Effect of plantar desensitization on postural adjustments prior to step initiation.

Plantar cutaneous afferent provides information about the contact between the body and the support surface and could affect the anticipatory postural adjustments (APAs). This study investigated the effect of plantar desensitization on the APAs for step initiation. Twenty-five healthy young adults participated in this study and were instructed to begin walking as fast as possible under 4 plantar desensitization conditions, none (NoneD), and desensitization of the stepping, supporting or bilateral (BilD) plantar surfaces, with eyes open or closed. The desensitization was achieved by cold water immersion of the plantar surface for 15 min. Foot switches recorded the timing of the stepping events. Surface electromyography (EMG) recorded the activation of bilateral tibialis anterior. The center of pressure (COP) and ground reaction force (GRF) data were derived from the force platform on which the subject initiated walking. The results showed that during the anticipation phase, the peak COP displacement toward the stepping leg was significantly smaller in BilD than in unilateral desensitization, which in turn was smaller than in NoneD, regardless of vision. The time to reach the peak COP displacement was significantly sooner with plantar desensitization in the eyes open condition. The GRF, EMG and anteroposterior COP displacement or the timing of the stepping events was not affected by plantar desensitization. These findings indicate that plantar cutaneous afferent contributed to the control of the APAs for step initiation by scaling the displacement of the mediolateral COP displacement and loss of its sensitivity could not be compensated by visual inputs.

Age-related changes in the performance of forward reach.

Aging is widely considered to be associated with limited balance capacity. It is not clear if forward reach ability is also affected by aging. The purpose of this study was to determine if aging was associated with reduced ability of forward reach or changes in movement patterns. Thirty-three young and 31 older adults were instructed to reach forward as far as possible without losing balance. A motion analysis system was used to record the body kinematics to calculate the joint angle and estimate the motion of center of mass (COM) using a five-segment model. Reach distance (measured from the finger marker), COM displacement, and the distance that the COM exceeded the 2nd toe marker (COM-toe) were used to represent reach performance. The movement patterns were classified as hip, ankle or mixed strategies based upon joint kinematics. It was found that the initial location of the COM was significantly more anterior in the older adults. Older adults were found to have significantly smaller COM displacement and greater hip flexion, but did not differ from young adults in reach distance or COM-toe. Older adults overwhelmingly adopted a hip strategy, but none adopted an ankle strategy. The distribution of the different strategies also differed significantly between groups. These findings suggest that aging appears to be associated with modifications in movement patterns, but not necessarily with a reduction in the ability to approach the boundary of stability. Clinically, balance training for older adults may include the exploration and instruction of atypical movement patterns.

Association between sensorimotor function and forward reach in patients with diabetes.

Deterioration in the function of the sensorimotor system is often seen in patients with diabetes and could be related to balance impairments. The purpose of this study was to determine the association between sensorimotor function and forward reach ability in patients with diabetes. Thirty-one patients with Type 2 diabetes went through a monofilament test of plantar touch-pressure threshold, an ankle joint reposition test for joint position sense, and a series of strength tests of the lower leg. These patients also performed the forward reach test in standing to measure the reach distance and displacement of the center of mass (COM), using a motion analysis system. Correlational and regressional analyses were conducted to determine the association between sensorimotor and balance parameters. It was found that greater reach distance and COM displacement were significantly correlated with lower plantar touch-pressure threshold and greater plantarflexion strength. Regression analysis showed that after controlling the variance in the subject characteristics, plantar touch-pressure threshold was a significant predictor for reach distance and COM displacement, while plantarflexion strength was also a significant predictor for COM displacement. These findings highlight the importance of the assessment of plantar sensitivity and the need for detailed balance or fall risk assessment for patients with impaired plantar insensitivity.

Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist.

Truncation of the original piperidino-2(S)-methyl piperazine lead structure 2, from a family of muscarinic antagonists, gave compound 8 which has improved selectivity for the HIV-1 co-receptor CCR5 over muscarinic receptors. Further optimization for pharmacokinetic properties afforded Sch-350634 (1), a prototypical piperazine-based CCR5 antagonist, which is a potent inhibitor of HIV-1 entry and replication in PBMCs. The title compound (1) has excellent oral bioavailability in rat, dog, and monkey.

Engineering of a stable mutant malic enzyme by introducing an extra ion-pair to the protein.

A double mutant (R9E/M17K) of pigeon liver malic enzyme with glutamate and lysine replaced for arginine and methionine at positions 9 and 17, respectively, was found to be much more stable in urea and thermal denaturation, but was enzymatically less active than the wild-type enzyme (WT). Unfolding of the enzyme by urea produced a large red shifting of the protein fluorescence maximum from 320 to 360 nm, which was completely reversible upon dilution. Analysis of the denaturation curves monitored by enzyme activity lost suggested that a putative intermediate was involved in the denaturation process. The half unfolding urea concentration, measured by fluorescence spectral changes, increased from 2.24 M for WT to 3.13 M for R9E/M17K. The melting temperature increased by approximately 10 degrees C for R9E/M17K compared with that for WT. Kinetic analysis of the thermal inactivation at 58 degrees C also conformed to a three-state model with the rate constant for the intermediate state of R9E/M17K (k2 = 0.03 min(-1)) being much smaller than the WT value (k2 = 2.39 min(-1)). Results obtained from single mutants indicated that the decreasing enzyme activity of R9E/M17K was exclusively due to R9 mutation, which increased the K(mMn) and K(mMal) by at least one order of magnitude compared with WT. Consequently, a decrease occurred in the specificity constant [k(cat)/(K(mMm)K(mNADP)K(mMal))] for the R9 mutants at least four orders of magnitude smaller than the WT. M17K has similar properties to the WT, while R9E is more labile than the WT enzyme. The above results indicate that the extra stability gained by the double mutant possibly occurs through the introduction of an extra ion-pair between E9 and K17, which freezes the double mutant in the putative intermediate state. Examination of the N-terminal amino acid sequence of pigeon liver malic enzyme reveals that position 15 is also a lysine residue. Since the R9E mutant, which has an extra Glu9-Lys15 ion-pair, is less stable than the WT, we conclude that the contribution to malic enzyme stability is specific for the Glu9-Lys17 ion-pair.