Impaired parasite attachment as fitness cost of metronidazole resistance in Giardia lamblia.

Infections with the diarrheagenic protozoan pathogen Giardia lamblia are most commonly treated with metronidazole (Mz). Treatment failures with Mz occur in 10 to 20% of cases and Mz resistance develops in the laboratory, yet clinically, Mz-resistant (Mz(r)) G. lamblia has rarely been isolated from patients. To understand why clinical Mz(r) isolates are rare, we questioned whether Mz resistance entails fitness costs to the parasite. Our studies employed several newly generated and established isogenic Mz(r) cell lines with stable, high-level resistance to Mz and significant cross-resistance to tinidazole, nitazoxanide, and furazolidone. Oral infection of suckling mice revealed that three of five Mz(r) cell lines could not establish infection, while two Mz(r) cell lines infected pups, albeit with reduced efficiencies. Failure to colonize resulted from a diminished capacity of the parasite to attach to the intestinal mucosa in vivo and to epithelial cells and plastic surfaces in vitro. The attachment defect was related to impaired glucose metabolism, since the noninfectious Mz(r) lines consumed less glucose, and glucose promoted ATP-independent parasite attachment in the parental lines. Thus, resistance of Giardia to Mz is accompanied by a glucose metabolism-related attachment defect that can interfere with colonization of the host. Because glucose-metabolizing pathways are important for activation of the prodrug Mz, it follows that a fitness trade-off exists between diminished Mz activation and reduced infectivity, which may explain the observed paucity of clinical Mz(r) isolates of Giardia. However, the data also caution that some forms of Mz resistance do not markedly interfere with in vivo infectivity.

Predominance of younger age, advanced stage, poorly-differentiated and mucinous histology in Israeli Arab patients with colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) incidence in the Israeli population is higher in the Jewish population than among Arabs. MATERIALS AND METHODS: To determine the differences in demographic, clinical, histopathological and molecular characteristics of CRC between these two ethnic groups, 125 Arab patients treated at 3 community hospitals over a 20-year period were compared to a group of 208 consecutive Jewish patients. The mutator (replication error-positive [RER]) phenotype was detected by immunohistochemical evaluation of hMLH1 and hMSH2 protein expression in tumor tissue. RESULTS: The Arab patients were younger than the Jewish patients with a higher percentage of poorly-differentiated and mucinous cancers and a higher percentage of advanced stage cancers (Dukes' C+D) at presentation. The mutator phenotype was detected at similar rates in both ethnic groups. CONCLUSION: Our study demonstrated that CRC patients from two major ethnic populations in Israel, Arabs and Jews, differed in terms of the prevalence of the disease, pathological features and age at presentation, but not in frequency of mismatch-repair-positive cancers.