How disturbed visual processing early in life leads to disorders of gaze-holding and smooth pursuit.

When synergistic interactions between visual and oculomotor systems are impaired early in life, strabismus, gaze instability, smooth pursuit asymmetry, and loss of visual function are likely to occur. These disorders are relatively common, permanent, and difficult to treat. We have developed effective animal models for infantile strabismus by raising infant monkeys (Macaca mulatta) with restricted binocular visual experience. We have found that the specific oculomotor disorders that occur with early onset strabismus depend on the type of early visual experience. Our approach allows us to examine the neural substrate associated with different components of infantile strabismus including latent nystagmus (LN) and smooth pursuit asymmetry. For example, we have found LN is most associated with loss of binocular visual sensitivity normally present in neurons of pretectal nucleus of the optic tract (NOT). In contrast, nasalward bias in smooth pursuit of strabismic monkeys could be associated with loss of binocular visual and eye movement sensitivity of neurons in medial superior temporal (MST) area.

A 4-methyl-substituted meta-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells.

PURPOSE: As a part of our efforts to develop a meta-iodobenzylguanidine (MIBG) analogue with improved characteristics for the diagnosis and treatment of neuroendocrine tumours, 3-[131I]iodo-4-methyl-benzylguanidine ([131I]MeIBG) has been developed. The purpose of this study was to evaluate [131I]MeIBG in vitro using the uptake-1 positive SK-N-SH neuroblastoma cell line and in vivo in normal mice and mice bearing human neuroblastoma xenografts. METHODS: The ability of SK-N-SH human neuroblastoma cells to retain [131I]MeIBG in vitro over a period of 4 days, in comparison to [125I]MIBG, was determined by a paired-label assay. Paired-label biodistributions of [131I]MeIBG and [125I]MIBG were performed in normal mice as well as in athymic mice bearing SK-N-SH and IMR-32 human neuroblastoma xenografts. RESULTS: Retention of [131I]MeIBG by SK-N-SH cells in vitro was increased by factors of 1.2, 1.5, 2.0, 2.5 and 3.1 compared with [125I]MIBG at 8, 24, 48, 72 and 96 h, respectively. In normal mice, the uptake of [131I]MeIBG in the heart was similar to that of [125I]MIBG at 1 and 4 h; in contrast, myocardial uptake of [131I]MeIBG was 1.6-fold higher than that of [125I]MIBG (p<0.05) at 24 h. When mice were pre-treated with the uptake-1 inhibitor desipramine (DMI), the heart uptake of both tracers was reduced to about half that in untreated controls at 1 h post injection (p<0.05). The hepatic uptake of [131I]MeIBG was two- to threefold lower than that of [125I]MIBG. On the other hand, blood levels of [131I]MeIBG were substantially higher (up to sixfold), especially at early time points. Uptake of [131I]MeIBG in heart and tumour at 1 h in the murine SK-N-SH model was specific and comparable to that of [125I]MIBG. However, [131I]MeIBG uptake was 1.6- to 1.7-fold lower than that of [125I]MIBG over 4-48 h. While the uptake of both tracers in IMR32 xenografts was similar, it was not uptake-1 mediated. CONCLUSION: Introduction of a methyl group at the 4-position of MIBG seems to be advantageous in terms of higher tumour retention in vitro and lower hepatic uptake in vivo. However, the slower blood clearance of MeIBG may be problematic for some applications.