Validation of a limited sampling model to determine etoposide area under the curve

STUDY OBJECTIVE: To validate the utility of a previously reported 3-point limited sampling model (LSM) for determining etoposide area under the curve to infinity (AUC(infinity)). DESIGN: Secondary analysis of data from two clinical trials of etoposide. SETTING: University medical center clinical research center. PATIENTS: Thirty-four patients with different malignancies. INTERVENTIONS: Etoposide was administered as a 2-hour infusion to 34 patients. Serial plasma samples were drawn over 24 hours after the infusion and analyzed for etoposide by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The 3-point LSM AUC was compared with a 14-point actual AUC calculated by the linear trapezoidal rule. Actual and predicted AUC(infinity) by the LSM were highly correlated (r=0.97, p<0.0001). The LSM predictions had a mean absolute error of 10.9% (95% CI -14.1, -5.3) and a mean error of -9.7% (95% CI 6.9, 14.9). Nine patients with poor AUC(infinity) estimations by the LSM (error > 12%) tended to have abnormally low or high peak concentrations. CONCLUSION: Our findings suggest the development of more robust LSM using other techniques, such as pharmacostatistical models, that can accommodate a greater degree of pharmacokinetic variability.     

Cotrel-Dubousset instrumentation. Results in 52 patients

Fifty-two posterior spinal fusions were performed for pediatric idiopathic, congenital, and neuromuscular scoliotic curves. Cotrel-Dubousset instrumentation was used in all patients. Nine had prior anterior spinal releases and fusions. The patterns were mixed, with a predominance of right thoracic curvatures. The average preoperative curve measured 60.6 degrees, with correction to 29. Seven patients required revision surgery, and 17 wore orthoses after operation. There were 17 complications in this group, including hook pullout, prominent hardware, infection, pseudarthrosis, and two cases of broken Cotrel-Dubousset instrumentation rods. Fatigue failure of this instrumentation, secondary to pseudarthrosis, has not been reported previously, and these two cases are presented in detail. The operative morbidity and difficulty were increased in the larger idiopathic curves and in neuromuscular and congenital scoliosis. Cotrel-Dubousset instrumentation is an overall excellent tool for the multiplanar correction of scoliosis and is amenable to revision surgery.     

Ceftiofur hydrochloride: plasma and tissue distribution in swine following intramuscular administration at various doses

Coccidioides immitis, the primary pathogenic fungus that causes coccidioidomycosis, is most commonly found in the deserts of the southwestern United States and Central and South America. During the early 1990s, the incidence of coccidioidomycosis in California increased dramatically. Even though most infections are subclinical or self-limited, the outbreak is estimated to have cost more than $66 million in direct medical expenses and time lost from work in Kern County, California, alone. In addition to the financial loss, this pathogen causes serious and life-threatening disseminated infections, especially among the immunosuppressed, including AIDS patients. This article discusses factors that may be responsible for the increased incidence of coccidioidomycosis (e.g., climatic and demographic changes and the clinical problems of coccidioidomycosis in the immunocompromised) and new approaches to therapy and prevention.     

Pulmonary carcinogenicity of relatively low doses of beta-particle radiation from inhaled 144CeO2 in rats

This study was conducted to examine the carcinogenic effects of inhaled beta-particle-emitting radionuclides, particularly in lower dose regions in which there were substantial uncertainties associated with available information. A total of 2751 F344/N rats (1358 males and 1393 females) approximately 12 weeks of age at exposure were used. Of these, 1059 rats were exposed to aerosols of 144CeO2 to achieve mean desired initial lung burdens (ILBs) of 18 kBq (low level), 247 rats to achieve mean ILBs of 60 kBq (medium level) and 381 rats to achieve mean ILBs of 180 kBq (high level). Control rats (total of 1064) were exposed to aerosols of stable CeO2. Based on the 95% confidence intervals of the median survival times and the cumulative survival curves, there were no significant differences in the survival of groups of female and male exposed rats relative to controls. The mean lifetime beta-particle doses to the lungs of the rats in the four groups were: low level, 3.6 +/- 1.3 (+/-SD) Gy; medium level, 12 +/- 4.5 Gy; and high level, 37 +/- 5.9 Gy. The crude incidence of lung neoplasms increased linearly with increasing doses to the lungs (controls, 0.57%; low level, 2.0%; medium level, 6.1%; and high level, 19%). The estimated linear risk coefficients for lung neoplasms per unit of dose to the lung were not significantly different for the three dose levels studied. The risk coefficient at the lower level was 39 +/- 14 (+/-SE) excess lung neoplasms per 10(4) rat Gy; at the medium level the risk was 47 +/- 12; and at the higher level the risk was 50 +/- 9.0. The relationship of beta-particle dose to the lung and the crude incidence of lung neoplasms was described adequately by a linear function. We concluded that the risk of lung neoplasms in rats per unit of radiation dose did not increase with decreasing mean beta-particle dose to the lung over the range of 3.6 to 37 Gy. The weighted average of these three values was 47 +/- 6.4 (+/-SE) excess lung neoplasms per 10(4) rat Gy. To extend the risk coefficients for lung neoplasms to lower doses by experimentation will require much larger numbers of rats than used in this study.     

Growth and function of human parathyroid tissue transplanted to athymic mice

The morphology, cell proliferation and function of transplanted normal, hyperplastic and adenomatous human parathyroid tissue was studied after transplantation to athymic mice. The iPTH was evaluated in relation to morphology. Human parathyroid tissue collected during surgery for hyperparathyroidism was implanted subcutaneously into athymic mice (nu/nu-BALB/cA) and was analysed 1, 4, 7 and 12 weeks after transplantation. The transplants were examined by light and electron microscopy and by autoradiography after continuous infusion of 3H-thymidine. The relative amount of viable tissue was evaluated using a computer image analysing programme. Graft function was evaluated by measuring human iPTH in mouse serum. A transplant take ratio of 93% was observed. The proliferation rate in adenoma grafts at 12 weeks after transplantation was five and fifteen times that observed in normal and hyperplastic transplants, respectively. In normal and adenoma groups, a continuous increase in iPTH concentrations was observed, but in the hyperplastic group the iPTH remained on the same level. The secretion of iPTH in relation to the amount of transplanted tissue and the fraction of viable tissue was at the same level at 12 weeks in normal and adenomatous grafted animals. In conclusion, human parathyroid tissue was successfully transplanted and maintained its original structure. The growth potential, but not the iPTH secretion, was significantly higher in adenoma grafts compared to grafts from hyperplastic and normal glands.     

Prediction of postoperative knee flexion in Insall-Burstein II total knee arthroplasty

Postoperative knee flexion in patients undergoing Insall-Burstein-II total knee arthroplasty at 2 years was evaluated regarding two basic questions: what groups of patients gain or lose the most flexion and what groups of patients have the best or worst postoperative flexion. Thirteen preoperative variables (maximum flexion, flexion arc, tibiofemoral angle, quadriceps strength, extensor lag, Knee Society score, Knee Society patient assessment, gender, age, height, weight, diagnosis, and surgeon) and four postoperative variable (leg length change, tibiofemoral angle, distance from patella to the joint line, and the tibial prosthesis anteroposterior translation on a lateral radiograph) were used in an attempt to explain postoperative flexion. The analysis was performed on 164 consecutive Insall-Burstein-II total knees in which the data were gathered prospectively on a time oriented medical record database. A regression tree analysis was used to identify several groups of patients, characterized by preoperative factor values, who had markedly above average performance on postoperative flexion. The preoperative factors identified include preoperative flexion, flexion arc, tibiofemoral angle, extensor lag, diagnosis, and age. The only postoperative variable of significance was tibiofemoral angle. Among the potential determinants of postoperative flexion that failed to appear predictive were the Knee Society scores and surgeon. Preoperative flexion is known to be a critical determinant of postoperative flexion in total knee replacement. However, in the current study, preoperative flexion accounted for only half of the difference between the best (122 degrees) and the worst (88 degrees) group, as determined with regression tree analysis.     

The Interactive Effects of Task and External Feedback on Practice Performance and Learning

Just a few decades ago, the saccharides bound to glycoproteins were considered little more than an irritation. They increased the difficulty of purifying and characterizing proteins, making proteins run as several bands on gels and smearing them on columns. They were considered a nuisance and were typically cleaved away to reveal the 'important part', the protein moiety, for structural (e.g. via X-ray crystallography or nuclear magnetic resonance) and functional studies. We now realize that that the saccharide is often as important as the protein itself, and that glycosylation can have many effects on the function, structure, physical properties and targeting of a protein. There are a myriad of reviews and books on this subject, reflecting the nearly overwhelming number of articles in print discussing saccharide structures, glycoprotein processing enzymes and the biological implication of glycosylation. This review discusses, in turn, the extent and biological relevance of glycosylation; the structures observed; how glycosylated proteins are formed in vivo; the clinical relevance of glycosylation, in terms of the correlations between disease states and unusual glycosylation patterns; and, finally, the molecules, both natural and synthetic, that can be used to study the role of carbohydrates in glycoprotein structure and function or to disrupt various carbohydrate recognition processes and enzymatic reactions in the glycoprotein synthetic pathway.