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PubMed2003

Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability.

The phenotypic markers of colorectal carcinomas with microsatellite instability have been widely studied and include mucinous or poor differentiation, prominent host response, a circumscribed growth pattern, histologic heterogeneity, and right-sided location. As part of a population-based case-control study of colorectal cancer in northern Israel, we reviewed the pathology and microsatellite status of 528 consecutively diagnosed colorectal cancers. Phenotypic analysis was performed by one pathologist (J.K.G.) and included assessment of grade, mucinous histology (>50%, or focal), histologic heterogeneity, growth pattern, necrosis, and host response. Microsatellite status was determined on microdissected portions of formalin-fixed, paraffin-embedded tissue using a panel of 5 NCI consensus primers. Fifty-two of 528 colorectal carcinomas were microsatellite unstable (9.85%). Multivariate analysis found that >2 tumor infiltrating lymphocytes per high power field (p <0.0001), the lack of dirty necrosis (p = 0.0054), a Crohn's-like host response (p = 0.0064), right-sided location (p = 0.032), well or poor differentiation (p = 0.037), and any mucinous differentiation (p = 0.039) were independent predictors of microsatellite instability. Tumor infiltrating lymphocytes were the single best histologic predictor of microsatellite instability. The absence of dirty necrosis and the presence of well-differentiated tumors and tumors with only focal mucinous differentiation were also important markers for microsatellite instability that have not been emphasized previously. The combination of >2 tumor infiltrating lymphocytes per high power field and/or any mucinous differentiation and/or the absence of dirty necrosis identified all MSI-H tumors in this study.

Adenocarcinoma↗
PubMed1990

The management of detrusor instability.

Detrusor instability is a urodynamic diagnosis made when the detrusor is shown objectively to contract, spontaneously or on provocation, during the filling phase of a cystometrogram while the patient is attempting to inhibit micturition. It often is responsible for symptoms of urgency, frequency, nocturia, urge incontinence, and nocturnal enuresis, but is not synonymous with any of them. Furthermore, it may be responsible for urinary incontinence which appears to be simple stress incontinence, and should be excluded before an operation for genuine stress incontinence is undertaken. Patients with mixed incontinence should have their detrusor instability treated before an attempt at surgical correction of stress incontinence is made. A number of therapeutic options exist for the unstable bladder. The simplest is bladder drill. My own preference is to start patients on bladder drill in conjunction with oxybutynin chloride 5 mg orally three times daily, with the plan of weaning them off the medication if possible in 3-6 months. Propantheline bromide in dosages of 15-30 mg orally four times daily also appears to be effective. Imipramine, in dosages of 25-50 mg orally twice daily, or up to 75 or 100 mg orally at night also may be helpful, especially if the patient suffers from nocturia or nocturnal enuresis. The effects of imipramine appear to be additive to those of other drugs, and this makes it a useful adjunct in therapy. Emepronium bromide and flavoxate hydrochloride appear to be less useful pharmacologic agents. The expected addition within the next few years of terodiline hydrochloride to the drugs available in the United States is likely to improve significantly our ability to treat detrusor instability. The use of prostaglandin synthetase inhibitors in women with perimenstrual exacerbations of their symptoms may be useful on a case-by-case basis. Patients who do not experience improvement with behavioral intervention and pharmacologic treatment may be candidates for electric stimulation therapy or surgery. The efficacy of electric stimulation therapy is diminished in many cases by poor patient acceptance. The most effective surgical treatment for refractory detrusor instability appears to be augmentation cystoplasty, which should be attempted only by a trained reconstructive urologist, and which should be reserved for the most refractory and difficult cases.

Female↗
PubMedDate not supplied

Discoid lateral meniscus: prevalence of peripheral rim instability.

The purpose of this study was to determine the prevalence of peripheral rim instability in discoid lateral meniscus. A consecutive series of 112 patients (128 knees) (mean age 10.0 years [range 1 month to 22 years]) who underwent arthroscopic evaluation and treatment of a discoid lateral meniscus between 1993 and 2001 was reviewed. Of those discoid menisci classified intraoperatively (n = 87), 62.1% (n = 54) were complete discoid lateral menisci and 37.9% (n = 33) were incomplete discoid lateral menisci. An associated meniscal tear was present in 69.5% (n = 89) of all knees studied. Overall, 28.1% (n = 36) of discoid lateral menisci had peripheral rim instability: 47.2% (n = 17) were unstable at the anterior-third peripheral attachment, 11.1% (n = 4) at the middle-third peripheral attachment, and 38.9% (n = 14) at the posterior-third peripheral attachment. Thirty-one of the 36 unstable discoid menisci underwent repair of the peripheral meniscal rim attachment. One patient underwent a complete, open meniscectomy. Peripheral rim instability was significantly more common in complete discoid lateral menisci (38.9% vs. 18.2%; P = 0.043) and in younger patients (8.2 vs. 10.7 years; P = 0.002). The frequency of peripheral instability mandates a thorough assessment of meniscal stability at all peripheral attachments during the arthroscopic evaluation and treatment of discoid lateral meniscus, particularly in complete variants and in younger children.

Adolescent↗
PubMed1998

Experimental bladder instability following bladder outlet obstruction in the female rat.

PURPOSE: In rats, urethral obstruction was previously shown to lead to detrusor instability, but bladder instability in conscious animals has not been well characterized. The present study was designed to describe the consequences of bladder outlet obstruction on urodynamic parameters in the conscious rat. A categorization of different types of bladder instability in conscious rats is described. MATERIALS AND METHODS: Cystometry was performed on conscious animals with chronically implanted lines. Recordings of the micturition pattern and the bladder pressure during the micturition cycle were made from normal female rats and those with instability caused by infravesical outflow obstruction. RESULTS: In control rats, the peak micturition pressure was low (45.6+/-2.5 cm. H2O) and only small pressure fluctuations occurred before or after micturition. Rats with outlet obstruction exhibited bladder hypertrophy, high micturition pressure (95.5+/-6.8 cm. H2O) as well as marked spontaneous activity throughout the micturition cycle. According to the spontaneous activity profile we identified four main patterns of abnormal micturition cycles. CONCLUSION: Urethral obstruction in rats leads to a significant increase in bladder weight and to altered micturition patterns which reveal clear similarities with features of the cystometric profiles performed in men with infravesical outflow obstruction. These modifications are not consistently correlated with an increase in bladder weight.

Animals↗
PubMed1999

Urethral afferent nerve activity affects the micturition reflex; implication for the relationship between stress incontinence and detrusor instability.

PURPOSE: A causative relationship between stress urinary incontinence (SUI) and detrusor instability has been suspected but never proven. Many women with mixed incontinence have resolution of detrusor instability after surgical correction of SUI. We sought experimental support that stimulation of urethral afferent nerves can induce or change reflex detrusor contractions. MATERIALS AND METHODS: Urethral perfusion pressure and isovolumetric bladder pressure were measured with catheters inserted through the bladder dome in urethane anesthetized female S.D. rats (250 to 300 grams; n = 12). The catheter assembly was seated securely in the bladder neck to block passage of fluid between the bladder and urethra without affecting the nerve supply to the organs. The external urethra was not catheterized. Responses were examined in the control state at a urethral saline perfusion speed of 0.075 ml. per minute. Intraurethral drugs were administered following blockade of striated sphincter activity with intravenous alpha-bungarotoxin (0.1 mg./kg.). RESULTS: Stopping the urethral saline infusion caused a significant decrease in micturition frequency in approximately 50% of the animals studied (n = 12). Intraurethral lidocaine (1%) infused at 0.075 ml. per minute caused a slight decrease in urethral perfusion pressure but no change in detrusor contraction amplitude. However, intraurethral lidocaine caused a significant (45%) decrease in the bladder contraction frequency (n = 5). The micturition frequency returned to baseline 30 minutes after stopping lidocaine infusion. Intraurethral infusion of nitric oxide (NO) donors (S-nitroso-N-acetylpenicillamine [SNAP] (2 mM) or nitroprusside (1 mM) immediately decreased urethral perfusion pressure by 30 to 37% (n = 5). A 45 to 75% decrease (n = 5) in bladder contraction frequency was also seen, which was similar to that observed following lidocaine. Neither NO donor changed the amplitude of bladder contractions. CONCLUSIONS: These results indicate that in the anesthetized rat activation of urethral afferents by urethral perfusion can modulate the micturition reflex. Thus in patients with stress urinary incontinence, leakage of urine into the proximal urethra may stimulate urethral afferents and facilitate voiding reflexes. This implies that stress incontinence can induce and/or increase detrusor instability. These findings have significant implications for the treatment of patients with mixed urge and stress incontinence. Correction of stress incontinence by surgery or pelvic floor exercise in patients with mixed incontinence may resolve the detrusor instability.

Anesthetics, Local↗
PubMed2001

Computerized assessment of detrusor instability in patients treated with sacral neuromodulation.

PURPOSE: We previously described an automatic procedure for diagnosing and grading detrusor instability using a cystometric study. In our current study we applied a modified version of the program in patients with urge incontinence treated with sacral neuromodulation to test its capacity to detect changes after therapeutic intervention and understand the mode of action of neuromodulation. MATERIALS AND METHODS: We analyzed cystometric studies before and after neuromodulation in 26 consecutive patients, including 22 women and 4 men, and evaluated parameter changes. We also assessed the relationship of instability parameters at baseline with symptomatic results, which were derived from voiding-incontinence diaries, in female patients to identify urodynamic prognosticators of success. RESULTS: The automatic procedure correctly diagnosed stability and instability in our patients in 51 of the 52 measurements considered. Neuromodulation had an average suppressive effect on the amplitude of unstable contractions. At baseline the amplitude of the maximum unstable contraction and mean active pressure during unstable episodes were significantly less in the 7 women who achieved stability than in the 15 who did not. However, no urodynamic parameters were identified that predicted the symptomatic outcome of treatment. CONCLUSIONS: Our algorithm accurately diagnoses and grades detrusor instability, and provides parameters with predictive value in regard to the probability that a bladder may or may not become stable with neuromodulation. However, the symptomatic result of this treatment option seems to depend on noncystometric factors.

Algorithms↗
PubMed1983

Unrecognized spinal instability associated with seemingly "simple" cervical compression fractures.

This paper described 27 patients who had seemingly stable compression cervical vertebral fractures. All were treated in cervicothoracic orthoses. None was initially treated in a Halo device or with surgery. Twenty patients were stable and healed without progressive displacement, angulation, or pain. One patient demonstrated an angular deformity, which spontaneously stabilized within six months with anterior bony ankylosis in a kyphotic position. Six patients demonstrated persistent progressive post-injury instability related to posterior ligament rupture. As muscle spasm diminished, the patients could be given a more reliable flexion-extension radiographic examination, unmasking the hidden posterior instability. Five of the six who demonstrated this instability were disabled because of pain. Two of the six patients were treated with a two-segment fusion. The other four have had fusion recommended and are currently being followed clinically. This paper emphasizes the need for better initial criteria of potential instability and close follow-up of patients with simple compression fractures of the cervical spine.

Adolescent↗
PubMed1987

Cervical ligamentous instability in a canine in vivo model.

A canine in vivo model of midcervical ligamentous instability was developed by dividing the anterior longitudinal ligament, anulus fibrosus, and all posterior ligamentous structures including the ligamentum flavum. The natural history of healing in the model, the effect on its healing by an adjacent one-level arthrodesis, and the effect of a one-level arthrodesis on normal adjacent ligamentous structures were studied radiographically, mechanically, and histologically. The authors determined that healing takes place primarily by anterior scar formation in their instability model but not to a degree sufficient to recreate normal mechanical stability. After three months, healing in the model was not affected by an adjacent arthrodesis; however, acutely, instability apparently was increased as three animals became quadriplegic between the second and fourth postoperative days. Arthrodesis did not affect adjacent normal ligamentous structures, during this period. Incomplete healing in the authors' model supports those who advocate arthrodesis as the treatment of choice for destabilizing cervical ligamentous injury. The authors previously reported the case of a patient who sustained bilateral facet dislocations adjacent to an arthrodesed segment and questioned whether this resulted from a stress-concentrating effect. This study indicates that this could well have been the case acutely. Thus, inadvertent exclusion of an unstable segment from an arthrodesis has potentially catastrophic results. Finally, the authors also have previously questioned whether arthrodesis of a midcervical segment could lead to instability of adjacent normal segments. This project does not support such a concern, at least for the three postoperative months of study.

Animals↗
PubMed1989

Multidirectional instabilities of traumatic cervical spine injuries in a porcine model.

Spinal injuries due to high-speed trauma are significant problems. The method of treatment depends on the stability determination of the injured spine. Young pig spines were injured at high speed to produce clinically relevant fractures and dislocations. The injuries were produced by dropping a mass onto the superior vertebra and causing three major types of trauma: flexion-compression, extension-compression, and pure compression. The multidirectional instability of each spine was measured before and after trauma by applying pure moments to the three vertebrae segments. Lateral radiographs were taken of each intact and injured spine. Flexion trauma produced the greatest instabilities in flexion and extension, while extension trauma produced the greatest instabilities in axial rotation and lateral bending. Lateral radiographs were found to be inaccurate predictors of spinal instability.

Acceleration↗
PubMed1993

Evaluation of clinical lumbar instability using the treadmill.

The physical signs of lumbar instability have not yet been clearly defined. Furthermore, they do not always coincide with the abnormal movement on flexion-extension radiographs. Thus, the treadmill was used to evaluate clinical lumbar instability. The subjects were 82 patients with degenerative lumbar disease aggravated by walking or daily physical activities. The reproduction and provocation of low-back pain or pain in the lower extremities was examined during walking on a treadmill. The responses of the reproduction and provocation of the symptoms were divided into four grades. Fifteen cases were examined again using a treadmill after body casting to determine the indication for fusion surgery. As a result, the responses in the reproduction or provocation test using a treadmill manifest more dominant reflection of clinical symptoms suggesting clinical lumbar instability than the existence of the abnormal movement on flexion-extension radiographs. Reexamination after body casting was useful to determine the indications of fusion operations. The reproduction or provocation test using a treadmill was implied as a possible functional evaluation method of clinical lumbar instability.

Casts, Surgical↗
PubMed1998

Low incidence of microsatellite instability in patients with cervical carcinomas.

Alterations in microsatellite sequences have been reported in a variety of human cancers. Microsatellite instability is thought to reflect the inactivation of genes involved in DNA mismatch repair (MMR), which could predispose to the accumulation of further genetic errors in affected cells. Genomic instability in human cancers might also result from the inactivation of cell cycle controls such as the p53-dependent G1 checkpoint that prevents cell replication in response to DNA damage. High-risk human papillomavirus (HPV) is thought to contribute to the development of HPV-associated cancers, including cervical carcinoma, through the interaction of the E6 and E7 viral oncoproteins with two major cell cycle regulatory proteins, namely p53 and the retinoblastoma gene product (pRb). Although the high-risk HPV is prevalent in cervical carcinomas, viral DNA is not detected in a minor proportion of the cases. The HPV infection is insufficient for the development of cervical cancer, which indicates that additional genetic events are involved in the process. This study reports the potential role of MMR gene defects (in addition to or independent of HPV infection) in patients with cervical carcinogenesis. Microsatellite instability and HPV status were analyzed in a series of 54 patients with cervical carcinomas and in two associated cell lines. Microsatellite alterations were examined at 10 loci located in different chromosomes by using semiautomated fluorescent DNA technology and polymerase chain reaction. The HPV types were detected by a general primer polymerase chain reaction method. The results indicate that microsatellite instability is very infrequent in cervical carcinoma and occurs independently of HPV status.

Adenocarcinoma↗
PubMedDate not supplied

Treatment of recurrent patellar instability with a modification of the Roux-Goldthwait technique.

Recurrent instability of the patella may be a significant disability in the childhood and adolescent population. Numerous surgical procedures to address this instability have been described, with variable outcome. This has led to considerable confusion in the literature as to how to treat patellofemoral problems in children. This study retrospectively reviews 30 knees in 20 patients with chronic recurrent patellar instability who were treated with a modified Roux-Goldthwait technique including the release of contracted lateral structures by a single surgeon over a 13-year period, with an average of 6.2 years follow-up. By Insall's criteria, 26 knees had an excellent result, 3 good result, and 1 fair result. Ten patients evaluated using a dynamometer showed that strength achieved in the operated leg was greater than 90% in 8 patients and greater than 80% in 2 patients. Here, we report upon a single operation to treat patellar instability performed in the pediatric population with consistently excellent results.

Adolescent↗
PubMed2007

Neighborhood socioeconomic deprivation and residential instability: effects on incidence of ischemic heart disease and survival after myocardial infarction.

BACKGROUND: Previous literature has shown that neighborhood socioeconomic position influences the risk of ischemic heart disease, but little is known about the mechanisms linking the residential context to ischemic heart disease incidence and mortality. We examined whether neighborhood socioeconomic position and neighborhood residential stability (as a determinant of social interaction patterns) have an influence on ischemic heart disease risk. Moreover, we investigated whether dissimilar contextual influences operate at different stages of the disease process, ie, on incidence, 1-day case-fatality, and long-term survival after acute myocardial infarction (MI). METHODS: Using a large 27-year longitudinal cohort (baseline: 1 January 1996) defined in the Scania region, Sweden, we estimated multilevel survival models adjusted for individual sociodemographic factors and previous diseases of the persons. RESULTS: After adjustment, multilevel survival models indicated that the incidence of ischemic heart disease increased with neighborhood socioeconomic deprivation but was only weakly associated with neighborhood residential instability (for high vs low residential instability, hazard ratio = 1.2; 95% credible interval = 1.0-1.4). Conversely, beyond effects of individual and contextual socioeconomic circumstances and distance to the hospital, we saw a markedly higher 1-day case-fatality (4.9; 1.8-15) and shorter survival time after MI among individuals still alive 28 days after MI (4.3; 1.2-17) in neighborhoods with a high versus low residential instability. CONCLUSIONS: Effects of residential instability on post-MI survival may be mediated by the lower availability of social support in residentially unstable neighborhoods, suggesting a new class of intermediate processes that should be taken into account when investigating contextual influences on ischemic heart disease. Moreover, dissimilar contextual effects may operate at various stages of the disease process (ie, on incidence, case-fatality, and survival after MI).

Cohort Studies↗
PubMed2005

The assessment of baroreflex sensitivity in patients with chronic kidney disease: implications for vasomotor instability.

PURPOSE OF REVIEW: Autonomic dysfunction is well recognized in chronic kidney disease. The baroreflex arc is an important component of the autonomic nervous system and influences vasodilatation and heart rate in response to information derived from baroreceptors located in the aorta and common carotid arteries. Appropriate regulation of systemic blood pressure is therefore dependent upon the integrity and normal function of the baroreflex arc. Vasomotor instability during haemodialysis has traditionally been identified as a pathophysiological state largely due to the failure of compensatory mechanisms during ultrafiltration. This review article discusses autonomic dysfunction as a key factor contributing to the systemic haemodynamic instability that may occur during dialysis. RECENT FINDINGS: Relationships have begun to be established between markers of reduced baroreflex sensitivity and abnormal cardiovascular structure, such as left ventricular dysfunction, left ventricular hypertrophy and arterial stiffness. SUMMARY: Pathological relationships between cardiovascular structure and function remain important in the understanding of both haemodynamic instability and cardiovascular mortality in chronic kidney disease patients. Understanding the associations between conventional markers of haemodynamic instability and autonomic function will allow early identification of patients likely to benefit from individualizing dialysis therapy.

Arrhythmias, Cardiac↗
PubMed2004

Pharmacologic management of behavioral instability in medically ill pediatric patients.

PURPOSE OF REVIEW: Behavioral instability in children and adolescents is a vexing problem faced by many clinicians. This dilemma is magnified when it presents in a child with an acute medical condition. Effective treatment in these cases with medications may help to reduce morbidity and facilitate appropriate medical care for the underlying condition. RECENT FINDINGS: There are many reviews, but few studies examine the treatment of behavioral instability in the pediatric population. There are even fewer that address behavioral instability in the presence of a comorbid medical condition. Many effective agents may worsen a given condition or interfere with the treatment of that condition. There are no prospective studies addressing this issue. SUMMARY: Many psychotropic medications must be considered when treating behavioral instability in medically ill children. Antihistamines, benzodiazepines, and antipsychotics may be of particular benefit. Definitive research is lacking and necessary to develop appropriate clinical guidelines. This article considers the most current literature and provides an overall summary of the topic.

Adolescent↗
PubMed1984

The effect of inhibitors of DNA repair on the genetic instability of Streptomyces cattleya.

Various streptomycetes show well defined instabilities that do not appear to be attributable to plasmid loss. The unstable phenotype, in many cases, arises at frequencies too high to be explained by point mutations. The frequency of instability can be enhanced by UV irradiation. Two major repair systems have been found in Escherichia coli: the 'error-free' system which is inhibited by caffeine and the 'error-prone' system which is inhibited by arsenite. Using spores of Streptomyces cattleya NRRL 8057 and the virulent actinophage VC11 we have shown that a caffeine inhibitable, host mediated UV repair system is active in spores during early development. Some evidence was also found for the presence of an arsenite inhibitable UV repair system. The caffeine inhibitable UV repair system was found to be involved in the induction of genetic instability in S. cattleya. The arsenite system may be implicated in the repair of such events. Genetic instability was also induced by single strand breaks in DNA caused by 32P.

Arsenic↗
PubMed1992

Evidence for instability of mRNAs containing AUUUA motifs mediated through translation-dependent assembly of a > 20S degradation complex.

Many short-lived mRNAs, including those encoding lymphokines, cytokines, and proto-oncogenes, contain an AU-rich sequence in their 3'-untranslated regions. These AU domains and, more specifically, AUUUA motifs within them, are widely thought to mediate the extreme instability of the corresponding mRNAs. This is most clearly true for granulocyte monocyte colony stimulating factor (GM-CSF) mRNA whose AUUUA motifs are conserved phylogenetically and whose presence in an otherwise stable beta-globin mRNA results in a 50-fold decrease in accumulated mRNA level. We show that RNA instability conferred by the GM-CSF AU motif requires the mRNA to be actively translated and the AU motif to be within the 3'-untranslated region. By analysis of the sedimentation characteristics, we identify a large (> 20S), divalent cation-independent complex found only on unstable RNAs. Like instability, complex formation (1) is dependent on translation of the RNA, (2) requires intact AUUUA motifs, and (3) is blocked by ribosome translocation across the AU-rich motif. We propose that RNA instability mediated by the AU motif is achieved through translation-dependent assembly of this large mRNA-destabilizing complex.

Animals↗
PubMed2001

Self-consistent linear analysis of slow cyclotron and Cherenkov instabilities.

Slow cyclotron and Cherenkov instabilities are analyzed self-consistently for unbounded and cylindrical slow wave systems considering electron beam propagating along the direction of a guiding magnetic field. There are two electromagnetic modes present in the beam that are self-consistent solutions of Maxwell's equations. The wave equation in the beam becomes the Altar-Appelton-Hartree equation in the limit of zero beam velocity. For the unbounded system, the beam couples with the electromagnetic modes corresponding to the X and O modes, resulting in the slow cyclotron and Cherenkov instabilities, respectively. For the cylindrical system, axisymmetric electromagnetic modes in the beam are obtained by superposing the plane normal modes of the unbounded system. Since self-consistent boundary conditions require all field components, axisymmetric electromagnetic modes of cylindrical system are hybrid modes, which are classified as axisymmetric EH and HE modes. The slow cyclotron and Cherenkov instabilities occur for both axisymmetric modes. The temporal growth rate is calculated for each of the instabilities and compared.

Journal Article↗