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PubMed2004

Outer breast quadrants demonstrate increased levels of genomic instability.

BACKGROUND: Theory holds that the upper outer quadrant of the breast develops more malignancies because of increased tissue volume. This study evaluated genomic patterns of loss of heterozygosity (LOH) and allelic imbalance (AI) in non-neoplastic tissues from quadrants of diseased breasts following mastectomy to characterize relationships between genomic instability and the propensity for tumor development. METHODS: Tissues from breast quadrants were collected from 21 patients with various stages of breast carcinoma. DNA was isolated from non-neoplastic tissues using standard methods and 26 chromosomal regions commonly deleted in breast cancer were examined to assess genomic instability. RESULTS: Genomic instability was observed in breast quadrants from patients with ductal carcinomas in situ and advanced carcinomas. Levels of instability by quadrant were not predictive of primary tumor location (P =.363), but outer quadrants demonstrated significantly higher levels of genomic instability than did inner quadrants (P =.017). Marker D8S511 on chromosome 8p22-21.3, one of the most frequently altered chromosomal regions in breast cancer, showed a significantly higher level of instability (P =.039) in outer compared with inner quadrants. CONCLUSIONS: Non-neoplastic breast tissues often harbor genetic changes that can be important to understanding the local breast environment within which cancer develops. Greater genomic instability in outer quadrants can partially explain the propensity for breast cancers to develop there, rather than simple volume-related concepts. Patterns of field cancerization in the breast appear to be complex and are not a simple function of distance from a developing tumor.

Breast↗
PubMed2003

Are chromosomal instabilities induced by exposure of cultured normal human cells to low- or high-LET radiation?

Radiation-induced genomic instability has been proposed as a very early, if not an initiating, step in radiation carcinogenesis. Numerous studies have established the occurrence of radiation-induced chromosomal instability in various cells of both human and rodent origin. In many of these studies, however, the cells were not "normal" initially, and in many cases they involved tumor-derived cell lines. The phenomenon clearly would be of even greater interest if it were shown to occur generally in cells that are normal at the outset, rather than cells that may have been "selected" because of a pre-existing susceptibility to induced instability. As a test of the generality of the phenomenon, we studied low-passage normal diploid human fibroblasts (AG1521A) to determine whether they are susceptible to the induction of chromosomal instability in the progeny of surviving cells after exposure in G(0) to low- and high-LET radiation. Cytogenetic assays for instability were performed on both mixed populations of cells and clones of cells surviving exposure. We found no evidence for the induction of such instability as a result of radiation exposure, though we observed a senescence-related chromosomal instability in the progeny of both irradiated and unirradiated cell populations.

Cell Cycle↗
PubMed2001

DNA instability and human disease.

It is now well established that non-Mendelian examples of DNA instability are associated with human disease. Most malignancies are associated with various chromosomal instabilities, such as aneuploidy, gene amplification, and chromosomal deletion. Furthermore, widespread microsatellite instability (MSI) is associated with a variety of tumors, and instability at specific dynamic repeat expansions underlies a family of neurologic disorders. Inactivation of DNA mismatch repair genes results in genomic instabilities affecting microsatellite regions. Mutations in genes involved in DNA polymerization or Okazaki fragment processing are also associated with MSI. Such instabilities convey a 'mutator' phenotype which is pathogenic. The mechanisms controlling trinucleotide repeat expansions are less well understood. Why this type of genomic instability is particularly pathogenic to neurons is also not clear. An understanding of what normally maintains stability is the first step towards preventing such loss of control and maintaining health.

Cell Transformation, Neoplastic↗
PubMed1982

Detrusor instability score in the evaluation of stress urinary incontinence.

The major cause of failure in the surgical treatment of stress urinary incontinence (SUI) in women is an occult detrusor instability. In order to detect detrusor instability and its degree, urological histories were standardized by scoring the replies to ten specific questions with O (indicative of SUI), 1 or 2 (slightly and markedly indicative of detrusor instability, respectively). The sum of the scores was termed the "detrusor instability score" (DIS). The DIS was calculated for 134 patients both preoperatively and 2 years after operation, and 112 of these women were also evaluated by bead-chain urethrocystography (UCG) before operation. The 10% failure rate among the 72 patients with a DIS of 0-7 (exclusive or nearly exclusive detrusor instability) was significantly less than the 32% rate in the 62 women with a DIS of 8-16 (SUI complicated by marked detrusor instability). The 38% failure rate in 47 women of peri- or post-menopausal age and having a DIS of 8-16 was higher than the 10% in the other 87 women. An increased risk of failure was also found in patients who had a DIS of 8-16 together with either a urethral inclination angle of 80 degrees or less (46% failure rate in 28 women) or a posterior urethrovesical angle of 160 degree or less (43% failure rate in 30 women) in lateral bead-chain UCG during straining. The mean DIS decreased after successful surgery, but remained constant in cases of failure. The scored urological data facilitate the detection of patients with detrusor instability. This is potentiated by those lateral bead-chain UCG findings which indicate a low motility of the proximal urethra or bladder neck.

Adult↗
PubMed1983

Effect of microrheology of blood on the apparent flow instability in a rotational viscometer.

Flow instability (formation of vortices and a concurrent increase in the apparent viscosity) was studied in the rotational rhombospheroid viscometer of 3 degrees, 5 degrees and 10 degrees gaps over a range of speeds from 10 to 300 r.p.m.. Comparisons between different blood systems were carried out mainly at 250 r.p.m. Experiments were carried out on blood samples obtained directly from human subjects, or from the Blood Bank, or from horses. Reconstituted suspensions of red cells in albumin or dextran were also used. Apparent flow instability was found to be not solely a function of blood viscosity, but a multiple function of many viscosity factors or blood subphases, including instability-decreasing factors such as haematocrit and aggregation of red cells; and instability-increasing factors such as rigidity of red cells; and thus specific to and characteristic of individual blood samples. Apparent instability can be described by multiple regressions as a function, Z, of red cell rigidity, Tk, blood viscosity, napp, and aggregation of red cells, AG; for example: Z = -28.29 + 26.24 Tk + 0.109 napp (r = 0.816; P less than 0.001), or Z = 5.90 - 0.0165 AG - 0.752 napp (r = 0.573; P less than 0.05). The apparent instability can be seen only in one-third of blood samples obtained from horses, and in more than half of blood samples obtained from human donors; majority of human donors shows apparent instability below 3 per cent.

Animals↗
PubMedDate not supplied

The DNA-instability test as a specific marker of malignancy and its application to detect cancer clones in borderline malignancy.

Recent progress in cytogenetic and biochemical mutation assay technologies has enabled us to detect single gene alterations and gross chromosomal rearrangements, and it became clear that all cancer cells are genetically unstable. In order to detect the genome-wide instability of cancer cells, a new simple method, the DNA-instability test, was developed. The methods to detect genomic instability so far reported have only demonstrated the presence of qualitative and quantitative alterations in certain specific genomic loci. In contrast to these commonly used methods to reveal the genomic instability at certain specific DNA regions, the newly introduced DNA-instability test revealed the presence of physical DNA-instability in the entire DNA molecule of a cancer cell nucleus as revealed by increased liability to denature upon HCl hydrolysis or formamide exposure. When this test was applied to borderline malignancies, cancer clones were detected in all cases at an early-stage of cancer progression. We proposed a new concept of "procancer" clones to define those cancer clones with "functional atypia" showing positivities for various cancer markers, as well as DNA-instability testing, but showing no remarkable ordinary "morphological atypia" which is commonly used as the basis of histopathological diagnosis of malignancy.

Animals↗
PubMed1998

[Detrusor instability--an important but underestimated factor in urinary incontinence in women].

157 consecutive female patients complaining of urinary incontinence were studied by history and urodynamics. 21 of them (13.4%) demonstrated urge-incontinence due to severe detrusor instability, 20 (12.7%) showed mixed (both urge and stress) incontinence, 14 (9%) only detrusor instability and 12 (7.6%)--stress incontinence accompanied by detrusor instability. Pure stress incontinence was diagnosed in 79 cases (50.3%) while 11 patients (7%) manifested no abnormality during the urodynamics. A total of 67 patients (42.7%) showed urodynamic evidence of detrusor overactivity. In 55 (35% of the studied subjects) it was the main urodynamic finding. The prevalence of detrusor instability was higher among those with recurrent incontinence and was the highest (60%) among the women with more than one previous operations. When urge incontinence was present it occurred at detrusor pressures lower than the maximum urethral closure pressure, which implies possible failure of the sphincteric mechanisms associated with detrusor instability. 14% of the women with detrusor instability did not report complaints typical for this disorder but had history of stress incontinence alone. The authors confirm the necessity of objective assessment of the lower urinary tract in all cases with history suspicious of detrusor instability as well as when surgical treatment for stress incontinence is planned.

Adult↗
PubMed1999

Radiation-induced cytogenetic instability in vivo.

Radiation-induced cytogenetic instability has been well documented in a number of laboratories, and we have hypothesized that such instability is the initiating event in the process leading to radiation-induced cancer. To date most studies of radiation-induced instability have used systems in which cells are rapidly dividing. For this phenomenon to have significance for radiation carcinogenesis, it must be established that instability can be induced in vivo in less rapidly dividing fully differentiated tissues known to be at risk. In the present study, we have examined the kinetics of radiation-induced cytogenetic instability in mammary epithelial cells after irradiation in vivo. Having established that instability could arise in vivo in intact mammary tissue, we subsequently demonstrated a dose-response relationship both in vitro and in vivo and demonstrated a lower frequency of instability after fractionated exposures.

Animals↗
PubMed1999

Microsatellite instability and loss of heterozygosity in primary and secondary proliferative lesions of the parathyroid gland.

Clonality and genetic abnormalities were evaluated to characterize proliferative lesions of the parathyroid gland. Fourteen lesions from patients with single-gland proliferation (adenomas [PA]), 6 lesions from patients with multiple-gland proliferation (primary hyperparathyroidism [PHPT]), and 47 lesions from 16 patients with secondary hyperparathyroidism (SHPT) were examined. Based on the X chromatin inactivation pattern, which was revealed by a HUMARA assay of lesions from female patients (n = 34; 24 informative cases), monoclonality was demonstrated in 6 of 10 PA (60%), 2 of 5 PHPT (40%), and 6 of 9 SHPT lesions (14 of 27 lesions, 52%). By PCR analysis using 17 microsatellite markers on eight chromosomes (chromosomes 1, 2, 3, 5, 6, 11, 13, and 17), loss of heterozygosity was sporadically observed in 4 of 14 PA, 3 of 6 PHPT, and 7 of 47 SHPT lesions, in most cases on a single locus of chromosome 11. On the other hand, microsatellite instability was observed more frequently: ie, in six PA, five PHPT, and nine SHPT lesions. The profile of microsatellite instability depended on the type of proliferation: microsatellite instability (MI) seemed to cluster in the region of chromosome 11 in PA. Microsatellite instability on TP53 was observed in 3 of 6 PHPT lesions and in 2 of 47 SHPT lesions but in no PA lesions. Microsatellite instability on Mfd47 was observed in only some cases of SHPT. Although no significant correlation was identified among histologic features, clonality, and genetic abnormalities in cases of primary proliferation, genetic abnormalities were more frequently observed in SHPT lesions that lacked fat tissues. Thus, genetic instability might be important in proliferative disorders of the parathyroid gland, either with or without uremia. However, genetic instability seems to be induced by different mechanisms in the three types of proliferation studied. In SHPT, the absence of fat tissues may indicate that the proliferation is accompanied by genetic changes.

Adenoma↗
PubMed2000

Genetic instability and hematologic disease risk in Werner syndrome patients and heterozygotes.

Werner syndrome (WRN) is an uncommon autosomal recessive disease in which progeroid features are associated with genetic instability and an elevated risk of neoplasia. We have used the glycophorin A (GPA) somatic cell mutation assay to analyze genetic instability in vivo in WRN patients and heterozygotes. GPA variant frequencies were determined for 11 WRN patients and for 10 heterozygous family members who collectively carry 10 different WRN mutations. Genetic instability as measured by GPA O/N allele loss variant frequency was significantly increased, and this increase was strongly age-dependent in WRN patients. GPA O/N allele loss variants were also significantly elevated in heterozygous family members, thus providing the first evidence for in vivo genetic instability in heterozygous carriers in an autosomal recessive genetic instability syndrome. Our results and comparable data on other human genetic instability syndromes allow an estimate of the level of genetic instability that increases the risk of human bone marrow dysfunction or neoplasia.

Adolescent↗
PubMed2001

Intrachromosomal genomic instability in human sporadic colorectal cancer measured by genome-wide allelotyping and inter-(simple sequence repeat) PCR.

We have used genome-wide allelotyping with 348 polymorphic autosomal markers spaced, on average, 10 cM apart to quantitate the extent of intrachromosomal instability in 59 human sporadic colorectal carcinomas. We have compared instability measured by this method with that measured by inter-(simple sequence repeat) PCR and microsatellite instability assays. Instability quantitated by fractional allelic loss rates was found to be independent of that detected by microsatellite instability analyses but was weakly associated with that measured by inter-(simple sequence repeat) PCR. A set of seven loci were identified that were most strongly associated with elevated rates of fractional allelic loss and/or inter-(simple sequence repeat) PCR instability; these seven loci were on chromosomes 3, 8, 11, 13, 14, 18, and 20. A lesser association was seen with two loci flanking p53 on chromosome 17. Coordinate loss patterns for these loci suggest that at least two separate sets of cooperating loci exist for intrachromosomal genomic instability in human colorectal cancer.

Alleles↗
PubMed2001

[Antero-lateral impingement syndrome and evaluation of chronic post-traumatic instability in the talo-crural joint].

The aim of this paper was to asses whether the antero-lateral impingement syndrome is a sequel of ligamentous-capsular element failure in the talo-crural joint. The authors evaluated stability of the talocrural joint on a stand by one of the authors (E. G.). Using Zwipp's method and the authors own method the kind and degree of instability were assessed. Radiological features of antero-lateral instability were found in 17 patients (4.6%)--7 female (1.9%) and 10 male patients (2.7%) aged from 25 to 54 years. 4 grade II antero-lateral instabilities 2 grade III lateral instabilities and 1 grade V instability concomitant to antero-lateral impingement were found in the female patients. Whereas among the male patients 6 grade II antero-lateral instabilities and 4 grade III instabilities were found.

Adult↗
PubMed2002

Efficacy of the Star Excursion Balance Tests in Detecting Reach Deficits in Subjects With Chronic Ankle Instability.

OBJECTIVE: Chronic instability after lateral ankle sprain has been shown to cause balance deficits during quiet standing. Although static balance assessment in those with ankle instability has been thoroughly examined in the literature, few researchers have studied performance on more dynamic tasks. Our purpose was to determine if the Star Excursion Balance Tests (SEBTs), lower extremity reach tests, can detect deficits in subjects with chronic ankle instability. DESIGN AND SETTING: We performed all testing in a university athletic training facility. We tested lower extremity reach using the SEBTs, which incorporates single-leg stance with maximal reach of the contralateral leg. SUBJECTS: Twenty subjects with unilateral, chronic ankle instability (age = 19.8 +/- 1.4 years, height = 176.8 +/- 4.5 cm, mass = 82.9 +/- 21.2 kg) and 20 uninjured subjects matched by sex, sport, and position (age = 20.2 +/- 1.4 years, height = 178.7 +/- 4.1 cm, mass = 82.7 +/- 19.9 kg). MEASUREMENTS: We measured the reach distances in centimeters (cm) and averaged 3 reaches in each of the 8 directions while the subjects stood on each leg for data analysis. RESULTS: The group with chronic ankle instability demonstrated significantly decreased reach while standing on the injured limb compared with the matched limb of the uninjured group (78.6 cm versus 82.8 cm). Additionally, subjects with chronic ankle instability reached significantly less when standing on their injured limbs as compared with their uninjured limbs (78.6 cm versus 81.2 cm). CONCLUSIONS: The SEBTs appear to be an effective means for determining reach deficits both between and within subjects with unilateral chronic ankle instability.

Journal Article↗
PubMed2000

Understanding multidirectional instability of the shoulder.

OBJECTIVE: To provide an overview of the evaluation and treatment of the patient with multidirectional shoulder instability. DATA SOURCES: I searched MEDLINE for the years from 1980 to 2000 using the key words "shoulder joint," "instability," "dislocation," "multidirectional shoulder instability," and "inferior capsular shift." DATA SYNTHESIS: Multidirectional instability is symptomatic glenohumeral subluxation or dislocation in more than 1 direction: anterior, inferior, or posterior. The primary pathology is a loose and patulous capsule, and the entity is more common than previously recognized. Multidirectional instability affects young, sedentary patients with generalized ligamentous laxity, often with bilateral symptoms and an atraumatic history, but it also affects athletes, many of whom have sustained injuries. Patients with multidirectional instability may also have Bankart lesions and humeral head impression defects. CONCLUSIONS/RECOMMENDATIONS: Patients with multidirectional instability must be identified before appropriate treatment can be initiated. If a course of rehabilitation fails to improve the patient's symptoms, an inferior capsular shift procedure has been demonstrated to be an effective surgical option.

Journal Article↗
PubMed1979

[Gonarthrosis following persisting knee joint instability (author's transl)].

It is frequently assumed that persisting instability of the knee joint leads to gonarthrosis. We have reviewed recent and primary radiograms of 32 patients with old knee trauma resulting in prolonged capsular and ligamentous instability in order to study the eventual development of secondary gonarthrosis. Our results were as follows: All primarily intact joints developed gonarthrosis after an average of 46 months of permanent instability. Primarily existing gonarthrosis increased with exception of 3 cases. The tendency to develop an arthrosis seems to be proportional to the duration of instability; the type of instability apparently has no influence on the development of an instability gonarthrosis. Operative procedures having been performed prior to final stabilysing surgery obviously do not cause the development of secondary gonarthrosis. The persisting instability of the knee joint after combined discontinuation of capsule and ligaments therefore may be regarded as a prearthrotic factor.

Adult↗
PubMed1984

Classification of carpal instability.

A classification of carpal instability is presented based on anatomic and kinematic characteristics of the wrist. Three main types of instability are recognized. Lateral carpal instability may occur between the scaphoid and the trapezium-trapezoid, the scaphoid and the capitate, and the scaphoid and the lunate. Scapholunate dissociation or rotatory subluxation of the scaphoid is the most frequent representative of this type. Medical carpal instability may take place between the triquetrum and the lunate, or the triquetrum and the hamate. Dissociation between lunate and triquetrum results in static forms of instability, while disruption of triquetrohamate support leads to dynamic forms of instability. Proximal carpal instability may lead to disruption at the level of the radiocarpal joint or at the level of the midcarpal joint.

Aged↗
PubMed1983

[Instability of recombinant molecules].

The regions and mechanisms of recombinant DNAs instability are reviewed, in particular, the mechanisms of the replication instability expressed as elimination of recombinant DNA from cells and the mechanisms of structural instability revealed as spontaneous alteration of the chemical structure of these DNAs. The replication instability is subdivided into that induced by ineffective replication systems, and that induced by disturbances in the process of correct partitioning of the plasmids between dividing cells. The structural instability is subdivided into topological one occurring due to formation in the hybrid plasmids of the anomalous elements of the secondary structure-"loops", the regulatory instability caused by nonbalanced transcription streams and metabolic instability induced because of the protein superproduction which is energy capacious and not necessary for normal cell growth.

Base Sequence↗
PubMed1984

Generation of spatially periodic patterns by a mechanical instability: a mechanical alternative to the Turing model.

We have studied the generation of spatial patterns created by mechanical (rather than chemical) instabilities. When dissociated fibroblasts are suspended in a gel of reprecipitated collagen, and the contraction of the gel as a whole is physically restrained by attachment of its margin to a glass fibre meshwork, then the effect of the fibroblasts' traction is to break up the cell-matrix mixture into a series of clumps or aggregations of cells and compressed matrix. These aggregations are interconnected by linear tracts of collagen fibres aligned under the tensile stress exerted by fibroblast traction. The patterns generated by this mechanical instability vary depending upon cell population density and other factors. Over a certain range of cell concentrations, this mechanical instability yields geometric patterns which resemble but are usually much less regular than the patterns which develop normally in the dermis of developing bird skin. We propose that an equivalent mechanical instability, occurring during the embryonic development of this skin, could be the cause not only of the clumping of dermal fibroblasts to form the feather papillae, but also of the alignment of collagen fibres into the characteristic polygonal network of fibre bundles - which interconnect these papillae and which presage the subsequent pattern of the dermal muscles serving to control feather movements. More generally, we suggest that this type of mechanical instability can serve the morphogenetic functions for which Turing's chemical instability and other reaction-diffusion systems have been proposed. Mechanical instabilities can create physical structures directly, in one step, in contrast to the two or more steps which would be required if positional information first had to be specified by chemical gradients and then only secondarily implemented in physical form. In addition, physical forces can act more quickly and at much longer range than can diffusing chemicals and can generate a greater range of possible geometries than is possible using gradients of scalar properties. In cases (such as chondrogenesis) where cell differentiation is influenced by the local population density of cells and extracellular matrix, the physical patterns of force and distortion within this extracellular matrix should even be able to accomplish the spatial control of differentiation, usually attributed to diffusible 'morphogens'.

Animals↗