Previous studies have suggested that polymorphisms in delta-aminolevulinic acid dehydratase (ALAD), a heme synthetic enzyme, may be associated with differences in blood lead levels, perhaps due to differential binding of lead in erythrocytes. The authors examined associations of ALAD genotype with blood lead and zinc protoporphyrin (ZPP) levels, exposure duration, sex, and plant in 308 currently exposed lead workers in three lead storage battery manufacturing plants in the Republic of Korea in 1993. The overall prevalence of the variant allele, ALAD2, was 11%, but prevalence varied by plant (p = 0.02: 8.6% in plant A, 20% in plant B, and 22% in plant C). While ALAD2 was not associated with mean blood lead levels, the allele was associated with blood lead levels greater than or equal to 40 micrograms/dl (crude odds ratio (OR) = 2.6, 95% confidence interval (CI) 1.1-6.3; adjusted OR = 2.3, 95% CI 0.8-6.2, with adjustment for sex, plant, and exposure duration) and with exposure durations greater than 6 years (adjusted OR = 2.5, 95% CI 1.2-5.4, with adjustment for blood lead, sex, and plant). Among workers in plant C, the highest exposure plant, ALAD2 was associated with lower ZPP levels when controlling for blood lead levels. These data suggest that lead toxicokinetics may be modified by ALAD genotype and that ALAD2 may be protective for the health effects of lead. ALAD genotype also appears to have been a selection factor for current lead exposure status in the studied workers.
Infection with cytomegalovirus (CMV) remains a significant cause of morbidity and mortality among hematopoietic cell transplant (HCT) recipients. We describe two pediatric HCT recipients who developed persistent and severe drug-resistant CMV infections. CMV resistance to foscarnet and ganciclovir was detected after only 6 and 11 weeks of therapy, respectively. Viral pol mutations associated with drug resistance in these patients included T838A (a novel mutation) and D588N, which were shown by marker transfer to confer foscarnet and multidrug resistance, respectively. Each of these mutations significantly reduced in vitro replication of CMV, suggesting that they may decrease viral fitness. This finding was further supported by the disappearance of mutations upon withdrawal of antiviral pressure in one patient. Novel antivirals or combination therapy may be required for the treatment of drug-resistant CMV in HCT recipients and perhaps in other severely immunocompromised patients.
The incidence of cytomegalovirus (CMV) disease, once the most common and highly feared viral complication of AIDS, has dramatically decreased with the advent of highly active antiretroviral therapy (HAART). HAART-associated changes in the epidemiology of CMV disease resulted from the increase in CMV-specific immune responses coupled with the decrease in CMV reactivation. However, CMV disease continues to afflict HIV-infected patients on HAART when CD4+ cell counts fail to rise above 100 cells/mm(3) and when reconstitution of normal CMV-specific immune responses does not occur. The latter scenario may lead to recurrent or de novo CMV end-organ disease, or to the recently described CMV immune recovery vitritis. HAART-associated immune reconstitution offers unique opportunities to investigate the virological and immunological correlates of protection against CMV disease. Although the full extent of CMV-specific immune reconstitution has not been defined thus far, CMV-specific interferon-gamma production has been shown to be significantly associated with protection against CMV reactivation and recurrent disease.
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