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PubMed1975

Lateral knee compartment osseous pseudoligamentous instability.

Five occurrences of intra-articular lateral knee compartment osseous pseudoligamentous instability associated with three cases of fractures of the posterior lateral femoral condyle are reported. The instability being located within the knee joint region was termed false in that it was due to fracture instability rather than the usual ligamentous, or true, instability. The main clinical diagnostic guide to this type of instability was a positive manual straight-knee adduction snap-click test that consisted of an initial snap followed in sequence by a click on release of adduction. The positive adduction snap-click test is an adjunct to the roentgenographic recognition of lateral knee compartment osseous pseudoligamentous instability.

Adult↗
PubMed1999

Inherited and inducible chromosomal instability: a fragile bridge between genome integrity mechanisms and tumourigenesis.

Cancer is a multi-step process evolving as the result of the accumulation of a number of mutational events. The growing body of evidence implicating genetic instability as a key feature of this evolutionary process and the risk of malignancy associated with chromosomal instability syndromes highlight the importance of understanding the mechanisms that cells use to maintain the integrity of their genomes. Classic examples of inherited chromosomal instability with cancer predisposition are Bloom's syndrome, ataxia telangiectasia, and Fanconi anaemia, although the mechanisms involved are far from understood. Selected features of these inherited disorders are reviewed to provide a background to the more recently discovered inducible chromosomal instability, a phenotype in which apparently normal cells that have survived ionizing radiation and certain chemical insults may produce descendants exhibiting a high frequency of de novo chromosome aberrations and gene mutations. The phenotype is induced at frequencies considerably greater than conventional mutation frequencies but little is understood of the underlying mechanism(s). To date, chromosomal instability induced by ionizing radiation has been the most extensively studied phenotype and it is evident that the expression of inducible instability has a strong dependence on the type of radiation exposure, the cell type irradiated, and the genetic 'predisposition' of the irradiated cell.

Animals↗
PubMed1996

Analysis for microsatellite instability and mutations of the DNA mismatch repair gene hMLH1 in familial gastric cancer.

We examined 30 gastric-cancer patients with a varying degree of family history of stomach cancer and/or synchronous gastric tumors for microsatellite instability. We observed microsatellite instability at at least 1 of 8 loci tested in tumors of 14/30 patients; of these 14, 8 had single locus alterations and 6 had alterations at at least half of the 8 loci. Among the patients with microsatellite instability at > or = 4 loci, 3 patients showed a strong familial clustering of gastric cancer. Mutation analysis of the DNA mismatch repair gene hMLHl on paired non-tumorous and tumor DNA from 10 patients, 6 with microsatellite instability at > or = 4 loci and 4 with an alteration at one locus, revealed a novel missense mutation, present in the normal and tumor DNA of one patient with microsatellite instability at multiple loci in his tumor. His family history of cancer included one second-degree relative affected with gastric cancer. These data suggest that germline mutations in the hMLHl gene occur in some gastric-cancer patients and that in the majority of cases microsatellite instability in gastric tumors may be due to defects in other genes responsible for DNA replication fidelity than the hMLHl.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Rare alleles at different VNTR loci among lung-cancer patients with microsatellite instability in tumours.

Work in our laboratory has shown a significantly higher frequency of microsatellite mutations in tumours from lung-cancer patients with rare alleles at the HrasI VNTR locus compared with those with common alleles. In 137 lung-cancer patients, the association between microsatellite instability and rare alleles at the HrasI VNTR locus was confirmed with 17 microsatellite markers. We found a significant association between LOH in lung tumours of marker D3s966 with microsatellite instability. In samples with LOH at marker D3s966 (3p21.3) 22% of loci tested showed instability, whereas 8% showed instability without LOH at D3s966. To investigate whether rare alleles at the HrasI locus are linked to rare alleles at other loci, a second minisatellite (D17S4) was genotyped. In a population of 406, 4 individuals with D 17S4 rare alleles were detected of whom 3 also had rare alleles at the HrasI VNTR locus. The probability of this association to occur by chance is low. Thus, rare alleles at the HrasI locus may be associated with rare alleles at other loci, and could be an indication of germline instability. The findings indicate that microsatellite instability in lung tumours is not strictly associated with features in the HrasI proto-oncogene, but may be the result of the same mechanism(s) that generate(s) new alleles at the HrasI and D17S4 loci.

Alleles↗
PubMed1990

The role of recombinational hotspots in genome instability in mammalian cells.

Genome instability has been associated with progression of transformed cells to high tumorigenicity. Although genome instability may result from a variety of factors, some studies suggest that DNA in the region of a chromosome rearrangement can subsequently have much higher rates of DNA deletions or gene amplification. One approach to studying the factors that produce these high rates of DNA rearrangement is by analysis of unstable integration sites for DNA transfected into mammalian cells. Integrated sequences commonly show a temporary instability, and at rare locations this instability is continuous and can be observed even after multiple subclonings. These continuously unstable locations undergo DNA amplification of both the integrated sequences and the surrounding cell DNA, and it can occur either at the original site or on episomes after looping out from the chromosome. Because the adjacent cell DNA plays a role in this instability, and the region can be shown to be stable before integration, the results indicate that these recombinational hotspots can be formed de novo by the process of integration. Current studies are attempting to determine which sequences are responsible for the high rates of recombination and whether similar types of event are involved in the instability associated with endogenous cellular genes in cancer cells.

Animals↗
PubMed2002

Aberrant expression of cell-cycle regulator cyclin D1 in breast cancer is related to chromosomal genomic instability.

To account for the accumulation of genomic alterations required for tumor progression, it has been suggested that the genomes of cancer cells are unstable and that this instability results from defective mutators (the "mutator phenotype" theory). To examine the hypothesis that abnormal cell-cycle regulators act as the mutators contributing to genomic instability, the present study, based on primary tumor tissues from 71 patients with breast cancer, was performed to determine whether there was an association between aberrant expression of cell-cycle regulators (cyclin A, cyclin D1, cyclin E, RB1, p21, and p27) and chromosomal instability. Comparative genomic hybridization was used to measure chromosomal changes, reflecting genomic instability in individual tumors, whereas immunohistochemistry was used to detect aberrant expression of cell-cycle regulators. Overexpression of cyclin D1 was found to be significantly correlated with increased chromosomal instability (defined as harboring more than 7 chromosomal changes), with 63% of tumors overexpressing and 27% of tumors not overexpressing, with cyclin D1 showing chromosomal instability (P < 0.05). Interestingly, this relationship was independent of cell outgrowth (as detected by the proliferation marker Ki-67) and was particularly significant in tumors not expressing p27 or in tumors with detectable RB1. These results suggest that cyclin D1 plays an alternative role in the regulation of genomic stability.

Adult↗
PubMed2002

Prognostic implications of BAX and TGFBRII mutations in colon cancers with microsatellite instability.

Microsatellite instability in sporadic colon cancer is associated with an improved prognosis. Recent studies, however, have suggested that microsatellite unstable cancers with mutations in the proapoptotic gene BAX have a relatively poor prognosis, whereas those with mutations in transforming growth factor-beta receptor type II (TGFBRII) have a relatively good prognosis. Using instability in the non-coding mononucleotide repeat BAT-26 as a measure of generalized microsatellite instability, we evaluated the prognosis of unstable colon cancers with and without frameshift mutations in the coding mononucleotide repeats of BAX and TGFBRII in a population-based sample of 1,427 individuals. BAX mutations were identified in 39.0% (64/164) of unstable colon cancers, whereas TGFBRII mutations were identified in 79.3% (138/174) of unstable colon cancers. Unstable colon cancers with and without instability in BAX and TGFBRII were associated with very similar and statistically indistinguishable percentage 5-year survivals and Kaplan-Meier survival curves; stable colon cancers were associated with a significantly worse 5-year survival and Kaplan-Meier survival (P < 0.001 and P < 0.013, respectively, compared against BAT-26 unstable). The age- and stage-adjusted risk of death associated with BAX or TGFBRII mutations was not significantly different from that of unstable tumors without such mutations. We conclude that instability-induced mutations in BAX or TGFBRII do not have a significant impact on the good prognosis of colon cancers with microsatellite instability.

Colonic Neoplasms↗
PubMed2001

Age-dependent and tissue-specific CAG repeat instability occurs in mouse knock-in for a mutant Huntington's disease gene.

Huntington's disease (HD) is a neurodegenerative disorder characterized by the expansion of CAG repeats in exon 1 of the HD gene. To clarify the instability of expanded CAG repeats in HD patients, an HD model mouse has been generated by gene replacement with human exon 1 of the HD gene with expansion to 77 CAG repeats. Chimeric proteins composed of human mutated exon 1 and mouse huntingtin are expressed ubiquitously in brain and peripheral tissues. One or two CAG repeat expansion was found in litters from paternal transmission, whereas contraction of CAG repeat in litters was observed through maternal transmission. Elderly mice show greater CAG repeat instability than younger mice, and a unique case was observed of an expanded 97 CAG repeat mouse. Somatic CAG repeat instability is particularly pronounced in the liver, kidney, stomach, and brain but not in the cerebellum of 100-week-old mice. The same results of expanded CAG repeat instability as observed in this HD model mouse were confirmed in the human brain of HD patients. Glial fibrillary acidic protein (GFAP)-positive cells have been found to be increased in the substantia nigra (SN), globus pallidus (GP), and striatum (St) in the brains of 40-week-old affected mice, although without neuronal cell death. The CAG repeat instability and increase in GFAP-positive cells in this mouse model appear to mirror the abnormalities in HD patients. The HD model mouse may therefore have advantages for investigations of molecular mechanisms underlying instability of CAG repeats.

Age Factors↗
PubMed2001

Instability of chromosome 8 as an indicator of aggressive tumor phenotype in pancreatic cancer.

BACKGROUND AND OBJECTIVES: Chromosomal instability is a common feature of pancreatic carcinoma, but its biological significance remains unclear. In this study, we investigated the association between chromosomal instability and biological aggressiveness in human pancreatic cancer cells. METHODS: Fluorescence in situ hybridization was performed to examine changes in chromosomal numbers in a total of 13 pancreatic cancer cell lines. We also assessed the potential for tumor aggressiveness within cancer cells by in vitro migration and invasion assay and by subcutaneous implantation into nude mice. RESULTS: Chromosomal instability, characterized by numerical variations in copy numbers of chromosome 8, was observed in most cell lines, and the magnitude of instability was correlated well with both motility (P < 0.001) and invasion rate (P < 0.001) of these cells. Furthermore, a significant positive correlation existed between chromosome instability and tumor growth in vivo (P < 0.01). CONCLUSIONS: These results suggest that the increased level of chromosomal instability may play a critical role in the development of aggressive tumor phenotype during pancreatic cancer progression. J. Surg. Oncol. 2001;76:181-187.

Animals↗
PubMed1996

Microsatellite instability and mutations of p53 and TGF-beta RII genes in gastric cancer.

To investigate the molecular mechanism of gastric carcinogenesis, we analyzed genetic instability and p53 gene mutations in 40 primary gastric carcinomas. Tumor samples were from untreated patients with no family history suggestive of genetic predisposition to cancer. We screened six microsatellite loci by the polymerase chain reaction (PCR) method, and exons 5-8 of the p53 gene by the PCR-based denaturing gradient gel electrophoresis and sequencing techniques. Microsatellite instability was detected in 32.5% (13/40), and gene mutations in 40% (16/40), of the tumors analyzed. No statistically significant associations were found between genetic alterations and clinico-pathological variables (with the exception of diffusion of lymph node metastases, which was inversely associated with the presence of microsatellite alterations; P < 0.01). Interestingly, a negative association was found between genetic instability and p53 gene mutations: 11 out of 13 tumors showing instability proved to carry a nonmutated p53 gene versus 2/13 carrying a mutated gene (P = 0.03). These observations suggest that genetic instability and p53 gene mutations play a crucial role in the gastric carcinogenic process, but likely act through distinct pathways during cancer development. However, genetic instability is not in and of itself neoplastic. Therefore, we investigated whether insertion/deletion mutations of the polyadenine tract within the transforming growth factor-beta type II receptor gene (TGF-beta RII) were frequently present in gastric tumors with an RER+ (replication error) phenotype. We found RII mutations in 8/40 (20%) samples: mutations were present in 7/13 (54%) RER+ tumors versus 1/27 (4%) RER- cases (P < 0.001).

DNA Mutational Analysis↗
PubMed2004

Association between recurrence of sporadic colorectal cancer, high level of microsatellite instability, and loss of heterozygosity at chromosome 18q.

PURPOSE: Microsatellite instability and loss of heterozygosity of chromosomes 18q, 8p, and 4p are genetic alterations commonly found in colorectal cancer. We investigated whether these genetic markers allow for the stratification of patients with Stage II to III colorectal cancer into groups with different recurrence risks, and with different prognoses. METHODS: Tumors of 113 patients were evaluated for loss of heterozygosity of chromosomes 18q, 8p, and 4p and for microsatellite instability by use of six microsatellite markers. Genetic alterations involving each of these genetic markers were examined for association with disease recurrences and survival. RESULTS: Loss of heterozygosity of chromosomes 18q, informative in 96 percent of cases, in Stage III tumors was associated with higher risk of overall recurrence ( P< 0.001), local recurrence ( P< 0.001), distant metastases ( P< 0.001), decreased overall survival ( P= 0.002), and disease-free survival ( P< 0.001). The recurrence rates and survival rates among patients with Stage II colorectal cancer were independent of loss of heterozygosity of chromosome 18q. Stage III and loss of heterozygosity of chromosome 8p also were associated with a higher risk of recurrences when these factors were considered individually. In multivariate analysis, only loss of heterozygosity of chromosome 18q was independently associated with risk of recurrences ( P < 0.001) and with disease-free survival ( P= 0.001). No correlation was observed between microsatellite instability and recurrence rates. However, microsatellite instability was associated with improved overall survival ( P= 0.04) and with a longer disease-free interval ( P= 0.002). Only in five cases (16.7 percent) was it possible to perform resection of recurrences; two of these patients had microsatellite instability tumor. In no cases was it possible to resect recurrence of tumors with loss of heterozygosity of chromosome 18q. CONCLUSIONS: Loss of heterozygosity of chromosome 18q is an informative genetic marker, which in resected Stage III colorectal cancer can be used to predict recurrences and survival. Microsatellite instability identified cases that, even in the case of recurrence, have a more favorable prognosis.

Aged↗
PubMed2006

Family instability and child maladjustment trajectories during elementary school.

This study examines the relation between family instability and child maladjustment over a 6-year period in 369 children from four communities. Measures were collected annually from kindergarten through fifth grade. In associative growth curve models, family instability trajectories predicted children's externalizing and internalizing behavior trajectories during this time period. High levels of family instability also incrementally predicted the likelihood of meeting criteria for a DSM IV diagnosis during elementary school, above and beyond prediction from earlier measures of maladjustment. However, the timing of family instability had a different effect on externalizing versus internalizing disorders. In general, stronger relations were found between family instability and externalizing behaviors relative to internalizing behaviors, although children with comorbid disorders experienced the highest levels of family instability.

Adaptation, Psychological↗
PubMed1995

Genetic instability associated with adenoma to carcinoma progression in hereditary nonpolyposis colon cancer.

BACKGROUND & AIMS: Genetic instability related to defective DNA mismatch repair genes may be involved in the pathogenesis of carcinoma in hereditary nonpolyposis colon cancer (HNPCC). However, nonneoplastic tissues from patients inheriting defects in human MSH2 or human MLH1 do not show significant genetic instability. The aim of this study was to determine whether acquisition of genetic instability at the adenoma stage promotes malignant transformation by studying adenoma-carcinoma progression in HNPCC. METHODS: Dinucleotide repeat loci were analyzed by polymerase chain reaction from microdissected adenoma and/or carcinoma stages from formalin-fixed paraffin-embedded HNPCC tumors. RESULTS: Although genetic instability was observed at some loci in almost all cases, the proportion of microsatellite loci altered was significantly less (P < 0.01) in completely benign adenomas (24%) than in benign areas of adenomas with malignancy (54%). Molecular fingerprints indicated intratumor heterogeneity, with evolution of related subclones of neoplastic cells. However, in all cases of tumor progression, at least one subclone from the adenoma stage was closely related to the carcinoma. CONCLUSIONS: Some genetic instability develops at the benign adenoma stage in most HNPCC tumors. Adenomas with a greater rate of genetic instability are more likely to progress to carcinoma. Topographic genotyping data provides evidence supporting the hypothesis of adenoma-carcinoma progression in HNPCC.

Adenoma↗
PubMed2005

Orthostatic instability in a population-based study of chronic fatigue syndrome.

PURPOSE: Autonomic nervous system dysfunction has been suggested as involved in the pathophysiology of chronic fatigue syndrome. This population-based case control study addressed the potential association between orthostatic instability (one sign of dysautonomia) and chronic fatigue syndrome. SUBJECTS AND METHODS: Fifty-eight subjects who fulfilled criteria of the 1994 chronic fatigue syndrome research case definition and 55 healthy controls participated in a 2-day inpatient evaluation. Subjects had been identified during a 4-year population-based chronic fatigue syndrome surveillance study in Wichita, Kan. The present study evaluated subjects' current medical and psychiatric status, reviewed past medical/psychiatric history and medication use, used a stand-up test to screen for orthostatic instability, and conducted a head-up tilt table test to diagnose orthostatic instability. RESULTS: No one manifested orthostatic instability in the stand-up test. The head-up tilt test elicited orthostatic instability in 30% of eligible chronic fatigue syndrome subjects (all with postural orthostatic tachycardia) and 48% of controls (50% with neurally mediated hypotension); intolerance was present in only nonfatigued (n=7) subjects. Neither fatigue nor illness severity were associated with outcome. CONCLUSIONS: Orthostatic instability was similar in persons with chronic fatigue syndrome and nonfatigued controls subjects recruited from the general Wichita population. Delayed responses to head-up tilt tests were common and may reflect hydration status. These findings suggest reappraisal of primary dysautonomia as a factor in the pathogenesis of chronic fatigue syndrome.

Adolescent↗
PubMed1999

Genomic instability is an early event during the progression pathway of ulcerative-colitis-related neoplasia.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon associated with a high risk of colorectal cancer. This increased cancer risk is thought to result from the cellular damage induced by the inflammatory field. The aim of this study was to determine the pattern and time course of genomic instability occurring in UC-related neoplasia. Sites of cancer, dysplasia, and nondysplasia from 14 UC colectomy cases containing cancer were analyzed for chromosomal alterations by comparative genomic hybridization (CGH) and for microsatellite instability using a series of 10 microsatellite markers. Clonal chromosomal alterations were present in 85% of cancer sites, 86% of dysplasia sites, and 36% of nondysplasia sites. Losses of chromosome 18 or 18q and chromosome 5 or 5q were common in cancer and dysplasia and were occasionally detected in nondysplasia. High-level microsatellite instability was detected in the cancer and dysplasia of two cases. Samples that demonstrated high-level microsatellite instability were unlikely to have chromosomal alterations demonstrable by CGH. These studies suggest that the predominant type of genomic instability in UC-related neoplasia is associated with chromosomal alterations and that this type of genomic instability frequently occurs before the development of histologically defined dysplasia.

Adult↗
PubMed2001

Phase 2 prolongation, in the absence of instability and triangulation, antagonizes class III proarrhythmia.

OBJECTIVE: To evaluate whether prolongation of the plateau of the action potential duration, in the absence of instability and triangulation, can reverse the proarrhythmia elicited by a class III antiarrhythmic agent. METHODS: The effects of almokalant, erythromycin and their combination, on cardiac electrophysiological parameters (action potential duration (APD), instability, triangulation and ectopics) were evaluated in isolated hearts from female albino rabbits. In this study, proarrhythmia was estimated quantitatively by number of ectopic beats. RESULTS: Erythromycin lengthened the APD primarily by a prolongation of the plateau, while having only minor effects upon phase 3 repolarization. The prolongation did not induce much instability, triangulation or reverse use dependence and, as expected, erythromycin did not induce significant proarrhythmia. Almokalant also lengthened APD, but it did not lengthen the plateau; instead, it prolonged phase 3 repolarization. The prolongation markedly triangulated the action potential, elicited much instability and marked reverse use dependence. This combination of effects induced very marked proarrhythmia. When almokalant and erythromycin were combined, their effects upon APD appeared additive: both the plateau and the repolarization phase were prolonged. However, the larger prolongation of APD did not lead to more proarrhythmia; this suggests that a prolongation of APD is not proarrhythmic per se. On the contrary, proarrhythmia as a function of APD prolongation was reduced in the presence of erythromycin (P<0.05). CONCLUSION: Instability plus triangulation consistently lead to serious proarrhythmia especially when combined with reverse use dependence, but prolongation of APD in itself is not necessarily proarrhythmic. In fact, APD prolongation in the absence of instability and triangulation can be antiarrhythmic.

Action Potentials↗
PubMed2002

Urethral sphincter morphology in women with detrusor instability.

OBJECTIVE: To determine whether sonographic urethral sphincter morphology is different in patients with detrusor instability than in those with normal urodynamic testing. METHODS: Patients from a population of women presenting for evaluation of urinary incontinence or pelvic organ prolapse underwent intraurethral ultrasonography before multichannel urodynamic testing. Maximal rhabdosphincter thickness, total urethral diameter, total urethral circumference, and longitudinal smooth muscle thickness, diameter, and circumference were measured. For patients with detrusor instability, the strength of the involuntary detrusor contraction and the bladder volume at its onset were recorded. These data were compared with information from history questionnaires and urodynamic evaluations. RESULTS: The 17 patients with detrusor instability and 16 patients with normal urodynamic testing did not differ with respect to age, vaginal parity, race, weight, body mass index, prior continence surgery, or maximal total urethral closure pressure. Patients with detrusor instability, had decreased urethral longitudinal smooth muscle thickness (3.0 +/- 0.9 mm vs 4.1 +/- 0.7 mm, P =.001), total urethral diameter (18.0 +/- 1.6 mm vs 19.4 +/- 1.4 mm, P =.01), and total urethral circumference (5.65 +/- 0.5 cm vs 6.1 +/- 0.4 cm, P =.012) compared with those with normal urodynamic tests. A linear relationship between rhabdosphincter thickness and strength of involuntary detrusor contraction was observed (r =.686, P =.002). CONCLUSION: Urethral sphincter morphology is different in patients with detrusor instability compared with those who have normal urodynamic tests. These findings provide an anatomic basis for the physiologic findings in patients with "urethrogenic" detrusor instability.

Adult↗
PubMed1998

Evaluation and treatment of clinical instability associated with pseudoarthrosis after anterior cervical surgery for ossification of the posterior longitudinal ligament.

BACKGROUND: Between 1989 to 1993, clinical instability associated with pseudarthrosis was evaluated in 76 patients with cervical ossification of the posterior longitudinal ligament (OPLL). Average 2.5 level extended anterior diskectomy and fusion and average 3.0 level anterior corpectomy and fusion were performed without anterior plate instrumentation using iliac crest or fibular strut autografts. METHODS: Fusion versus pseudarthrosis resulting in clinical instability, as defined by White and Panjabi, was assessed using flexion and extension X-rays 3 and 6 months post-operatively. Radiographic instability was defined by > 3.5 mm. of sagittal plane translation (or 20%) and > 20 degrees of sagittal plane rotation on dynamic X-rays. Two and 3 dimensional (D) computed tomography (CT) scans, also obtained 3 months postoperatively, either confirmed fusion or indicated failed bony union. The average clinical follow up period was 3 years (range, 25-52 months). RESULTS: Three months postoperatively, dynamic X-rays in 20 patients demonstrated radiographic instability consistent with pseudarthrosis, whereas 2 and 3D CT studies indicated a lack of fusion. At 6 months, flexion and extension X-rays revealed that 10 patients were fused and that another 7 were clinically stable despite persistent, irregular, linear lucencies at graft/body interfaces. Three (4%) patients with clinical instability associated with pseudarthrosis required secondary posterior wiring and fusion. CONCLUSION: Only 4% of patients undergoing average 2.75 level anterior OPLL surgery without anterior plate instrumentation required secondary posterior wiring and fusion for clinical instability associated with pseudarthrosis.

Aged↗