Determining mechanisms of visual loss in glaucoma using Rarebit perimetry.

PURPOSE: Evidence for ganglion cell visual dysfunction in human glaucoma is often indirect, being either measured at the cellular level in animal models or being inferred from the pooled responses of a large number of ganglion cells in human observers. Rarebit perimetry (RBP) uses repeated, intense (150 cd/m2) stimuli-whose size is close to the spatial scale of a ganglion cell-to search for small retinal areas with zero sensitivity. Decreasing the stimulus luminance to 64 cd/m2 in normal observers does not alter the percentage of RBP stimuli detected [the mean hit rate (MHR)], and so we hypothesized that a similar response robustness should occur in glaucoma if the elements detecting the RBP target show no signs of visual dysfunction. METHODS: Nineteen glaucoma subjects and 19 age-matched controls were tested with a customized RBP test at 13 stimulus luminances (10 to 150 cd/m2, 0.14 log unit intervals). A four-parameter (threshold, spread, false positive proportion, and miss rate) cumulative Gaussian psychometric function was fitted to the response rate data from a glaucoma-affected region (glaucoma subjects; MHR >50% and <80%) and from the corresponding region in an age-matched normal control. Our hypothesis would predict that only the miss rates should differ between groups. RESULTS: Glaucoma subjects showed significantly higher miss rates (0.18 vs. 0.04, p < 0.001), lower false positive proportions (0.009 vs. 0.025, p = 0.004), greater spreads (0.30 vs. 0.19, p = 0.002), and elevated thresholds [1.57 log(cd/m2) vs. 1.13 log(cd/m2), p < 0.001]. CONCLUSIONS: Responses to RBP stimuli are not robust to decreasing luminances in glaucoma. Our results more directly imply the presence of ganglion cell visual dysfunction in human glaucoma than studies using larger targets where contrast sensitivity losses could result through ganglion cell death alone. Such dysfunction may not be detected by Rarebit's MHR given that dysfunctional elements may still respond to the very intense RBP stimulus.

Cellular mechanisms mediating the anti-invasive properties of the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) in human breast cancer cells.

We have shown that inhibition of polyamine biosynthesis with alpha-difluoromethylornithine (DFMO) reduces in vitro invasiveness and metastatic capacity of MDA-MB-435 breast cancer cells. These experiments investigated the mechanisms mediating the anti-invasive properties of DFMO. DFMO did not affect phosphorylation of FAK or Akt, but increased ERK phosphorylation by approximately threefold. To test the biologic significance of this finding, we tested the effect of the MEK inhibitor PD98059 on in vitro invasiveness of MDA-MB-435 breast cancer cells, both in the absence and in the presence of the proinvasive peptide hepatocyte growth factor (HGF) as a chemoattractant. We observed that PD98059 treatment reversed the anti-invasive effect of DFMO under both experimental conditions. Next, we tested the influence of DFMO on the production of the prometastatic peptide osteopontin (OPN) and the anti-metastatic protein thrombospondin-1 (TSP-1). DFMO treatment, while not affecting OPN production, markedly increased the TSP-1 level in the conditioned media. This effect was abolished by putrescine administration, thus indicating the specificity of the DFMO action through the polyamine pathway. PD98059 completely blocked the stimulatory effect of DFMO on TSP-1 production, which supports a mediatory role for activation of the MAPK pathway in the upregulation of this anti-metastatic peptide by DFMO. In summary, our results show that the increase in ERK phosphorylation induced by DFMO plays a critical role in the anti-invasive action of the drug and in its ability to upregulate TSP-1 production.

Historical perspective of parathyroid disease.

This article highlights key historical developments in the understanding of parathyroid function and disease, a story that involves many clinical investigators and classic scientific debate. The current medical community is certainly indebted to the innate curiosity and perseverance of these historical figures.