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PubMedDate not supplied

[Factors determining the instability of the conformation of human mutant hemoglobins. A method for evaluating the instability].

A method that allows to estimate the influence of single amino acid substitutions on the stability of proteins with known three-dimensional structure was developed. The role of 20 different physico-chemical properties of amino acids and some characteristics of the three-dimensional structure in the destabilization of protein structure caused by mutations was analyzed. Analysis of 54 proteins led us to reveal the characteristics of the three-dimensional structure. The parameters of the method were calculated on the basis of experimental data for 330 mutant human hemoglobins. The prediction accuracy of the method is on average 81%. The method may be used for the analysis of the total mutational spectra of the proteins and also for the estimation of effects of the single amino acid substitution on the protein structure in gene-engineering experiments.

Amino Acid Sequence↗
PubMed1996

Low-molecular-weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group.

BACKGROUND: Intravenous heparin is at least as effective as aspirin in preventing new cardiac events after an episode of unstable coronary artery disease (CAD), though the benefits are short-lived. Low-molecular-weight heparin has similar antithrombotic properties but can be given subcutaneously and is therefore suitable for long-term treatment. We have investigated whether subcutaneous low- molecular-weight heparin, in addition to aspirin and antianginal drugs, is protective against new cardiac events in unstable CAD. METHODS: 1506 patients with unstable CAD (unstable angina or non-Q-wave myocardial infarction) took part in a double-blind trial and were randomly assigned subcutaneous dalteparin (Fragmin; 120 IU per kg bodyweight [maximum 10 000 IU] twice daily for 6 days then 7500 IU once daily for the next 35-45 days) or placebo injections. The primary endpoint was the rate of death and new myocardial infarction during the first 6 days. Secondary endpoints were the rates of death and new myocardial infarction after 40 and 150 days, the frequency of revascularisation procedures and need for heparin infusion, and a composite endpoint. FINDINGS: During the first 6 days the rate of death and new myocardial infarction was lower in the dalteparin group than in the placebo group (13 [1.8%] vs 36 [4.8%]; risk ratio 0.37 [95% CI 0.20-0.68]), as were the frequencies of need for intravenous heparin (28 [3.8%] vs 58 [7.7%]; 0.49 [0.32- 0.75]) and need for revascularisation (3 [0.4%] vs 9 [1.2%]; 0.33 [0.10-1.10]). The composite endpoint (death, myocardial infarction, revascularisation, intravenous heparin) also showed a significant difference in favour of dalteparin (40 [5.4%] vs 78 [10.3%]; 0.52 [0.37-0.75]). At 40 days the differences in rates of death and myocardial infarction and the composite endpoint persisted, although subgroup analysis showed that the effect was confined to non-smokers (80% of sample). Survival analysis showed a risk of reactivation and reinfarction when the dose was decreased, more pronounced in smokers. 4-5 months after the end of treatment, there were no significant differences in the rates of death, new myocardial infarction, or revascularisation. The regimen was safe and compliance was adequate. INTERPRETATION: We recommend that treatment with a combination of dalteparin and aspirin for at least 6 days should be considered in patients with unstable CAD to reduce the risk of new cardiac events and to allow time for risk stratification and selection of a long-term treatment strategy. Long-term dalteparin treatment instead of or in addition to early invasive procedures warrants further assessment.

Adult↗
PubMed2001

[Chronic instability and fixed dislocation of the shoulder].

Chronic instabilities may be traumatic or atraumatic, unidirectional or multidirectional. It is important to distinguish between symptomatic instability and asymptomatic hyperlaxity. Posttraumatic, unidirectional anterior instability without hyperlaxity is the most common form of instability. The patient presents apprehension, the sulcus-sign is negative. Posttraumatic, unidirectional instability with hyperlaxity is due to an adequate trauma, both the apprehension test and the sulcus sign are positive. The treatment of traumatic instability is surgically with respect to the underlying pathology of the ligaments, labrum and capsule. The "golden standard" is the reconstruction of the capsulolabral complex. The repetitive microtraumatic instability is seen in overhead athletes with elongation or disruption of the capsule. The typical patient presents with painful subluxations, the instability may be unidirectional or multidirectional. The treatment is conservatively. Multidirectional instability with hyperlaxity is defined as symptomatic instability in at least two directions of instability with multidimensional hyperlaxity. These individuals will also report on pain rather than instability. The apprehension test is positive in at least two directions, the sulcus sign is positive as well. The patients are responsive to an intensive rehabilitation program for 6-12 months. Open capsular shift or thermal capsular shrinkage may be successful after failed conservative treatment. Multidirectional instability without hyperlaxity is extremely rare and is due to more than one adequate trauma with traumatic instability in different directions. The apprehension test is positive, the sulcus sign negative. The treatment is surgically. The fixed dislocation is posterior in most of the cases and frequently being missed primarily. It is seen in unconscious, multiple-injured patients or after grand mal or electroshock seizures. The reduction may be either closed or open depending on the interval between trauma and diagnosis. Voluntary instability represents a subset of individuals with atraumatic instability. The patients can dislocate and reduce their shoulder, have no pain and do not develop arthritis. They do not require a special therapy.

Adult↗
PubMed1996

p53 tumor suppressor gene status and the degree of genomic instability in sporadic colorectal cancers.

BACKGROUND: Genomic instability reflects the propensity and the susceptibility of the genome to acquire multiple alterations and, in turn, is believed to be a driving force behind multistep carcinogenesis. Although the molecular basis of genomic instability in sporadic colorectal cancers remains largely a mystery, mutation of the p53 tumor suppressor gene (also known as TP53) has been proposed to play an integral role in this process. However, a dilemma exists in that p53 mutation appears to be a late event in the progression of sporadic colorectal tumors, whereas genomic instability, serving as a facilitator of tumor progression, is envisioned as occurring early in this process. PURPOSE: We evaluated the relationship between p53 mutation and the major form of genomic instability in sporadic colorectal tumors, namely, that involving DNA breakage, which leads to chromosomal translocations, insertions, deletions, and gene amplification. METHODS: Fifty-eight sporadic colorectal tumors that had been previously evaluated for genomic instability were analyzed for p53 mutations. These tumors were from consecutively diagnosed patients. Genomic instability was quantified by use of inter-simple sequence repeat polymerase chain reaction analysis that employed (CA)8RG and (CA)8RY primers (R = purine [A or G]; Y = pyrimidine [C or T]); a genomic instability index (a measure of the number of alterations in tumor DNA in comparison with normal DNA, expressed as a percent) was calculated for each tumor. Mutation of the p53 gene in exons 5-9 was determined by use of single-strand conformational polymorphism-polymerase chain reaction analysis and DNA sequencing. Chi-squared analysis was used to determine the statistical significance of differences between groups of tumors. Reported P values are two-sided. RESULTS: p53 mutations were identified in 29 (50%) of the 58 tumors. The median genomic instability index value was 3.3%. Nineteen (65.5%) of the 29 tumors with p53 mutations had genomic instability indices that were less than the median value (range, 0%-2.6%); the remaining 10 (34.5%) tumors had genomic instability indices that were greater than the median (range, 3.9%-13.0%). Eleven (37.9%) of the 29 tumors with wild-type p53 genes had genomic instability indices that were less than the median value (range, 0%-2.6%), whereas the remaining 18 tumors had genomic instability indices above the median (range, 3.9%-11.7%). There was a statistically significant association between a lesser degree of genomic instability and the presence of p53 mutations (P = .032). CONCLUSIONS AND IMPLICATIONS: Tumors with no or minimal evidence of genomic instability are more likely to harbor p53 mutations than tumors with evidence of substantial genomic instability. p53 mutations play an important role in the development of cancers but do not appear to initiate or promote genomic instability in sporadic colorectal tumors.

Chromosome Aberrations↗
PubMed1997

Subtalar ankle instability. A review.

The aetiology of chronic functional lateral ankle instability is fairly well understood. Pathophysiological factors such as mechanical instability, proprioceptive deficit and peroneal muscle weakness have been demonstrated. Subtalar instability has been in focus during the last years as one of the possible factors behind chronic functional instability of the foot. The exact aetiology and the true incidence of subtalar ligament injuries remain unknown. Most subtalar ligamentous injuries probably occur in combination with injuries of the talo-tibial articulation. Subtalar instability can have the characteristics of chronic lateral instability or recurrent ankle sprains. Patients with chronic subtalar instability typically complain of 'giving way' symptoms and a history of recurrent sprains. Clinical examination including increased inwards rotation and forward displacement of the calcaneus may not be sufficient for the differentiation between ankle and subtalar instability. Radiographic imaging using stress radiographs may be necessary to assess subtalar instability. Subtalar instability can be defined as chronic functional instability with increased values of talar tilt and talo-calcaneal displacement as measured with standardised stress radiographs. Few authors have addressed the treatment of subtalar instability and the condition has not been clearly defined. Subtalar instability can be treated either with a tendon transfer or tenodesis procedure, such as the Chrisman-Snook or triligamentous tenodeses, or with an anatomic ligament reconstruction using the calcaneo-fibular, lateral talo-calcaneal and cervical ligaments combined with a reinforcement of the inferior extensor retinaculum. There have been no studies comparing anatomical and non-anatomical reconstructions and the long term results after ligamentous stabilisation are unknown. The focus of this article is on subtalar instability causing chronic functional ankle instability.

Chronic Disease↗
PubMed2007

Anterior and posterior instability of the long head of the biceps tendon in rotator cuff tears: a new classification based on arthroscopic observations.

PURPOSE: The purpose of this study was to evaluate arthroscopically the frequency and type of instability of the long head of the biceps (LHB) tendon in patients undergoing rotator cuff repair. METHODS: In 200 consecutive patients undergoing arthroscopic rotator cuff repair, LHB instability was assessed statically and dynamically in the anteroposterior direction. In addition, macroscopic lesions of the LHB, as well as lesions of the adjacent rotator cuff tendons, were documented. RESULTS: LHB instability (subluxation or dislocation) was found in 45% of patients, with isolated anterior instability in 16%, isolated posterior instability in 19%, and combined anteroposterior instability in 10%. Whereas LHB subluxations were observed in both directions, dislocations were only seen in anterior LHB instability. Anterior instability was more associated with a subscapularis lesion, whereas posterior instability was more associated with a supraspinatus tear. Lesions of the LHB tendon were strongly associated with LHB instability and the size of the rotator cuff tear. CONCLUSIONS: In 200 patients with rotator cuff tears LHB instability could be observed arthroscopically in 45%, with 16% being anterior, 19% being posterior, and 10% being anteroposterior. LHB instability was associated with LHB lesions, with 15% of the LHB tendons showing a normal appearance when unstable versus 70% when stable. Preoperative O'Brien and Speed tests did not correlate with intraoperative observed LHB pathology. The size of the rotator cuff tear could be correlated with the grade of LHB lesion, becoming more significant with augmenting tear size. On the basis of these observations, we created a new arthroscopic classification of LHB instability with respect to the direction and extent of LHB instability, lesions of the LHB, and status of the adjacent rotator cuff tendons. LEVEL OF EVIDENCE: Level IV, diagnostic study with poor reference standard.

Activities of Daily Living↗
PubMed2004

Aneuploidy, the primary cause of the multilateral genomic instability of neoplastic and preneoplastic cells.

Cancers have a clonal origin, yet their chromosomes and genes are non-clonal or heterogeneous due to an inherent genomic instability. However, the cause of this genomic instability is still debated. One theory postulates that mutations in genes that are involved in DNA repair and in chromosome segregation are the primary causes of this instability. But there are neither consistent correlations nor is there functional proof for the mutation theory. Here we propose aneuploidy, an abnormal number of chromosomes, as the primary cause of the genomic instability of neoplastic and preneoplastic cells. Aneuploidy destabilizes the karyotype and thus the species, independent of mutation, because it corrupts highly conserved teams of proteins that segregate, synthesize and repair chromosomes. Likewise it destabilizes genes. The theory explains 12 of 12 specific features of genomic instability: (1) Mutagenic and non-mutagenic carcinogens induce genomic instability via aneuploidy. (2) Aneuploidy coincides and segregates with preneoplastic and neoplastic genomic instability. (3) Phenotypes of genomically unstable cells change and even revert at high rates, compared to those of diploid cells, via aneuploidy-catalyzed chromosome rearrangements. (4) Idiosyncratic features of cancers, like immortality and drug-resistance, derive from subspecies within the 'polyphyletic' diversity of individual cancers. (5) Instability is proportional to the degree of aneuploidy. (6) Multilateral chromosomal and genetic instabilities typically coincide, because aneuploidy corrupts multiple targets simultaneously. (7) Gene mutation is common, but neither consistent nor clonal in cancer cells as predicted by the aneuploidy theory. (8) Cancers fall into a near-diploid (2 N) class of low instability, a near 1.5 N class of high instability, or a near 3 N class of very high instability, because aneuploid fitness is maximized either by minimally unstable karyotypes or by maximally unstable, but adaptable karyotypes. (9) Dominant phenotypes, because of aneuploid genotypes. (10) Uncertain developmental phenotypes of Down and other aneuploidy syndromes, because supply-sensitive, diploid programs are destabilized by products from aneuploid genes supplied at abnormal concentrations; the maternal age-bias for Down's would reflect age-dependent defects of the spindle apparatus of oocytes. (11) Non-selective phenotypes, e.g., metastasis, because of linkage with selective phenotypes on the same chromosomes. (12) The target, induction of genomic instability, is several 1000-fold bigger than gene mutation, because it is entire chromosomes. The mutation theory explains only a few of these features. We conclude that the transition of stable diploid to unstable aneuploid cell species is the primary cause of preneoplastic and neoplastic genomic instability and of cancer, and that mutations are secondary.

Aneuploidy↗
PubMed2003

The effect of variation in definition on the diagnosis of multidirectional instability of the shoulder.

BACKGROUND: There currently is a wide variation in the definition of multidirectional instability of the shoulder in the literature. The purpose of this study was to determine if these variations influence the distribution of the diagnoses in a cohort of patients with shoulder instability. METHODS: A cohort of 168 patients who underwent shoulder surgery for instability of any type was studied. Statistical analysis was performed in two steps. First, the instability of the shoulder in each patient was classified with the use of four existing systems, and the number of patients classified as having multidirectional instability was compared among the classification systems. Second, the definition of multidirectional instability was modified so that the result of laxity testing was the criterion for making the diagnosis, and the changes in the distribution of patients with a diagnosis of multidirectional instability were analyzed. RESULTS: Classification with the four existing systems resulted in significant differences in the number of patients diagnosed as having multidirectional instability, with two (1.2%), seven (4.2%), thirteen (7.7%), and fourteen patients (8.3%) so diagnosed (p < 0.05). Modification of the definition of multidirectional instability so that it was based on laxity testing resulted in a wide variation in the number of patients diagnosed as having multidirectional instability; these numbers ranged from fourteen (8.3%) to 139 (82.7%) (p < 0.05). CONCLUSIONS: This study demonstrated that variations in the criteria used for the diagnosis of multidirectional instability significantly affect the distribution of patients with that diagnosis. The use of laxity testing tends to result in an overestimation of the number of patients with this condition. This observation is important because the results of studies may vary if patients with traumatic instability are considered to have multidirectional instability on the basis of laxity testing. Investigators studying patients with multidirectional instability should carefully define the inclusion criteria that they used.

Adolescent↗
PubMed2003

Thermal capsular shrinkage for treatment of multidirectional instability of the shoulder.

BACKGROUND: Capsular laxity is the main pathology in patients with multidirectional instability, and thermal shrinkage has been commonly employed to treat this condition. The objective of this study was to evaluate thermal capsular shrinkage as a treatment of multidirectional instability of the shoulder. METHODS: Nineteen consecutive patients with multidirectional instability were treated with thermal shrinkage. Fifteen patients had involuntary instability, and four had voluntary instability. The predominant direction of the instability was anteroinferior in ten patients and posterior in five; four patients had instability in multiple directions. Patients were followed for a minimum of two years or until surgical failure and recurrence of symptoms. Postoperatively, the patients wore a sling for three weeks, and they were evaluated regularly at three, six, and twelve months. The Western Ontario Shoulder Instability Index as well as subjective and objective evaluations of the patient's function, range of motion, pain, and instability were used as clinical outcome measures. RESULTS: Nine patients had recurrence of the instability at an average of nine months (range, seven to fourteen months) following the surgical procedure. Four patients had sensory dysesthesias in the axillary nerve distribution, and one of them had deltoid weakness. All neurological symptoms resolved within nine months. The surgical procedure failed in the five patients with predominantly posterior instability. It failed in only two of the ten patients with predominantly anteroinferior instability, and overall this group had objective improvement. CONCLUSIONS: Thermal capsular shrinkage used to treat multidirectional instability had a substantial failure rate with associated postoperative complications, including recurrence of instability (nine of the nineteen patients), stiffness (five patients), and neurological symptoms (four patients).

Adolescent↗
PubMed1994

[Post-operative instability after lamino-arthrectomy for degenerative lumbar stenosis].

PURPOSE OF THE STUDY: The purpose of this paper was to investigate the post-operative instability after laminoarthrectomy for degenerative lumbar stenosis, and to evaluate the functional results when instability was present. MATERIAL AND METHOD: Thirty-eight patients presenting with degenerative lumbar stenosis were operated on at a mean age of 64 years, and were reviewed after a 6 years average follow-up (range 4-8). A laminectomy with partial arthrectomy removing the medial aspect of the articular facets was performed in all cases, extended on one level in 16 cases, 2 levels in 16 cases, 3 levels in 4 cases, and 4 levels in 2 cases. Functional results were evaluated according to Lassale criteria. Radiographic evaluation included measurement of static instability by comparing pre operative and last available X-Rays according to Johnsson and Lassale, and measurement of dynamic instability according to Dupuis. RESULTS: Mean relative gain was 57 per cent; result was rated as excellent in 11 cases, good in 17 cases, and poor in 10 cases. No instability was observed in 14 cases. A pre-existing instability was not modified at follow-up in 10 cases; spinal instability was aggravated or induced by surgery in 14 cases, with 8 antelisthesis (mean slip 6 mms), 2 retrolisthesis, and 4 scoliosis with rotatory dislocation: mean pre-operative angulation was 7 degrees; mean angulation at follow-up was 17 degrees. A dynamic instability was observed in 4 cases. Mean relative gain of the 14 patients with instability at follow-up was 58 per cent; relative gain was 62 per cent in patients with antero-posterior instability, relative gain was 40 per cent in patients with rotatory instability and scoliosis. No correlation was observed between functional results and static or dynamic instability. RESULTS: These results suggest that post-operative dynamic instability is uncommon after lamino-arthrectomy in elderly. On the other hand, a static instability is observed in half of patients at follow-up. Increase of a pre-existing slip is frequently observed but is moderate and does not impair the functional result. Increase of a pre-existing scoliosis is more worrying and is associated with less satisfactory functional results. Internal fixation should be recommended particularly when a scoliosis is present.

Aged↗
PubMed1997

Cytogenetic abnormalities and microsatellite instability in endometrial adenocarcinoma.

Recently various authors described a new mechanism involved in the genesis of some tumors, which is characterized by a tendency for replication mistakes and by genomic instability of microsatellite repeats. This instability can be revealed through the shift in the electrophoretic mobility of the analyzed fragments, which is due to a different number of repeat units. This phenomenon is widely documented in colorectal tumors of patients affected by hereditary nonpolyposis colorectal carcinoma (HNPCC). We performed a cytogenetic and molecular study of 23 endometrial adenocarcinomas to investigate the presence of genomic instability and to evaluate the possibility of a positive correlation with specific chromosomal changes. The study of genomic instability was performed using 23 microsatellites localized over 8 chromosomes. Genomic instability of microsatellites was observed in 3 cases over all 8 analyzed chromosomes. The tumoral stage of cases with microsatellite instability does not differ significantly from the remaining tumors. As a matter of fact several cases showing no evidence of instability were more advanced (II B, III A) than tumors with instability. In ten cases we observed trisomy of chromosome 10, in some as a sole anomaly. The 3 cases with genomic instability revealed a near-diploid karyotype and all showed the presence of a supernumerary marker derived from chromosome 1 rearrangements. A derivative chromosome 1 was revealed in 4 cases without evidence of microsatellite instability. It should be noted that the presence of many unidentified markers and the small number of tumors with instability do not allow us to give a definitive significance to this observation. Our results indicate that there is not an apparent correlation between microsatellite instability and specific chromosomal abnormalities. Moreover, we did not find any correlation between pathological characteristics of the tumor and genomic instability. Microsatellite instability appears to be a relatively rare event in endometrial carcinoma.

Adenocarcinoma↗
PubMed2005

Signet ring cell carcinoma of the colorectum: correlations between microsatellite instability, clinicopathologic features and survival.

Colorectal cancer with microsatellite instability has a characteristic clinicopathologic profile, featuring right-sided, lymphocyte-rich tumors with a better prognosis than microsatellite stable (MSS) carcinoma. Mucinous and signet ring cell carcinomas are both over-represented among microsatellite instability-high cancers. The clinicopathologic features of mucinous microsatellite instability-high cancer parallel those of the overall microsatellite instability-high set, but it is not known whether the same is true for signet ring cell carcinoma, particularly given the fact that signet ring histology is a well-documented adverse prognostic factor. We recorded age, sex, tumor size, site, grade, stage, histologic pattern, growth pattern, Crohn-like reaction, vascular invasion and tumor-infiltrating lymphocytes in 72 resected signet ring cell carcinomas of the colorectum. Microsatellite instability was determined by a combination of polymerase chain reaction and immunohistochemical stains for hMLH1, hMSH2 and hMSH6. Tumors with instability at >30% of informative markers and/or loss of hMLH1 or hMSH2 expression were designated microsatellite instability-high; all others were classified as MSS. A total of 22 (31%) signet ring cell carcinomas were microsatellite instability-high. Compared to MSS signet ring cell carcinoma, they were more likely to be right-sided (81 vs 45%, P=0.005) and to affect older patients (68 vs 26%, P=0.0007) of female sex (59 vs 28%, P=0.03). Crohn-like reaction (45 vs 16%, P=0.02) and high tumor infiltrating lymphocyte counts (32 vs 8%, P=0.03) were more common in the microsatellite instability-high setting. There was no significant difference in 5-year survival in microsatellite instability-high vs MSS patients (41 vs 34%, P=0.3). In conclusion, approximately one-third of signet ring carcinomas of the colorectum are microsatellite instability-high. Microsatellite instability-high signet ring carcinomas share clinicopathologic features with other microsatellite instability-high cancers: older age group, female preponderance, right-sided location, Crohn-like reaction and numerous tumor-infiltrating lymphocytes. Microsatellite instability status does not appear to be a significant predictor of survival in signet ring cell carcinoma of the colorectum.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Development and reliability of the ankle instability instrument.

CONTEXT: Functional ankle instability has been defined in a variety of ways. Factors that are frequently used in this definition include a history of a severe ankle sprain, a history of multiple ankle sprains, and a recurrent feeling of instability or "giving way." With all the variations in defining functional ankle instability, it becomes increasingly important to develop a more consistent framework for assessing this instability. OBJECTIVE: To develop a new ankle instability assessment tool, the Ankle Instability Instrument, and evaluate the reliability of this instrument. DESIGN: Test-retest reliability was evaluated using intraclass correlation coefficients (2,1) for each item, each factor, and the total score between test days 1 and 2. Cronbach alpha was calculated to estimate internal consistency of the 12 items. SETTING: Classrooms, offices, athletic fields, and private residences. PATIENTS OR OTHER PARTICIPANTS: College students (29 males, 72 females, age = 20.7 +/- 2.7 years), including 73 (72%) with and 28 (28%) without a history of ankle injury. MAIN OUTCOME MEASURE(S): Subjects were asked to complete the Ankle Instability Instrument on 2 occasions approximately 1 week apart. RESULTS: An exploratory factor analysis of the Instrument produced 3 factors and reduced it from 21 to 12 items. The factors accounted for 32.3%, 10.7%, and 7.0% of the variance, respectively. Together, these factors accounted for 50.0% of the variance in the responses to the Instrument. Test-retest reliability ranged from .70 (SEM = 0.28) to .98 (SEM = 0.06) for the individual items and .95 (SEM = 1.85) for the Instrument overall. The Cronbach alpha coefficient was .92 for factor 1 (severity of initial ankle sprain), .87 for factor 2 (history of ankle instability), .81 for factor 3 (instability during activities of daily life), and .89 for the Instrument overall. CONCLUSIONS: The creation of the Ankle Instability Instrument is a first step in recognizing a more objective way of identifying patients suffering from functional ankle instability. The high reliability we found shows that self-reporting of ankle symptoms is a feasible, appropriate way to obtain information on the presence of instability symptoms. Additionally, through this preliminary study, we found 3 factors that represent unique and important components of functional ankle instability. Clinicians and researchers can, therefore, use these 12 items, either alone or in combination with other information, to determine if functional ankle instability is present.

Journal Article↗
PubMed1997

Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer.

Two recent lines of evidence raise the possibility that instability in germ-line or somatic cells arises by a common mechanism that involves defective mismatch repair. Mutations in mismatch-repair proteins are known to cause instability in hereditary nonpolyposis colorectal cancer, instability that is physically similar to germ-line instability observed in Huntington disease (HD). Furthermore, both germ-line and somatic-cell instability are likely to be mitotic defects, the former occurring early in embryogenesis. To test the hypothesis that defective repair is a common prerequisite for instability, we have utilized two disease groups that represent different instability "conditions." Germ-line instability within simple tandem repeats (STR) at 10 loci in 29 HD families were compared with somatic instability at the same loci in 26 colon cancer (CC) patients with identified or suspected defects in mismatch-repair enzymes. HD is known to be caused by expansion within the CAG repeat of the locus, but the extent or pattern of STR instability outside this region has not been examined systematically. We find a distinctly different pattern of STR mutation in the two disease groups, suggesting different mechanisms. Instability in HD is generally confined to a single locus, whereas instability is widespread for the same loci in CC. Our data do not support a causative role for defective mismatch-repair enzymes in instability associated with HD; rather, our data are consistent with a model in which DNA structure may inhibit normal mismatch repair at the expansion site.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2006

Immunohistochemical staining of hMLH1 and hMSH2 reflects microsatellite instability status in ovarian carcinoma.

Microsatellite instability is due to defects in the family of DNA repair genes, primarily hMLH1 and hMSH2, which can be detected by immunohistochemical staining. However, it is unclear whether immunohistochemical staining can accurately predict microsatellite instability status. We sought here to evaluate the sensitivity, specificity, and predictive values of immunostaining for the expression of the DNA mismatch-repair genes hMLH1 or hMSH2 in predicting microsatellite instability in ovarian carcinoma. Tissue microarrays with specimens from 322 women with primary ovarian carcinoma were stained with antibodies to hMLH1 and hMSH2; cases in which either hMLH1 or hMSH2 were negative were analyzed for microsatellite instability with the five-marker panel recommended by the National Cancer Institute (BAT26, BAT25, D5S346, D2S123, and D17S250). Microsatellite instability was also analyzed in another 19 cases selected at random in which both hMLH1 and hMSH2 were positive. Tumors with instability at two or more of the five NCI markers were considered to have a high level of microsatellite instability; tumors showing instability at only one marker were considered microsatellite instability-low; and tumors in which no markers exhibited microsatellite instability were considered microsatellite stable. We found that negative staining for hMLH1 protein (five cases) or hMSH2 protein (two cases) was associated with high level of microsatellite instability. The sensitivity and specificity of immunohistochemical staining for hMLH1 were 62 and 100% and those of hMSH2 alone were 25 and 100%. Combining loss of expression of both hMLH1 and hMSH2 led to sensitivity, specificity, and positive and negative predictive values of 87, 100, 100, and 95%. These results suggest that use of a two-molecule panel (hMLH1 and hMSH2) can accurately determine the microsatellite instability status of patients with ovarian cancer.

Adaptor Proteins, Signal Transducing↗