome and histopathologically proven sebaceous gland carcinoma were studied immunohistochemically for the presence of fragile histidine triad protein. Polymerase chain reaction-based analysis of the markers BAT25, BAT26, D2S123, D5S346, and D17S250 was performed for microsatellite instability in tumorous and matching normal tissues. RESULTS: Fragile histidine triad protein was detectable in the sebaceous gland carcinoma from one patient with microsatellite instability. It was not detectable in sebaceous gland carcinoma specimens from five patients without any evidence of microsatellite instability. CONCLUSION: Inactivation of fragile histidine triad tumor suppressor gene or inactivation of the mismatch-repair system resulting in microsatellite instability may contribute to the development of periocular sebaceous gland carcinoma in Muir-Torre syndrome.

Acid Anhydride Hydrolases↗

Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability.

The colorectum and uterine endometrium are the two most commonly affected organs in hereditary nonpolyposis colon cancer (HNPCC), but the genetic basis of organ selection is poorly understood. As tumorigenesis in HNPCC is driven by deficient DNA mismatch repair (MMR), we compared its typical consequence, instability at microsatellite sequences, in colorectal and endometrial cancers from patients with identical predisposing mutations in the MMR genes MLH1 or MSH2. Analysis of non-coding (BAT25, BAT26, and BAT40) and coding mononucleotide repeats (MSH6, MSH3, MLH3, BAX, IGF2R, TGF beta RII, and PTEN), as well as MLH1- and MSH2-linked dinucleotide repeats (D3S1611 and CA7) revealed significant differences, both quantitative and qualitative, between the two tumor types. Whereas colorectal cancers displayed a predominant pattern consisting of instability at the BAT loci (in 89% of tumors), TGF beta RII (73%), dinucleotide repeats (70%), MSH3 (43%), and BAX (30%), no such single pattern was discernible in endometrial cancers. Instead, the pattern was more heterogeneous and involved a lower proportion of unstable markers per tumor (mean 0.27 for endometrial cancers versus 0.45 for colorectal cancers, P < 0.001) and shorter allelic shifts for BAT markers (average 5.1 bp for unstable endometrial cancers versus 9.3 bp for colorectal cancers, P < 0.001). Among the individual putative "target" loci, PTEN instability was associated with endometrial cancers and TGF beta RII instability with colon cancers. The different instability profiles in endometrial and colorectal cancers despite identical genetic predisposition underlines organ-specific differences that may be important determinants of the HNPCC tumor spectrum.

Adaptor Proteins, Signal Transducing↗

Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis.

Colorectal cancers with high-frequency microsatellite instability show peculiar clinicopathological features and a favorable clinical outcome. We investigated whether the improved prognosis for these cancers is related to the content of activated cytotoxic intraepithelial T lymphocytes. Microsatellite instability and the amount of activated cytotoxic lymphocytes were analyzed according to clinicopathological features, survival, and disease recurrence in 109 right-sided colon carcinomas from 245 consecutive patients with stage II/III colon cancer that underwent radical surgery. High-frequency microsatellite instability was found in 43% of stage II/III proximal colon cancers and was associated with significantly higher numbers of activated cytotoxic lymphocytes. High-frequency microsatellite instability, as well as the content of intratumoral-activated cytotoxic T lymphocytes correlated with improved overall and disease-free survival, particularly in patients with stage III tumors. Multivariate analysis revealed that patients with both features had a risk of death and relapse markedly lower than that associated with microsatellite status or intratumoral cytotoxic lymphocytes separately. The presence of local cytotoxic immune responses is probably the major determinant of the good clinical course of patients with microsatellite unstable colon cancer. Furthermore, high-frequency microsatellite instability coupled with a high content of intratumoral cytotoxic lymphocytes may identify a subset of colon cancer patients with a favorable clinical outcome, particularly in stage III disease.

Aged↗

BAT-26 and BAT-40 instability in colorectal adenomas and carcinomas and germline polymorphisms.

Analysis of the mononucleotide repeats BAT-26 and BAT-40 has reportedly revealed significant microsatellite instability in sporadic colorectal adenomas, whereas studies with dinucleotide and tetranucleotide repeats have not. In addition, BAT-26 has been reported to be "quasimonomorphic" in the germline. We evaluated BAT-26 and BAT-40 in a series of colorectal tumors previously analyzed with a panel of tetranucleotide repeats. Instability in BAT-26 or BAT-40 was significantly associated with tetranucleotide repeat instability in sporadic adenomas and carcinomas (P < 0.0001) and was similarly much less common in adenomas than in carcinomas. Germline polymorphisms in both BAT-40 and BAT-26 were identified, and the frequency of BAT-26 polymorphisms was significantly higher in African Americans than in Caucasians (7.7% versus 0.08%, P < 0.001). BAT-26 and BAT-40 may be very useful in evaluating instability in small tumors, as sufficient DNA to be amplified by large panels of microsatellites is not always available from such lesions. Polymorphisms in these microsatellites, however, limit their utility in determinations of microsatellite instability without corresponding normal DNA.

3-Hydroxysteroid Dehydrogenases↗

Giggle incontinence in children: a manifestation of detrusor instability.

PURPOSE: To our knowledge the prevalence and cause of giggle incontinence in children is not known. We hypothesized that laughter may induce unstable detrusor contractions in children susceptible to detrusor instability. We evaluated the prevalence of diurnal voiding symptoms of urinary urgency, urge incontinence, pelvic withholding maneuvers and hesitancy in patients with giggle incontinence, the prevalence of giggle incontinence in patients with diurnal voiding symptoms, the prevalence of the 2 conditions in first degree relatives of patients with giggle incontinence, the influence of treatment for detrusor instability on the frequency of giggle incontinence and the prevalence of diurnal voiding symptoms in control children with giggle incontinence. MATERIALS AND METHODS: Of 1,421 children 5 to 15 years old referred to the pediatric nephrology department for various problems 109 were diagnosed with giggle incontinence and 460 had diurnal voiding symptoms. A total of 627 children visiting the pediatrician office whose parents completed a survey questionnaire served as controls. RESULTS: Diurnal voiding symptoms were noted in 95% of the patients with giggle incontinence, while giggle incontinence was noted in 23% of those with diurnal voiding symptoms. Of the patients with giggle incontinence a positive family history for that entity and diurnal voiding symptoms was noted in 13% and 28%, respectively. Giggle incontinence improved in all patients after treatment for detrusor instability and it resolved completely in 89%. Giggle incontinence recurred with a relapse of diurnal voiding symptoms in 28 cases and improved with improved diurnal voiding symptoms during modification of therapy. Diurnal voiding symptoms were present in 43% of the 157 controls with giggle incontinence. CONCLUSIONS: Giggle incontinence results from detrusor instability induced by laughter and it improves with effective treatment of detrusor instability.

Adolescent↗

Methods for registration of spontaneous DNA instability in mammalian cells.

A phenomenon of spontaneous DNA instability displays itself as the low level of repair DNA synthesis that takes place during any cell cycle phases. However, there is a problem in detection of very low intensive repair DNA synthesis. This paper suggests two approaches to detect the spontaneous DNA instability. The first method involves a blockade of the DNA gaps sealing by a combination of inhibitors, hydroxyurea and arabinofuranosyl cytosine. An accumulation of single strand gaps leads to production of DNA double strand breaks and results to reproductive inactivation of cells. It was shown that registration of both these events by different methods (such as viscoelastometry of DNA, orthogonal pulse electrophoresis or comet assay for double strand breaks as well as effectiveness of colony growth for cell inactivation) may be used as suitable measure of the spontaneous DNA instability. The second approach bases on photolysis of bromodeoxyuridine incorporated into repair DNA patches during the spontaneous repair DNA synthesis. Long wave UV irradiation of cells containing bromodeoxyuridine labeled DNA stained with Hoechst 33342 causes their inactivation. Experimental results presented confirm that both methods actually detect the spontaneous DNA instability. It takes note of the spontaneous DNA instability varies for cells from different tissues and species and increases during aging.

Benzimidazoles↗

Radiation induced chromosomal instability in human T-lymphocytes.

Chromosomal instability in proliferating mammalian cells is characterized by a persistent increase of chromosomal aberrations and rearrangements occurring de novo during successive cell generations. Recent results from many laboratories using a variety of cells and cytogenetic end points show that this phenotype can be induced by low as well as high LET irradiation. A typical feature of chromosomal instability in primary human G0-lymphocytes exposed to gamma-irradiation at both high dose rate (45 Gy h-1) and low dose rate (0.024 Gy h-1) is the appearance of novel aberrations in the clonal progeny of the irradiated cell, many generations after the exposure. The same phenotype was observed in lymphocytes that were allowed to recover for 5 days in G0 after the radiation exposure, as well as in hprt-mutant T cell clones. These results demonstrate that neither the acute genotoxic stress caused by high dose rate as compared to low dose rate irradiation, nor a hypothesized conflict between mitogen induced growth stimulation and growth arrest due to radiation damage, seem to be critical conditions for the development chromosomal instability in these cells. In contrast to observations in other cells, no evidence of a persistent decrease of cloning ability was observed in the progeny of radiation-exposed human lymphocytes, and no alteration was observed in their sensitivity to a second radiation exposure. Furthermore, the frequency of CA-repeat length variation at three loci was not increased in the progeny of X-irradiated T cells as compared to non-irradiated cells, which indicates that microsatellite instability is not part of the chromosomal instability phenotype in human T-lymphocytes.

Chromosome Aberrations↗

Microsatellite instability induced by hydrogen peroxide in Escherichia coli.

Damage to DNA by reactive oxygen species may be a significant source of endogenous mutagenesis in aerobic organisms. Using a selective assay for microsatellite instability in E. coli, we have asked whether endogenous oxidative mutagenesis can contribute to genetic instability. Instability of repetitive sequences, both in intronic sequences and within coding regions, is a hallmark of genetic instability in human cancers. We demonstrate that exposure of E. coli to low levels of hydrogen peroxide increases the frequency of expansions and deletions within dinucleotide repetitive sequences. Sequencing of the repetitive sequences and flanking non-repetitive regions in mutant clones demonstrated the high specificity for alterations with the repeats. All of the 183 mutants sequenced displayed frameshift alterations within the microsatellite repeats, and no base substitutions or frameshift mutations occurred within the flanking non-repetitive sequences. We hypothesize that endogenous oxidative damage to DNA can increase the frequency of strand slippage intermediates occurring during DNA replication or repair synthesis, and contribute to genomic instability.

Catalase↗