Apoptosis is the programmed cell death mechanism responsible for regulation of cell number during tissue development and maturity. However, dysregulation of apoptosis has pathological consequences, particularly in the brain, where 'inappropriate' apoptosis leads to neurodegeneration. Neuronal apoptosis is primarily initiated by release of the respiratory protein cytochrome c from mitochondria, the organelles responsible for aerobic respiration. Considerable interest has been focussed on the mechanism of cytochrome c release, but surprisingly little on the nature of the cytochrome c signal itself. It has been claimed that release is all-or-none, however this is inconsistent with accumulating evidence of cytosolic mechanisms for 'buffering' cytochrome c. This study has addressed two primary methodological weaknesses in the field, by modelling an underlying disease pathology, rather than artificially inducing apoptosis, and by using a truly quantitative assay for measuring cytochrome c concentration. These experimental advantages have yielded the first demonstration that cytochrome c is released in proportion to the severity of pathological insult. The model adopted was reduced activity of the mitochondrial NADH:ubiquinone oxidoreductase, a recognised feature of Parkinson's disease, induced in this case by rotenone titration. The controlled, proportional release observed invited the hypothesis that a low level of cytochrome c release is insufficient to induce apoptosis. In support of this suggestion, the mechanism of release was determined to be conducive to cell survival given hypothetical 'sub-threshold' release. It was also demonstrated that release is likely to be induced following mitochondrial generation of reactive oxygen species, of which there is believed to be a constitutive basal level. Finally it was established that in primary cortical neurons, respiratory inhibition can induce cytochrome c release which is sub-threshold for induction of apoptosis. The study has generated considerable support for therapeutic exploitation of the cytosolic 'Inhibitor of Apoptosis Proteins', for delaying progression of Parkinson's and other neurodegenerative diseases.

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<i>Objectives</i>- To investigate the relationship between neuropsychological symptoms, as measured by questionnaire, and formal measurements of neurological and psychological function.  To investigate the relationship between neuropsychological symptoms and solvent exposure estimates.  To test the hypothesis that neuropsychological disorder in solvent exposed workers is more likely to those with genetic predisposition. <i>Methods </i>- A nested case-control study was carried out in a cohort of former dockyard painters and community controls.  The 78 painters and 42 community controls had previously participated in a postal study that had shown an excess of neuropsychological symptoms amongst painters.  The 120 participants in the nested - case control study underwent detailed neuropsychological testing, colour vision testing, estimation of solvent exposure indices and genetic testing for GSTM1, GSTT1, NAT1 and NAT2 enzyme polymorphisms. <i>Results </i>-  A case-control analysis of 68 patients failed to demonstrate significant differences in neuropsychological function between symptomatic and asymptomatic painters as measured by the Q16.  Subsequent regression analyses of all 120 subjects showed a range of neuropsychological deficits with an exposure response relationship.  There was no convincing evidence of risk modification by any of the enzyme polymorphisms studied.  During the study a pattern of deficits was recognised, sufficient to constitute a syndrome of impaired colour vision, cognitive impairment impaired vibration perception and resting tremor. <i>Conclusions </i>- Exposure to mixed solvents is associated with neuropsychological impairment, the risk increasing with increasing intensity of exposure.  The risk of impairment was not altered in this study by the presence of different enzyme polymorphisms.