Motor neuron syndromes in cancer patients

Previous reports indicate that motor neuron disease (MND) may rarely be associated with systemic cancer. We have encountered 14 patients with MND and cancer who formed three distinct groups. Group 1: Three patients developed a rapidly progressive MND, less prominent symptoms of involvement of other areas of the nervous system, and anti-Hu antibodies. Group 2: Five women developed signs of upper motor neuron (UMN) disease, initially resembling primary lateral sclerosis (PLS), and breast cancer. In 4, symptoms of UMN occurred within 3 months of cancer diagnosis or tumor recurrence. They had no metastases or spinal cord compression. Serum anti-neuronal antibodies were negative. Three patients are alive (follow-up of 156, 15, and 12 months), and 2 remain without lower motor neuron signs. Group 3: Six patients developed MND resembling amyotrophic lateral sclerosis between 47 months before and 48 months after their cancer diagnosis. In group 1, the MND associated with the anti-Hu antibody is unequivocally paraneoplastic. In group 2, the proximate onset of MND with the diagnosis of cancer or its recurrence, its pure or long-lasting UMN signs, and its association with breast cancer, suggest that the disorder may be paraneoplastic. Although for most cancer patients who develop MND the occurrence of both disorders is probably coincidental, in some patients with MND a careful search for an underlying cancer is warranted (ie, patients in groups 1 and 2).     

Structure-activity relationships for 1-phenylbenzimidazoles as selective ATP site inhibitors of the platelet-derived growth factor receptor

1-Phenylbenzimidazoles are shown to be a new class of ATP-site inhibitors of the platelet-derived growth factor receptor (PDGFR). Structure-activity relationships (SARs) are narrow, with closely related heterocycles being inactive. A systematic study of substituted 1-phenylbenzimidazoles showed clear SARs. Substituents at the 4'- and 3'-positions of the phenyl ring are tolerated but do not significantly improve activity, while substituents at the 2'-position abolish it. Substituents in the 2-, 4-, and 7-positions of the benzimidazole ring (with the exception of 4-OH) also abolish activity. Most substituents at the 5- and 6-positions maintain or increase activity, with the 5-OH, 5-OMe, 5-COMe, and 5-CO2Me analogues being >10-fold more potent than the parent 1-phenylbenzimidazole. The 5-OMe analogue was both the most potent inhibitor, and showed the highest selectivity (50-fold) between PDGFR and FGFR isolated enzymes, and also a moderately effective inhibitor (IC50 = 1.9 microM) of PDGF-stimulated PDGFR autophosphorylation in rat aorta smooth muscle cells.     

Enhanced mitosis in cultured protoplasts: beneficial effects of oxygenated perfluorocarbon and haemoglobin

Cell suspension-derived protoplasts of Petunia hybrida cv. Comanche were cultured for up to 10 d in (1) aqueous medium, (2) aqueous medium overlaying an oxygenated (10 mbar, 15 min) perfluorochemical liquid (perfluorodecalin; PFC), (3) aqueous medium containing 1:50 (v:v) of the commercial haemoglobin (Hb) solution (Erythrogen), (4) aqueous medium supplemented with 1:50 (v:v) of Erythrogen overlaying oxygenated PFC. Treatments 2, 3, and 4 enhanced mean mitotic division by 111%, 80% and 139% respectively, compared to controls. Both fresh-Hb and stored-Hb significantly (P < 0.05) enhanced mitotic division, although this was 45% greater with fresh-Hb compared to stored-Hb. Both oxygenated PFC and Erythrogen provide approaches for enhancing cellular oxygen supply to eukaryotic cells. Commercially, the recoverability and recycleability of PFCs make these compounds a more attractive option in comparison to Erythrogen, despite a high initial investment cost.     

Modulatory role of endothelial and nonendothelial nitric oxide in 5-hydroxytryptamine-induced contraction in cerebral arteries after subarachnoid hemorrhage

OBJECTIVE: Endothelial dysfunction is claimed to play a role in the pathogenesis of delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). We have examined the effect of experimental SAH on the modulatory action of endothelial and nonendothelial nitric oxide (NO) in the contractile response of goat middle cerebral artery to 5-hydroxytryptamine (5-HT). METHODS: We compared the 5-HT-induced contractile responses of cerebral arteries from control goats and from goats with SAH that had been experimentally induced 3 days earlier by delivery of autologous arterial blood into the subarachnoid space. Contractile responses were examined by recording the isometric tension in isolated cerebral arteries. To assess the influence of endothelium, this cell layer was mechanically removed in some of the arteria, segments (rubbed arteries) from both control goats and goats with SAH. RESULTS: In arteries from control goats, contractile responses to 5-HT were significantly higher in rubbed arteries than in arteries with intact endothelium; 5-HT-induced contractions were significantly enhanced by a competitive inhibitor of NO synthesis, NG-nitro-l-arginine, in arteries both with and without endothelium. In arteries from goats with SAH, 5-HT contracted cerebral arteries without showing significant differences between segments with endothelium and those that had been rubbed; in both cases, 5-HT-induced contractions were significantly higher than those obtained in arteries from control goats. NG-Nitro-l-arginine significantly enhanced the contractile response to 5-HT of cerebral arteries from goats with SAH. CONCLUSION: These results suggest that cerebral arteries after SAH exhibit hyperreactivity to 5-HT via a mechanism that involves the absence of the modulatory role of endothelial NO, that SAH does not modify the modulatory role of nonendothelial NO, and that impairment of the modulatory action of endothelial NO on vascular responses to 5-HT could contribute to the pathogenesis of cerebral vasospasm after SAH.     

The importance of pH in the regulation of ruminal acetate to propionate ratio and methane production in vitro

Grain feeding often causes a decrease in ruminal pH, and experiments were conducted to define the role of pH in regulating the acetate to propionate ratio and production of CH4. Cows that were fed 90% concentrate had lower ruminal pH values (6.22 vs. 6.86), higher VFA concentrations (85 vs. 68 mM), and lower acetate to propionate ratios (2.24 vs. 4.12) than did cows that were fed forage only. When mixed ruminal bacteria from cows that were fed 90% concentrate or 100% forage were incubated (48 h) with hay (10 g/L) or cracked corn (5 g/L) in a medium containing bicarbonate (38 mM) and tricarballylate (50 mM), the final pH values were less than 0.3 units lower than the initial pH. At final pH values less than 5.7, hay fermentation was inhibited, the acetate to propionate ratio and CH4 production declined more than twofold, and the inoculum source was without effect. Small amounts of H2 were detected at pH values less than 5.5. Total VFA production from cracked corn decreased when pH declined, but only if the inoculum was obtained from cows that were fed 90% concentrate. The acetate to propionate ratio of cracked corn incubations declined from 1.2 to 0.6 when final pH was decreased from 6.5 to 5.3, and CH4, as a percentage of total VFA production, also decreased. At pH values less than 5.3, the acetate to propionate ratio of cracked corn increased more than fourfold, and large amounts of H2 could be detected. Over the final pH range of 6.5 to 5.3, CH4 production was highly correlated with acetate to propionate ratio, which was dependent on pH and substrate (CH4 = 0.02 + 0.05 pH; r2 = 0.80). Calculations based on the differences between pH 6.5 and 5.8 indicated that as much as 25% of the decrease in acetate to propionate ratio could be explained by the effect of pH alone.