Gait variability in Parkinson's disease: levodopa and walking direction.

BACKGROUND: Levodopa treatment has been shown to improve gait spatio-temporal characteristics in both forward and backward walking. However, effect of levodopa on gait variability during backward walking compared with forward walking has not been reported. AIMS OF STUDY: To study the effects of levodopa on gait variability of forward and backward walking in individuals with Parkinson's disease (PD). METHODS: Forty individuals with PD were studied. Their mean age was 68.70 ± 7.46 year. The average time since diagnosis was 9.41 ± 5.72 year. Gait variability was studied while 'OFF' and 'ON' levodopa when the participants walked forward and backward at their usual speed. Variability in step time, swing time, stride length, double support time, and stride velocity were compared between medication condition and walking direction. RESULTS: Variability of step time, swing time, stride length, and stride velocity decreased significantly during forward and backward walks (P < 0.001; P < 0.001; P = 0.003, P = 0.001, respectively) after levodopa administration. Variability of double support time was not changed after levodopa administration (P = 0.054). CONCLUSIONS: Levodopa had positive effects on gait variability of forward and backward walking in individuals with PD. However, variability in double support time was not affected by the levodopa.

The relation of falls to fatigue, depression and daytime sleepiness in Parkinson's disease.

OBJECTIVE: To characterize non-motor symptoms in individuals with Parkinson's disease (PD) who experience falls compared to those who do not fall. METHODS: Fifty-four individuals with PD were studied. Thirty-six were fallers and 18 were non-fallers. Fatigue was assessed by the Iowa Fatigue Scale. Excessive daytime sleepiness was assessed by the Epworth Sleepiness Scale, and depressive symptomatology was assessed by the short-form Center for Epidemiologic Studies Depression Scale. RESULTS: Compared to non-fallers, fallers had more severe disability, greater general physical fatigue (p = 0.024), lower energy levels (p = 0.042) and less productivity (p = 0.007). Fallers had more depressive symptomatology than the non-fallers (p = 0.01). Excessive daytime sleepiness was not different between the two groups (p = 0.695). CONCLUSIONS: Individuals with PD who fell had more severe motor and non-motor symptoms than those who did not fall. These non-motor symptoms included physical fatigue, energy, productivity and depressive symptomatology.

An investigation of two interventions for micrographia in individuals with Parkinson's disease.

OBJECTIVE: This pilot study was designed to compare a change in micrographia between using grid lines and parallel horizontal lines as visual cues in individuals with Parkinson's disease. DESIGN: Single group pre- and post-test. SETTING: Research lab. PARTICIPANTS: Eleven males with Parkinson's disease. INTERVENTIONS: Practice writing words with parallel and grid lines. The sequence of practising was randomized. MAIN OUTCOME MEASURES: Length of words. RESULTS: The length of the words after practising with parallel lines was longer than in the initial free writing condition (17.83 ± 3.93 cm vs. 23.36 ± 5.82 cm, P =0.008). The length of the words after practising with grid lines was also longer than during free writing (17.83 ± 3.93 cm vs. 22.65 ± 4.04 cm, P =0.003). The length of the words after practising with parallel lines was not different from that after practising with grid lines. CONCLUSION: Improvements in letter size after practising with horizontal parallel lines and grid lines were not different. The addition of vertical lines to form a grid did not appear to improve the writing more than horizontal lines alone in persons with Parkinson's disease who experienced micrographia.

An evaluation of self-administration of auditory cueing to improve gait in people with Parkinson's disease.

OBJECTIVE: To evaluate a self-administration of auditory cueing on gait difficulties in people with Parkinson's disease over a one-week period. DESIGN: Single group pre and post test. SETTING: Research lab, community. PARTICIPANTS: Twenty-one individuals with Parkinson's disease. INTERVENTIONS: Self-application of an auditory pacer set at a rate 25% faster than preferred cadence. MAIN OUTCOME MEASURES: Self-selected gait speed, cadence, stride length, and double support time with and without the pacer at the initial visit and after one week of pacer use. RESULTS: During the initial visit, the auditory pacer improved gait speed (79.57 (18.13) cm/s vs. 94.02 (22.61) cm/s, P<0.0005), cadence (102.88 (11.34) step/min vs. 109.22 (10.23) steps/min, P=0.036) and stride length (94.33 (21.31) cm vs. 103.5 (22.65) cm, P =0.012). After one week, preferred gait speed was faster than the initial preferred speed (79.57 (18.13) vs. 95.20 (22.23) cm/s, P<0.0005). Stride length was significantly increased (94.33 (21.31) vs. 107.67 (20.01) cm, P =0.001). Double support time was decreased from 21.73 (5.23) to 18.94 (3.59)% gait cycle, P =0.016. CONCLUSION: Gait performance in people with Parkinson's disease improved significantly after walking with the auditory pacer for one week.

A two-year toxicology study of bisphenol A (BPA) in Sprague-Dawley rats: CLARITY-BPA core study results.

We report the data from the guideline-compliant two-year toxicology study conducted as part of the Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity (CLARITY-BPA). BPA (0, 2.5, 25, 250, 2,500, and 25,000 µg/kg body weight (bw)/day) was administered daily by gavage in 0.3% carboxymethylcellulose vehicle to NCTR Sprague-Dawley rats from gestation day 6 through the start of parturition and then directly to pups from the day after birth until postnatal day 21 (stop-dose arm) or continuously until termination at one or two years. The stop-dose arm was included to assess the potential for any BPA effects that were due to developmental exposure. No BPA-related effects were evident in the in-life and non-histopathology data. Neoplastic and nonneoplastic lesions diagnosed in both females and males were common age-associated lesions that were variable across control and BPA-treated groups. The lack of consistent responses within the continuous- and stop-dose arms within and across tissues brought into question the plausible relationship of most of these lesions to BPA treatment. There was a possible relationship between the increased incidences of lesions in the female reproductive tract and the male pituitary and exposure to the 25,000 µg BPA/kg bw/day dose level.

Hemoglobin adducts of 4-aminobiphenyl in smokers and nonsmokers.

A quantitative method has been developed for the analysis of 4-aminobiphenyl (4-ABP) covalently bound as the sulfinic acid amide to the 93 beta cysteine of human hemoglobin. The method uses mild basic hydrolysis of hemoglobin to release the parent amine, derivatization to form the pentafluoropropionamide, and capillary gas chromatography with detection by negative-ion chemical ionization mass spectrometry. The method is precise and gives reproducible results on multiple blood samples taken from individuals over 48 h. Application of this method to blood samples from cigarette smokers and nonsmokers revealed consistently higher adduct levels in smokers. The mean value for smokers was 154 pg 4-ABP per g Hb compared to 28 pg/g Hb for nonsmokers, with no overlap of adduct levels between the two groups. Studies on quitting smokers revealed that adduct levels declined over a period of 6-8 weeks to nonsmoker levels. The finding of 4-ABP adducts in all nonsmokers was not anticipated but is consistent with low-level ubiquitous contamination of air, food, or water. In other animals sampled, rats and dogs had measurable adduct levels, but monkeys and fish did not. The hemoglobin adduct of 4-ABP is the product of a series of reactions between the hemoprotein and N-hydroxy-4-ABP. The formation of hydroxylamines from carcinogenic aromatic amines and their subsequent reactions with DNA are generally thought to be critical events in the initiation of bladder tumors. We suggest that the observed hemoglobin adduct levels formed by this proximate carcinogen will reflect the extent to which these steps have occurred. This is the first report of 4-ABP adducts in human blood.

Decline of the hemoglobin adduct of 4-aminobiphenyl during withdrawal from smoking.

The hemoglobin adduct of the human bladder carcinogen 4-aminobiphenyl (4ABP-Hb) declined in the blood of 34 smokers enrolled in a withdrawal program, from a mean of 120 +/- 7 (SE) pg/g of hemoglobin at the start to a mean of 82 +/- 6 pg/g after 3 weeks and a mean of 34 +/- 5 pg/g among the 15 exsmokers who had not resumed smoking after 2 months. Although 4ABP-Hb declined faster than expected under the assumption that the human erythrocyte has a life span of 120 days, it persisted much longer than cotinine. Therefore, 4ABP-Hb may complement the use of cotinine as a marker of exposure to tobacco smoke. The strength of the within-person association of 4ABP-Hb with smoking, coupled with the weakness of the between-person association (correlation coefficient, 0.33), is evidence that between-person variation in modifying factors is substantial. Study of the modifiers of 4ABP-Hb levels may help elucidate the etiology of human susceptibility to aromatic amine-induced bladder cancer.

In vivo dosimetry of 4-aminobiphenyl in rats via a cysteine adduct in hemoglobin.

The feasibility of monitoring doses of 4-aminobiphenyl (ABP) via adduction to hemoglobin was investigated. Rats dosed with ABP (from 0.5 micrograms/kg to 5 mg/kg) formed a stable covalent hemoglobin:ABP adduct. Approximately 5% of a single dose was bound as hemoglobin:ABP; chronic dosing led to an accumulation of the adduct to a level 30 times greater than that found after a single dose. Facile in vitro hydrolysis of the adduct regenerated ABP, allowing detection at the sub-ng level. Human hemoglobin was also readily adducted, using N-hydroxy-ABP in vitro. The predominant site of adduction appeared to be the cysteine residue in hemoglobin. The use of such adducts as dosimeters for arylamine exposures in humans is discussed.

Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice.

We have been developing a series of nonpeptidic, small molecule farnesyl protein transferase inhibitors that share a common tricyclic nucleus and compete with peptide/protein substrates for binding to farnesyl protein transferase. Here, we report on pharmacological and in vivo studies with SCH 66336, a lead compound in this structural class. SCH 66336 potently inhibits Ha-Ras processing in whole cells and blocks the transformed growth properties of fibroblasts and human tumor cell lines expressing activated Ki-Ras proteins. The anchorage-independent growth of many human tumor lines that lack an activated ras oncogene is also blocked by treatment with SCH 66336. In mouse, rat, and monkey systems, SCH 66336 has excellent oral bioavailability and pharmacokinetic properties. In the nude mouse, SCH 66336 demonstrated potent oral activity in a wide array of human tumor xenograft models including tumors of colon, lung, pancreas, prostate, and urinary bladder origin. Enhanced in vivo efficacy was observed when SCH 66336 was combined with various cytotoxic agents (cyclophosphamide, 5-fluorouracil, and vincristine). In a Ha-Ras transgenic mouse model, prophylactic treatment with SCH 66336 delayed tumor onset, reduced the average number of tumors/mouse, and reduced the average tumor weight/animal. In a therapeutic mode in which gavage treatment was initiated after the transgenic mice had developed palpable tumors, significant tumor regression was induced by SCH 66336 in a dose-dependent fashion. This was associated with increased apoptosis and decreased DNA synthesis in tumors of animals treated with SCH 66336. Enhanced efficacy was also observed in this model when SCH 66336 was combined with cyclophosphamide. SCH 66336 is presently being evaluated in Phase I clinical trials.