Possible neurotransmitter dysfunction or imbalances have been proposed in ADHD for quite some time (see Sagvolden, 2005; Pliszka, McCracken, & Maas, 1996 for reviews). Initially, these rested chiefly on the responses of ADHD children to differing drugs. ADHD children respond remarkably well to stimulants, most of which act by increasing the availability of dopamine via various mechanisms, and producing some effects on the noradrenergic pathways as well (Connor, 2006). Consequently, it seemed sensible to hypothesize that these two neurotransmitters might be involved in the disorder. Given the findings that normal children show a positive, albeit lesser, response to stimulants (Rapoport et al., 1978), however, partially undermines this logic. Other, more direct evidence comes from studies of cerebral spinal fluid in ADHD and normal children that indicated decreased brain dopamine in ADHD children (Raskin, et al., 1984). Similarly, other studies used blood and urinary metabolites of brain neurotransmitters to infer deficiencies in ADHD, largely related to dopamine regulation. Early studies of this sort proved conflicting in their results (Shaywitz, Shaywitz, Cohen, & Young, 1983; Shaywitz, Shaywitz, Jatlow, et al., 1986; Zametkin & Rapoport, 1986). A subsequent study continued to find support for reduced noradrenergic activity in ADHD as inferred from significantly lower levels of a metabolite of this neurotransmitter (Halperin et al., 1997). What limited evidence there is from this literature seems to point to a selective deficiency in the availability of both dopamine and norepinephrine, but this evidence cannot be considered conclusive at this time. Far greater evidence for involvement of these and other neurotransmitters comes from the rapidly growing evidence for the role of gene polymorphisms involved in regulating these neurotransmitters that reveals different gene variations in ADHD than in typical population samples (for reviews, see Banaschewski et al., 2010; Smith et al., 2009; Wu et al., 2012).
Inhibition of protein synthesis in the mitochondria of bone-marrow cells has been considered as a mechanism by which bone-marrow depression is induced by chloramphenicol. The underlying cytotoxicity may be caused by the similarity between mitochondrial ribosomes and bacterial ribosomes, both of which are 70S. Thus chloramphenicol can also inhibit mitochondrial protein synthesis in mammalian cells, particularly in erythropoietic cells, which appear to be sensitive to the drug (Sande & Mandell, 1993; Kucers et al., 1997). It was reasoned that the inhibition of mitochondrial protein synthesis suppressed the division of mitochondria and resulted in the formation of megamitochondria. Investigation of the toxicity caused by chloramphenicol in mouse hepatic cells in vivo, however, showed that antioxidants prevented the formation of megamitochondria (Matsuhashi et al., 1996). The role of antioxidants in reducing the cytotoxic effects of chloramphenicol was also reported to occur in vitro in a study using a monkey kidney-derived cell line and haematopoietic progenitor cells from human neonatal cord blood. Also, in cells in culture, the cytotoxic effects of chloramphenicol on apoptosis and suppression of progenitor cell growth were not pronounced when cells were co-cultured with antioxidants such as mercaptoethylamine or vitamin C (Holt et al., 1997). Both studies suggested that toxicity caused by chloramphenicol relates intimately to oxidative stress, with a possible link between a metabolic event—the production of free radicals—and bone marrow suppression.
a hypothetical metabolic pathway is depicted below
...ven if they are fundamental pathways such as the sugar metabolism (see Fig. 1). Some examples of the applications of computer analysis to pathways are (1) pathway reconstruction (Mavrovouniotis 1993; =-=Gaasterland and Selkov 1995-=-; Goto et al. 1997) (where the input consists of substrates and products for each of enzymes, and the output is a set of potential pathways) ; (2) pathway clustering (Forst and Schulten 1999) (where t...