David Simon

OBJECTIVE: To determine whether adults with past exposure to neurotoxicants have progressive declines in cognitive function years after exposure has ceased, and whether tibia lead is a predictor of the magnitude of change. METHODS: A total of 535 former organolead manufacturing workers with a mean age of 55.6 years, a mean duration of 16 years since last occupational lead exposure, and low blood lead levels at the first study visit and 118 controls were evaluated with neurobehavioral tests two to four times over 4 years. "Peak" tibia lead levels, estimated from current levels measured by X-ray fluorescence, were used to predict changes in cognitive function over time. RESULTS: In former lead workers, peak tibia lead ranged from -2.2 to 98.7 microg Pb/g bone mineral. Compared to controls, former lead workers performed worse over time for three tests of visuo-constructive ability and verbal memory and learning (p < 0.05). In former lead workers, peak tibia lead predicted declines for six tests of verbal memory and learning, visual memory, executive ability, and manual dexterity (p < 0.05 for four tests and < 0.10 for two additional tests). On average, for these six tests, an increase of 15.7 microg/g of peak tibia lead was equivalent in its effects on annual test decline to 5 more years of age at baseline. CONCLUSIONS: These are the first data to suggest that cognitive function can progressively decline due to past occupational exposures to a neurotoxicant.

OBJECTIVE: This article estimates lost work days and lost work day equivalents in a population sample of migraineurs, differentiating work loss due to headache episodes that met criteria for migraine from migrainous headaches not meeting full criteria and nonmigrainous headaches. METHODS: A random digit dialing survey of 5,071 adults identified 800 subjects with migraine headaches. By clinical examination, a subsample of 225 met migraine diagnostic criteria; 174 of these patients completed at least 11 weeks of daily diaries. This report concerns the subgroup of 122 individuals with regular paid employment. Subjects completed a daily diary over a 3-month period to assess the occurrence of headaches and International Headache Society (IHS) criteria for each headache occurrence. We report estimates of lost work days and lost work day equivalents by type of headache. RESULTS: Participants reported headaches on 8.1 work days, of which 2.2 headache days met criteria for migraine (IHS 1.1, 1.2), and an additional 2.1 headache days were migrainous without meeting full migraine criteria (IHS 1.7). On average, migraineurs missed 1.1 days of work due to headache in 3 months, of which 0.7 lost work days were due to migraine and 0.3 were due to migrainous headaches. When at work with headache, work effectiveness was reduced 41% for migraine headaches, 28% for migrainous headaches, and 24% for other headaches. Over 3 months, migraineurs experienced an average of 3.0 lost work day equivalents, of which 1.4 were due to migraine and an additional 0.7 were due to migrainous headaches. The most disabled 20% of the participants accounted for 77% of the lost work days; 40% of subjects accounted for 75% of the lost work day equivalents. CONCLUSIONS: Employed migraine sufferers experienced considerable work loss and reduced work performance due to headache. The most severely affected migraineurs accounted for most of the reduced work performance. Targeting the most severely affected persons may be necessary to reduce work loss among migraineurs substantially.

Axon degeneration initiated by trophic factor withdrawal shares many features with programmed cell death, but many prior studies discounted a role for caspases in this process, particularly Caspase-3. Recently, Caspase-6 was implicated based on pharmacological and knockdown evidence, and we report here that genetic deletion of Caspase-6 indeed provides partial protection from degeneration. However, we find at a biochemical level that Caspase-6 is activated effectively only by Caspase-3 but not other "upstream" caspases, prompting us to revisit the role of Caspase-3. In vitro, we show that genetic deletion of Caspase-3 is fully protective against sensory axon degeneration initiated by trophic factor withdrawal, but not injury-induced Wallerian degeneration, and we define a biochemical cascade from prosurvival Bcl2 family regulators to Caspase-9, then Caspase-3, and then Caspase-6. Only low levels of active Caspase-3 appear to be required, helping explain why its critical role has been obscured in prior studies. In vivo, Caspase-3 and Caspase-6-knockout mice show a delay in developmental pruning of retinocollicular axons, thereby implicating both Caspase-3 and Caspase-6 in axon degeneration that occurs as a part of normal development.