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Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation.

BACKGROUND: The objective of the current study was to verify the ability to predict response to imatinib therapy using in vitro assays to evaluate the inhibition of Wilms tumor gene (WT1) expression and colony growth after samples obtained from patients with chronic myelogenous leukemia (CML) before the start of treatment were subjected to short-term incubation with imatinib. METHODS: WT1 transcript levels and colony growth in bone marrow (BM) samples from 23 patients with CML that was later identified as being responsive to imatinib and from 13 patients with CML that was later identified as not being responsive to imatinib were evaluated after incubation of these samples with imatinib at a concentration of 1 microM for 18 hours. In addition, real-time quantitative polymerase chain reaction (RQ-PCR) analysis of WT1 expression was performed during follow-up, and the results were analyzed for associations with cytogenetic response and with BCR/ABL transcript levels as determined using RQ-PCR analysis. RESULTS: Before treatment, it was found that WT1 expression was elevated in BM samples obtained from all patients with CML. WT1 expression and colony growth were reduced significantly after an 18-hour incubation with imatinib in samples obtained from patients who were later identified as responders to treatment, but not in samples obtained from patients who did not experience responses to treatment. Inhibition of WT1 expression in vitro was associated with inhibition of imatinib-induced BCR-ABL tyrosine kinase activity, a finding that also has been made in studies involving certain Philadelphia chromosome (Ph)-positive and Ph-negative cell lines. CONCLUSIONS: Inhibition of WT1 transcript levels after a short period of in vitro exposure of pretherapy BM samples to imatinib was correlated with inhibition of colony growth and may represent the basis for an easy test that is capable of predicting the sensitivity of CML to treatment with imatinib for individual patients.

Animals↗

Use of the heterologous ovum penetration test to predict the fertilising capacity of human spermatozoa.

The ability of human spermatozoa to penetrate zona-free hamster ova in a heterologous ovum penetration (HOP) test was compared with the fertilisation of human oocytes in 54 normospermic couples. Concordant results were seen in 45/54 (83%) cases. However, false-positive HOP test results occurred in 5/45 (11%) couples and false-negative results in 4/9 (44%) couples. The data suggest that a positive HOP test result is a good indication that fertilisation will occur, although a negative HOP test result does not necessarily mean that fertilisation will not take place.

Animals↗

Physical, mental, and social predictors of functional outcome in unilateral lower-limb amputees.

OBJECTIVE: To study the value of physical, mental, and social characteristics as predictors of functional outcome of elderly amputees. DESIGN: Prospective, inception cohort study; comparisons with reference populations. SETTING: Main hospitals, rehabilitation centers, nursing homes, patients' own residence settings in 1 of the 3 northern provinces in the Netherlands. PARTICIPANTS: Forty-six patients older than 60 years, with unilateral transtibial or transfemoral amputation or knee disarticulation because of vascular disease. INTERVENTIONS: Measurement of physical, mental, and social predictors 2 and 6 weeks postamputation. MAIN OUTCOME MEASURES: The Sickness Impact Profile (SIP-68), Groningen Activity Restriction Scale (GARS), Timed up and go (TUG) test, and prosthetic use. RESULTS: A total of 15% of amputees died within the first year after amputation. Seventy percent lived independently at home 1 year postamputation. The functional level of the patients was low, as shown by high scores on the SIP-68 (mean, 23.6), GARS (mean, 41.2), and TUG test (mean, 23.9s). Functionally effective prosthetic use, as measured with the classification of Narang and Pohjolainen, was reached by 49%. For the SIP-68 scores, age, comorbidity, 1-leg balance, and the 15-word test predicted functional outcome in 69% of amputees. For the GARS score, age, 1-leg balance, and the 15-word test predicted functional outcome in 64%. For the TUG test, age and 1-leg balance predicted functional outcome in 42% of amputees. After correction for age, the only significant predictor for prosthetic use was 1-leg balance. CONCLUSIONS: Elderly patients with a leg amputation had a low functional level 1-year postamputation. An important part of functional outcome could be predicted 2 weeks after amputation by age at amputation, 1-leg balance on the unaffected limb, and cognitive impairment. Severe comorbidity probably also played a role. The results may be used in the general policy concerning leg amputees.

Activities of Daily Living↗

Predictive chemosensitivity testing in malignant melanoma: reliable methodology--ineffective drugs.

A retrospective and a prospective trial were carried out in patients with malignant melanomas to investigate the predictive value of an in vitro chemosensitivity assay based on the Courtenay and Mills soft agar cultivation method. Evaluable in vitro chemosensitivity data for the three agents DTIC, CCNU, and vinblastine were obtained in 153 cases. In the retrospective study in which the patients received chemotherapy without prior knowledge of the test results, 50 in vitro/in vivo correlations (40 patients) were made, and in the prospective study, where patients received the single agent most active in vitro, 55 correlations (45 patients) were performed. In both studies the sensitivity of the test (the ability to identify patients who will respond to chemotherapy) was approximately 100% and the specificity (the ability to identify patients who will not respond) was 87-98%. Depending on whether 'no change' and 'mixed response' were classified as sensitivity or resistance, the predictive value of a negative test was approximately 100% and that of a positive test 37.5-87.5%. The response rate was low in both series, and although it was somewhat higher in the prospective than in the retrospective trial, the difference was not significant. The median survival time was not significantly different in the two treatment series. We conclude that the chemosensitivity assay here used is reliable and has predictive value, but that the chemotherapeutic agents currently available for treatment of melanoma are too ineffective to warrant routine use of the assay in this disease.

Dacarbazine↗

Utility of tuberculin and anergy skin testing in predicting tuberculosis infection in human immunodeficiency virus-infected persons in Thailand.

SETTING: Chiang Rai, the northernmost province of Thailand, where extensive human immunodeficiency virus (HIV) transmission has resulted in a rapid increase in tuberculosis. OBJECTIVE: To assess the utility of tuberculin and anergy skin testing to identify latent Mycobacterium tuberculosis infection in HIV-infected persons. DESIGN: A cross-sectional study and analysis were conducted to examine reactivity to tuberculin and two control antigens (mumps and candida) in HIV-negative and HIV-positive blood donors and female sex workers. RESULTS: HIV-positive persons had markedly decreased tuberculin reactivity; 14%, 19%, and 40% had an induration of > or = 10 mm, > or = 5 mm, > or = 2 mm, respectively, while 51% of 525 HIV-negative persons had an induration of > or = 10 mm (P < 0.001). Mumps and candida positivity (reactions of > or = 3 mm) were found in 94% and 78% of HIV-negative persons compared with 72% and 61% of HIV-positive persons, respectively (P < 0.001). Although HIV-positive persons had markedly less tuberculin reactivity even at higher CD4+ cell counts (> 400 cells/microL), reactivity to mumps and candida was present in more than half of HIV-positive persons with low CD4+ cell counts (< or = 200 cells/microL). Reaction to control antigens did not predict tuberculin reactivity. CONCLUSION: In this setting, tuberculin and anergy skin testing have a low predictive value in detecting M. tuberculosis infection in HIV-infected persons, and therefore such testing has a limited role in identifying HIV-infected persons who may benefit from tuberculosis preventive therapy programs.

AIDS-Related Opportunistic Infections↗

Umbilical artery blood velocity waveform analysis in predicting the small-for-dates fetus.

Doppler umbilical artery blood velocity waveforms were recorded longitudinally in 78 randomly selected pregnancies. The waveform maximal (A) to minimal (B) Doppler shift frequency ratios were determined to provide a semi-quantitative measure of impedance to blood flow in the fetoplacental circulation. Fifty-eight of these pregnancies and their outcomes were normal. The A/B ratios from this normal group were used to derive a normal range of this index throughout the second half of pregnancy. A further 45 pregnancies, also randomly selected, were studied once within 2 weeks of delivery. Using those measurements, plus those from the longitudinal groups sampled within 2 weeks of delivery, the predictive values of the A/B ratio in detecting the small for gestational age fetus have been derived. The sensitivity of the umbilical artery A/B ratio in predicting a small for gestational age infant within 2 weeks of delivery was 58% with a specificity of 94%. The positive test predictive value was 69% with a negative test predictive value of 90%. These predictive values are lower than those previously published, probably because high-risk pregnancies were over-represented in earlier studies. Waveform analysis within 2 weeks of delivery did, however, appear to identify fetuses destined to develop a range of perinatal problems. Large prospective studies are needed before the predictive value of Doppler waveform analysis is clarified.

Blood Flow Velocity↗

Why test children for adult-onset genetic diseases?

The genetics community has developed guidelines recommending that predictive testing of children for adult-onset genetic conditions should be withheld. Genetics policy makers have maintained that their restriction of predictive testing of children is justified because (a) it shows respect for children's autonomy and confidentiality, (b) it protects children from harm, and (c) there are no compensating benefits of testing when no effective treatment for the condition is available. Although this approach seems reasonable on its face, a careful examination of the arguments shows that each of the three justifications for restricting testing is flawed. Specifically, I argue that the consensus position is not justified because (a) the appeal to autonomy in this context is baseless and confused, (b) there is no evidence of harm from disclosure, and (c) the claim that there are no benefits from early testing is based on an unjustifiably narrow view of benefits that ignores significant advantages that testing actually provides. Ultimately, for reasons that pediatricians usually consider important, I argue that pediatricians should encourage parents to pursue genetic testing of children at a young age.

Adult↗

Chemically-induced unscheduled DNA synthesis in primary rat hepatocyte cultures: a comparison with bacterial mutagenicity using 218 compounds.

The autoradiographic identification of unscheduled DNA synthesis (UDS) in primary cultures of adult rat hepatocytes (HPC) has been proposed as a predictive test for mutagens/carcinogens. To assess the predictive value of this test, results in the hepatocyte UDS assay were compared with data for bacterial mutagenicity using a modified Ames test. Over 200 compounds representing a variety of chemical classes consisting of procarcinogens, ultimate carcinogens, and noncarcinogens were tested in each system. The accurate discrimination of many carcinogens/noncarcinogens was demonstrated by both systems. The induction of UDS in hepatocytes showed an excellent correlation with bacterial mutagenesis in response to polycyclic aromatic hydrocarbons, aromatic amines, biphenyls, nitrosamines, carbamates, azo-compounds, acridines, halogenated compounds, nitrosureas, quinolines, pyridines, purines, pyrimidines, esters and carbamates. Nitrocompounds, although active in bacteria, were poor inducers of UDS. The results support the complementary and confirmatory nature of these tests for genotoxic chemicals and indicate the usefulness of the hepatocyte UDS system as a component in a battery of short-term predictive tests for mutagens/carcinogens.

Animals↗

The Rorschach test for predicting suicide among depressed adolescent inpatients.

With the decreasing length of psychiatric hospitalizations, identification of test indicators of suicide risk becomes critically important. This Rorschach study was designed to model a clinical decision-making scenario concerning adolescent suicide risk. Using Psychiatric Evaluation Form (PEF) scores, we selected a sample of 25 severely depressed and suicidal adolescents; 26 severely depressed, not suicidal adolescents; and 28 not suicidal, not depressed adolescent inpatients at The Sheppard and Enoch Pratt Hospital. A Rorschach Index using the Exner (1986) Comprehensive System for scoring was developed to predict group membership. Four of six of the features on this index selected 64% of suicidal subjects. This constellation included traditional affective variables (vista responses, color-shading blends, color dominated responses, and morbid content) as well as measures of cognitive distortion (inaccurately perceived human movement responses [M-] and special scores). We discuss the implications of these findings for the diagnosis and treatment of the suicidal adolescent.

Adolescent↗

The accuracy of the critical power test for predicting time to exhaustion during cycle ergometry.

The purpose of this study was to determine the relationship between actual time to exhaustion or time limit (ATLIM) during bicycle ergometry and predicted time to exhaustion (PTLIM) from the Critical Power (CP) test. fourteen males (means +/- SD = 22.36 +/- 2.13 years) volunteered as subjects for this investigation. The subjects visited the laboratory on seven occasions separated by at least 24 h. The first two visits were used for the determination of CP; during the remaining sessions the subjects rode a Monarch bicycle ergometer at power loadings of CP - 20%, CP, CP + 20%, CP + 40% and CP + 60% for the determination of ATLIM. Theoretically, power loadings less than or equal to CP can be maintained indefinitely without exhaustion and the PTLIM for power loadings greater than CP can be estimated from the results of the CP test. The accuracy of the CP test for estimating the time to exhaustion during bicycle ergometry was determined by comparing ATLIM to PTLIM using correlation coefficients, standard error of estimates and related t-tests. The results of this study indicated that there were no significant (p greater than 0.05) differences between ATLIM and PTLIM for power loadings greater than CP (ATLIM vs PTLIM at CP + 20% = 8.19 +/- 3.90 vs 7.13 +/- 2.69 min, t = 2.106, r = 0.893, SEE = 1.21 min; CP + 40% = 3.60 +/- 1.37 vs 3.46 +/- 1.18 min, t = 0.842, r = 0.882, SEE = 0.556 min; CP + 60% = 2.36 +/- 0.95 vs 2.32 +/- 0.79 min; t = 0.328 r = 0.841, SEE = 0.428 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Usefulness of the minute ventilation test in predicting successful extubation in newborn infants: a randomized controlled trial.

OBJECTIVE: We performed a prospective, randomized clinical trial to compare the usefulness of the minute ventilation test (MVT) with clinical judgement in predicting readiness for extubation in preterm newborns with respiratory distress syndrome requiring surfactant therapy and mechanical ventilation. STUDY DESIGN: A total of 42 preterm infants with respiratory distress syndrome were randomized when they reached preselected ventilator settings. The primary outcome measure was the time from study entry to extubation, provided the infant remained extubated for at least 24 hours. RESULTS: Infants evaluated by the MVT were extubated in a significantly shorter period of time (mean of 8 hours) than those evaluated clinically (mean of 36 hours). The extubation failure rate was similar in the two groups. CONCLUSION: The MVT is an easily performed objective measure that can be used to predict readiness for extubation in preterm infants. In this study, it significantly shortened the time for extubation and was not associated with a higher rate of reintubation.

Device Removal↗

Development of a branching submaximal treadmill test for predicting VO2max.

This study determined the reliability and validity of a branching treadmill protocol in predicting VO2max. Thirty-seven, apparently healthy individuals (19 women and 18 men); volunteered to participate. On 2 separate testing days, each subject underwent maximal exercise testing using the protocol developed. Stepwise regression analysis indicated that the percentage of age-predicted maximum heart rate (APMHR) achieved at stage 3, speed and grade at stage 3, and APMHR accounted for 89% of the variance in VO2max. The 4 predictor variables were statistically significant (p < 0.01), and the standard error of the estimate was 4.56 ml x kg(-1) min(-1). Results indicate that health and fitness professionals can incorporate this protocol into their practices for the purpose of predicting VO2max for their clients outside the laboratory environment. Furthermore, our results indicate that using the proposed regression model is reliable and has received preliminary construct validity support.

Adult↗

A test of the predictions of the boundary model regarding supernumerary limb structure.

The model proposed in the preceding paper (Meinhardt, 1983) makes specific predictions about the handedness of supernumerary limbs generated after 180 degrees rotation of blastemas. These predictions are tested here by re-examining, in detail, the structure of 100 of these supernumeraries. Of the four predictions, only one was found not to hold. The other three are remarkably precise in their predictions and fit perfectly with the data. A possible reason for the failure of this one prediction is suggested.

Ambystoma↗

How well does IQ predict neuropsychological test performance in normal adults?

The strength and nature of the association between IQ and performance on other cognitive tests has both practical and conceptual significance for clinical neuropsychology. In this study, 28 measures derived from 16 cognitive tests were analyzed as a function of IQ in 221 adults. Participants were grouped by their IQ scores as having below average (BA), average (A), or above average (AA) intelligence. Planned comparisons revealed that A adults performed significantly better than BA adults on 25 of the 28 cognitive measures, and that AA adults performed significantly better than A adults on 19 of 28 measures. Effect sizes averaged.74 for BA-A comparisons and.41 for A-AA comparisons. Linear, quadratic, and cubic functions described the relationships between IQ and cognitive test performance equally well for most individual test measures and for a composite index of test performance, whereas quadratic and cubic functions explained the proportion of abnormal performances better than a linear function. These findings confirm that IQ predicts concurrent neuropsychological performance across the entire spectrum of intelligence, but more so among persons of average IQ or less than among those with above average IQ.

Adult↗

Ethical principles and pitfalls of genetic testing for dementia.

Progress in the genetics of dementing disorders and the availability of clinical tests for practicing physicians increase the need for a better understanding of multifaceted issues associated with genetic testing. The genetics of dementia is complex, and genetic testing is fraught with many ethical concerns. Genetic testing can be considered for patients with a family history suggestive of a single gene disorder as a cause of dementia. Testing of affected patients should be accompanied by competent genetic counseling that focuses on probabilistic implications for at-risk first-degree relatives. Predictive testing of at-risk asymptomatic patients should be modeled after presymptomatic testing for Huntington's disease. Testing using susceptibility genes has only a limited diagnostic value at present because potential improvement in diagnostic accuracy does not justify potentially negative consequences for first-degree relatives. Predictive testing of unaffected subjects using susceptibility genes is currently not recommended because individual risk cannot be quantified and there are no therapeutic interventions for dementia in presymptomatic patients.

Algorithms↗

Integration of B-type natriuretic peptide levels with clinical data and exercise testing for predicting coronary artery disease.

Natriuretic peptides have been shown to be high in patients with myocardial ischemia. We sought to create a diagnostic score using clinical data, stress testing, and B-type natriuretic peptide (BNP) levels to improve noninvasive prediction of coronary artery disease (CAD). Patients with stable angina pectoris and normal systolic left ventricular function were eligible for this prospective cohort study. Patients with arrhythmias, valvular heart disease, impaired left ventricular function, or renal dysfunction were excluded. All patients underwent clinical evaluation, bicycle stress testing, BNP testing, and coronary angiography. Then a diagnostic risk score was derived that combined cardiovascular risk factors, results of exercise testing, and BNP measurements and added 1 point for the presence of each of these variables. Seventy-one patients (52 years of age, range 31 to 61; 46 men) were included in the study. Prevalence of CAD, defined by 50% narrowing of > or =1 coronary artery on coronary angiography, was 45%. For 0 point in the risk score system, the negative predictive value was 93% with a negative likelihood ratio of 0.1 (95% confidence interval [CI] 0.02 to 0.38); for a score of 3 points, the positive predictive value was 93% with a positive likelihood ratio of 15.9 (95% CI 2.19 to 114.7). Serum BNP level >50 ng/L at rest was the best single diagnostic parameter, with 66% sensitivity and 97% specificity, and a positive likelihood ratio of 25.6 (95% CI 3.64 to 180) and a negative likelihood ratio of 0.35 (95% CI 0.22 to 0.57). In conclusion, a diagnostic score combining exercise testing, clinical data, and serum BNP values at rest can distinguish patients with CAD from those without CAD with high accuracy.

Adult↗