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March 2001
Online reminders of drug effects on lab results
More than 40,000 instances of drugs altering laboratory test results have been catalogued in the literature. The prevalence of these effects has been reported to reach 12 percent in some clinical settings. Though published compendia of drug-lab test interactions are commonly used, they are cumbersome and are not readily available to clinicians when they order tests. The ideal system would be a computerized prompting system focused specifically on orders for medications or laboratory tests. The authors analyzed the approach taken at Turku University Central Hospital in Finland, which began developing a drug-laboratory effect code in 1995 and an online reminder system built on the DLE database in 1998. The effects of drugs on endocrine test results specifically were defined, along with the criteria prompting reminders, and links were established between this database and those containing individual patient medications and test results. During the first 10 months of operation, 11 percent of hormone test results were accompanied by reminders—the most common drugs to trigger reminders were glucocorticoids, furosemide, and metoclopramide. The reminders resulted in 74 percent of clinicians surveyed refraining from ordering additional tests. All respondents considered the reminders clinically useful.
Kailajärvi M, Takala T, Grönroos P, et al. Reminders of drug effects on laboratory test results. Clin Chem. 2000;46:1395-1400.
Reprints: Marita Kailajärvi, Central Laboratory, Turku University Central Hospital, Kiinamyllynkatu 4-8, FIN-20520, Turku, Finland
Women’s attitudes toward maternal serum screening
The maternal serum triple screen (alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol) is becoming increasingly available and employed as a method for antenatal detection of increased risk for Downs syndrome, open neural tube defect, and trisomy 18. It has been documented that "average" women, in general, do not know much about these conditions and, therefore, may have only limited understanding of the meaning or value of triple screening. The authors studied six focus groups of Canadian women who had given birth between 1994 and 1996 and who had had triple screening at that time but were not currently pregnant. They found that women want to make a properly informed choice about such screening and that their decision to undergo the procedure was influenced by three main factors: personal values (including their philosophy of life, moral and religious values, and attitudes towards Down’s syndrome and disability), social support networks (including their partners, families, and friends), and the quality of information offered by their health care providers. Women want to receive unbiased, accurate information face-to-face and as early as possible.
Carroll JC, Brown JB, Reid AJ, et al. Women’s experience of maternal serum screening. Can Fam Physician. 2000;46:614-620.
Reprints: Dr. June C. Carroll, 600 University Ave., Suite 413, Toronto, Ontario M5G 1X5, Canada
Transfusion of group B red blood cells that have been
enzymatically converted to group O
After using a recombinant a-galactosidase to remove terminal galactose from group B RBCs, the safety and efficacy of enzyme-converted group-B-to-group-O red blood cell components were studied in transfusion-dependent patients. Twenty-one group A or O patients were transfused with treated group B RBCs, and 18 of the patients also received untreated group O RBCs. Both products gave similar hemoglobin increments at 24 hours and two weeks after transfusion. No clinical transfusion reactions were observed. Of the patients tested, five had an increase in anti-B titers two weeks after transfusion with the treated RBCs. Only one patient had more than a two-tube increase; this patient also received group AB platelets on the day of the transfusion with treated RBCs. This study demonstrated the feasibility of using enzymatically altered red blood cells for transfusion. Because group B RBC donors compose only about 12 percent of the population, the more difficult process of converting group A RBCs to group O needs to be studied.
Kruskall MS, AuBuchon JP, Anthony KY, et al. Transfusion to blood group A and O patients of group B RBCs that have been enzymatically converted to group O. Transfusion. 2000;40:1290-1298.
Reprints: Dr. Margot S. Kruskall, Division of Laboratory & Transfusion Medicine, Yamins 309, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215; mkruska1@caregroup.harvard.edu
Proficiency testing in andrology
Under CLIA ’88, all moderate and high-complexity laboratories in the United States are required to enroll in a government-approved proficiency testing program, if one is available, or demonstrate an alternative method of establishing proficiency. No such PT program was available for sperm testing until the American Association of Bioanalysts established one in 1996. The AAB program involves PT challenges in the areas of detecting anti-sperm antibodies, sperm counting, sperm morphology, and sperm vitality. PT samples were mailed to participating laboratories. On the anti-sperm antibody procedure, 81 percent of laboratories used Immunobead ASAB procedures; 14 percent used mixed antiglobulin reaction; and five percent used “other.” There was 95.6 ± 1.2 percent agreement on the presence or absence of ASAB. The majority of laboratories (79 percent) used manual semen-analysis methods. Coefficients of variation in sperm counts ranged from 24 to 138 percent, with computerized semen analysis showing lower overall CV than manual methods. Wide variation in percent normal morphology was noted on sperm morphology assessment. Laboratories using criteria of the American Society of Clinical Pathologists for this determination reported values clustered in the normal range (11/12 samples), while those using strict criteria were clustered in the abnormal range (10/12 samples). Good agreement in sperm vitality (overall mean CV, 18 percent) was noted. The data highlighted the need to improve andrology testing and demonstrated the feasibility of proficiency testing in this area.
Keel BA, Quinn P, Schmidt CF Jr, et al. Results of the American Association of Bioanalysts national proficiency testing programme in andrology. Hum Reprod. 2000;5:680-686.
Reprints: Brooks A. Keel, Women’s Research Institute, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214
Venipuncture-induced causalgia: relations of veins and nerves
Not all clinical cases of causalgia (Complex Regional Pain Syndrome, Type 2) are associated with improper venipuncture technique. Causalgia is defined as persistent burning, shooting, “electrical” pain in a specific peripheral nerve distribution. The author explored the anatomic relationships of superficial veins and cutaneous nerves by dissecting 14 upper limbs of seven randomly selected cadavers. He found a great deal of variability among cadaver specimens and between limbs of the same cadaver. Major branches of cutaneous nerves overlaid veins in six extremities. Nerves and veins were frequently intertwined and difficult to separate by dissection. Sometimes the relationship changed along the course of the nerve and vein. The nerves and veins frequently were on the same fascial plane. The author concluded that venipuncture needle contact with nerve is common, even though venipuncture-induced nerve injuries are rare. Factors other than needle-nerve contact apparently are necessary for causalgia to occur.
Horowitz SH. Venipuncture-induced causalgia: anatomic relations of upper extremity superficial veins and nerves, and clinical considerations. Transfusion. 2000;40:1036-1040.
Reprints: Dr. Steven H. Horowitz, Division of Neurology, M-741, University of Missouri School of Medicine, 1 Hospital Dr., Columbia, MO 65212; horowitzs@health.missouri.edu
Relationship of total, free, and complexed PSA to
volume of the prostatic transition zone
Three different molecular forms or fractions of prostate-specific antigen exist in serum: PSA unbound to any serum anti-protease binding proteins (free PSA), PSA bound to such proteins (complexed PSA), and total measured PSA (free and complexed or total PSA). Three leading commercial assays—from Bayer, Diagnostic Products Corp. (DPC), and Hybritech—are available. They provide potentially comparable measurements of their fractions and various ratios (free/total, free/complexed, complexed/total). Appropriate comparison of these variables should involve receiver operating characteristic analysis of test performance versus transrectal ultrasound-guided biopsy results adjusted for prostate volume. This study retrospectively reviewed 809 cases that were biopsy-positive for at least a 5 mm diameter tumor, 90 control subjects who were biopsy-negative (x2), and subsets of 38 of each group who were matched by total prostate volume, PSA, and age. Transrectal ultrasound measurements determined total volume of the prostate and volume of the transition zone of the organs. Free, complexed, and total PSA and their ratios were determined by the Bayer, DPC, and Hybritech assays, and ROC analysis was performed on the results. All three commercial methods performed comparably. On cases unadjusted for prostate volumes, total PSA was the least discriminatory assay, marginally exceeded by complexed PSA. Free PSA performed better than both, and the ratios of free/total and complexed/total performed best. Factoring in prostate volume, total PSA performed as well as the ratios. The authors also observed that using transition zone volume instead of total prostate volume further improved performance. They recommended that future studies of PSA analytes be related to three categories of transition zone volume: less than 20 g, 20 to 60 g, and more than 60 g.
Stamey TA, Yemoto CE. Examination of the 3 molecular forms of serum prostate specific antigen for distinguishing negative from positive biopsy: relationship to transition zone volume. J Urology. 2000;163:119-126.
Reprints: Dr. Thomas A. Stamey, Dept. of Urology, S-287, Stanford University Medical Center, 300 Pasteur Dr., Stanford, CA 94305
Intrauterine parvovirus B19 infection detected using PCR assays
Human parvovirus B19 has been recognized as a potential cause of prenatal mortality, and B19 infection may be somewhat common during pregnancy. The authors assayed chorionic villi and amniotic fluid cells for B19 using polymerase chain reaction for B19 sequence-specific amplification. The DNA of these cells was extracted for the PCR assays. The amniotic fluid was obtained from 26 women attending an antenatal clinic because they were over 35 years old. The samples were collected from May 1997 to June 1998. The gestational ages of the pregnancies were within the second trimester. Sixty-one specimens of chorionic villi were obtained from women attending the antenatal clinic for induced abortion. The gestational age of these pregnancies was within the first trimester. Two B19-positive specimens of chorionic villi and one B19-positive specimen of amniotic fluid were found. This verified the existence of B19 intrauterine infection in early pregnancy. Vertical transmission of human parvovirus B19 during early pregnancy, therefore, may be a means of intrauterine infection. PCR could be adapted as a diagnostic test for B19 intrauterine infection.
Dong ZW, Se SY, Li Y, et al. Detection of human parvovirus intrauterine infection with the polymerase chain reaction. J Reprod Med. 2000;45:410-412.
Reprints: Dr. Zhao-wen Dong, Dept. of Molecular Biology, National Research Institute for Family Planning, 12 Da Hui Si, Hai Dian District, 100081 Beijing, China; zwdong@ihw.com.cn
Population stratification in epidemiologic studies of common genetic traits and cancer
Population stratification is a form of bias. When risk of a disease varies between ethnic groups, any other factor that also varies between those groups will appear to be related to the disease. Concerns about this source of confounding have led to recommendations to use related controls in case-control studies of genetic factors to eliminate bias. The authors investigated the degree of bias from population stratification in U.S. cancer studies among non-Hispanic Caucasians of European origin. They calculated the ratio of the effect of the genetic factor on risk of disease with and without adjusting for ethnicity—that is, the confounding risk ratio to measure the potential bias from population stratification. This was done specifically for a study on the frequency of N-acetyltransferase (NAT2) slow acetylation genotype and incidence rates of male bladder/female breast cancer in non-Hispanic U.S. Caucasians whose ancestry could be traced to eight European countries. The authors found that ignoring ethnicity led to a bias of one percent or less in studies of NAT2. Furthermore, sensitivity analysis on allele frequencies and cancer rates among European populations showed that the risk ratio is biased by less than 10 percent in most U.S. studies. The authors concluded that bias from population stratification will be small in well-designed case-control studies of genetic factors that ignore ethnicity among non-Hispanic U.S. Caucasians of European origin.
Wacholder S, Rothman N, Caporaso N. Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. J Natl Cancer Inst. 2000;92:1151-1158.
Reprints: Dr. Sholom Wacholder, National Institutes of Health, EPS 8046, 6120 Executive Blvd., Bethesda, MD 20892-7244; wacholder@nih.gov
IGF-1 as a prostate CA tumor marker
Preliminary prospective studies have shown a positive association between serum levels of insulin-like growth factor-1 (IGF-1) and risk for prostate cancer. Studies of prostate cancer-derived cell lines in tissue culture have shown mitogenic and anti-apoptotic effects of IGF-1. The authors conducted their own two-part study of IGF-1. The first part was a retrospective matched case-control study of batched serum from 171 prostate cancer patients and 67 age-matched male control subjects. The second part was a prospective study of 19 newly diagnosed prostate cancer patients who were monitored before and during testicular androgen withdrawal therapy using luteinizing hormone-releasing hormone analogs and antiandrogens. IGF-1 levels were determined using chemiluminescent assay and radioimmunoassay, and testosterone levels were also determined in group B. The mean serum IGF level in patients with prostate cancer was 158.6 ng/mL; in controls, it was 159.1 ng/mL. Similarly, there were no significant differences in IGF-1 levels before and after antiandrogen therapy. Before androgen therapy, the mean testosterone level was 4.81 µ/L, but mean IGF-1 was 169.7 ng/mL, not significantly changed from pretreatment levels. The authors concluded that there was no significant association between IGF-1 serum levels and prostate cancer.
Kurek R, Tunn UW, Eckart O, et al. The significance of serum levels of insulin-like growth factor-1 in patients with prostate cancer. BJU Int. 2000;85:125-129.
Reprints: H. Renneberg, Dept. of Anatomy and Cell Biology, Robert Koch Str. 6, 35033 Marburg, Germany
A side-by-side comparison of five immunoassay analyzers
The new generation of immunoassay analyzers feature advances in assay technology, such as chemiluminescent methodologies, and automated random-access workstation design that increasingly resembles that of automated chemistry analyzers. Five examples of these newer products are the Bayer (formerly ACS) Centaur, Abbott Architect i2000, Roche-Boehringer Mannheim Elecsys 2010 tandem, Diagnostic Products Corp. (DPC) Immulite 2000, and the Johnson & Johnson Vitros ECi. A study was conducted to compare the analyzers directly under identical laboratory conditions operating on a routine workload, including stats, reflex tests, dilutions, and within-run calibration of a new reagent lot number. The analyzers were rated in terms of hands-on labor time, unattended time, throughput, and relative productivity index (RPI)-that is, number of reportable results/(processing time - unattended time). RPI also was observed for analyzers linked to automated sample-handling systems. The Centaur, overall, had the least total hands-on labor time and the Vitros ECi had the most. The Centaur had the highest measured throughput, including and excluding initialization time (193 tests/hr and 217 tests/hr, respectively) and came the closest to approximating the manufacturer’s claimed maximum throughput (120 tests/hr). The Vitros ECi had the lowest measured throughput (46 and 61 tests/hr, respectively). RPIs varied with the length of unattended time for each analyzer. The Centaur had the highest maximum RPI (at zero unattended time) of 1,100 reportable results/operator hr without an automated front-end and 2,800 reportable results/operator hr with automation. For other unattended time intervals, the RPI of the Centaur without automation was comparable to that of the DPC Immulite 2000. The Vitros ECi again had the lowest volumes using the RPI measure.
Hendricks HA, Kortlandt W, Verweij WM. Standardized comparison of processing capacity and efficiency of five new-generation immunoassay analyzers. Clin Chem. 2000;46:105-111.
Reprints: Henriëtte Alice Hendricks, Stichting Artsen Laboratorium, Nooderstraat 8, 3512 VX Utrecht, The Netherlands
Neuropsychologic dysfunction and S-100ß after cardiac surgery
During cerebral injury, the glial protein S-100ß leaks from damaged cerebral cells into the cerebrospinal fluid and hence across the blood-brain barrier into serum. S-100ß levels have been used in a research context to identify cerebral injury following cardiac surgery. The authors related serum S-100ß levels to short- and long-term neuropsychological measures postoperatively in patients undergoing cardiopulmonary bypass. They prospectively examined 100 patients undergoing elective cardiopulmonary bypass, none of whom had a previous history of neurologic impairment. Serial measurements of S-100ß were made using a chemiluminescent assay on blood samples (excluding cardiotomy suction or retransfused blood) up to eight hours postoperatively. The patients also underwent extensive testing of cognitive function on a battery of 11 tests preoperatively, before discharge from the hospital, and three months later. No correlation was found between perio-operative S-100ß levels and neuropsychological measures at five days or three months postoperatively.
Westaby S, Saatvedt K, White S, et al. Is there a relationship between serum S-100ß protein and neuropsychologic dysfunction after cardiopulmonary bypass? J Thorac Cardiovasc Surg. 2000;119:132-137.
Reprints: S. Westaby, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DU, England
Determining whether to culture acute burns
Though the incidence of bacterial wound infection in patients with burns has been significantly reduced by early excision and grafting and advances in antibiotic therapy, infection remains a leading cause of death in patients with burns covering more than 30 percent of their body and in those in whom excision is contra-indicated. The latter types of cases, however, represent a distinct minority of burn cases. The standard of care in most burn units is to routinely culture all burn wounds within 24 hours of admission and/or to obtain urine, blood, sputum, and wound cultures (pan-culturing) from all burn patients with temperatures higher than 38.5°C during the first 24 hours. This is done despite a lack of evidence that such routine culturing is beneficial. The authors performed a retrospective chart review of 598 burn patients, 447 of whom were in the hospital for less than one day (outpatients) and 151 of whom were admitted for longer periods (inpatients). Wound cultures were obtained on 42 (10 percent) of the outpatients and 45 (30 percent) of the inpatients. None of the outpatients and 24 (16 percent) of the inpatients were pan-cultured. Seventy-one percent (30/42) of outpatient cultures showed no growth, and 29 percent (12/42) grew mixed common skin flora. One patient grew enterococcus species from an initial wound culture and was treated with antibiotics. No other antibiotics were ordered on the basis of cultures. The authors concluded that routine culturing of acute burn patients is not cost-effective and that charges could be reduced by $14,000 a year by eliminating this practice.
Miller PL, Matthey FC. A cost-benefit analysis of initial burn cultures in the management of acute burns. J Burn Care Rehabil. 2000;21:300-303.
Reprints: Penny L. Miller, University of California, Davis Medical Center, Division of Emergency Medicine, PSSB 2100, 2315 Stockton Blvd., Sacramento, CA 95817
Crohn’s disease linked to chromosome 14q11-12
Genetic factors play a role in Crohn’s disease and ulcerative colitis. The relative risk to siblings of affected individuals is 30 to 40 for Crohn’s disease and 10 to 20 for ulcerative colitis, and the diseases occur together in the same families with greater frequency than chance. Both forms of inflammatory bowel disease have greater concordance in monozygotic than dizygotic twins, Ashkenazi Jews, and familial aggregation. The authors scanned 751 microsatellite loci in 127 CD-affected relative pairs from 62 families. They used the Genehunter-Plus software to perform a single-point nonparametric linkage analysis and determined LOD scores of 3.00 and 1.70, respectively, for linkage to two adjacent loci (D14S261 and D14S283) on chromosome 14q11-12. The linkage to the first of these loci confirms the results of a previous independent study and thus satisfies the criteria for a confirmed linkage. The authors propose designating the region of interest on chromosome 14q11-12 as the IBD4 locus.
Duerr RH, Barmada MM, Zhang L, et al. High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11-12. Am J Hum Genet. 2000;66:1857-1862.
Reprints: Dr. Richard H. Duerr, 565 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261
WBC counts in synovial fluid
In the context of a total knee arthroplasty, diagnosing sepsis in the joint can be difficult because physical exam and radiologic findings may be inconclusive. Synovial fluid culture is the most commonly ordered laboratory test, but it has been reported to yield inconsistent results. The white blood cell count and differential on synovial fluid is a routine criterion for determining infection in knees that have not been operated on, but reference values for knees post TKA are not readily available. The authors undertook a study to examine the synovial fluid WBC count and differential in patients with aseptically failed TKA. They determined cell count and differential on 79 TKAs in patients admitted to the University of Arizona for revision following aseptic failure over a five-year period. The overall mean WBC count in these specimens was 782/mL (range, 11-7,200/mL). The mean monocyte cell count represented 87 percent and the mean PML cell count was 13 percent in the differential. Eight patients (10.4 percent) had WBC counts greater than 2,000/mL and differentials of more than 50 percent PMLs. In osteoarthritis patients, a synovial fluid WBC of less than 2,000/mL with a differential of less than 50 percent PMLs had a 98 percent negative predictive value for the absence of infection. The study indicates a role for synovial fluid WBC count and differential as an adjunctive test for infection in the evaluation of failed TKA.
Kersey R, Benjamin J, Marson B. White blood cell counts and differential in synovial fluid of aseptically failed total knee arthroplasty. J Arthroplasty. 2000;15:301-304.
Reprints: Dr. James Benjamin, 395 N. Campbell Ave., Tucson, AZ 85719
Distribution of a1-antitrypsin alleles in bronchiectasis
Bronchiectasis occurs in patients with emphysema as well as on a spontaneous basis, and the condition has been reported to occur in patients with homozygous a1-antitrypsin deficiency. A study was undertaken to see if a relationship could be established between a1-antitrypsin genotype (determined by isoelectric focusing on serum) and the occurrence of bronchiectasis. The authors determined a1-antitrypsin allele frequencies and phenotype in 202 patients (104 men, 98 women; mean age, 63.7 years) with bronchiectasis and 11,030 unrelated healthy male and female blood donors. The bronchiectasis was primary in 121 cases and secondary in 81 and was diagnosed radiologically. The allelic frequencies among patients were: M, 89.1 percent; S, 7.67 percent; Z, 2.72 percent; and I, 0.49 percent. The phenotypic frequencies were: MM, 81.18 percent; MS, 11.88 percent; MZ, 3.46 percent; IZ, 0.49 percent; IM, 0.49 percent; SS, 1.48 percent; SZ, 0.49 percent; and ZZ, 0.49 percent. There were no significant differences in the distribution of alleles or phenotypes between patients and controls or between patients with primary versus secondary bronchiectasis. The only significant difference was in the occurrence of PI*Z alleles in the subset of bronchiectasis patients with coexisting emphysema. The authors concluded that, within the statistical power of their study, no significant relationship appears to exist between a1-antitrypsin genotype and bronchiectasis. They suggest that bronchiectasis in PI*Z patients may be a consequence of emphysema rather than a primary gene effect.
Cuvelier A, Muir J-F, Hellot M-F, et al. Distribution of a1-antitrypsin alleles in patients with bronchiectasis. Chest. 2000;117:415-419.
Reprints: Dr. Antoine Cuvelier, Respiratory and Intensive Care Dept., Hôpital de Bois-Guillaume, CHU de Rouen, 76031 Rouen CEDEX, France
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