Mortality among Paris sewage workers.

OBJECTIVES: To describe the mortality of Paris sewage workers. METHODS: A cohort of all Paris sewage workers since 1970 was established and followed up in mortality until 1999. The causes of death were determined by matching with a national database. The mortality rates were compared to the rates of a local reference population. RESULTS: A large excess in mortality (standardised mortality ratio (SMR) = 1.25; 530 cases, 95% CI 1.15 to 1.36) and in particular mortality from cancer (SMR = 1.37, 235 cases) was detected which was particularly important in the subgroup of subjects who had left employment because they resigned or were laid off (SMR = 1.77; 50 cases). The excess mortality is to a large extent due to alcohol related diseases (SMR = 1.65, 122 cases) especially malignant (SMR = 1.85, 16 cases) and non-malignant (SMR = 1.68, 38 cases) liver diseases, lung cancer (SMR = 1.47, 68 cases), and infectious diseases (SMR = 1.86, 25 cases). The SMRs for some diseases (all cancers, cancers of the oesophagus and lung, all alcohol related diseases) seem to increase with duration of employment as a sewage worker. Other than lung cancer, smoking related diseases were not in excess. CONCLUSION: The increased mortality by both malignant and non-malignant liver diseases is probably due to excessive alcohol consumption, but could be partially the result of occupational exposure to chemical and infectious agents and interactions of these factors. The excess lung cancer is unlikely to be due to an increased smoking prevalence.

Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells.

Zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) are the reference antiretroviral therapy in patients with AIDS. A toxic mitochondrial myopathy can be observed in patients treated with AZT, but not with ddI and ddC. All 3 compounds can inhibit mitochondrial (mt)DNA polymerase and cause termination of synthesis of growing mtDNA strands and mtDNA depletion. The propensity to injure particular target tissues is unexplained. In our work, cultured muscle cells prepared from human muscle biopsies, were exposed to various concentrations of AZT (4-5000 micromol/l), ddI (5-1000 micromol/l) and ddC (1-1000 micromol/l) for 10 days. We evaluated cell proliferation and differentiation and measured lipid droplet accumulation, lactate production and respiratory chain enzyme activities. All 3 compounds induced a dose-related decrease of cell proliferation and differentiation. AZT seemed to be the most potent inhibitor of cell proliferation. AZT, ddI and ddC induced cytoplasmic lipid droplet accumulations, increased lactate production and decreased activities of COX (complex IV) and SDH (part of complex II). NADHR (complex I) and citrate sinthase activities were unchanged. Zalcitabine (ddC) and, to a lesser extent, ddI, were the most potent inhibitors of mitochondrial function. In conclusion, AZT, ddI and ddC all exert cytotoxic effects on human muscle cells and induce functional alterations of mitochondria possibly due to mechanisms other than the sole mtDNA depletion. Our results provide only a partial explanation of the fact that AZT, but not ddI and ddC, can induce a myopathy in HIV-infected patients. AZT myopathy might not simply result from a direct mitochondrial toxic effect of crude AZT.

Tubular aggregates and partial cytochrome c oxidase deficiency in skeletal muscle of patients with AIDS treated with zidovudine.

We report on two patients, who had myalgias while receiving long-term zidovudine treatment for an HIV infection, in whom muscle biopsy findings included a partial cytochrome c oxidase (CCO) deficiency, a feature of zidovudine myopathy, and tubular aggregates, a finding hitherto unreported in HIV-infected patients. The CCO deficit was observed in 28% and 24% of muscle fibers, respectively. Tubular aggregates were the prominent histopathological feature in patient 1, and were detected by systematic electron microscopy in patient 2. Inflammation and myonecrosis were not detected. In patient 1, the typical mitochondrial and myofibrillar changes of zidovudine myopathy were present and 12% of fibers showed tubular aggregates. The aggregates were not stained at CCO reaction, and 96% of myofibers enclosing tubular aggregates showed a decreased CCO activity. This suggested more than a chance association between mitochondrial dysfunction and the formation of tubular aggregates. We conclude that tubular aggregates are detected in some patients treated by zidovudine, and that the finding could be related to the long-term administration of the drug.