Although it is clear that errors in genotyping data can lead to severe errors in linkage analysis, there is as yet no consensus strategy for identification of genotyping errors. Strategies include comparison of duplicate samples, independent calling of alleles, and Mendelian-inheritance-error checking. This study aimed to develop a better understanding of error types associated with microsatellite genotyping, as a first step toward development of a rational error-detection strategy. Two microsatellite marker sets (a commercial genomewide set and a custom-designed fine-resolution mapping set) were used to generate 118,420 and 22,500 initial genotypes and 10,088 and 8,328 duplicates, respectively. Mendelian-inheritance errors were identified by PedManager software, and concordance was determined for the duplicate samples. Concordance checking identifies only human errors, whereas Mendelian-inheritance-error checking is capable of detection of additional errors, such as mutations and null alleles. Neither strategy is able to detect all errors. Inheritance checking of the commercial marker data identified that the results contained 0.13% human errors and 0.12% other errors (0.25% total error), whereas concordance checking found 0.16% human errors. Similarly, Mendelian-inheritance-error checking of the custom-set data identified 1.37% errors, compared with 2.38% human errors identified by concordance checking. A greater variety of error types were detected by Mendelian-inheritance-error checking than by duplication of samples or by independent reanalysis of gels. These data suggest that Mendelian-inheritance-error checking is a worthwhile strategy for both types of genotyping data, whereas fine-mapping studies benefit more from concordance checking than do studies using commercial marker data. Maximization of error identification increases the likelihood of linkage when complex diseases are analyzed.

Purpose: Human interleukin-21 (IL-21) is a pleiotropic class I cytokine that activates CD8 + T cells and natural killer cells.We report a phase 1study of recombinant human IL-21in patients with surgically incurable metastatic melanoma. The primary objective was to investigate safety and tolerability by determining dose-limiting toxicity (DLT). The secondary objectives were to identify a dose response for various biomarkers in the peripheral blood, estimate the minimum biologically effective dose, determine the pharmacokinetics of IL-21, determine if anti-IL-21 antibodies were induced during therapy, and measure effects on tumor size according to Response Evaluation Criteria in Solid Tumors. Experimental Design: Open-label, two-arm, dose escalation trial of IL-21 administered by i.v. bolus injection at dose levels from 1 to 100 Ag/kg using two parallel treatment regimens: thrice weekly for 6 weeks (3/wk) or three cycles of daily dosing for 5 days followed by 9 days of rest (5+9). Results: Twenty-nine patients entered the study. IL-21was generally well tolerated and no DLTs were observed at the 1, 3, and 10 Ag/kg dose levels. In the 3/wk regimen, DLTs were increased in alanine aminotransferase, neutropenia, and lightheadedness with fever and rigors. DLTs in the 5+9 regimen were increased in aspartate aminotransferase and alanine aminotransferase, neutropenia, fatigue, and thrombocytopenia. The maximum tolerated dose was declared to be 30 Ag/kg for both regimens. Effects on biomarkers were observed at all dose levels, including increased levels of soluble CD25 and up-regulation of perforin and granzyme B mRNA in CD8 + cells. One partial tumor response observed after treatment with IL-21 for 2 Â 6 weeks (3/wk) became complete 3 months later. Conclusions: IL-21 is biologically active at all dose levels administered and is generally well tolerated, and phase 2 studies have commenced using 30 Ag/kg in the 5+9 regimen.

Mastitis occurs in numerous species. Antimicrobial agents are used for treatment of infectious mastitis in dairy cattle, other livestock, companion animals, and humans. Mastitis is an economically important disease of dairy cattle and most mastitis research has focused on epidemiology and control of bovine mastitis. Antibiotic treatment of clinical and subclinical mastitis in dairy cattle is an established component of mastitis control programs. Research on the treatment of clinical and subclinical mastitis in other dairy species such as sheep and goats has been less frequent, although the general principles of mastitis therapy in small ruminants are similar to those of dairy cattle. Research on treatment of clinical mastitis in humans is limited and as for other species empirical treatment of mastitis appears to be common. While antimicrobial susceptibility testing is recommended to direct treatment decisions in many clinical settings, the use of susceptibility testing for antibiotic selection for mastitis treatments of dairy cattle has been challenged in a number of publications. The principle objective of this review is to summarize the literature evaluating the question, "Does antimicrobial susceptibility predict treatment outcome for intramammary infections caused by common bacterial pathogens?" This review also addresses current issues related to antimicrobial use and treatment decisions for mastitis in dairy cattle. Information on treatment of mastitis in other species, including humans, is included although research appears to be limited. Issues related to study design, gaps in current knowledge and opportunities for future research are identified for bovine mastitis therapy.

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