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PubMed1996

Intergenerational instability of the CAG repeat of the gene for Machado-Joseph disease (MJD1) is affected by the genotype of the normal chromosome: implications for the molecular mechanisms of the instability of the CAG repeat.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by unstable expansion of a CAG repeat in the MJD1 gene at 14q32.1. To identify elements affecting the intergenerational instability of the CAG repeat, we investigated whether the CGG/GGG polymorphism at the 3' end of the CAG repeat affects intergenerational instability of the CAG repeat. The [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes were found to result in significantly greater instability of the CAG repeat compared to the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)nGGG]/[normal (CAG)n-GGG] haplotypes. Multiple stepwise logistic regression analysis revealed that the relative risk for a large intergenerational change in the number of CAG repeat units (< -2 or > 2) is 7.7-fold (95% CI: 2.5-23.9) higher in the case of paternal transmission than in that of maternal transmission and 7.4-fold (95% CI: 2.4-23.3) higher in the case of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes than in that of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The combination of paternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes resulted in a 75.2-fold (95% CI: 9.0-625.0) increase in the relative risk compared with that of maternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The results suggest that an inter-allelic interaction is involved in the intergenerational instability of the expanded CAG repeat.

Chromosomes, Human, Pair 14↗
PubMed1981

Anterolateral rotational instability in the ankle joint. An experimental study of anterolateral rotational instability, talar tilt, and anterior drawer sign in relation to injuries to the lateral ligaments.

In seven amputated legs the ankle region was dissected free, and anterolateral rotational instability, talar tilt, and anterior drawer sign in the talocrural joint were studied in relation to varying degrees of injury to the lateral ligaments of the ankle and in relation to various positions of the foot. This revealed a good correlation between the degree of ligamentous injury and the degree of the three different types of instability. Anterolateral rotational instability was maximal when the investigation was performed with the ankle joint in the plantar flexion, whereas the talar tilt was more pronounced with the ankle joint in the neutral position and the anterior drawer sign most distinct when the ankle joint was in dorsal flexion. Compared with the other two signs, the anterior drawer sign proved to be a relatively inconstant type of instability.

Ankle Joint↗
PubMed2000

Frequent chromosomal instability but no microsatellite instability in hepatocellular carcinomas.

Microsatellite instability (MSI) phenotype, caused by a deficiency of DNA mismatch repair genes, has been detected in a subset of tumors in the gastrointestinal tract. However, it is not clear how MSI is involved in the tumorigenesis of hepatocellular carcinomas (HCC). Results with HCC are controversial, with positive results published with American and European tumors, but negative with Japanese tumors. We report the absence of MSI in 39 Korean HCCs after analysis with 6 mononucleotide- and over 150 dinucleotide-repeat markers. Only one such dinucleotide-repeat (D2S213) exhibited a reproducible shift in mobility, representing a somatic mutation present in only some of the tumor cells. This may be the result of a spontaneous error of replication due to the intrinsic mutability of these unstable sequences and without any connection to true genomic instability. In support of this interpretation, no frameshift mutations were found at the coding repeats of target genes for the microsatellite mutator phenotype including TGF-betaRII, BAX, hMSH3, and hMSH6. In contrast, we observed frequent allelic losses on chromosomes 4q, 8p, 16q, and 17p by the analysis of dinucleotide repeats (microallelotyping), reflecting a high degree of tumor chromosomal instability, which was significantly associated to the tumor differentiation (p=0.036, Fisher's exact test). These results suggest that, unlike chromosomal instability, widespread MSI plays no role in the development or progression of HCC.

Adolescent↗
PubMed2002

Is There a Link Between Chronic Ankle Instability and Postural Instability?

OBJECTIVE: To provide clinicians and researchers with an expanded perspective on the association between functional ankle instability and postural control. DATA SOURCES: I searched MEDLINE and SPORT Discus for the years 1966-2001 using the key words ankle, instability, and balance. Additional information was obtained from cross-referencing pertinent articles. DATA SYNTHESIS: Conflicting reports have been published about whether postural control is disrupted in people with chronic ankle instability. The variety of testing methods and operational definitions used by various investigators make drawing a consensus difficult. In contrast, the results of investigations considering postural-control strategy disruptions in persons with chronic ankle instability have been compatible. Depending upon the effectiveness of an altered strategy, postural-control deficiencies may fail to be revealed in the absence of challenging tasks and environmental conditions. CONCLUSIONS/RECOMMENDATIONS: If we accept the idea that postural control is disrupted after orthopaedic injury, the next step becomes identifying the causative factors within the postural-control system. Experimental evidence surrounding the role of lateral ankle-ligament mechanoreceptors in posture suggests that they cannot be the sole source of the alterations revealed. Consideration should be directed to other potential areas within the postural-control system, as outlined in the text, during ankle evaluations and rehabilitation.

Journal Article↗
PubMed1978

Fusion for instability and potential instability of the cervical spine in children and adolescents.

Instability and potential instability of the cervical spine in the child and adolescent not presenting as emergencies may be due to many causes. We have reviewed 30 patients treated surgically over a seven year period and have grouped them under four general headings: isolated congenital anomalies of the cervical spine, postlaminectomy instability, traumatic instability with delayed presentation, and bony or ligamentous inadequacy secondary to miscellaneous conditions. The variety of conditions permits few generalizations. However, an overview of the entire group supports the concept that abnormal motion in an immature spine or the potential for such motion should be viewed cautiously by the orthopedist, for it may herald severe neurologic compromise. When compromise has occurred, the decision to intervene is made easier. Should only increased motion or the potential for such be present, the natural history of the lesion, if available, should be the guide to treatment. If the natural history of a cervical spine lesion is not available and structural integrity is compromised with abnormal motion present, fusion is advised. Appropriate patient counseling as to the lack of an alternative, with the exception of prolonged bracing to avoid the hazards of life, is essential in this group of individuals.

Adolescent↗
PubMed2004

[Operative stabilization of traumatic instabilities of the lower cervical spine. Experience with an angle instable anterior plate-screw system in 95 patients].

Traumatic instabilities of the cervical spine between C2 and T1 can successfully be treated by anterior spondylodesis with a plate and a tricortical iliac bone graft in most cases. Various plate-screw systems are available.Ninety-five patients with traumatic instability of the lower cervical spine were operated on using the Codman anterior cervical plate system (ACPS). The mean age was 42.1 years, and the mean follow-up was 14.9 months.Twenty-three patients with initial neurological deficits demonstrated an improvement of their symptoms at follow-up. No pseudarthrosis was detected among the 86 patients who were reexamined. Implant-related complications included one pulling out of a plate and one asymptomatic screw loosening. The Codman anterior cervical plate system (ACPS) is easy to use, safe, and a reliable method to stabilize instable injuries of the cervical spine by an anterior approach. The risk of dural or neurological injury is avoided. Implant-related complications are rare.

Adolescent↗
PubMed1996

Midcarpal instability: is capitolunate instability pattern a clinical condition?

Five cases are presented with clinical findings of capito-lunate instability pattern of the wrist. All painful areas and tender points were dorsal, but variable in location and intensity. All plain radiographs and fluoroscopic instability series were normal. None of the cases had an explanation for the dorsal wrist pain other than a positive dorsal capitate-displacement test. Four out of five cases were treated in a cast for 4 weeks and two had subsequent splint immobilization. Although at short-term follow-up two of these five patients became pain-free, none was completely pain-free at long-term follow-up. Three patients treated with a cast had long-term follow-up. Only one could perform his original work. These findings support a clinical condition of midcarpal instability producing dorsal wrist pain reproduced with a simple stress test. Conservative, non-operative treatment will not usually produce long-term pain relief.

Adult↗
PubMed1984

Triquetrohamate and triquetrolunate instabilities (medial carpal instability).

Anatomic and kinematic information needed for the understanding of radiocarpal instability is reviewed. Based on this, and on the concept of the columnar carpus, medial carpal instabilities are defined as those taking place between the triquetrum (medial column) and the hamate and lunate (central column). Therefore, two types of medial instability are recognized: triquetrohamate, across the mid-carpal joint, with loss of stability of the central column present only during ulnar or radial deviation (dynamic DISI and VISI), and triquetrolunate, producing the loss of the dorsiflexion influence of the triquetrum on the lunate and, consequently, a static type of VISI collapse. Treatment aimed at restoration of mid-carpal (triquetrohamate) and triquetrolunate dissociation is discussed, and illustrative cases presented.

Adult↗
PubMed1997

A dynamic approach to spinal instability. Part I: Sensitization of intersegmental motion profiles to motion direction and load condition by instability.

STUDY DESIGN: Human lumbar functional spinal units (FSUs) were moved throughout their range of motion in sagittal and lateral bending while the dynamics of this movement were computed in vitro. Functional spinal units were tested intact and after subsequent discectomy and unilateral facetectomy. OBJECTIVE: To establish "normal" velocity and acceleration curves during lumbar intersegmental bending in the intact FSU and then evaluate the changes of this dynamic behavior due to surgically induced component instability. SUMMARY OF BACKGROUND DATA: In preliminary clinical studies, researchers have provided evidence that dynamic motion measurements may be useful in the assessment of spinal impairment. METHODS: Human lumbar FSUs moved from extension to flexion, flexion to extension, left to right, and right to left a pure moment. Range of motion, as well as velocity and acceleration patterns of the main and coupled motions, were evaluated in six degrees of freedom by position changes of attached infrared light-emitting diodes recorded by cameras. Functional spinal units were tested in three surgical conditions (intact, discectomy, and unilateral facetectomy) under two preload conditions (no preload and 400 N preload). RESULTS: Motion of intact FSUs progressed with velocity and acceleration patterns that were relatively independent from motion direction and preload condition. After surgery, however, the dynamic motion became unequal between opposite motion directions (even if range of motion was equal between directions) and more sensitive to preload condition. CONCLUSION: The results suggest that equilibrium of dynamic motion parameters within a range of motion is an element of segmental stability. From this approach, segmental instability appears to change intersegmental acceleration and velocity patterns as a function of motion direction and load conditions. Whereas dynamic motion patterns in an intact FSU are relatively invariable between reversed motion directions, instability is characterized by a considerable diversity of dynamic motion parameters between reversed motion directions.

Acceleration↗
PubMed2002

Gene expression differences between the microsatellite instability (MIN) and chromosomal instability (CIN) phenotypes in colorectal cancer revealed by high-density cDNA array hybridization.

Two distinct pathways of tumorigenesis exist in sporadic colorectal cancer. The microsatellite instability pathway (MIN), which is characterized by widespread microsatellite instability due to aberrant mismatch repair machinery, accounts for 15% of all sporadic colorectal cancers. The chromosomal instability (CIN) phenotype, which accounts for 85% of sporadic colorectal cancers, is characterized by gross chromosomal lesions but the underlying mechanism remains unclear. We have addressed differences in gene expression between the MIN and CIN colorectal cancer phenotypes in vitro by the use of high density cDNA filters to compare gene expression patterns between MIN and CIN colorectal cancer cell-lines yielding a panel of 73 consistently differentially expressed genes. Nine of these genes were subjected to confirmatory analysis by independent methods, of which six were confirmed as being differentially expressed; PLK, RanBP2 and CCNA2 were overexpressed in CIN lines while BTF3, H2AZ and PTPD1 were overexpressed in MIN lines. These six genes are involved in diverse processes, such as maintenance of chromatin architecture, DNA-damage checkpoint and cell cycle regulation, which may contribute to the CIN and MIN phenotypes.

Adenocarcinoma↗
PubMed2002

Comparison of microsatellite instability and chromosomal instability in predicting survival of patients with T3N0 colorectal cancer.

BACKGROUND: At least 2 apparently independent mechanisms, microsatellite instability (MSI) and chromosomal instability, are implicated in colorectal tumorigenesis. Their respective roles in predicting clinical outcomes of patients with T3N0 colorectal cancer remain unknown. METHODS: Eighty-eight patients with a sporadic T3N0 colon or rectal adenocarcinoma were followed up for a median of 67 months. For chromosomal instability analysis, Ki-ras mutations were determined by single-strand polymerase chain reaction, and p53 protein staining was studied by immunohistochemistry. For MSI analysis, DNA was amplified by polymerase chain reaction at 7 microsatellite targets (BAT25, BAT26, D17S250, D2S123, D5S346, transforming growth factor receptor II, and BAX). RESULTS: Overall 5-year survival rate was 72%. p53 protein nuclear staining was detected in 39 patients (44%), and MSI was detected in 21 patients (24%). MSI correlated with proximal location (P <.001) and mucinous content (P <.001). In a multivariate analysis, p53 protein expression carried a significant risk of death (relative risk = 4.0, 95% CI = 1.6 to 10.1, P =.004). By comparison, MSI was not a statistically significant prognostic factor for survival in this group (relative risk = 2.2, 95% CI = 0.6 to 7.3, P =.21). CONCLUSIONS: p53 protein overexpression provides better prognostic discrimination than MSI in predicting survival of patients with T3N0 colorectal cancer. Although MSI is associated with specific clinicopathologic parameters, it did not predict overall survival in this group. Assessment of p53 protein expression by immunocytochemistry provides a simple means to identify a subset of T3N0 patients with a 4-times increased risk for death.

Adult↗
PubMed2004

Relationship between mitochondrial DNA instability, mitochondrial DNA large deletions, and nuclear microsatellite instability in head and neck squamous cell carcinomas.

Mitochondrial DNA (mtDNA) mutations in coding and noncoding regions have been reported in a variety of human cancers. Despite a greater number of studies, the relationship between such alterations and nuclear microsatellite instability (nMSI) of the tumor cells remains controversial. To contribute new data to this discussion, we investigated head and neck squamous cell carcinomas (HNSCC) for mutations and mitochondrial microsatellite instability (mtMSI) in 2 parts of the mitochondrial D-loop as well as mutations in 2 mitochondrial genes and for the delta4977 mtDNA deletion. These results were compared with data of an analysis for microsatellite instability at IGFIIR, hMSH3, hMSH6, and 5 dinucleotide repeats. We found mtMSI, low nMSI, and high nMSI in 42%, 36%, and 13% of HNSCC primary tumors, respectively. A de novo delta4977 mtDNA deletion could be demonstrated in 25% of HNSCCs. A correlation between mtMSI and nMSI or between a de novo occurrence of the delta4977 mtDNA deletion and nMSI could not be detected in our HNSCC samples (P values 0.527 and 0.078, respectively). Nevertheless, the high rate of mtMSI suggests an involvement of mtDNA alterations in the tumorigenesis of this head and neck cancer and supports the proposal that this aberration may be a new tumor marker.

Adult↗
PubMed2003

Age distribution of three radiologic factors for lumbar instability: probable aging process of the instability with disc degeneration.

STUDY DESIGN: Cross-sectional study of 880 outpatients with low back and/or leg pain regarding age distribution of three radiologic factors. OBJECTIVES: To investigate the proportion and relationship of three individual radiologic factors with age on segmental instability in sagittal plane in consecutive age groups. SUMMARY OF BACKGROUND DATA: Previous studies revealed relationships between radiologic factors for instability and symptoms; however, little is known about the relationship between factors and age except in degenerative spondylolisthesis. METHODS: Excessive segmental motion, defined as more than 10 degrees angulation, more than 3 mm translation, and more than 3 mm slip in neutral position, at the L4-L5 segment in 880 outpatients (389 men, 491 women) with low back and/or leg pain aged from 14 to 84 years was investigated by 3 observers. The number and rate of the patients with each excessive motion were evaluated in continuous age groups of 5 years. RESULTS: The mean ages of patients with excessive angulation, translation, and slip in neutral position were 41.7, 50.0, and 62.8 years, respectively. Both rates of excessive angulation and translation showed two peak patterns demonstrating peaks in the teens and 20s groups and in the over 46 age groups; however, angulation was predominant in younger age groups and translation was predominant in older age groups. Slip in neutral position was frequently observed in age groups over 46 and increased with age. CONCLUSIONS: The presence of patients with excessive angulation and translation in younger age groups suggests they have a hypermobile segment with least degenerated discs. Different predominant patterns of these radiologic factors may reveal the probable aging process of the instability.

Adolescent↗
PubMed2000

Microsatellite instability in tumor and nonneoplastic colorectal cells from hereditary non-polyposis colorectal cancer and sporadic high microsatellite-instable tumor patients.

Genetic alterations such as loss of heterozygosity (LOH) and microsatellite instability (MSI) have been frequently studied in various tumor types. Genetic heterogeneity of nonneoplastic cells has not yet been sufficiently investigated. However, genomic instability in normal cells could be a potentially important issue, in particular when these cells are used as reference in LOH and MSI analyses of tumor samples. In order to investigate possible genetic abnormalities in normal colorectal cells of tumor patients, MSI analyses of normal colonic mucosa were performed. Up to 15 different laser-microdissected normal regions containing 50-150 cells were investigated in each of 15 individual microsatellite-stable, sporadic high microsatellite-instable (MSI-H) and hereditary non-polyposis coli cancer (HNPCC) colorectal cancer patients. Frequent MSI and heterogeneity in the MSI pattern were found both in normal and tumor cells from 10 HNPCC and sporadic MSI-H tumor patients whose tumors had defect mismatch repair protein expressions. This observation shows that MSI can also occur in nonneoplastic cells which has to be considered in MSI analyses for molecular HNPCC screening. In addition, considerable genetic heterogeneity was detected in all MSI-H (sporadic and HNPCC) tumors when analyzing five different regions with less than 150 cells, respectively. These differences were not detectable in larger tumor regions containing about 10,000 cells. Thus, heterogeneity of the MSI pattern (e.g. intratumoral MSI) is an important feature of tumors with the MSI-H phenotype.

Cell Separation↗
PubMed1990

[Bladder instability and kinesitherapy. The concept of deficient bladder instability].

The authors present a series of 30 unstable bladders treated only by perineal muscular reeducation by contact. The best results are obtained in the group presenting with pelvic floor hypotonia and USI (urinary stress incontinence) (efficiency 71.5%), especially when the closure pressure is normal (100%). The urodynamic control and the ominous disappearance of the associated USI confirm a muscular role of the treatment rather than a psychogenic one, the stabilization of the bladder being achieved through the perineo-detrusor inhibitory reflex. Because of this specific and efficient treatment the attention is drawn to the pelvic muscular weakness in the genesis of detrusor instability which is then called "deficitory instability". The interest of a clinical classification of detrusor instability is discussed.

Adult↗
PubMed2005

Mucinous carcinomas of the colon and rectum show higher rates of microsatellite instability and lower rates of chromosomal instability: a study matched for T classification and tumor location.

BACKGROUND: The clinicopathologic significance of mucinous carcinomas (Muc) of the colon and rectum has been widely discussed, but there have been few studies on Muc regarding genetic and epigenetic alterations. The current study analyzed genetic and epigenetic alterations of Muc to clarify their differences from well differentiated adenocarcinomas (WD). METHODS: Thirty-nine cases of Muc and 39 cases of WD were investigated. Cases of WD were matched with cases of Muc for T classification and tumor location. Microsatellite instability (MSI) status and loss of heterozygosity (LOH) of four loci (2p, 5q, 17p, 18q) were evaluated. The methylation status of the hMLH1 promoter region in Muc was also examined. RESULTS: "MSI tumors" were defined as those that showed MSI-high, and "chromosomal instability (CIN) tumors" were defined as those that showed LOH but not MSI-high. MSI tumors were significantly more frequent in Muc (30.8%) than in WD (5.1%). CIN tumors were significantly less frequent in Muc (53.8%) than in WD (87.2%). In Muc, MSI tumors were significantly more frequent in the proximal colon (55.6%) than in the distal colon (9.5%). Also, methylation of the hMLH1 promoter region in Muc was significantly more frequent in MSI tumors (83.3%) than in CIN tumors (27.8%) (P = 0.0077). CONCLUSIONS: When matched for T classification and tumor location, Muc shows higher rates of MSI and lower rates of CIN than WD.. Muc shows different characteristics according to tumor location, and methylation of the hMLH1 promoter region strongly correlates with Muc tumors showing MSI.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Mitochondrial microsatellite instability in colorectal carcinomas--frequency and association with nuclear microsatellite instability.

The D310 mononucleotide repeat in the D-loop region in mitochondrial DNA has been identified as a hotspot for alterations in primary tumours. We examined D310 alterations as well as repeats in the ND1 and ND5 genes, in 95 colorectal carcinomas and in 95 controls without known gastrointestinal malignancy. D310 alterations were found in 32 (34%) of the carcinomas, in contrast to two persons (2%) in the control group. Thus, when frequency is concerned, D310 seems to be a hotspot for alterations in colorectal cancer. No mutations were found in the ND1 and ND5 genes. D310 instability was not associated with nuclear microsatellite instability, indicating different mechanisms of occurrence.

Adolescent↗
PubMed2004

Pancreatic insulinomas in multiple endocrine neoplasia, type I knockout mice can develop in the absence of chromosome instability or microsatellite instability.

Multiple endocrine neoplasia, type I (MEN1) is an inherited cancer syndrome characterized by tumors arising primarily in endocrine tissues. The responsible gene acts as a tumor suppressor, and tumors in affected heterozygous individuals occur after inactivation of the wild-type allele. Previous studies have shown that Men1 knockout mice develop multiple pancreatic insulinomas, but this occurs many months after loss of both copies of the Men1 gene. These studies imply that loss of Men1 is not alone sufficient for tumor formation and that additional somatic genetic changes are most likely essential for tumorigenesis. The usual expectation is that such mutations would arise either by a chromosomal instability or microsatellite instability mechanism. In a study of more then a dozen such tumors, using the techniques of array-based comparative genomic hybridization, fluorescent in situ hybridization, loss of heterozygosity analysis using multiple microsatellite markers across the genome, and real time PCR to assess DNA copy number, it appears that many of these full-blown clonal adenomas remain remarkably euploid. Furthermore, the loss of the wild-type Men1 allele in heterozygous Men1 mice occurs by loss and reduplication of the entire mutant-bearing chromosome. Thus, the somatic genetic changes that are postulated to lead to tumorigenesis in a mouse model of MEN1 must be unusually subtle, occurring at either the nucleotide level or through epigenetic mechanisms.

Alleles↗