Some 4- and 2-(nitrobenzyloxycarbonyl)-1, 2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines (4, 6, and 7) were synthesized and evaluated for their ability to exert preferential toxicity to hypoxic EMT6 mammary carcinoma cells using a colony-forming assay. Of these, the 4,5-dimethoxy-2-nitro analogue 6 (50 microM, 1-h exposure) caused greater than 3 logs of kill of hypoxic cells, with relatively minor toxicity to corresponding aerobic cells. The ability of 4-nitro (4) and 4,5-dimethoxy-2-nitro (6) analogues to reach and kill hypoxic cells of solid tumors was also demonstrated using intradermally implanted EMT6 solid tumors in mice. In addition, a possible source of toxicity to normal tissue, i. e., the activation of the 4-nitrobenzyl derivative 4 by glutathione S-transferase-catalyzed thiolysis, was essentially eliminated by replacing one of the benzylic methylene protons by a methyl group. The 4-nitro (4) and 4,5-dimethoxy-2-nitro (6) analogues also appear to be reduced more easily under acidic conditions (pH 6.0) than under neutral conditions, as measured by differential pulse polarography. Since the pH in hypoxic regions is often lower than that in adjacent aerobic regions, this property should aid in the cytotoxic action of these agents against hypoxic cells of solid tumors.
Greater force is elicited by increasing amplitude than by similar increase in phase-duration; however, the associated discomfort is also higher. Clinicians may use phase-duration while conditioning for NMES.
Deficits in executive function, visuospatial abilities, and cognitive embodiment may impair gait performance. This study aimed to investigate the effect of age on random number generation (RNG) performance during forward and backward locomotion to assess cognitive flexibility and cognitive embodiment during walking. Another aim was to examine the effect of age on the associations of RNG performance during walking with stride time variability (STV), the percentage of double support (DS%), and visuospatial abilities as measured by a spatial orientation test (SOT). Twenty old (age 68.8 ± 5.3, 65% female) and 20 young (age 25.2 ± 2.2, 45% female) adults generated random numbers during backward walking (BW) and forward walking (FW) over-ground and over a treadmill with an internal focus of attention and visual-attentive distraction; six walking conditions in total. To assess cognitive flexibility, sample entropy was calculated for each RNG sequence. The average of the first 5 numbers in each RNG task was calculated to assess the relationship between small/large numbers and movement direction. STV and DS% were recorded using inertial measurement units, and spatial orientation was measured using a computerized test. The older subjects had less flexibility in generating random numbers in three of the six walking conditions. A negative correlation between RNG flexibility and STV was found in older adults during treadmill BW with visual-attentive distraction and forward over-ground walking, whereas no correlations were demonstrated in the young group. The spatial orientation score (a higher value means a worse outcome) correlated positively with RNG flexibility in the older group under all walking conditions, suggesting that older adults with better visuospatial orientation have lower cognitive flexibility, and vice versa. There was no correlation between small/large numbers and direction of motion in either group. The correlation between RNG flexibility and STV may indicate similar executive control of verbal and gait rhythmicity in old adults. Conversely, our results suggest that cognitive flexibility and visuospatial ability may decline differently.
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