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PubMed2006

Simulated humeral avulsion of the glenohumeral ligaments: a new instability model.

Humeral avulsion of the glenohumeral ligaments (HAGL) is an infrequent cause of shoulder instability. Experimental studies on this lesion are rare. This study was undertaken to determine the extent of humeral-based capsuloligamentous damage required for dislocation to occur. In 65 fresh cadaver shoulders, a humeral-sided ligamentous cutting sequence was done. After each step, degree of sulcus, translation, and instability were evaluated with an electromagnetic tracking device. There was a high degree of correlation between the amount of cut done and the resulting degree of instability. The order of the ligamentous cuts had no significant influence. For a dislocation to occur at least 3 zones had to be cut. Simulated HAGL can be used as a model for shoulder instability, although further experiments are needed to validate this model fully. Extensive capsuloligamentous lesions on the humeral side seem to be required before dislocation can occur. This may be a factor explaining the relative paucity of HAGL in clinical series.

Aged↗
PubMed2006

Reconstruction for persistent instability of the elbow after coronoid fracture-dislocation.

The results of reconstruction for chronic instability after coronoid fracture have not been previously described. Patients with persistent instability after coronoid fracture-dislocation were assessed after reconstruction. A satisfactory outcome was considered to be present based on the Mayo Elbow Performance Score and on the patient's willingness to repeat the operation. The length of follow-up was a minimum of 2 years, averaging over 5 years. Overall, 13 of 21 patients (62%) were classified as having a successful outcome objectively, and 17 of 21 (81%) were classified as having a successful outcome subjectively. The duration of the delay to definitive treatment was closely associated with the ultimate outcome (P < .01), as the outcome of only 1 of 7 elbows with a delay greater than 7 weeks was classified as an objective success. Of the patients, 19 had a fractured radial head, 11 of which were initially treated with a radial head excision; none was subsequently reconstructed. Sixteen patients were treated with a hinged external fixator. Of the elbows, 13 remained reduced whereas 8 had variable amounts of anterior or posterior instability. Two failures were ultimately reconstructed with a total elbow arthroplasty. Instability that persists after the initial unsuccessful management of a coronoid fracture and an elbow dislocation is a difficult problem to salvage with subsequent reconstruction. This experience emphasizes the need for better reconstructive options and especially underscores the need for appropriate initial management of this difficult injury.

Adult↗
PubMed2005

Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis.

It has been well established that tumor progression is correlated with genetic instability. Growing evidence suggests that the tumor microenvironment itself constitutes a significant source of such genetic instability. The adverse conditions of this microenvironment are associated with the induction of mutagenesis and numerous types of DNA damage, including DNA strand breaks and oxidative base damage. While such DNA lesions pose a significant threat to genome integrity, recent studies now suggest that genetic instability in the tumor microenvironment also may arise from the dysregulation of DNA repair pathways. In this review, we will summarize the case for the tumor microenvironment as a key culprit in the induction of genetic instability and the potential mechanisms by which this phenomenon occurs.

Animals↗
PubMed2005

The role of p53-mediated apoptosis as a crucial anti-tumor response to genomic instability: lessons from mouse models.

Genomic instability is a major force driving human cancer development. A cellular safeguard against such genetic destabilization, which can ensue from defects in telomere maintenance, DNA repair, and checkpoint function, is activation of the p53 tumor suppressor protein, which commonly responds to these DNA damage signals by inducing apoptosis. If, however, p53 becomes inactivated, as is typical of many tumors and pre-cancerous lesions, then cells with compromised genome integrity pathways survive inappropriately, and the accrual of oncogenic lesions can fuel the carcinogenic process. Studies of mouse models have been instrumental in providing support for this idea. Mouse knockouts in genes important for telomere function, DNA damage checkpoint activation and DNA repair - both non-homologous end joining and homologous recombination - are prone to the development of genomic instability. As a consequence of these DNA damage signals, p53 becomes activated in cells of these mutant mice, leading to the induction of apoptosis, sometimes at the expense of organismal viability. This apoptotic response can be rescued through crosses to p53-deficient mice, but has dire consequences: mice predisposed to genomic instability and lacking p53 are susceptible to tumorigenesis. Thus p53-mediated apoptosis provides a crucial tumor suppressive mechanism to eliminate cells succumbing to genomic instability.

Animals↗
PubMed2004

IR-inducible clusterin gene expression: a protein with potential roles in ionizing radiation-induced adaptive responses, genomic instability, and bystander effects.

Clusterin (CLU) plays numerous roles in mammalian cells after stress. A review of the recent literature strongly suggests potential roles for CLU proteins in low dose ionizing radiation (IR)-inducible adaptive responses, bystander effects, and delayed death and genomic instability. Its most striking and evident feature is the inducibility of the CLU promoter after low, as well as high, doses of IR. Two major forms of CLU, secreted (sCLU) and nuclear (nCLU), possess opposite functions in cellular responses to IR: sCLU is cytoprotective, whereas nCLU (a byproduct of alternative splicing) is a pro-death factor. Recent studies from our laboratory and others demonstrated that down-regulation of sCLU by specific siRNA increased cytotoxic responses to chemotherapy and IR. sCLU was induced after low non-toxic doses of IR (0.02-0.5 Gy) in human cultured cells and in mice in vivo. The low dose inducibility of this survival protein suggests a possible role for sCLU in radiation adaptive responses, characterized by increased cell radioresistance after exposure to low adapting IR doses. Although it is still unclear whether the adaptive response is beneficial or not to cells, survival of damaged cells after IR may lead to genomic instability in the descendants of surviving cells. Recent studies indicate a link between sCLU accumulation and cancer incidence, as well as aging, supporting involvement of the protein in the development of genomic instability. Secreted after IR, sCLU may also alter intracellular communication due to its ability to bind cell surface receptors, such as the TGF-beta receptors (types I and II). This interference with signaling pathways may contribute to IR-induced bystander effects. We hypothesize that activation of the TGF-beta signaling pathway, which often occurs after IR exposure, can in turn activate the CLU promoter. TGF-beta and IR-inducible de novo synthesized sCLU may then bind the TGF-beta receptors and suppress downstream growth arrest signaling. This complicated negative feedback regulation most certainly depends on the cellular microenvironment, but undoubtedly represents a potential link between IR-induced adaptive responses, genomic instability and bystander effects. Further elucidation of clusterin protein functions in IR responses are clearly warranted.

Animals↗
PubMed2006

Indirect mechanisms of genomic instability and the biological significance of mutations at tandem repeat loci.

Radiation induction of genomic instability has two features: induction of untargeted mutation and delayed mutation. These phenomena have been studied mostly in tissue culture cells, but analyses have also been conducted in whole body systems. The study of response in whole body systems frequently applies repeat sequences as markers to detect mutations. These studies have generated conflicting findings. In addition, lack of knowledge of the mechanisms involved in repeat mutation confounds the interpretation of the biological significance of increased rates of repeat mutation. In this review, some of the existing controversies of genomic instability are discussed in relation to the mechanism of repeat mutation. Analyses of published and unpublished studies indicate a mechanistic similarity between radiation-induced genomic instability at repeat loci and dynamic mutations of triplet repeats. Because of their repetitive nature, repeat sequences frequently block progression of replication forks and are consequently resolved by slippage and/or recombination. Irradiation of cells induces S checkpoints and promotes slippage/recombination mediated repeat mutations. Thus, genomic instability at repeat loci might be viewed as a consequence of cellular attempts to restore the stability of replication in the face of the stalled replication fork; this process can occur both spontaneously as well as after exposure to radiation.

Animals↗
PubMed2006

Instability of expanded simple tandem repeats is induced in cell culture by a variety of agents: N-Nitroso-N-ethylurea, benzo(a)pyrene, etoposide and okadaic acid.

Expanded simple tandem repeat (ESTR) sequences have proven useful biomarkers to detect genotoxicity in vivo. Their high sensitivity has been used to assess environmentally relevant doses of mutagens such as ionizing radiation, DNA alkylating agents and airborne particulate pollution, for germline mutations in mouse assays. The mutagenic response involves size alteration of these ESTR loci induced by agents causing a variety of cellular damage. The mechanistic aspects of this induced instability remain unclear and have not been studied in detail. Mechanistic knowledge is important to help understand the relevance of increased ESTR mutation frequencies. In this study, we applied a murine cell culture system to examine induced response to four agents exhibiting different modes of toxic action including: N-nitroso-N-ethylurea (ENU), benzo(a)pyrene (BaP), okadaic acid and etoposide at slightly sub-toxic levels. We used single-molecule-polymerase chain reaction (SM-PCR) to assess the relative mutant frequency after 4-week chemical treatments at the Ms6-hm ESTR sequence of cultured C3H/10T1/2 cells (a mouse embryonic cell line). Increased mutation was observed with both 0.64 mM ENU (1.95-fold increase, P<0.0001), 1 microM benzo(a)pyrene (1.87-fold increase, P=0.0006) and 3 nM etoposide (1.89-fold increase, P=0.0003). The putative ESTR mutagen okadaic acid (1.27-fold increase, P=0.2289), administered at 0.5 nM, did not affect the C3H/10T1/2 Ms6-hm locus. Therefore, agents inducing small and bulky adducts, and indirectly causing strand breaks through inhibition of topoisomerase, caused similar induction of instability at an ESTR locus at matched toxicities. As size spectra for induced mutations were identical, the data indicate that although these chemicals exhibit distinct modes of action, a similar indirect process is influencing ESTR instability. In contrast, a potent tumour promoter that is a kinase inhibitor does not contribute to induced ESTR instability in cell culture.

Animals↗
PubMed2006

Non-B DNA structure-induced genetic instability.

Repetitive DNA sequences are abundant in eukaryotic genomes, and many of these sequences have the potential to adopt non-B DNA conformations. Genes harboring non-B DNA structure-forming sequences increase the risk of genetic instability and thus are associated with human diseases. In this review, we discuss putative mechanisms responsible for genetic instability events occurring at these non-B DNA structures, with a focus on hairpins, left-handed Z-DNA, and intramolecular triplexes or H-DNA. Slippage and misalignment are the most common events leading to DNA structure-induced mutagenesis. However, a number of other mechanisms of genetic instability have been proposed based on the finding that these structures not only induce expansions and deletions, but can also induce DNA strand breaks and rearrangements. The available data implicate a variety of proteins, such as mismatch repair proteins, nucleotide excision repair proteins, topoisomerases, and structure specific-nucleases in the processing of these mutagenic DNA structures. The potential mechanisms of genetic instability induced by these structures and their contribution to human diseases are discussed.

Base Sequence↗
PubMed2007

aCGH local copy number aberrations associated with overall copy number genomic instability in colorectal cancer: coordinate involvement of the regions including BCR and ABL.

In order to identify small regions of the genome whose specific copy number alteration is associated with high genomic instability in the form of overall genome-wide copy number aberrations, we have analyzed array-based comparative genomic hybridization (aCGH) data from 33 sporadic colorectal carcinomas. Copy number changes of a small number of specific regions were significantly correlated with elevated overall amplifications and deletions scattered throughout the entire genome. One significant region at 9q34 includes the c-ABL gene. Another region spanning 22q11-q13 includes the breakpoint cluster region (BCR) of the Philadelphia chromosome. Coordinate 22q11-q13 alterations were observed in 9 of 11 tumors with the 9q34 alteration. Additional regions on 1q and 14q were associated with overall genome-wide copy number changes, while copy number aberrations on chromosome 7p, 7q, and 13q21.1-q31.3 were found associated with this instability only in tumors from patients with a smoking history. Our analysis demonstrates there are a small number of regions of the genome where gain or loss is commonly associated with a tumor's overall level of copy number aberrations. Our finding BCR and ABL located within two of the instability-associated regions, and the involvement of these two regions occurring coordinately, suggests a system akin to the BCR-ABL translocation of CML may be involved in genomic instability in about one-third of human colorectal carcinomas.

Adult↗
PubMed2004

Genomic instability in oral squamous cell carcinoma: relationship to betel-quid chewing.

Genomic instability in repeated DNA sequences is exhibited by a variety of cancer types, including oral squamous cell carcinoma. Exposure to carcinogenic compounds may further increase the instability. We have used Inter-Simple Sequence Repeat (Inter-SSR) PCR methodology to detect genetic alterations in 37 oral cancer patients who had chewed betel-quid. Thirty-eight percent of DNA from tumors had genomic alterations in the sequences flanked by (CA)(8) and (GT)(8) repeats. Patients with tumor DNAs harboring genomic alterations had a two-fold higher consumption of betel-quid than patients without alterations in tumor DNA. Matched normal and tumor DNAs were also screened for microsatellite instability where four patients (10.8%) showed alterations in at least one microsatellite marker but there was no relationship between this phenotype and betel-quid chewing. These data indicate that exposure to carcinogens present in the betel-quid may contribute to genomic instability detected by inter-SSR PCR in a subset of oral tumors.

Adult↗
PubMed2004

Genome wide instability scanning in chewing-tobacco associated oral cancer using inter simple sequence repeat PCR.

Genomic instability plays a major role in cancer, facilitating tumour progression and tumour heterogeneity. Inter simple sequence repeat PCR (ISSR-PCR) is a sensitive tool for detection of whole genome scanning. In fifteen oral cancer patients, using tumor tissue and adjacent normal tissue DNA, we investigated genomic instability regions using ISSR-PCR assay. The genomic fragments were cloned, sequenced and identified. Two-anchored dinucleotide repeat primers, (CA)(8)A/GG and (CA)(8)A/GC/T, were used in the study. About 40-50 fragments were observed on polyacrylamide gel electrophoresis, with 25 distinct fragments of less than 2 kb. The electrophoretic pattern highlighted several distinct fragments in tumor adjacent normal tissues. The distinct fragments of 258, 325, 430, 440, 600 and 900 bp sizes using (CA)(8)A/GG primer, and 300, 475, 675 and 800 bp using (CA)(8)A/GC/T primers, in the normal tissues showed partial (>50%) or complete loss in multiple tumor tissues. These fragments were eluted from the gel, cloned in pMos Blue vector and subjected to nucleotide sequencing. Insilico analysis defined the specific genomic sequences, given as follows: RP11-399D2 () on chromosome (chr)4; RP1-39J2 (), NKp44RG () and RP11-518I13 () on chr6; NC-T-2 () on chr7; RP11-586K2 () and RP11-495O10 () on chr8; RP11-101K10 () on chr9; R-794A8 () on chr14; and RP11-679B19 () on chr16. The sequences of our clones have been submitted to NCBI gene bank, accession numbers to , and . The Genomic Instability Index was calculated and ranged from 6% to 28.5% (median 12%) in the oral cancer samples, excluding one case where genomic instability was not observed. Thus, our results indicate presence of widespread genomic alterations in chewing-tobacco associated oral cancers.

Adult↗
PubMed2004

GAA repeat instability in Friedreich ataxia YAC transgenic mice.

Friedreich ataxia (FRDA) is primarily caused by an unstable GAA repeat-expansion mutation within intron 1 of the FRDA gene. However, the exact mechanisms leading to this expansion and its consequences are not fully understood. To study the dynamics of this mutation, we have generated two lines of human FRDA YAC transgenic mice that contain GAA repeat expansions within the appropriate genomic context. We have detected intergenerational instability and age-related somatic instability in both lines, with pronounced expansions found in the cerebellum. The dynamic nature of our transgenic GAA repeats is comparable with previous FRDA patient somatic tissue data. However, there is a difference between our FRDA YAC transgenic mice and other trinucleotide-repeat mouse models, which do not show pronounced repeat instability in the cerebellum. This represents the first mouse model of FRDA GAA repeat instability that will help to dissect the mechanism of this repeat.

Aging↗
PubMed2003

Interrater reliability of clinical examination measures for identification of lumbar segmental instability.

OBJECTIVE: To determine the interrater reliability of common clinical examination procedures proposed to identify patients with lumbar segmental instability. DESIGN: Single group repeated-measures interrater reliability study. SETTING: Outpatient physical therapy (PT) clinic and university PT department. PARTICIPANTS: A consecutive sample of 63 subjects (38 women, 25 men; 81% with previous episodes of low back pain [LBP]) with current LBP was examined by 3 pairs of raters. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Repeat measurements of clinical signs and tests proposed to identify lumbar segmental instability. RESULTS: Kappa values for the trunk range of motion (ROM) findings varied (range,.00-.69). The prone instability test (kappa=.87) showed greater reliability than the posterior shear test (kappa=.22). The Beighton Ligamentous Laxity Scale (LLS) for generalized ligamentous laxity showed high reliability (intraclass correlation coefficient=.79). Judgments of pain provocation (kappa range,.25-.55) were generally more reliable than judgments of segmental mobility (kappa range, -.02 to.26) during passive intervertebral motion testing. CONCLUSIONS: The results agree with previous studies suggesting that segmental mobility testing is not reliable. The prone instability test, generalized LLS, and aberrant motion with trunk ROM demonstrated higher levels of reliability.

Adult↗
PubMed1998

Ankle orthoses effect on single-limb standing balance in athletes with functional ankle instability.

OBJECTIVE: To test whether a rigid or a flexible ankle orthosis affects postural sway in single-limb stance as quantified by stabilometry. DESIGN: Crossover trial. SETTING: University laboratory. PARTICIPANTS: Twenty-two athletes with functional ankle instability (consecutive sample of patients with recurrent ankle sprains but without mechanical instability) and 22 healthy athletes (control group of volunteers matched to age, height, weight, physical activity). INTERVENTIONS: Stabilometry in single-limb stance on a force platform. Participants were tested on each leg with and without a rigid or a flexible ankle orthosis. The order of test conditions was randomized. MAIN OUTCOME MEASURES: Sway velocities, sway pattern, and sway area as calculated from center of pressure movements. The two groups were compared by Mann-Whitney test, and the different orthoses within each group were compared by Wilcoxon test, paired samples (type I error 5%, Bonferroni adjustment). RESULTS: In athletes with functional ankle instability, both a rigid and a flexible ankle orthosis significantly reduced mediolateral sway velocity. A flexible ankle orthosis also changed sway pattern significantly, by reducing the percentage of linear movements of less than 5 degrees per .01 sec. CONCLUSIONS: In athletes with functional ankle instability, ankle orthoses reduce mediolateral sway velocity, possibly because of improved mediolateral proprioception.

Adult↗
PubMed1987

Atlantoaxial instability in Down syndrome: roentgenographic, neurologic, and somatosensory evoked potential studies.

To identify patients with Down syndrome and asymptomatic atlantoaxial instability who are at increased risk for developing neurologic symptoms, we studied 27 patients with this skeletal disorder and compared them with an age- and sex-matched group of 27 patients with Down syndrome without atlantoaxial instability. A third group of six patients had symptomatic atlantoaxial instability. The mean atlanto-dens intervals and the mean spinal canal widths among the three groups were significantly different. There were no significant differences in mean composite neurologic scores and somatosensory evoked responses between patients in the asymptomatic group and those in the control group. However, when a subsample of patients with high and low latencies (greater than 1 SD below and above the mean) was formed and comparisons were made with roentgenographic findings, there was a high correspondence between somatosensory evoked potential latencies and atlanto-dens interval measurements. We conclude that no single assessment technique, but a combined approach using roentgenographic, CT scan, neurologic, and neurophysiologic investigations, will provide information of the risk status of patients with Down syndrome and atlantoaxial instability.

Adolescent↗
PubMed2001

Posterior instability.

Posterior shoulder instability is a pathology that is increasingly seen in athletes. Excessive capsular laxity was originally proposed as the key component. Recent cadaveric and arthroscopic work has identified the importance of glenolabral integrity and glenoid depth in maintaining glenohumeral stability. Arthroscopic techniques to treat posterior instability are emerging. Until recently, reports of arthroscopic reconstruction focused entirely on capsular glenohumeral stability by altering two separate mechanisms: deepening of the glenoid concavity and reducing the capsular joint volume. This is accomplished by shifting the capsule to buttress the glenoid labrum. Thus increasing capsular tension increases the resultant compressive force vector into a deepened glenolabral concavity that, when combined together, enhances glenohumeral stability. In clinical and laboratory settings, we have shown that posteroinferior shoulder instability is associated with both capsular laxity and well-defined pathological lesions of the glenolabral concavity. Our results indicate that arthroscopic posterior capsulolabral repair and augmentation is a useful tool to restore the depth of the glenolabral concavity and to reduce the redundant posteroinferior capsule. This technique is effective in treating posteroinferior instability.

Adult↗
PubMed2004

[Surgical treatment of posterior instability of the shoulder joint using an iliac bone block or an acromial pediculated bone block: outcome in eighteen patients].

PURPOSE OF THE STUDY: The posterior bone block procedure is a popular option for the treatment of involuntary posterior instability of the shoulder. The purpose of this study was to analyze the long-term results of this procedure using an iliac bone graft and to point out the advantages of Kouvalchouk technique using an acromial pediculated block. MATERIAL AND METHODS: Eighteen patients, ten men and eight women, mean age 27 years, were reviewed: thirteen were active in sports activities including four at the competition level. The duration of symptoms before surgery was four years on the average. One patient experienced recurrent dislocation, twelve suffered regular involuntary subluxation, and five had painful shoulders possibly related to posterior instability considering the arthroscopic findings. For nine patients (group 1), an iliac block was combined with the soft-tissue procedure. In nine others (group 2), the procedure described by Kouvalchouk was used to create a posterolateral acromial bone block with pediculated deltoid fibers. Functional outcome was assessed with the 100-point Duplay score. The position of the bone block and osteoarthritis were assessed on plain x-rays. RESULTS: Mean follow-up was 13.5 years in group 1 and 3.5 years in group 2. Four patients needed a revision procedure to remove a screw. At last follow-up, the average Duplay score was 78 points. Nine patients returned to their former sports activities. Seven patients were pain free and ten had moderate discomfort at effort. We did not observe any recurrent dislocation no subluxation but did have six patients who described apprehension. The mean Duplay score was 70 points in group 1 and 86 points in group 2. In two patients in group 1, the x-rays showed signs of grade 3 or 4 osteoarthritis, which was related to an intra-articular screw in one; the other patient had had the same degenerative signs before surgery. Two patients developed grade 1 osteoarthritis. DISCUSSION AND CONCLUSION: The bone block procedure is effective for posterior instability of the shoulder. Occurrence of osteoarthritis, compared with the anterior bone block, is lower after long-term follow-up. The results of the Kouvalchouk procedure with an acromial pediculated bone block look promising. We recommend an additional capsuloplasty when inferior hyperlaxity is associated with posterior instability.

Acromion↗
PubMed2003

Application of screw displacement axes to quantify elbow instability.

OBJECTIVES: To determine if screw displacement axis patterns describing elbow joint motion: (1) change after ligament transection in vitro; (2) can reflect subtle changes in stability as a function of forearm position; (3) can reflect dynamic stabilization of the ligament insufficient elbow provided by muscle activity.Design. An in vitro kinematic study of eighteen cadaveric specimens tested in a joint simulator. BACKGROUND: In the elbow joint, screw displacement axes have been employed for proper positioning and design of endoprostheses. The effect of instability on screw displacement axes has not been previously reported. METHODS: Passive and simulated active flexion, with the forearm maintained in both pronation and supination, was performed on eighteen intact and ligament insufficient elbows. Instability was produced by transection of the medial collateral or lateral collateral ligament complexes. Kinematics were recorded using an electromagnetic tracking device and analyzed with a repeated measures design. RESULTS: During passive motion, division of either ligament caused deviation of screw displacement axes compared to the intact state (P<0.05). Transection of the medial/lateral collateral ligament generated greater instability with the forearm maintained in pronation/supination compared to supination/pronation (P<0.05). Muscle activation increased stability similar to the intact state (P>0.05). CONCLUSIONS: These results are consistent with observations determined using traditional kinematic descriptors. Screw displacement axes can readily detect changes in stability due to ligament sectioning. RELEVANCE: Clinicians can employ the screw displacement axis technique as a succinct descriptor of motion to readily detect elbow instability.

Aged↗