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PubMed1991

Ambulatory monitoring and electronic measurement of urinary leakage in the diagnosis of detrusor instability and incontinence.

The ability of conventional artificial filling urodynamic studies (CMG) and ambulatory monitoring during natural bladder filling (AM) to detect phasic detrusor activity (detrusor instability) and incontinence was studied in 52 patients suspected on clinical grounds of having bladder dysfunction, but in whom a CMG had not provided an adequate explanation of their symptoms. Detrusor instability (DI) was found on AM in 31 patients who were not unstable on conventional CMG using the criteria of the International Continence Society: DI was diagnosed on filling in 20 patients and on provocation in a further 11. Incontinence was demonstrated by electronic nappy testing in 23 patients: 13 had urge incontinence due to DI, 7 had genuine stress incontinence alone and 3 had both genuine stress incontinence and detrusor instability. Thus DI was diagnosed significantly more frequently by AM than by CMG. Ambulatory monitoring was more sensitive in the diagnosis of instability and incontinence and it may prove to be a valuable aid in the diagnosis of bladder dysfunction not detected during conventional cystometry.

Adult↗
PubMed1999

Pure stress leakage symptomatology: is it safe to discount detrusor instability?

OBJECTIVE: To determine whether the combination of a urological history and urinary diary, with rigorous selection criteria, can be used to define a group of women on whom urodynamic assessment is unnecessary prior to offering surgery for urinary stress incontinence. DESIGN: Retrospective review of the urodynamic records of women attending for assessment between January 1992 and December 1996. SETTING: Urodynamic Department, Southmead Hospital, Bristol. POPULATION: 5193 women who attended the urodynamic clinic during the five year study period. METHODS: Self-completion of a urinary diary in the preceding week before urodynamic assessment and a detailed urological history before undergoing cystometry by all women in the study period. Data were entered onto a computer database. Women reporting stress incontinence in the absence of bladder filling symptoms, with a normal urinary diary showing daytime frequency of seven times or less and nocturia of no more than once, had the results of their filling cystometry analysed. RESULTS: Of 5193 women, 555 had symptoms of pure stress incontinence and a normal urinary diary. Incontinence was confirmed objectively in 81%, with 9% having incontinence secondary to detrusor instability; 5% had detrusor instability as the sole cause of their incontinence with 4% having a mixed picture of detrusor instability incontinence and urethral sphincter weakness. CONCLUSION: Genuine stress incontinence cannot be diagnosed reliably from a urological history, even when rigorous selection criteria are used in combination with a normal urinary diary. Without cystometry, incontinence secondary to detrusor instability will be missed.

Female↗
PubMed2002

Why do women have voiding dysfunction and de novo detrusor instability after colposuspension?

OBJECTIVE: To investigate the causes of voiding dysfunction and new detrusor instability after colposuspension. DESIGN: Prospective, observational study. SETTING: Urogynaecology unit, district general hospital. POPULATION: Seventy-seven women undergoing colposuspension for genuine stress incontinence. METHODS: The following factors were investigated: 1. bladder neck elevation by magnetic resonance imaging before and after surgery; 2. urethral compression by measuring bladder neck approximation to the pubis with magnetic resonance imaging after surgery (anterior compression) and the distance between the medial stitches during surgery (lateral compression); 3. clinical and urodynamic factors. MAIN OUTCOME MEASURES: 1. Post-operative voiding function (i.e. first day of voiding and day of catheter removal); 2. objective evidence of detrusor instability three months post-operatively. RESULTS: Pre-operative peak flow rate (P = 0.004), straining during voiding (P = 0.005), increasing age (P < 0.001), operative elevation (P < 0.001) and anterior urethral compression (P = 0.001) were associated with the number of days of post-operative catheterisation. Increasing age (P = 0.02), previous bladder neck surgery (P = 0.04), operative elevation (P = 0.049) and anterior urethral compression (P < 0.001) were associated with detrusor instability at three months. CONCLUSION: Surgical factors (bladder neck elevation and compression) are associated with voiding dysfunction and detrusor instability after colposuspension. These findings have implications for prevention.

Adult↗
PubMed1992

Urethral instability.

Urethral instability is still evolving as a clinical entity. Using pressure variation of 15 cm water or more at the point of maximum urethral pressure (MUP), urethral pressure profilometry on patients referred for urodynamic assessment for lower urinary tract symptoms revealed urethral instability in 6.4% of 608 patients. The close association between urethral and detrusor instability was noted. Urethral instability appears to be a cause of frequency and urgency of micturition, and its presence increase the risk of urinary incontinence.

Adult↗
PubMed2006

Evidence of increased chromosomal instability in infertile males after exposure to mitomycin C and caffeine.

AIM: To evaluate the genetic instability of 11 fertile and 25 infertile men. METHODS: The methodology of sister chromatid exchanges (SCEs) was applied to cultures of peripheral blood lymphocytes, and the levels of SCEss were analyzed as a quantitative index of genotoxicity, along with the values of the mitotic index (MI) and the proliferation rate index (PRI) as qualitative indices of cytotoxicity and cytostaticity, respectively. The genotoxic and antineoplastic agent, mitomycin C (MMC), and caffeine (CAF)--both well-known inhibitors of DNA repair mechanism--were used in an attempt to induce chromosomal instability in infertile men, so as to more easily detect the probable underlying damage on DNA. RESULTS: Our experiments illustrated that infertile men, compared with fertile ones, demonstrated a statistically significant DNA instability in peripheral blood lymphocytes after being exposed simultaneously to MMC and CAF. CONCLUSION: The current study showed vividly that there was genetic instability in infertile men which probably contributes to the development of an impaired reproductive capacity.

Adult↗
PubMed1991

Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n.

The sequence of a Pst I restriction fragment was determined that demonstrate instability in fragile X syndrome pedigrees. The region of instability was localized to a trinucleotide repeat p(CCG)n. The sequence flanking this repeat were identical in normal and affected individuals. The breakpoints in two somatic cell hybrids constructed to break at the fragile site also mapped to this repeat sequence. The repeat exhibits instability both when cloned in a nonhomologous host and after amplification by the polymerase chain reaction. These results suggest variation in the trinucleotide repeat copy number as the molecular basis for the instability and possibly the fragile site. This would account for the observed properties of this region in vivo and in vitro.

Base Sequence↗
PubMed1985

Large-scale preparation of ribulosebisphosphate carboxylase from a recombinant system in Escherichia coli characterized by extreme plasmid instability.

An ampicillin-resistant, RecA- strain of Escherichia coli (HB101) harboring the multicopy pBR322 plasmid containing the structural gene for ribulosebisphosphate carboxylase from Rhodospirillum rubrum was used to prepare large quantities of the carboxylase protein. This recombinant system was characterized by extreme plasmid instability, which resulted in part from the 1.7-fold faster growth rate of plasmid-free cells and in part from very rapid rates of plasmid segregation. The plasmid-containing organisms produced and excreted a large amount of beta-lactamase activity, with the result that ampicillin selection could only be maintained for a very short period of time, after which the plasmid-containing (carboxylase-producing) cells were overgrown by plasmid-free cells. The instability was so severe that even isolated colonies prepared on ampicillin-containing plates were impure and contained plasmid-free cells. Nevertheless, large quantities of carboxylase protein could be obtained from this system by using a highly dilute inoculum which allows selection of ampicillin-resistant (carboxylase-producing) organisms for a sufficient period of time so that the period of growth under nonselective conditions was minimized, and cells harvested at high cell densities contained large amounts of the carboxylase protein. In the present instance, 300-liter fermentations were initiated with a 0.3-microliter inoculum of freshly grown cells. After 20 h of growth in rich medium containing ampicillin, the harvested cells contained 74 g of ribulosebisphosphate carboxylase protein (average of two separate cultures). These results are discussed in terms of the general nature of plasmid instability and protocols available to minimize the effects of such instability.

Ampicillin↗
PubMed2004

Genetic instability of heterozygous, hybrid, natural wine yeasts.

We describe a genetic instability found in natural wine yeasts but not in the common laboratory strains of Saccharomyces cerevisiae. Spontaneous cyh2(R)/cyh2(R) mutants resistant to high levels of cycloheximide can be directly isolated from cyh2(S)/cyh2(S) wine yeasts. Heterozygous cyh2(R)/cyh2(S) hybrid clones vary in genetic instability as measured by loss of heterozygosity at cyh2. There were two main classes of hybrids. The lawn hybrids have high genetic instability and generally become cyh2(R)/cyh2(R) homozygotes and lose the killer phenotype under nonselective conditions. The papilla hybrids have a much lower rate of loss of heterozygosity and maintain the killer phenotype. The genetic instability in lawn hybrids is 3 to 5 orders of magnitude greater than the highest loss-of-heterozygosity rates previously reported. Molecular mechanisms such as DNA repair by break-induced replication might account for the asymmetrical loss of heterozygosity. This loss-of-heterozygosity phenomenon could be economically important if it causes sudden phenotype changes in industrial or pathogenic yeasts and of more basic importance to the degree that it influences the evolution of naturally occurring yeast populations.

Crosses, Genetic↗
PubMed1988

La Crosse virus infection of mammalian cells induces mRNA instability.

La Crosse virus infection of BHK cells leads to a dramatic shutoff of not only host protein synthesis but also viral protein synthesis later in infection. This shutoff can be accounted for by the loss of the cytoplasmic cellular and viral mRNAs. The induction of mRNA instability requires extensive virus replication, since when cycloheximide is added early in infection the preexisting viral and cellular mRNAs do not decrease upon incubation of the cultures. Pretreatment of the cultures with actinomycin D does not affect the ability of La Crosse virus infection to induce mRNA instability, and examination of the rRNAs shows no evidence of specific degradation due to activation of the interferon-associated latent RNase. The induction of mRNA instability therefore does not appear to operate through an interferon pathway. Viral mRNA synthesis, on the other hand, is not turned off during infection, and the cap-dependent endonuclease involved in viral mRNA initiation may be responsible for the mRNA instability.

2',5'-Oligoadenylate Synthetase↗
PubMed1999

Increased instability of human CTG repeat tracts on yeast artificial chromosomes during gametogenesis.

Expansion of trinucleotide repeat tracts has been shown to be associated with numerous human diseases. The mechanism and timing of the expansion events are poorly understood, however. We show that CTG repeats, associated with the human DMPK gene and implanted in two homologous yeast artificial chromosomes (YACs), are very unstable. The instability is 6 to 10 times more pronounced in meiosis than during mitotic division. The influence of meiosis on instability is 4.4 times greater when the second YAC with a repeat tract is not present. Most of the changes we observed in trinucleotide repeat tracts are large contractions of 21 to 50 repeats. The orientation of the insert with the repeats has no effect on the frequency and distribution of the contractions. In our experiments, expansions were found almost exclusively during gametogenesis. Genetic analysis of segregating markers among meiotic progeny excluded unequal crossover as the mechanism for instability. These unique patterns have novel implications for possible mechanisms of repeat instability.

Chromosomes, Artificial, Yeast↗
PubMed2002

Chromosome instability as a result of double-strand breaks near telomeres in mouse embryonic stem cells.

Telomeres are essential for protecting the ends of chromosomes and preventing chromosome fusion. Telomere loss has been proposed to play an important role in the chromosomal rearrangements associated with tumorigenesis. To determine the relationship between telomere loss and chromosome instability in mammalian cells, we investigated the events resulting from the introduction of a double-strand break near a telomere with I-SceI endonuclease in mouse embryonic stem cells. The inactivation of a selectable marker gene adjacent to a telomere as a result of the I-SceI-induced double-strand break involved either the addition of a telomere at the site of the break or the formation of inverted repeats and large tandem duplications on the end of the chromosome. Nucleotide sequence analysis demonstrated large deletions and little or no complementarity at the recombination sites involved in the formation of the inverted repeats. The formation of inverted repeats was followed by a period of chromosome instability, characterized by amplification of the subtelomeric region, translocation of chromosomal fragments onto the end of the chromosome, and the formation of dicentric chromosomes. Despite this heterogeneity, the rearranged chromosomes eventually acquired telomeres and were stable in most of the cells in the population at the time of analysis. Our observations are consistent with a model in which broken chromosomes that do not regain a telomere undergo sister chromatid fusion involving nonhomologous end joining. Sister chromatid fusion is followed by chromosome instability resulting from breakage-fusion-bridge cycles involving the sister chromatids and rearrangements with other chromosomes. This process results in highly rearranged chromosomes that eventually become stable through the addition of a telomere onto the broken end. We have observed similar events after spontaneous telomere loss in a human tumor cell line, suggesting that chromosome instability resulting from telomere loss plays a role in chromosomal rearrangements associated with tumor cell progression.

Animals↗
PubMed1977

Carpal instability in rheumatoid arthritis and calcium pyrophosphate deposition disease. Pathogenesis and roentgen appearance.

The roentgen appearance and pathogenesis of carpal instability are described in an evaluation of patients and cadavers with rheumatoid arthritis and calcium pyrophosphate deposition disease. Dorsiflexion (16%) and palmar flexion (8%) instability occurs in rheumatoid arthritis, particularly in patients with moderate to advanced disease. Navicular-lunate dissociation frequently accompanies dorsiflexion instability and results from involvement of the interosseous ligament between the two bones by rheumatoid pannus. Carpal instability and navicular-lunate dissociation also accompany pyrophosphate arthropathy, resulting from calcific deposition and cystic degeneration of ligamentous structures.

Adult↗
PubMed1999

Association of p53 genomic instability with the glutathione S-transferase null genotype in gastric cancer in the Portuguese population.

AIMS: p53 gene mutations are the most common genetic changes known to occur in human cancer. In previous studies, the presence of alterations to the p53 gene has been linked to the null phenotype of the glutathione S-transferase mu gene (GSTM1). GSTM1 appears to be part of a protective mechanism against the development of cancers in which environmental chemical carcinogens are involved. To screen for such an association in stomach cancer, p53 allelic loss and genomic instability and GSTM1 genotypes were investigated in gastric tumour DNA samples from 113 patients. METHODS: The polymerase chain (PCR) reaction was used to amplify a (CA) repeat array in the p53 locus; electrophoresis, genotyping, and allele quantification were performed using an automated DNA sequencer and Genescan software. The presence of the GSTM1 gene was determined by means of a differential PCR in which multiple genes were co-amplified in the same reaction tube. RESULTS: Loss of heterozygosity (LOH) of the p53 gene was found in 36 of 87 informative cases and genomic instability was present in eight of 113 cases. Further analysis into histological subtypes and sites of tumours did not show any positive association with p53 loss. An association between the presence of LOH and the GSTM1 null genotype was not seen; however, all the samples with genomic instability of the p53 gene (eight of 113) also showed a GSTM1 null genotype. CONCLUSION: This study does not support the hypothesis of an association between LOH in the p53 gene and the GSTM1 null genotype, but suggests that the GSTM1 null genotype might influence p53 genomic instability.

Alleles↗
PubMed2005

Undulation versus Frederiks instability in nematic elastomers in an external electric field.

We study the behaviour of a nematic side-chain elastomer under the influence of an external static electric field for a specific geometry. For this investigation, the nematic elastomer is considered to be a perfect insulator. On the basis of a macroscopic description we generalize the classical Frederiks transition in a low-molecular-weight (LMW) nematic liquid crystal to the elastomeric case. We predict, using a linear stability analysis, that the onset of the instability can be qualitatively different from the LMW case: in liquid crystalline elastomers an undulation instability can arise at onset. Whether the analogue of a Frederiks instability or an undulation instability occurs first depends on the sample thickness as well as on the material parameters. It turns out that the parameter which describes the coupling between the deformations of the elastomer and the relative rotations between the elastomer and the director field of the nematic phase is most important for the predicted response of the system. Furthermore, we find that the magnitude of the critical electric field is much higher in the elastomeric than in the low-molecular-weight case.

Journal Article↗
PubMed1978

Post-traumatic ligamentous instabilities of the wrist.

Dorsiflexion, palmar flexion, ulnar translocation, and dorsal carpal subluxation are four, not uncommon, post-traumatic carpal ligamentous instabilities. Palmar carpal subluxation is a theoretical possibility. Dorsiflexion and palmar flexion instabilities are named for the way the distal lunate articular surface dorsally and palmarly, respectively. Ulnar translocation, and dorsal and ventral carpal subluxations are named according to movement of the entire carpus at the radiocarpal joint. Early detection of traumatic carpal instabilities is necessary to encourage optimal treatment of these significant carpal malalignments. These and other patients with disabling wrist problems may be evaluated by a "ligamentous instability series."

Adult↗
PubMed2005

Chromosomal instability in unirradiated hemopoietic cells resulting from a delayed in vivo bystander effect of gamma radiation.

Untargeted effects of ionizing radiation (de novo effects in the unirradiated descendants or neighbors of irradiated cells) challenge widely held views about the mechanisms of radiation-induced DNA damage with implications for the health consequences of radiation exposures particularly in the context of the induction of malignancy. To investigate in vivo untargeted effects of sparsely ionizing (low linear energy transfer) radiation, a congenic sex-mismatch bone marrow transplantation protocol has been used to repopulate the hemopoietic system from a mixture of gamma-irradiated and nonirradiated hemopoietic stem cells such that host-, irradiated donor- and unirradiated donor-derived cells can be distinguished. Chromosomal instability in the progeny of irradiated hemopoietic stem cells accompanied by a reduction in their contribution to the repopulated hemopoietic system is consistent with a delayed genomic instability phenotype being expressed in vivo. However, chromosomal instability was also shown in the progeny of the nonirradiated hemopoietic stem cells implicating a bystander mechanism. Studies of the influence of irradiated recipient stromal microenvironment and experiments replacing irradiated cells with irradiated cell-conditioned medium reveal the source of the in vivo bystander effect to be the descendants of irradiated cells, rather than irradiated cell themselves. Thus, it is possible that a radiation-induced genomic instability phenotype in vivo need not necessarily be a reflection of intrinsically unstable cells but the responses to ongoing production of inflammatory-type damaging signals as a long-term unexpected consequence of the initial single radiation exposure.

Animals↗
PubMed2005

Morphologic instability and cancer invasion.

PURPOSE: A solid tumor embedded in host tissue is a three-dimensional arrangement of cells and extracellular matrix that acts as a sink of oxygen and cell nutrients, thus establishing diffusional gradients. This and variations in vascular density and blood flow typically produce intratumoral regions of hypoxia and acidosis, and may result in spatially heterogeneous cell proliferation and migration. Here, we formulate the hypothesis that through these mechanisms, microenvironmental substrate gradients may drive morphologic instability with separation of cell clusters from the tumor edge and infiltration into surrounding normal tissue. EXPERIMENTAL DESIGN: We used computer simulations and in vitro experiments. RESULTS: We provide evidence that morphologic instability could be suppressed in vivo by spatially homogeneous oxygen and nutrient supply because normoxic conditions act both by decreasing gradients and increasing cell adhesion and, therefore, the mechanical forces that maintain a well-defined tumor boundary. A properly working tumor microvasculature can help maintain compact noninfiltrating tumor morphologies by minimizing oxygen and nutrient gradients. In contrast, antiangiogenic therapy, by increasing microenvironmental heterogeneity, may promote morphologic instability, leading to invasive patterns even under conditions in which the overall tumor mass shrinks. CONCLUSIONS: We conclude that therapeutic strategies focused solely on reduction of vascular density may paradoxically increase invasive behavior. This theoretical model accounts for the highly variable outcome of antiangiogenic therapy in multiple clinical trials. We propose that antiangiogenic strategies will be more consistently successful when aimed at "normalizing" the vasculature and when combined with therapies that increase cell adhesion so that morphologic instability is suppressed and compact, noninvasive tumor morphologies are enforced.

Antineoplastic Agents↗
PubMed2006

Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability.

PURPOSE: Most breast cancers have chromosomal instability that seems related to defective mitotic spindle checkpoints. Because the molecular basis of this defect is unknown, we evaluated breast cancer cell lines and tissues for possible defects involving the major mitotic checkpoint genes responsible for maintaining chromosomal stability. EXPERIMENTAL DESIGN: We analyzed sequences and expression levels (RNA and protein) of eight major spindle checkpoint genes (MAD1L1, MAD2L1, MAD2L2, BUB1, BUB1B, BUB3, CDC20, and TTK) in a panel of 12 breast cancer cell lines, most with established genetic instability and defective spindle damage checkpoint response. mRNA levels of these genes were also measured in primary tumor samples, and immunohistochemical staining was used to evaluate BUB1B protein levels in a panel of 270 additional cases of breast cancer. RESULTS: No functionally significant sequence variations were found for any of the eight genes in the breast cancer cell lines with chromosomal instability. More surprisingly, the mRNA and protein levels for these checkpoint genes are significantly higher in the genetically unstable breast cancer cell lines and in high-grade primary breast cancer tissues than in the stable (and checkpoint proficient) MCF-10A and normal mammary epithelial cells, or in normal breast tissues. In fact, overexpression of the BUB1B protein is a marker that recognizes nearly 80% of breast cancers in paraffin-embedded tissues. CONCLUSIONS: Defective mitotic spindle checkpoints in breast cancer are most likely not caused by low expression or mutations of these eight checkpoint genes. High levels of these particular transcripts could represent a cellular compensation for defects in other molecular components of the mitotic spindle damage checkpoint, and increased expression of these genes might be markers of breast cancers with chromosomal instability.

Adenocarcinoma, Mucinous↗