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PubMed2001

Marangoni Flow Driven Instabilities and Marginal Regeneration.

Fingering instabilities in films moving along wetted surfaces, dimpling in horizontal liquid films, and the drainage of vertical soap films by marginal regeneration are caused by surface tension gradients along the perimeter of the thin film. These gradients lead to a mechanical instability which involves Marangoni type liquid flow. It is possible to describe the conditions for the onset of marginal regeneration with a critical number of the ratio between the driving force for the Marangoni flow and the friction of film elements that move relative to their surroundings. This ratio is called the Mysels number. A linear stability analysis leads to a scaling relation lambda approximately h(Ca)(-1/3) between the wavelength lambda of the instability and the capillary number Ca (Ca=/etaV(s)/gamma. In experiments with several Marangoni-driven instabilities this scaling relation has been found; it illustrates the general applicability in the understanding of flow phenomena of this type. Copyright 2001 Academic Press.

Journal Article↗
PubMed1994

DNA helical instability facilitates initiation at the SV40 replication origin.

Previous analysis of mutations in bacterial and yeast replication origins has identified a genetic component, termed a DNA unwinding element (DUE), whose intrinsic helical instability is essential for origin function. For the SV40 replication origin, we show here that the early palindrome (EP) and A + T-rich (AT) domains both exhibit helical instability, despite their dissimilar A + T compositions. To test the possible contribution of helical instability to SV40 origin function, the relationship between helical stability of mutant origin sequences and their known origin activity in vitro and in vivo was examined. Origin activity correlates inversely with the helical stability of mutations within the EP domain but not the AT domain or the T-antigen binding domain. The quantitative correlation holds for four different measures of origin activity determined in vitro and in vivo. An even better-correlated collection of mutations was found in a specific portion of the EP domain. This specific EP subdomain coincides with the sequence known to be strand-separated after T-antigen binds the origin in vitro and with the origin of bidirectional replication in vivo. Our analysis of origin mutations indicates that the helical instability of the specific EP subdomain is required to facilitate T-antigen-induced melting and the initiation of DNA replication. The sensitivity of the required EP subdomain to mutations that stabilize the DNA helix defines the DUE of the SV40 replication origin.

Adenine↗
PubMed1994

Mathematics of microbial plasmid instability and subsequent differential growth of plasmid-free and plasmid-containing cells, relevant to the analysis of experimental colony number data.

Differential growth of plasmid-containing and plasmid-free microbial cells occurs in many and probably most plasmid systems. Misinterpretation of differential growth as replicational, recombinational, or segregational stability or instability can unfortunately result in grossly erroneous conclusions about replication, recombination, or segregation in plasmid model systems for studies of such phenomena. The differential growth rate should ideally be measured every time that the rate of loss due to instability per se is measured. Unfortunately, the possibility of differential growth has been ignored in most plasmid model systems, since the mathematics of instability and differential growth has not usually been dealt with in ways that are intuitively understandable to experimental microbiologists. Nevertheless, rapid diagnosis of differential growth, and accurate estimation of differential growth rate and rate of loss due to instability per se, can be done by analysis of colony number data using only the relatively simple mathematics described in this review. This review is intended for experimental microbiologists rather than for theoretical population geneticists or for pure mathematicians. However, the same mathematics described in this review is also applicable to certain simple model systems for plasmid ecology or evolution in natural or clinical environments.

Bacteria↗
PubMed1997

Lymphocyte-specific genomic instability and risk of lymphoid malignancy.

Genetic instability is a force that links evolution, development and cancer. We have developed a quantifiable assay for a particular kind of lymphocyte-specific genetic instability (antigen receptor trans-rearrangements) mediated by the V(D)J recombinase complex. We find that the level of this type of instability correlates (at the population level) with risk for lymphoid malignancy. We have developed a murine model for this measure of instability to allow a more refined analysis of the genetic and environmental factors that sum to define population cancer risk.

Animals↗
PubMed1997

Genomic instability, as measured by microsatellite alterations, is not associated with liver tumor development in the genetically susceptible B6C3F1 mouse.

Certain human heritable forms of colon cancer have characteristically high frequencies of microsatellite alterations. These microsatellite changes are markers of genomic instability and the direct consequence of mutations in genes involved with DNA mismatch repair processes, which are in part responsible for maintaining the sequence integrity of the genome. Given that the B6C3F1 mouse is genetically predisposed to develop liver tumors we were interested in determining whether tumors derived in this strain of mouse may contain alterations in microsatellite sequences. The analysis of 48 tumors at 24 different microsatellite loci revealed that microsatellite alterations were detected in 12 of 48 tumors (25%). Although this frequency is relatively high, 11 of the 12 tumors exhibited only a single alteration and in 10 of those tumors this change was at the same microsatellite locus. Microsatellite alterations were also detected in the DNA isolated from 6 of 22 (27%) normal liver tissues with 4 of the 6 occurring at the same locus where the majority of changes were observed in the tumors. Based on these results, we conclude that the microsatellite alterations present in the mouse liver tumor tissue are most likely the result of spontaneous mutational events. Consequently, the genomic instability operational in a particular type of hereditary human colon cancer does not appear to be operational in the genetically predisposed B6C3F1 mouse liver. In addition, we demonstrated that the activation of the H-ras gene, which causes some forms of genetic instability in vitro, does not contribute to genetic instability within liver tumors as measured by microsatellite alterations.

Animals↗
PubMed1995

Genomic instability in B-cells and diversity of recombinations that activate c-myc.

Genetic rearrangements activating the proto-oncogene c-myc comprise a mandatory oncogenic step in plasma cell tumor development in BALB/cAnPt mice. In the majority of plasmacytomas, c-myc activating rearrangements take the form of reciprocal chromosomal translocations t(12;15) that juxtapose c-myc to the immunoglobulin heavy chain alpha locus (IgH alpha) in particular the switch alpha region (S alpha). The genetic basis for the prevalence of S alpha/c-myc recombinations in BALB/cAnPt plasmacytomas is not known but may be related to a hypothetical regional genomic instability of the c-myc and IgH alpha loci in BALB/cAnPt mice. We wished to test whether the genomic instability of both loci might be revealed by the diversity of genetic recombinations that can be observed in IgH alpha and c-myc. We employed PCR methods to detect new recombinations of c-myc and IgH alpha in the preneoplastic stage of plasma cell tumor development and found that c-myc can be joined to more genes or genomic regions than known before. This is indicative but does not formally prove a particular genomic instability of c-myc and IgH alpha in BALB/cAnPt B cells. Since defective DNA repair provides a mechanistic explanation for genomic instability, we measured the efficiency of repair in IgH alpha and c-myc using an assay that quantitates the removal of UV-induced pyrimidine dimers within specific genomic regions. We used plasmacytoma XRPC 24 as a model system and found that both IgH alpha and c-myc were poorly repaired, whereas c-abl, a proto-oncogene not related to conventional pristane-induced plasmacytoma-genesis, was efficiently repaired.

Animals↗
PubMed1976

[Rotatory instability of the knee joint in cases of previously treated "Unhappy Triad" (author's transl)].

The combined injury of the ligaments and capsular structures of the knee joint always causes rotatory instability as the sum of all or some a.m. injuries (Slocum; Nicholas). This has to be taken into account in the operative treatment. We have followed 14 patients with old "unhappy triad" injuries who had been operated upon with the question in mind whether the usual procedures with reefing of the ligaments or plastic replacements including meniscectomies, but without paying attention to the lax posterior capsule could correct the typical anteromedial rotatory instability. The results showed that this was true only in about half the cases. The remaining patients continued to complain about instability in the operated knee joint. Objectively, the pre-operatively positive rotatory drawer sign remained unchanged. Therefore we conclude that the anteromedial rotatory instability of the knee joint can be improved by the procedure devised by Slocum and Nicholas.

Adult↗
PubMed1989

Diagnostic approach in instability and irritative state of a "lumbar motion segment" following disc surgery--failed back surgery syndrome.

A diagnostic protocol for patients with suspected instability and irritative state of a "lumbar motion segment" following lumbar disc surgery is presented and the results of internal fixation are analyzed. In this group of patients the clinical picture and physical signs may be quite distinct and suggestive of instability and irritation of a "lumbar motion segment", however, in isolation, they do not allow to decide upon surgery. Radiological studies favour a decision for surgery only in cases with an obvious instability of a "motion segment". Anaesthethizing the articular nerves permits localization of the irritable segment and non-surgical therapeutic decisions (thermocoagulation) can only be taken in cases of an isolated facet-syndrome when instability has been ruled out. The trial plaster jacket holds the most important position with respect to the indication for internal fixation as demonstrated by the conformity of the results of the plaster jacket and the results of surgery. After internal stabilization excellent, good, satisfactory and moderate results were obtained in 20, 3, 1 and 1 patients, respectively.

Anesthesia, Spinal↗
PubMedDate not supplied

Metastatic instability of murine tumor metastases: dependence on tumor type.

Fifteen metastatic lines derived in vivo from three syngeneic murine tumors, the sarcomas SA-NH and SA-4020 and the hepatic carcinoma HCA-I, were assessed for their stability of metastasis formation upon isotransplantation for several successive generations in syngeneic animals. Change in the metastatic phenotype was actively encouraged by a new procedure, the artificial selection for increased or decreased metastasis formation. Metastatic instability was dependent on tumor type, with five of six lines of tumor SA-NH, one of four lines of tumor SA-4020, and possibly one of five lines of HCA-I changing in lung metastasis formation. The instability of lung metastasis formation was also assessed by analyzing changes in the variance of the lines. Concomitant with a change in metastatic potential for lung metastasis, we observed a similar change for abdominal lymph node metastasis. We also report the selection of a less metastatic line. The variance of lung metastasis increased significantly only in the SA-NH lines. The instability of metastasis formation was attributed to genetic instability of metastatic cell lines.

Animals↗
PubMed1997

Microsatellite instability in breast cancer.

BACKGROUND: Microsatellites are short repetitive nucleotide sequences that, through mutation, can undergo either expansion or contraction. This novel mutational mechanism known as microsatellite instability may play a role in carcinogenesis. We investigated the incidence of microsatellite instability in a series of primary breast carcinoma surgical specimens. METHODS: Using polymerase chain reaction techniques followed by polyacrylamide/urea gel electrophoresis, we analyzed 46 pairs of normal and primary breast tumor samples at seven different microsatellite loci, five of which were located on chromosome 17. RESULTS: Thirteen of our 46 tumors (28.2%) demonstrated microsatellite instability. Five tumors (10.8%) were unstable at two or more loci, and of those, four (8.7%) were unstable at different loci on different chromosomes. An additional five tumors demonstrated loss of heterozygosity alone when compared with their normal counterparts. CONCLUSIONS: These findings indicate that microsatellite instability is present in primary breast cancer populations and, although the mechanism of action has yet to be elucidated, may play a role in breast carcinogenesis.

Breast Neoplasms↗
PubMed2004

Can GH induce chromosome breaks or microsatellite instability in GH-deficient children?

The role of GH in carcinogenesis is unclear. We studied the effect of recombinant human GH (rhGH) in vitro on chromosomal and genomic instability. Thirteen children, aged 9.57 +/- 1.08 yr (mean +/- SEM), with complete (no.=5) or partial (no.=8) GH deficiency were evaluated before and during GH treatment. We examined the incidence of chromosome and chromatid breaks, and microsatellite instability after in vitro addition of two different doses of rhGH to peripheral blood lymphocytes obtained from the patients. No differences were observed between the samples of GH-deficient children before and after GH therapy as regards the percentage of chromosome and chromatids breaks, and in microsatellite instability. Our data show that in vitro addition of rhGH does not induce chromosomal and/or genomic instability in cultured lymphocytes.

Cells, Cultured↗
PubMed2003

Initiation of genetic instability and tumour formation: a review and hypothesis of a nongenotoxic mechanism.

Genetic instability in tumours results in cell-to-cell variability of genome which parallels the cell-to-cell variability of microscopic morphology and of behaviour (tumour cell heterogeneity) of these lesions. Genetic instability is therefore strongly supported as the fundamental process by which normal tissue cells become neoplastic. The commonest current suggestion for the mechanism of initiation of carcinogenesis is a 'direct hit' mutation of a 'cancer critical' gene in a somatic cell by carcinogenic agents. However, this mechanism does not account for the activity of carcinogens which are not mutagens, and does not explain why many mutagens are not carcinogens. This paper proposes a nonmutational (nongenotoxic) mechanism of initiation of genetic instability in previously normal cells as follows: 1) During S phase of local tissue stem cells, carcinogen binds to and disables the proofreading enzyme for a new DNA strand. 2) While it is disabled, the proofreading enzyme fails to correct illicit changes in the nucleotide sequence(s) for one or more genes for proofreading fidelity or repair of DNA in the new strand of DNA, which passes to one daughter cell. 3) When this daughter cell is a continuing stem cell, the resulting cell line remains immortal, and retains its prior differentiation commitment to produce daughter cells of a particular type. However, the acquired genetic instability in this cell line causes secondary mutations which lead to uncontrolled growth, and the heterogeneous morphologic and behavioural features of a tumour resembling the parent cell type.

Animals↗
PubMed2004

Social instability in female rats: effects on anxiety and buspirone efficacy.

RATIONALE: Buspirone produces inconsistent effects in laboratory rodents. Individual housing increases the efficacy of buspirone in male rats, suggesting that the effects of this (and other) compounds become conspicuous in animals showing anxiety-like states. The effect of individual housing was, however, weak, and evident only when the locomotor suppressive effects of buspirone dissipated (i.e. 4 h after treatment). OBJECTIVES: The effects of social instability, a recently developed model of social stress in female rats, was investigated on both anxiety and the anxiolytic efficacy of buspirone. METHODS: Female rats were exposed to alternate days of isolation and moderate crowding for 2 weeks. Group composition was changed for each crowding phase. Basal anxiety and the anxiolytic efficacy of buspirone were assessed by the social interaction test of anxiety 24 h after the last crowding phase. RESULTS: Crowding appeared stressful, as it increased plasma glucocorticoid levels in less than 1 h. Anxiety-like behaviours were increased by social instability compared with stable group housing. In group housed controls, buspirone markedly suppressed locomotion, without clear effects on anxiety-related behaviours. Social instability attenuated the locomotor suppressive effects of buspirone, but made the anxiolytic effects of the compound more conspicuous. The effects of individual housing (assessed earlier) and social instability (assessed here) on buspirone efficacy appear qualitatively different. CONCLUSIONS: Buspirone abolishes stress-induced anxiety, but has no anxiolytic effects in controls. This is consistent with clinical findings, as the drug decreases anxiety in anxious patients but not in healthy humans. Laboratory models involving stress-induced anxiety-like states can improve our understanding of drug effects and efficacy.

Animals↗
PubMed2000

Differential somatic CAG repeat instability in variable brain cell lineage in dentatorubral pallidoluysian atrophy (DRPLA): a laser-captured microdissection (LCM)-based analysis.

Employing a laser-captured microdissection (LCM), we have investigated the somatic instability of CAG repeats in the variable brain cell lineage in three patients with dentatorubral pallidoluysian atrophy (DRPLA). LCM enables the isolation of single lineage brain cells for subsequent molecular analysis. We have found that CAG repeat size and the range of CAG repeats in the cerebellar granular cells is smaller than those in cerebellar glial cells. Similarly, those in the cerebral neuronal cells are significantly shorter than those in cerebral glial cells. These data directly indicate that the CAG repeat is relatively more stable in neuronal cells than in glial cells. Furthermore, cerebellar granular cells show significantly smaller main CAG repeat size and CAG repeat range than either Purkinje cells or cerebral neuronal cells, suggesting that somatic instability in the CAG repeat is markedly variable even among the different types of neuronal populations. The cell-specific CAG repeat instability may thus be more complex than has previously been considered. LCM is a powerful tool for elucidating the mechanism of the triplet repeat instability of each cell type.

Adult↗
PubMed1997

Latent chromosomal instability in cancer patients.

There is increasing evidence that, similar to what is found with other genetic disorders, genomic instability is one of the most general features of cancer. Different forms of manifestation including latent instability have been suggested. To recognize latent chromosomal instability we treated lymphocyte cultures of cancer patients and healthy persons with caffeine, two different doses of bleomycin, and a combination of bleomycin and caffeine. The preliminary results demonstrate that, although the rate of spontaneous chromosomal aberrations is similar in both investigated groups, the lymphocytes of cancer patients display an increased susceptibility to treatment with bleomycin and caffeine. In distinguishing between healthy individuals and those with malignancy, treatment with 30 micrograms/ml bleomycin appears to be most important. Values of chromosomal change above one break per cell, more than 45% cells with chromosomal alterations, and more that two cells with chromosomal rearrangements are suggestive of malignancy. These findings imply that treatment of lymphocyte cultures with bleomycin and caffeine could be a useful assay for monitoring chromosomal instability, and thus detecting a predisposition to malignant disease. In this respect further investigations on a greater amount of material should be performed.

Adult↗
PubMed1990

Clinical, echocardiographic and Doppler correlates of clinical instability with onset of atrial fibrillation.

To identify clinical and Doppler echocardiographic correlates of instability with the onset of atrial fibrillation (AF), 87 consecutive patients with new-onset AF who had echocardiograms recorded during that hospital admission while in sinus rhythm were studied. Reviewers who were blinded to echocardiographic and Doppler data classified 51 patients (59%) as unstable because of the development of angina, congestive heart failure, syncope or hypotension with the onset of AF. Echocardiographic and Doppler data on transmitral blood flow velocity were analyzed by a single reviewer who was blinded to other clinical data. Multiple logistic regression analysis identified 3 variables as independent predictors of clinical instability with the onset of AF: (1) history of prior myocardial infarction (p less than 0.02); (2) echocardiographic evidence of left ventricular dysfunction (p less than 0.03); and (3) Doppler evidence of increased atrial filling fraction (p less than 0.0001). An atrial filling fraction threshold of 0.40 had a sensitivity for predicting clinical instability of 80% and a specificity of 72%. These data are consistent with the hypothesis that patients who are more dependent on the atrial contribution to ventricular filling are at increased risk of instability with AF due to the loss of atrial systole.

Aged↗
PubMed1992

Variations in expression and treatment of transient neurocardiogenic instability.

Whereas previous reports describe the head-up tilt test for the diagnosis of neurocardiogenic syncope, this study focuses on the events leading up to syncope. These events are part of a spectrum of neurocardiogenic instability; syncope is the extreme end point. This report is based on tilt studies of 108 patients, aged 4 to 22 years (mean 13), with histories of either unexplained syncope or episodes of visual blackout without loss of consciousness. The tilt study was positive in 74% of the patients. Five stages of neurocardiogenic instability were identified, ranging from excessive fluctuations in heart rate to full syncope. Uncommon reactions during the tilt study include dissociation of hypotension, bradycardia and vagal symptoms and extended asystole (greater than 6 seconds). Therapy with beta 1-selective blockers was highly successful in suppressing symptoms of neurocardiogenic instability. Repeat tilt testing with beta blockade has resulted in either normal or markedly improved stability in heart rate and blood pressure. Neurocardiogenic instability is a common condition occurring between age 10 and 20 years. It appears to be self-limited.

Adolescent↗
PubMed1991

The role of prostaglandins in detrusor instability.

To study the role of prostaglandin production by detrusor muscle in women with idiopathic primary detrusor instability, biopsies of detrusor muscle were obtained from 20 women. Nine women had detrusor instability, and 11 women had stable bladders. Prostaglandin F2 alpha and the stable metabolites of prostacyclin and thromboxane A2, namely, 6-keto-prostaglandin F1 alpha and thromboxane B2, respectively, were measured after in vitro incubations of detrusor muscle for 3 hours. A significant reduction in the production of 6-keto-prostaglandin1 alpha in women with detrusor instability was noted. There were no differences in the production of prostaglandin F2 alpha and thromboxane B2, between women with stable and unstable bladders. These results suggest for the first time that women with idiopathic primary detrusor instability may have a deficient production of prostacyclin.

6-Ketoprostaglandin F1 alpha↗