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PubMed1999

The influence of interstitial telomeric sequences on chromosome instability in human cells.

Although most telomere repeat sequences are found at the ends of chromosomes, some telomeric repeat sequences are also found at intrachromosomal locations in mammalian cells. Several studies have found that these interstitial telomeric repeat sequences can promote chromosome instability in rodent cells, either spontaneously or following ionizing radiation. In the present study we describe the extensive cytogenetic analysis of three different human cell lines with plasmids containing telomeric repeat sequences integrated at interstitial sites. In two of these cell lines, Q18 and P8SX, instability has been detected in the chromosome containing the integrated plasmid, involving breakage/fusion/bridge cycles or amplification of the plasmid DNA, respectively. However, the data suggest that the instability observed is characteristic of the general instability in these cell lines and that the telomeric repeat sequences themselves are not responsible. Consistent with this interpretation, the chromosome containing an integrated plasmid with 500 bp of telomeric repeat sequences is highly stable in the third cell line, SNG28, which has a relatively stable genome. The stability of the chromosome containing the integrated plasmid sequences in SNG28 makes this an excellent cell line to study the effect of ionizing radiation on the stability of interstitial telomeric sequences in human cells.

Carcinoma, Squamous Cell↗
PubMed2005

Consistency of urodynamic parameters in children with detrusor instability: how many times should the bladder be filled?

INTRODUCTION: It is recommended that the bladder be filled at least twice to perform a standard urodynamic study. However, the procedure is time-consuming and distressing for both the patient and the professional. The impact of the number of fillings on urodynamic parameters in children with normal urodynamic results and those with detrusor instability is presented in this study. PATIENTS AND METHODS: Urodynamic data from 70 children with detrusor instability and 42 with normal urodynamic parameters who had undergone 3 consecutive fillings in a single session during a 2-year period were reviewed retrospectively. The variable parameters that were compared between the 2 groups were the mean bladder capacity ratio, maximum filling pressure and the number of contractions during the filling phase. RESULTS: In the normal group, no difference was found in bladder capacities between the 3 fillings, but there was a significant decrease in the maximum bladder filling pressures in the subsequent fillings. In children with detrusor instability, the number of contractions in the 1st filling was significantly higher than those in the subsequent fillings. Also in this group, a significant difference in the mean bladder capacities between fillings was noted as well as a decrease in the maximum bladder filling pressures in contrast to normal bladders. CONCLUSION: In patients with suspected detrusor instability the bladder should be filled at least twice for a reliable urodynamic assessment. Two normal fillings without contractions, with normal capacity and normal maximum bladder filling pressure are highly suggestive of a normal 3rd filling.

Case-Control Studies↗
PubMed1984

Alpha-adrenergic blockade in the diagnosis of detrusor instability secondary to infravesical obstruction.

Detrusor instability secondary to infravesical obstruction is probably caused by overactive stretch receptors in the bladder wall. Since recent studies have shown that alpha-adrenergic blockade with phenoxybenzamine reduces the intravesical pressure under micturition, we undertook this investigation in order to see if phenoxybenzamine has an effect on detrusor instability caused by infravesical obstruction. We found that the detrusor instability was abolished by phenoxybenzamine, which supports the 'stretch receptor theory'. Further, phenoxybenzamine is probably a good test in the diagnosis of detrusor instability secondary to infravesical obstruction.

Aged↗
PubMed1985

Psychological features of women with idiopathic detrusor instability.

Psychological tests were completed by 57 incontinent women with idiopathic detrusor instability, and compared with those of 22 women with genuine stress incontinence (an anatomical disorder) and published norms. The previously reported findings of hysterical personality traits, situational stresses and sexual dysfunction in patients with detrusor instability were not confirmed. Higher scores for anxiety, neuroticism, hostility, and depression were found in patients with detrusor instability than in controls. These findings, known associations of psychosomatic disorders, lend further support to the view that idiopathic detrusor instability is a psychosomatic disorder.

Adult↗
PubMed2005

Association between 5-lipoxygenase expression and plaque instability in humans.

OBJECTIVE: The participation of 5-lipoxygenase (5-LO) in the development of atherosclerosis has been suggested by recent studies. However, a role for 5-LO as a modulator of atherosclerotic plaque instability has not been previously reported in humans. Thus, the aims of this study was to analyze the expression of 5-LO in human carotid plaques and to investigate the mechanism by which this enzyme could lead to plaque instability and rupture. METHODS AND RESULTS: We obtained atherosclerotic plaques from 60 patients undergoing carotid endarterectomy. We divided the plaques into symptomatic and symptomatic according to clinical evidence of plaque instability. Clinical evidence of plaque instability was provided by the assessment of recent ischemic symptoms attributable to the stenosis and by the presence of ipsilateral cerebral lesion(s) determined by computed tomography. Plaques were analyzed for CD68+ macrophages, CD3+ T cells, alpha-actin+ smooth muscle cells, 5-LO, cyclooxygenase 2, matrix metalloproteinase (MMP)-2, and MMP-9 by immunohistochemical, immunoblotting, and densitometric analyses. MMP activity was assessed by zymography. Leukotriene (LT) B4 and collagen were quantified by ELISA and Sirius red polarization, respectively. The percentage of macrophage-rich and T-cell-rich areas was larger in symptomatic compared with asymptomatic patients (25+/-6% versus 8+/-4%, P<0.0001, and 74+/-17 versus 18+/-4 cell/mm2, P<0.003). 5-LO expression was higher in symptomatic compared with asymptomatic plaques (24+/-4% versus 6+/-3%, P<0.0001) and was associated with increased MMP-2 and MMP-9 expression (27+/-4% versus 7+/-3%, P<0.0001, and 29+/-5% versus 8+/-2%, P<0.0001) and activity and with decreased collagen content (6.9+/-2.4% versus 17.8+/-3.1%, P<0.01). Immunofluorescence showed that 5-LO and MMPs colocalize in activated macrophages. Notably, higher 5-LO in symptomatic plaques correlated with increased LTB4 production (18.15+/-3.56 versus 11.27+/-3.04 ng/g tissue, P<0.0001). CONCLUSIONS: The expression of 5-LO is elevated in symptomatic compared with asymptomatic plaques and is associated with acute ischemic syndromes, possibly through the generation of LTB4, subsequent MMP biosynthesis, and plaque rupture.

Acute Disease↗
PubMed2006

A possible association between coronary plaque instability and complex plaques in abdominal aorta.

OBJECTIVE: Coronary plaque instability causes myocardial infarction (MI). Angiographic lesions with such instability are complex lesions. Complex carotid plaques were reported to be prevalent in unstable angina. We investigated associations between coronary plaque instability, such as MI and angiographic complex coronary lesions, and aortic plaques. METHODS AND RESULTS: Aortic MRI was performed in 146 patients undergoing coronary angiography, of whom 108 had coronary artery disease (CAD) and 44 also had MI. Prevalence of plaques in thoracic and abdominal aortas was higher in patients with than without CAD (73% and 94% versus 32% and 79%), but it was similar in CAD patients with and without MI. Notably, complex plaques in abdominal aorta were more prevalent in CAD patients with than without MI (36% versus 14%; P<0.025). In multivariate analysis, abdominal complex plaques were associated with MI (odds ratio [OR], 4.5; 95% CI, 1.5 to 13.8). Among patients without MI, thoracic and abdominal complex plaques were more prevalent in patients with than without complex coronary lesions (22% and 33% versus 2% and 7%; P<0.05). Abdominal complex plaques were also associated with complex coronary lesions (OR, 9.8; 95% CI, 1.1 to 85.9). CONCLUSIONS: Complex plaques in abdominal aorta were associated with MI and complex coronary lesions, suggesting a link between coronary and aortic plaque instability.

Adult↗
PubMed2004

Inflammation as a possible link between coronary and carotid plaque instability.

BACKGROUND: Multiple complex stenoses, plaque fissures, and widespread coronary inflammation are common in acute coronary syndromes. A systemic cause of atherosclerotic plaque instability is also suggested by studies of ischemic cerebrovascular disease. We investigated the association between coronary and carotid plaque instability and the potential common causal role of inflammation. METHODS AND RESULTS: The ultrasound characteristics of carotid plaques were evaluated retrospectively in patients scheduled for coronary bypass surgery, 181 with unstable and 92 with stable angina, and prospectively in a similar group of patients, 67 with unstable and 25 with stable angina, in whom serum C-reactive protein levels were also measured. The prevalence of carotid plaques was similar in the retrospective and prospective studies and >64% in both unstable and stable coronary patients. The prevalence of complex, presumably unstable carotid plaques was 23.2% in unstable versus 3.2% in stable patients (P<0.001) in the retrospective study and 41.8% versus 8.0% (P=0.002) in the prospective study. C-reactive protein levels were higher in patients with complex (7.55 mg/L) than in those with simple (3.94 mg/L; P<0.05) plaques or without plaques (2.45 mg/L; P<0.05). On multivariate analysis, unstable angina and C-reactive protein levels >3 mg/L were independently associated with complex carotid plaques (OR, 6.09; 95% CI, 1.01 to 33.72; P=0.039, and OR, 5.80; 95% CI, 1.55 to 21.69; P=0.009, respectively). CONCLUSIONS: In unstable angina, plaque instability may not be confined to coronary arteries, and inflammation may be the common link with carotid plaque instability. These observations may have relevant implications for understanding the mechanisms of acute widespread atherothrombotic plaque inflammation.

Aged↗
PubMed2004

Alveolar instability causes early ventilator-induced lung injury independent of neutrophils.

Intratracheal instillation of Tween causes a heterogeneous surfactant deactivation in the lung, with areas of unstable alveoli directly adjacent to normal stable alveoli. We employed in vivo video microscopy to directly assess alveolar stability in normal and surfactant-deactivated lung and tested our hypothesis that alveolar instability causes a mechanical injury, initiating an inflammatory response that results in a secondary neutrophil-mediated proteolytic injury. Pigs were mechanically ventilated (VT 10 cc/kg, positive end-expiratory pressure [PEEP] 3 cm H2O), randomized to into three groups, and followed for 4 hours: Control group (n = 3) surgery only; Tween group (n = 4) subjected to intratracheal Tween (surfactant deactivator causing alveolar instability); and Tween + PEEP group (n = 4) subjected to Tween with increased PEEP (15 cm H2O) to stabilize alveoli. The magnitude of alveolar instability was quantified by computer image analysis. Surfactant-deactivated lungs developed significant histopathology only in lung areas with unstable alveoli without an increase in neutrophil-derived proteases. PEEP stabilized alveoli and significantly reduced histologic evidence of lung injury. Thus, in this model, alveolar instability can independently cause ventilator-induced lung injury. To our knowledge, this is the first study to directly confirm that unstable alveoli are subjected to ventilator-induced lung injury whereas stable alveoli are not.

Animals↗
PubMedDate not supplied

Nutritional depletions in critically ill children: associations with physiologic instability and increased quantity of care.

The association of nutritional depletions with physiologic instability and quantity of care was examined in 60 critically ill children. Nutritional status was evaluated by anthropometric techniques. Physiologic stability was measured by the Physiologic Stability Index and quantity of care was measured by the Therapeutic Intervention Scoring System. Acute protein-energy malnutrition was significantly associated with increased physiologic instability and increased quantity of care (p less than 0.01). This association was present for the total group, children less than 24 months of age, and for these two groups with nonsurvivors excluded. Mortality was also significantly associated with acute protein-energy malnutrition (p less than 0.001). Physiologic instability and increased quantity of care were not associated with chronic protein-energy malnutrition, fat store depletion, or somatic protein store depletion. We conclude that acute protein-energy malnutrition in critically ill children is associated with increased physiologic instability and increased quantity of care.

Child↗
PubMedDate not supplied

Anterolateral rotatory instability of the knee. An analysis of the Ellison procedure.

In an attempt to correct anterolateral rotatory instability of the knee, 30 consecutive patients underwent a surgical procedure similar to that described by Ellison (Ellison AE: A modified procedure for the extra-articular replacement of the anterior cruciate ligament. American Orthopaedic Society for Sports Medicine Symposium, New Orleans, LA, July 15, 1975), called the iliotibial band transfer. Fashioning the passageway for the transfer closer to the attachment of the fibular collateral ligament on the femur and meticulous fascial closure over the transplant were not found to be crucial to success. Twenty-nine of the 30 patients were injured during athletic activities, and the remaining patient was injured in a motorcycle accident. They often complained of an unstable knee with symptoms of pain and giving way. Twenty-eight patients with a minimum followup of nine months (the average followup was 25 months) were evaluated subjectively by an interview and by objective clinical examination. Subjective results (including asymptomatic return to their previous level of athletic activity) and clinical improvement of anterolateral rotatory instability (based on the flexion-extension-valgus test or the Slocum anterolateral rotatory instability test) were encouraging. Areas of concern were that a small number of patients developed asymptomatic varus instability and a few had relative strength deficits which may or may not have long-term significance.

Accidents, Traffic↗
PubMed1998

Efficacy of divalproex sodium in patients with panic disorder and mood instability who have not responded to conventional therapy.

OBJECTIVE: To determine the efficacy of divalproex sodium in the treatment of psychiatric outpatients with treatment refractory panic disorder and comorbid mood instability. METHOD: This was an 8-week, open-trial, flexible-dose outcome study conducted at a tertiary care referral centre. Individuals with panic disorder who failed to respond to a cognitive behavioural treatment program and standard antipanic medication, who also suffered from mood instability, were chosen to participate in the study. Divalproex sodium was administered at a flexible dose to reach serum levels of 300 to 600 mumol/L (45 to 90 ug/ml) unless limited by tolerance. Patients were rated by self- and rater-administered questionnaires that measured the number of panic attacks, the degree of agoraphobic avoidance, the levels of depression, anxiety, and mood swings, and the perceived sense of well being. RESULTS: Thirteen subjects were enrolled in the study, and 10 subjects completed it. Two dropped out early because of the medication's side effects, and 1 was lost within the first month of follow-up. All 10 subjects showed significant improvement in depressive and anxiety symptoms and mood instability. There was also a statistically and clinically significant improvement in panic attacks and measures of quality of life. CONCLUSIONS: These findings suggest that divalproex sodium is useful in the treatment of patients with panic disorder and concomitant mood instability, who are refractory to conventional treatment. Double-blind trials will be required to verify these findings.

Adolescent↗
PubMed2005

Bystander effects in UV-induced genomic instability: antioxidants inhibit delayed mutagenesis induced by ultraviolet A and B radiation.

BACKGROUND: Genomic instability is characteristic of many types of human cancer. Recently, we reported that ultraviolet radiation induced elevated mutation rates and chromosomal instability for many cell generations after ultraviolet irradiation. The increased mutation rates of unstable cells may allow them to accumulate aberrations that subsequently lead to cancer. Ultraviolet A radiation, which primarily acts by oxidative stress, and ultraviolet B radiation, which initially acts by absorption in DNA and direct damage to DNA, both produced genomically unstable cell clones. In this study, we have determined the effect of antioxidants on induction of delayed mutations by ultraviolet radiation. Delayed mutations are indicative of genomic instability. METHODS: Delayed mutations in the hypoxanthine phosphoribosyl transferase (hprt) gene were detected by incubating the cells in medium selectively killing hprt mutants for 8 days after irradiation, followed by a 5 day period in normal medium before determining mutation frequencies. RESULTS: The UVB-induced delayed hprt mutations were strongly inhibited by the antioxidants catalase, reduced glutathione and superoxide dismutase, while only reduced glutathione had a significant effect on UVA-induced delayed mutations. Treatment with antioxidants had only minor effects on early mutation frequencies, except that reduced glutathione decreased the UVB-induced early mutation frequency by 24%. Incubation with reduced glutathione was shown to significantly increase the intracellular amount of reduced glutathione. CONCLUSION: The strong effects of these antioxidants indicate that genomic instability, which is induced by the fundamentally different ultraviolet A and ultraviolet B radiation, is mediated by reactive oxygen species, including hydrogen peroxide and downstream products. However, cells take up neither catalase nor SOD, while incubation with glutathione resulted in increased intracellular levels of glutathione. Previously, we have shown that ultraviolet induced delayed mutations may be induced via a bystander effect and that this effect is 5-fold higher for UVB radiation than for UVA radiation. Therefore, we propose that the antioxidants inhibit an ultraviolet radiation-induced bystander effect and that the effect is transmitted via the medium and via an internal transfer between cells, like gap junctional intercellular communication, for UVB radiation and only by the latter mechanism for UVA radiation.

Journal Article↗
PubMed2003

The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis.

The aim of this study was to test, in patients with multiple sclerosis (MS), whether the concept of helplessness might improve the understanding of the relationship between disease severity (neurological impairment) and personality characteristics (emotional instability) on one hand, and depressive mood and fatigue severity on the other hand. Data pertain to 89 patients with a definite diagnosis of MS (Expanded Disability Status Scale [EDSS] ratings: 1-8). Helplessness, fatigue severity, depressive mood and emotional instability were rated with validated questionnaires. Model testing revealed that more neurological impairment and more emotional instability were associated with more helplessness, while higher levels of helplessness were associated with more fatigue and depressive mood. The initially observed direct relationship between EDSS and fatigue disappeared. Emotional instability also had a direct significant relationship with depressive mood, and depressive mood had only a small relationship with fatigue severity. The results indicated that helplessness affected both depressive mood and fatigue severity and that fatigue was not merely a symptom of depressive mood. The correlation between neurological impairment and fatigue severity was largely explained by the mediating effect of helplessness. These findings suggest that MS patients troubled by disabling fatigue might benefit from a psychological intervention targeting unfavourable illness cognitions.

Adult↗
PubMed2001

Microsatellite instability is an independent indicator of recurrence in sporadic stage I-II endometrial adenocarcinoma.

PURPOSE: The aim of this study was to define the prognostic role of microsatellite status in 65 stage I-II primary sporadic endometrioid endometrial adenocarcinoma (EEA) patients. PATIENTS AND METHODS: Familiarity for neoplasia was ascertained in all patients on the basis of a questionnaire. Microsatellite status was assessed by matching normal and tumoral DNA probed for five dinucleotide repeats and one mononucleotide repeat marker. Microsatellite status was analyzed in relation to clinicopathologic characteristics of the patients and length of disease-free survival (DFS). RESULTS: Eleven tumors (17%) of 65 had instability at two or more loci and were considered as unstable or microsatellite instability (MI). Tumors with no instability or instability at one locus were classified as microsatellite stable (MS). The percentage of MI was significantly higher in poorly than in well to moderately differentiated tumors (50% v 9%; P =.003). The 5-year DFS rate of MI patients was 63% (95% confidence interval [CI], 35% to 91%) versus 96% (95% CI, 91% to 101%) of MS patients (P =.0004). In multivariate analysis, only the presence of MI, stage II of disease, and depth of myometrial invasion greater than 50% retained independent prognostic roles. CONCLUSION: The assessment of microsatellite status may provide useful information for preoperative prognostic characterization of stage I-II primary sporadic EEA patients in which more individualized treatment options can be attempted.

Adaptor Proteins, Signal Transducing↗
PubMed1990

The structure of microtubule ends during the elongation and shortening phases of dynamic instability examined by negative-stain electron microscopy.

Microtubules (MTs) are dynamic polymers that can exist in phases of elongation and rapid-shortening at steady-state. These phases have been observed in vitro and in living cells, and this property of MTs has been termed 'dynamic instability'. The purpose of this study was to use negative-stain electron microscopy (EM) to test if there are structural differences between the ends of MTs in the elongation and shortening phases, which could provide insight into the mechanisms of dynamic instability. MTs in the elongation phase were obtained by seeding either highly purified porcine brain tubulin (PC-tubulin) or tubulin containing microtubule-associated proteins (MTP), from isolated Tetrahymena axonemes. The results are that, in addition to intact cylindrical MTs, a significant fraction of the tubulin polymer in the elongation phase occurred as sheets of parallel protofilaments, as found in previous investigations with self-assembled MTs. Therefore, sheet formation is an intrinsic property of MT assembly that does not depend on the tubulin purity or the method of nucleation. Also, since sheets lack helical symmetry, at least a fraction of tubulin polymers seeded from axonemes did not assemble by helical addition of tubulin dimers to the ends, an assumption often made in mathematical models of dynamic instability. Sheets and intact MTs that were seeded from isolated axonemes, emanated both from the intact MT wall of the axoneme A-subfiber and from the incomplete wall of the B-subfiber. Therefore, axoneme seeds do not provide a homogeneous nucleation site for tubulin growth, or produce a homogeneous population of tubulin polymers under our conditions. Previous evidence has indicated that MT disassembly can occur by a segmental release of tubulin oligomers from the ends and at sites along the length of MTs. However, these studies were performed with MTP, and disassembly was induced by cold depolymerization. We examined MT shortening under conditions that closely represent shortening via dynamic instability, namely isothermal dilution at 37 degrees C of self-assembled MTs. This was compared with the morphology of cold-disassembled MTs. The cold-depolymerization of MTs composed of MTP showed rings and protofilament curls as previously observed using similar methods. Surprisingly, cold-depolymerization of MTs assembled from PC-tubulin induced not only shortening, but also the opening of a large fraction of MTs into sheets, suggesting that the MT lattice contains a cold-labile seam. Under conditions that mimic stochastic shortening, MTs were intact, closed cylinders with ends that were approximately blunt. Therefore, rapid shortening occurs at the ends of the MT, without a long-range disruption of the MT wall. In conclusion, MTs in the elongation phase can have highly irregular ends and need not elongate by a helical assembly process. Conversely, MTs in the shortening phase can have relatively blunt, even ends and can depolymerize in a relatively uniform fashion.

Animals↗
PubMed2005

Truncation of the projection domain of MAP4 (microtubule-associated protein 4) leads to attenuation of microtubule dynamic instability.

MAP4, a ubiquitous heat-stable MAP, is composed of an asymmetric structure common to the heat-stable MAPs, consisting of an N-terminal projection (PJ) domain and a C-terminal microtubule (MT)-binding (MTB) domain. Although the MTB domain has been intensively studied, the role of the PJ domain, which protrudes from MT-wall and does not bind to MTs, remains unclear. We investigated the roles of the PJ domain on the dynamic instability of MTs by dark-field microscopy using various PJ domain deletion constructs of human MAP4 (PJ1, PJ2, Na-MTB and KDM-MTB). There was no obvious difference in the dynamic instability between the wtMAP4 and any fragments at 0.1 microM, the minimum concentration required to stabilize MTs. The individual MTs stochastically altered between polymerization and depolymerization phases with similar profiles of length change as had been observed in the presence of MAP2 or tau. We also examined the effects at the increased concentrations of 0.7 microM, and found that in some cases the dynamic instability was almost entirely attenuated. The length of both the polymerization and depolymerization phases decreased and "pause-phases" were occasionally observed, especially in the case of PJ1, PJ2 or Na-MTB. No obvious change was observed in the increased concentration of wtMAP4 and KDM-MTB. Additionally, the profiles of MT length change were quite different in 0.7 microM PJ2. Relatively rapid and long depolymerization phases were sometimes observed among quite slow length changes. Perhaps, this unusual profile could be due to the uneven distribution of PJ2 along the MT lattice. These results indicate that the PJ domain of MAP4 participates in the regulation of the dynamic instability.

Amino Acid Sequence↗
PubMed1980

An operation for anteromedial rotatory instability of the knee. A preliminary report.

A method of repair for anteromedial rotatory instability of the knee is described and the results of operations on 36 knees reviewed. Complete static correction occurred in 30 of these patients (84 per cent), three patients showed improvement (8 per cent) and three showed no improvement (8 per cent). Although the operation was not reliable as a correction for valgus instability, it did not increase this instability. This operation may be combined with other procedures to correct all instabilities or problems of the knee.

Adolescent↗
PubMed2004

Observation of transverse instabilities in optically induced lattices.

We study experimentally the Bloch-wave instabilities in optically induced photonic lattices. We reveal two different instability scenarios associated with either the transverse modulational instability of a single Bloch wave or the nonlinear interband coupling between different Bloch waves. We show that the transverse instability is greatly enhanced in the induced lattice in comparison with homogeneous media.

Journal Article↗