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Cell cultures and their use in drug sensitivity prediction.

This paper reviews briefly the advantages of in vitro methods for predictive drug sensitivity testing and then summarizes the present situation. Clear evidence of variation in chemosensitivity at the cellular level is now available, the value of the test for predicting in vivo resistance is confirmed, and some evidence that treatment of advanced carcinoma of the ovary on the basis of a predictive test prolongs survival is presented. Ways in which the laboratory test might be improved are suggested and outstanding clinical problems, in particular the need for a very large number of patients in any prospective trial designed to detect a small improvement in treatment, are discussed.

Antineoplastic Agents↗

Heparin-induced platelet aggregation vs platelet factor 4 enzyme-linked immunosorbent assay in the diagnosis of heparin-induced thrombocytopenia-thrombosis.

Thrombosis occurs in an unpredictable subset of patients with heparin-induced thrombocytopenia (HIT). The diagnosis of HIT requires clinical suspicion and laboratory confirmation. Although the "gold-standard" diagnostic test is considered to be the serotonin release assay (SRA), most laboratories use heparin-induced platelet aggregation (HIPA), which is highly specific but reported to be less sensitive than the SRA. Recently, the heparin-platelet factor 4 (PF4) enzyme-linked immunosorbent assay (ELISA) has been reported to have comparable sensitivity to the SRA. We compared the HIPA and PF4 ELISA in serum samples from 146 patients examined for HIT and assessed whether either test predicted thrombotic risk. Results for 81 patients were positive for HIPA, PF4 ELISA, or both. Of these, 91% were HIPA-positive, while only 60% were PF4 ELISA-positive. Clinical information was available on 63 patients, 17 of whom had thrombotic events (10 venous, 6 arterial, and 1 both). Neither the HIPA nor the PF4 ELISA predicted thrombotic risk, but the HIPA proved to be a more sensitive test for laboratory confirmation.

Enzyme-Linked Immunosorbent Assay↗

Diagnosis of common bile duct stones by intravenous cholangiography: prediction by ultrasound and liver function tests compared with endoscopic retrograde cholangiography.

BACKGROUND: Routine intravenous cholangiography using the safer contrast medium, meglumine iotroxate, may be a useful investigation prior to laparoscopic cholecystectomy for the detection of suspected common bile duct stones. We compared this with endoscopic cholangiography. METHODS: Eighty-one consecutive nonjaundiced patients (mean age 62 years; range 20 to 90) with suspected common bile duct stones referred for endoscopic cholangiography to one center underwent intravenous cholangiography that was considered positive if it detected ductal stones. The ability of ultrasound scans and liver function tests to predict ductal stones was also assessed. RESULTS: Sixty patients had both endoscopic and intravenous cholangiograms performed. Thirteen out of 27 patients with ductal stones confirmed by endoscopic cholangiography had positive intravenous cholangiograms, and 29 out of 30 with no stones had negative intravenous cholangiograms. The sensitivity for intravenous cholangiography was 48%, specificity 97%, positive predictive value 93%, negative predictive value 67%, and accuracy 73%. For ultrasound scans the positive predictive value was 69%; negative predictive value was 78%. For liver function tests the positive predictive value was 68%; negative predictive value was 93%. CONCLUSIONS: Intravenous cholangiography cannot be recommended instead of endoscopic cholangiography except in situations where the latter is not readily available. Ultrasound and liver function tests are useful in predicting ductal stones.

Adult↗

[Respiratory function evaluation in esophageal surgery. Predictive value of tests].

In the context of major surgery the predictive significance of respiratory function tests in relation to postoperative pleuro-pulmonary complications is assessed. A statistical analysis is performed on a series of 85 oesophagectomy after thoracotomy and laparotomy. The most significant respiratory function indices are found to be those relating to volume restriction and the Mottley index.

Adult↗

Carboplatin skin testing: a skin-testing protocol for predicting hypersensitivity to carboplatin chemotherapy.

PURPOSE: A high incidence of moderate to severe hypersensitivity reactions (HRs) is noted in patients who have been treated with multiple courses of carboplatin. Presently, there is no reliable way to predict which patients may be at risk for this potentially severe adverse reaction. We developed a skin-test protocol to identify patients at high risk for HR to carboplatin chemotherapy. PATIENTS AND METHODS: Patients undergoing more than seven courses of carboplatin received a 0.02-mL intradermal injection of an undiluted aliquot of their planned carboplatin infusion 1 hour before each course of the agent. A positive skin test was prospectively defined as that resulting in a wheel of at least 5 mm with a surrounding flare. We recently reported a 27% incidence of HRs in patients receiving more than seven courses of carboplatin. These patients served as historical controls for the current study. RESULTS: Forty-seven patients with recurrent ovarian or primary peritoneal carcinoma receiving carboplatin were skin tested. Thirteen of 47 patients (28%) manifested a positive skin test at a median of nine total courses of carboplatin (range, eight to 17 courses). This rate of skin-test positivity was not significantly different from the incidence of documented HR reported in a historical control group (P =.89), suggesting comparable populations. A negative skin test accurately predicted the absence of HR in 166 of 168 courses of chemotherapy. Only two of 47 patients (4%) experienced a HR after a negative skin test. Thus, administering carboplatin only to patients with a negative skin test may result in a significant reduction in HRs relative to historical controls (P =.002). CONCLUSION: An easily performed skin test appears to predict patients in whom carboplatin may be safely administered. Treatment modifications based on the results of skin testing may reduce the incidence of HRs in patients receiving repeated courses of carboplatin.

Antineoplastic Agents↗

[Postpartum perineal assessment].

BACKGROUND: To evaluate the incidence of urogenital and anorectal dysfunctions during puerperium, verify the correlation between obstetric perineal damage observed during labour and puerperal symptoms, test the efficacy of tests to evaluate perineal function in pelvic floor dysfunctions consequent to vaginal birth. METHODS: A total of 693 consecutive puerperae were recruited two months after birth. All completed a clinical and anamnestic questionnaire and underwent clinical urogynecological examination, digital test, vaginal manometry and uroflowmetric evaluation of the voluntary capacity to interrupt micturition. From a statistical point of view, persistent urinary incontinence was identified by graphic representation on frequency tables and predictive tests, and statistical "kappa" was used to evaluate the correlation between perineal function tests. RESULTS: Stress urinary incontinence (15.1%) represents the most widespread symptom, a postpartum perineal inspection provides a sufficiently accurate estimate of posterior damage, but does not identify those puerperae who will develop urinary incontinence. None of the tests used was able to predict persistant urinary incontinence. CONCLUSIONS: Postpartum perineal inspection seems to be effective in predicting anorectal dysfunctions, but is not so useful for urethro-vesical disorders. None of the diagnostic methods examined allowed a sufficiently accurate selection of those puerperae at risk.

Fecal Incontinence↗

Forgotten person in the Huntington disease family.

Although spouses play a major role in managing the care of persons affected with Huntington disease (HD), often at the price of subordinating their own aspirations and needs, little or no professional attention has been given to them in the HD literature. Such factors as secrets kept from the spouse, the early age-of-onset of symptoms, gender, and the coping strategies employed by spouses of affected persons are discussed and illustrated. Also, the impact of predictive testing for HD on spouses of persons undergoing testing is briefly touched on.

Adaptation, Psychological↗

Evaluation of CD86 expression and MHC class II molecule internalization in THP-1 human monocyte cells as predictive endpoints for contact sensitizers.

The aim of this study was to explore the usefulness of a human monocyte cell line in the development of in vitro models for predictive testing of contact sensitizers. Several studies have shown that contact sensitizers induce CD86 expression and enhanced internalization of MHC class II molecules in dendritic cells (DCs). We used THP-1, a human monocyte cell line, as a replacement for DCs for evaluation of these phenotypical alterations as predictive endpoints for contact sensitizers. Known sensitizers and irritants were evaluated. After 24-h exposure to samples, the expression of CD86 on THP-1 cells was measured by flow cytometry. Sensitizers such as dinitrochlorobenzene (DNCB), 2-mercaptobenzothiazole (MBT), eugenol, p-phenylenediamine (PPDA) and ammonium tetrachloroplatinate (Pt) enhanced CD86 expression on THP-1 cells, while nickel sulfate, cobalt sulfate and irritants such as methylsalicylate (MS), sodium dodecyl sulfate (SDS) and dimethyl sulfoxide (DMSO) did not augment CD86 expression. A synergistic effect was observed when DNCB and IFN-alpha were added simultaneously to a culture of THP-1 cells. Furthermore, internalization of MHC class II molecules was observed when the cells were treated with some of sensitizers for 2 h. The inducing effects of chemicals on the two phenotypical alterations were the same. These results suggest that these test systems can be used to predict contact-sensitizing ability of chemicals as an in vitro sensitization assay.

Animal Testing Alternatives↗

A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss.

OBJECTIVE: To validate a simple, highly predictive test to discriminate between menorrhagia and normal menstrual blood loss. METHODS: The sanitary wear of 489 menstrual bleeding episodes was collected by 288 women for objective measurement of menstrual blood loss (alkaline hematin method); the women made a subjective assessment of the volume and, based on a pictorial chart, recorded the amount of and the degree to which their sanitary wear was soiled. Based on that degree, a score was calculated for each episode and a suitable cutoff point was chosen, above which the presence of menorrhagia was likely and below which it was unlikely. RESULTS: Using a score of 185 as the cutoff point, the predictive values of positive and negative tests were almost equally high, 85.9 and 84.8%, respectively. Whether or not the presence of clots was recorded, these values did not change. The predictive value of a woman's complaint of heavy bleeding for the presence of menorrhagia was 55.9% and that of anemia (hemoglobin less than 12.0 g/dL) was 74.4%. CONCLUSION: We validated and refined a new, simple, visual assessment technique and demonstrated that it is superior to a woman's subjective assessment of menstrual blood loss and the occurrence of anemia for predicting menorrhagia, even if it is performed only once. We also demonstrated that the volume that clots contribute to menstruation is not as large as many clinicians believe. With this technique, the quality of therapy can be enhanced by making it more adequate and rational.

Adult↗

An evaluation of milk ketone tests for the prediction of left displaced abomasum in dairy cows.

Two commercial milk ketone tests (Ketocheck) Great States, St. Joseph, MI and Ketolac BHB; Hoechst, Unterschleissheim, Germany) were used with milk samples collected within 2 wk postpartum to evaluate the use of these tests in the prediction of left displaced abomasum in dairy cows. Odds ratios, sensitivities, specificities, and likelihood ratios were determined. For the study of Ketocheck, 47 milk samples from 26 cows that were later diagnosed with left displaced abomasum were taken at a median of 6 d postpartum (12 d prior to diagnosis of the disease. For the study of Ketolac BHB, 26 milk samples from 15 cows that were later diagnosed with left displaced abomasum were taken at a median of 6 d postpartum (11 d prior to diagnosis of the disease). Each cow that was subsequently diagnosed with left displaced abomasum was matched with three control cows by herd and calving date. Positive Ketocheck results and Ketolac BHB results that indicated > or = 100 or > or = 200 mumol of beta-hydroxybutyrate (BHBA)/L of milk were significantly associated with the subsequent diagnosis of left displaced abomasum. The sensitivity of Ketocheck for the prediction of left displaced abomasum was 22%; specificity was 96%. The sensitivity of Ketolac BHB for the prediction of left displaced abomasum was 46% when the results indicated > or = 100 mumol of BHBA/L and was 34% when the results indicated > or = 200 mumol of BHBA/L. Ketocheck and Ketolac BHB might be used as tests for the prediction of left displaced abomasum when used with milk sampled within 2 wk postpartum. Hyperketolactia is a significant risk factor of left displaced abomasum.

Abomasum↗

Chemosensitivity testing of ovarian cancer: results of a rapid in vitro biochemical assay.

There is a need for a predictive test which will assist in the selection of an effective cytotoxic drug and thereby, provide a means of avoiding unnecessary drug-induced toxicity and tumour resistance. In the present study, the viable fraction of the tumour cell suspension from ovarian cancer was used as targets for the effect of the drug, cisplatin, in a 3-hour in vitro assay. DNA synthesis was measured by the incorporation of 3H-thymidine as an index of proliferative activity and RNA synthesis by the incorporation of 3H-uridine as an index of protein metabolism. There was a good correlation between cell activity as determined by the uptake of thymidine and uridine. The degree of drug inhibition was variable over the spectrum of tumour histologic types; thymidine uptake was significantly inhibited by cisplatin in 53% of serous cystadenocarcinomas, and uridine uptake in 21% of tumours. A clear difference in drug effect was observed between those patients who showed clinical response and those who did not. These results support the value of this assay as an indicator of drug sensitivity of the tumour.

Adenocarcinoma↗

Agrammatic aphasic subjects' comprehension of subject and object extracted Wh questions.

This study attempted to replicate the unusual wh question comprehension pattern of Hickok and Avrutin's (1996) subjects who showed an expected subject/object extraction asymmetry for which NP questions, but not for who questions. We also examined comprehension of what and which one questions, which are similar to who and which NP questions, respectively, and we examined passivized wh questions in order to test predictions of Grodzinsky's (1995) restrictive theory of trace deletion, the Trace-Based Account (TBA). Results, using both a figurine manipulation task and a picture pointing task, showed that only one of four agrammatic (Broca's) aphasic subjects showed the pattern reported by Hickok and Avrutin and that this pattern extended to comprehension of what and which one questions. One of the subjects showed subject/object asymmetry for all wh questions tested, as would be predicted by the original trace deletion hypothesis (Grodzinsky, 1984), and two subjects showed neither pattern. None of our subjects demonstrated ability to comprehend passivized wh questions as predicted by the TBA. We discuss our findings in terms of the lack of homogeneity of wh question comprehension among individuals with agrammatic aphasia and we explore alternatives to the syntactic explanation for differences between who and which NP question comprehension advanced by Hickok and Avrutin.

Aphasia, Broca↗

[Predictive value of the ajmaline test in dysfunction of the sinus node. Prospective 4-year follow-up relative to 77 patients].

To establish the usefulness of Ajmaline test for the evaluation of sinus node function, 77 pts (47 M, 30 F, mean age +/- SD = 61 +/- 15 yrs) first underwent an electrophysiologic study and then were followed-up for a mean period of 46.3 months. The following parameters were determined before and after i.v. administration of Ajmaline (1 mg/kg in 1 minute): sinus cycle length (SCL), corrected sinus node recovery time (CSNRT) and sino-atrial conduction time (SACT). The pts were divided into 3 groups: Group A: 10 pts without clinical or electrocardiographic signs of sinus node dysfunction (SND) and with normal control CSNRT and SACT (less than or equal to 500 and less than or equal to 120 msec, respectively); Group B: 46 pts with clinical-electrocardiographic signs of suspected or apparently not severe SND (sinus bradycardia greater than or equal to 40 beats/min and/or syncopes with positive vagal manoeuvres) and/or slightly abnormal control CSNRT (greater than 500 less than or equal to 600 msec) and/or SACT (greater than 120 less than or equal to 150 msec); Group C: 21 pts with clinical-electrocardiographic signs of apparently severe SND (sinus bradycardia less than or equal to 39 beats/min, sino-atrial block, sinus arrest) and/or definitely prolonged control CSNRT and/or SACT (greater than 600 and greater than 150 msec, respectively). The Ajmaline test was considered negative for the presence of a severe SND if SCL was not prolonged after the administration of the drug more than 20% and CSNRT and SACT were not prolonged more than 50% compared to the control values. Otherwise the Ajmaline test was considered positive. Twenty-seven out of the 77 pts studied underwent permanent pacemaker implantation (23 immediately after the electrophysiologic study and 4 during the follow-up). The following results were obtained: the Ajmaline test was negative in 100% of group A, 87% of group B and 48% of group C pts and positive in 0% of group A, 13% of group B and 52% of group C pts; during the follow-up a negative test resulted predictive in 56 out of 60 pts (92%) and a positive test in 16 out of 17 pts (94%). The predictive accuracy of the test was, therefore, 93.5%. These results indicate that Ajmaline test is an useful provocative test for disclosing, during electrophysiologic studies, pts who have severe SND and for selecting those who need pacemaker implantation.

Adolescent↗

Fluorescein test in the prediction of viability of skin flaps on pigs.

The fluorescein test is widely used in clinical and experimental studies for prediction of the viability of skin flaps. A thorough search of the literature revealed that the accuracy of this test had never been studied. Therefore, this study was designed to evaluate the accuracy of the fluorescein test in predicting the viability of skin flaps. A total of 212 unipedicle porcine skin flaps were used in this study. Statistical analysis demonstrated that the surviving area of the flap was significant greater than the staining area of the flap. We suggest that caution be exercised when the fluorescein dye test is used to assess skin flap viability and that the test be used for an approximate indication and not for an accurate prediction of the surviving flap area.

Animals↗

Measuring physicians' tolerance for ambiguity and its relationship to their reported practices regarding genetic testing.

Despite uncertainties in medicine, attempts to study physicians' tolerance for uncertainty have been few, and limited by the measurement instruments available. This paper describes development of a modified tolerance for ambiguity (TFA) scale, and correlates it with several physician characteristics and reported behaviors. Eighteen TFA items were included in a national survey of physicians' knowledge and attitudes about genetic testing. Sixty-five percent (n = 1,140) of 1,759 obstetricians, pediatricians, internists, family practitioners, and psychiatrists responded. After psychometric analyses, the scale was reduced to 7 items, demonstrating an acceptable reliability (Cronbach's alpha = .75). TFA was higher among psychiatrists than other specialties, among those who were older when they graduated from medical school, and among those willing to offer a new low-cost, accurate predictive test when none of their colleagues do. TFA was lower among those who indicated that attendance at religious services was important, among those who would make a recommendation to their patients regarding pregnancy termination after prenatal diagnosis, and among those who would withhold negative genetic test results. Future research is needed on the scale itself, and to assess factors affecting TFA, such as its susceptibility to modification, and its potential association with clinical practice in other areas of medicine that are characterized by ambiguity.

Abortion, Therapeutic↗

Immediate hypersensitivity to ovalbumin in children with hen's egg white allergy.

Serum concentrations of IgE, IgG1 and IgG4 antibodies to ovalbumin and basophil sensitivity to ovalbumin were compared with the results of a titrated oral provocation test with ovalbumin in 27 children sensitive to hen's egg white, of whom 17 responded with an immediate hypersensitivity reaction. Neither the serum level of IgE, IgG1 and IgG4 antibodies to ovalbumin nor a positive histamine release test predicted the clinical relevance of ovalbumin sensitivity. The children with a positive challenge test had a significantly higher IgE/IgE4 ratio and tended to be younger and to have higher serum IgE levels and a higher IgG1/IgG4 ratio than those with a negative challenge test. We conclude that an oral provocation test is necessary to confirm the diagnosis of food allergy.

Child↗

Correlations between therapeutic response of leukaemias and in-vitro drug-sensitivity assay.

To develop the differential staining cytotoxicity (DiSC) assay, an in-vitro drug sensitivity test designed specifically for use with fresh human haematological tumour cells, into a predictive test for response to therapy as well as a tool for identifying new treatment strategies, test results have been correlated with response in patients with haematological malignancies. 22 of 119 tests indicated extreme drug resistance (tumour cell survival greater than 55%) in vitro. None of these patients responded to chemotherapy. The proportion of patients responding to therapy and 50% patient survival rose with in-vitro drug sensitivity. 11 specimens showing extreme drug resistance to the agents prescribed for the patient were subjected to drug sensitivity tests of drugs not prescribed; patients showing some sensitivity to these drugs had better survival than did those with extreme drug resistance to all drugs tested. The DiSC assay can also be used to identify new agents worth testing in clinical trials, and cross resistance profiles of new agents may indicate what combinations might be useful.

Antineoplastic Agents↗