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.

A randomised test of the effect of medical v. lay idiom on assessment of perceived mental health condition in the USA.

AIMS: To test the impact of using different idioms in epidemiological interviews on the prevalence and correlates of poor mental health and mental health service use. METHODS: We conducted a randomised methodological experiment in a nationally representative sample of the US adult population, comparing a lay idiom, which asked about 'problems with your emotions or nerves' with a more medical idiom, which asked about 'problems with your mental health'. Differences across study arms in the associations of endorsement of problems with the Kessler-6 (a validated assessment of psychological distress), demographic characteristics, self-rated health and mental health service use were examined. RESULTS: Respondents were about half as likely to endorse a problem when asked with the more medical idiom (18.1%) than when asked with the lay idiom (35.1%). The medical idiom had a significantly larger area under the ROC curve when compared against a validated measure of psychological distress than the lay idiom (0.91 v. 0.87, p = 0.012). The proportion of the population who endorsed a problem but did not receive treatment in the past year was less than half as large for the medical idiom (7.90%) than for the lay idiom (20.94%). Endorsement of problems differed in its associations with age, sex, race/ethnicity and self-rated health depending on the question idiom. For instance, the odds of endorsing problems were threefold higher in the youngest than the oldest age group when the medical idiom was used (OR = 3.07; 95% CI 1.47-6.41) but did not differ across age groups when the lay idiom was used (OR = 0.76; 95% CI 0.43-1.36). CONCLUSION: Choice of idiom in epidemiological questionnaires can affect the apparent correlates of poor mental health and service use. Cultural change within populations over time may require changes in instrument wording to maintain consistency in epidemiological measurement of psychiatric conditions.

When left-handed mice live in right-handed worlds.

Many C57BL/6J inbred mice were tested for paw preference. In unbiased worlds, approximately 10 percent exhibited lateral preferences inconsistent with the world bias, and males were more strongly lateralized. Influences of world bias appear to be superimposed upon an already laterally dichotomized population. Initial left-right sense, it is posited, arises as an outcome of a seemingly random process.

Unilateral inhibition of sound-induced convulsions in mice.

Loud sound repeatedly presented to one ear after an initial bilateral exposure produces a lateralized inhibition of convulsibility in SJL/J mice. Inhibition of the right side does not affect the convulsible state of the left side. Processes leading to inhibition and convulsibility may develop independently within the same animal.

Audiogenic seizure prone (asp): a gene affecting behavior in linkage group 8 of the mouse.

The incidence of initial audiogenic seizures in mice from crosses between a susceptible and a resistant inbred strain is attributable to the effects of a single pair of alleles. The locus responsible for this behavioral variation is located in Linkage Group VIII of the mouse. Sensitization-dependent convulsions are influenced in whole or in part by alleles at an independent locus.

Mice unilaterally sensitized for audiogenic seizures.

Strain SJL/J mice exposed to loud bell-ringing (primed) with one ear blocked do not convulse, but are susceptible to audiogenic seizures 48 hours later when stimulated only through the ear open at priming. Mice stimulated through the ear blocked at priming do not convulse, but are convulsible when retested on the opposite ear. The site of sensitization appears to be either in the ear or in those portions of the auditory system receiving input only from one side.

Water-degradable polymers for controlled release of herbicides and other agents.

A new class of polymeric substances that degrade in the presence of water are formed by the reaction of carboxylic acids with metal ions in the presence of an aldehyde catalyst. Possible uses may be found in agricultural chemicals, packaging, and medicine. Important antipollution aspects are present in many of these applications.

Associations of Perceived Discrimination With Impaired Functioning in a Population Sample With Psychological Distress.

OBJECTIVE: To test associations between perceived discrimination based on mental health status and impaired functioning in a population sample with psychological distress. METHODS: Interviews were conducted with a sample of respondents to the California Health Interview Survey with mild, moderate, or severe psychological distress. Perceived discrimination was assessed using 14 items covering four domains in which discrimination is reported: social, partner, institutional, and work. Associations of perceived discrimination scores (total score and domain scores) with impaired functioning, measured by the likelihood and number of days out of role, were estimated with statistical adjustment for demographic characteristics and serious psychological distress. RESULTS: Discrimination domain scores are significantly correlated (r ranging from .34 to .65).Total discrimination score is associated with having days out of role (OR = 1.20, 95% CI = 1.10-1.30) and with number of days out of role (5.5 days) after adjustment for demographics and psychological distress. The high correlation among the domain scores makes the attribution of association to particular domains uncertain. Removal of the effect of discrimination using model-based simulation reduces past-year days out of role by 39.4 (SE 11.3) days. CONCLUSIONS: This observational study supports the suggestion that discrimination against people with mental illness contributes to their impaired functioning in a diverse range of social roles. The results provide preliminary evidence that reduction in discrimination against people with mental illness could improve social functioning and work productivity. Correlations among domain scores make it difficult to draw conclusions about domain-specific associations.

Organization and evolution of the mammalian genome: I. Polymorphism of H-2 linked loci.

To test the hypothesis that the H-2 polymorphism is adaptive, the degree of polymorphism of loci linked to the H-2 complex on chromosome 17 of the house mouse was compared to the degree of polymorphism of loci located on other chromosomes. Published theoretical analyses show that polymorphisms subject to natural selection usually reduce the polymorphism of linked neutral loci. The first test of the hypothesis was based on data obtained from a survey of the polymorphism of 12 isozyme-encoding loci in wild house mice from Europe, North Africa and South America. Results of this test showed that, on the average, H-2 linked loci were as polymorphic as loci located on other chromosomes. In fact, the data suggested that H-2 linked loci might be more polymorphic than other loci. To test this hypothesis more rigorously, data for the 12 isozyme-encoding loci were augmented with data from published surveys of the polymorphisms of 59 loci in house mice from Europe and North America. Results of these tests showed that polymorphic loci linked to the H-2 complex tended to be more, rather than less, polymorphic than loci located on other chromosomes. The cluster of highly polymorphic loci seems to be related to linkage of these loci to the highly polymorphic H-2 complex, but the way in which the influence is exerted could not be readily explained.

Blockade of the spontaneous midcycle gonadotropin surge in monkeys by RU 486: a progesterone antagonist or agonist?

Preovulatory ovarian secretion of progesterone (P4), several hours before the onset of the typical midcycle gonadotropin surge, occurs in humans and monkeys. We investigated the potentially obligatory role of preovulatory P4 secretion in stimulating the midcycle LH surge by administering a potent P4 antagonist, RU 486(17 beta-hydroxy-11 beta-[4-dimethylaminophenyl-1]17 alpha-[prop-1-ynyl]estra-4,9-dien-3-one), to sexually mature, normally ovulatory cynomolgus monkeys on days 10-12 of the menstrual cycle (n = 18). Monkeys were randomized to receive RU 486 alone (5 mg/day, im; group I); RU 486 plus dexamethasone (1 mg/day, im; group II); dexamethasone alone (group III); or vehicle (ethanol; 0.5 ml; group IV). Before drug treatment, the follicular phases were quite similar among groups. The administration of RU 486 blocked (delayed) the expected gonadotropin surge, despite rising estrogen concentrations (greater than 250 pg/ml). The expected LH surge was delayed by RU 486 (n = 5) or RU 486 with dexamethasone (n = 3) until 36 +/- 7 (+/- SEM) and 27 +/- 8 days in groups I and II, respectively. In contrast, groups III (n = 3) and IV (n = 5) had timely midcycle surges after the administration of dexamethasone or vehicle alone (4 +/- 2 and 6 +/- 2 days, respectively). The intermenstrual interval was lengthened by RU 486 administration in both group I and II animals (61 +/- 6 and 54 +/- 6 days) compared to controls (30 +/- 2; P less than 0.0001). In summary, RU 486 effectively blocked imminent midcycle gonadotropin surges, delayed subsequent folliculogenesis, and significantly extended the menstrual cycle length. If RU 486 acted as a pure P4 antagonist, then P4 is necessary for timely midcycle gonadotropin surges to occur. However, recent evidence showing agonistic properties of RU 486 (in the virtual absence of P4) at both endometrial and pituitary levels may favor a P4-like (agonistic) blockade of the estrogen-induced FSH/LH surges by RU 486.

Follicular stimulation versus ovulation induction in juvenile primates: importance of gonadotropin-releasing hormone dose.

We evaluated the dose of GnRH administered by 1-min pulsatile infusion necessary to achieve follicle growth vs. the dose needed for ovulation induction. Doses of 6.0, 0.6, and 0.06 micrograms GnRH were given to juvenile monkeys iv in 1 min once per h for 4 consecutive months. Monkeys receiving hourly 6.0-micrograms doses of GnRH had cyclic elevations of serum estradiol and had menses, but did not ovulate, as evidenced by lack of a corpus luteum at laparoscopy and consistently low progesterone concentrations. These monkeys ovulated only when hCG was administered near midcycle as a surrogate LH surge. In contrast, monkeys receiving 0.6-microgram doses of GnRH frequently had normal ovulatory menstrual cycles and characteristic elevations of progesterone during the luteal phase. Typically, juvenile monkeys receiving hourly 0.06-microgram doses of GnRH initially had development of a dominant follicle contemporaneous with a rise of serum estradiol, but never ovulated or had any subsequent follicular growth or elevated steroidogenic activity. In summary, ovarian follicular development and steroidogenesis in juvenile monkeys can be initiated by doses of GnRH ranging from 0.06-6.0 micrograms/h, although spontaneous ovulation and normal luteal function occurred frequently only with the 0.6 micrograms/h pulses of GnRH. Thus, the dose range of pulsatile GnRH needed for follicle growth is much broader than that required for induction of ovulatory menstrual cycles.

Human menopausal gonadotropin/human chorionic gonadotropin-induced ovarian hyperstimulation with transient hyperprolactinemia: steroidogenesis enhanced during bromocriptine therapy in monkeys.

To examine the role of gonadotropin-induced hyperprolactinemia on reproductive function, 17 euprolactinemic ovulatory monkeys were given extended fixed dose regimens of human menopausal gonadotropin (hMG) (12 days), followed by hCG the next day, and some animals then received bromocriptine. All animals were given hMG/hCG from day 3 (D3) until D14, with hCG on D15; those in group I (n = 12) received no further therapy, while those in group II (n = 5) received bromocriptine (0.25 mg/kg X day, im) daily from the day of hCG administration until menses. Ovarian hyperstimulation developed to various degrees in all animals. Based on serum estradiol (E2) levels, 13 were high responders (E2, greater than 1000 pg/ml), 2 were medium responders (E2, 500-1000 pg/ml), and 2 were low responders (E2, 150-500 pg/ml). In group I, transient hyperprolactinemia occurred in the luteal phases in 8 of the 12 animals compared to the follicular phase levels in the same animals (P less than 0.01). In group II, bromocriptine treatment in the luteal phase prevented hyperprolactinemia, but there was no change in the menstrual cycle or luteal phase lengths; however, significant luteal phase increases in progesterone (P less than 0.005) and E2 (P less than 0.02) secretion occurred during bromocriptine therapy. Deliberate hMG/hCG studies in euprolactinemic women seem indicated to learn whether women so treated experience estrogen-progesterone-induced hyperprolactinemia like that in monkeys and, if so, to determine its consequences on the reproductive process.

Fenoprofen, aspirin, and gold induction in rheumatoid arthritis.

Fenoprofen calcium (2,400 mg/day) or aspirin (3,900 mg/day) was administered in double-blind fashion to 20 rheumatoid patients during 6 months of gold induction therapy, and to 20 rheumatoid patients not receiving gold. Among both the gold-treated and nongold-treated patients, the fenoprofen and aspirin groups improved equally in all but one parameter of disease activity. Fenoprofen and aspirin did not differ significantly in the observed prevalences of abdominal discomfort, guaiac-positive stools, or peptic ulcers. Aspirin was associated with significantly higher mean serum glutamic oxaloacetic transaminase (SGOT) levels than fenoprofen, but only among patients undergoing gold induction. Comparison of efficacy parameters between patients treated with gold and patients treated with oral drugs alone revealed significant differences favoring gold.

Evaluation of nabumetone in the treatment of active adult rheumatoid arthritis.

The safety and efficacy of nabumetone and placebo were compared in a three-week, multicenter, double-blind, randomized, parallel evaluation involving patients with class II or III definite or classical rheumatoid arthritis. No patient received concomitant treatment with other nonsteroidal anti-inflammatory agents; however, disease-modifying agents (gold, steroids) were permitted. Of the 139 patients who entered the double-blind phase of the study, all were evaluable for safety, and 113 were evaluable for efficacy. Sixty-one patients received 1,000 mg of nabumetone per day at bedtime, and 50 were given placebo tablets; patients in both groups were permitted up to 3,250 mg of acetaminophen per day as needed for pain. After three weeks, nabumetone-treated patients exhibited a greater degree of improvement from baseline than did the placebo-treated patients, and the degree of improvement was statistically significant for four of seven variables.

Six-month multi-center study comparing nabumetone with naproxen in the treatment of osteoarthritis.

This six-month, double-blind, controlled, randomized, parallel study at 13 medical centers compared the safety and efficacy of nabumetone (1,000 mg taken at bedtime) with that of naproxen (250 mg twice daily) in the treatment of osteoarthritis in symptomatic adult outpatients. Five efficacy parameters were measured: patients' assessment of overall osteoarthritis activity and pain, physicians' assessment of overall osteoarthritis activity and pain, and physicians' assessment of pain with respect to a declined activity. All 489 patients who took medication were included in the evaluation of safety, and 455 patients (227 in the nabumetone group and 228 in the naproxen group) were evaluated for efficacy. Significant improvement in all five efficacy parameters occurred in both groups. No significant differences were found between the two groups at the end of the study in any of the five efficacy parameters. Twenty-three percent of nabumetone and 17 percent of naproxen patients withdrew from the study for lack of efficacy. At least one possible or probable treatment-related adverse experience was reported for 45 percent of nabumetone-treated patients and 42 percent of those given naproxen, and in 19 percent of the nabumetone-treated and 18 percent of the naproxen-treated patients these experiences were moderate or severe. However, only 7 percent of patients in each group withdrew from the study due to adverse experiences. Nabumetone and naproxen have comparable safety and efficacy, suggesting that a single, nighttime dose of nabumetone is a convenient, effective, and safe treatment for osteoarthritis.

Genotype and test experience determine responsiveness to morphine.

Initial responsiveness to morphine was studied in two inbred strains of mice, C57BL/6J and DBA/2J, and their F1 hybrid, using both a hot-plate analgesia test and a locomotor-activity test. Three dose levels of morphine were used, 0 mg/kg 5 mg/kg, and 15 mg/kg. The inclusion of the 0 mg/kg group revealed differences between the inbred strains in the effects of test experience. These data also led to some new conclusions about the differences in responsiveness to morphine between the strains studied. On both tests, the DBA mice showed no effect of morphine, the C57 mice showed large effects, and the F1 mice showed an intermediate effect.

Repeated methylphenidate treatment induces behavioral sensitization and decreases protein kinase A and dopamine-stimulated adenylyl cyclase activity in the dorsal striatum.

The behavioral effects of repeated methylphenidate (MPH) treatment were assessed in the adult rat. Protein kinase A (PKA) and adenylyl cyclase (basal and DA-stimulated) activity in the dorsal striatum (i.e., caudate-putamen) were measured to determine whether MPH-induced alterations in these enzymes correlate with the occurrence of behavioral sensitization. In two experiments, adult rats were injected (i.p.) on 5 consecutive pre-exposure days with saline or MPH (5, 10, 15, or 20 mg/kg). Sensitization was tested after a single abstinence day, with rats receiving a challenge injection of MPH prior to either a 40- or 150-min testing session (additional control groups received saline on the test day). Immediately after the 40-min testing session, rats were killed and tissue from the dorsal striatum was dissected for later analysis of PKA and adenylyl cyclase activity. Results showed that repeated MPH treatment sensitized the stereotyped sniffing, but not the locomotor activity, of adult rats. PKA activity was significantly depressed in rats treated with MPH (10 or 20 mg/kg) during both the pre-exposure and test day phases. DA-stimulated adenylyl cyclase activity was reduced after chronic MPH treatment, while basal adenylyl cyclase values were enhanced. Thus, the present study showed that MPH was able to sensitize the stereotyped behaviors of adult rats, an action that corresponded with drug-induced changes in dorsal striatal DA signal transduction mechanisms.

Kappa opioid-mediated behavioral sensitization in the preweanling rat: relationship to Fos immunoreactivity.

When given acutely, drugs that stimulate kappa opioid receptors (e.g., U-50,488) enhance the locomotor activity of preweanling rats and induce regional increases in Fos immunoreactivity (IR). In contrast, the effects of chronic treatment with kappa opioid agonists are unknown. The purpose of the present study was two-fold: first, to determine whether repeated treatment with a kappa opioid agonist would sensitize the locomotor activity of preweanling rats and, second, to determine whether changes in Fos IR correspond with the occurrence of locomotor sensitization. To test these hypotheses, rats were injected with U-50,488 (5 mg/kg, s.c.) or saline on either postnatal days (PD) 5-9 or PD 11-15. For rats pretreated on PD 5-9, a test day injection of U-50,488 or saline was given after either 1 or 7 abstinence days (i.e., at PD 11 or PD 17). For rats pretreated on PD 11-15, a test day injection of U-50,488 or saline was given after 1 abstinence day (i.e., at PD 17). In two additional experiments, the acute and chronic effects of U-50,488 treatment were assessed in adult rats. As expected, repeated treatment with U-50,488 produced locomotor sensitization at both PD 11 and PD 17, but only when the test day occurred 1, and not 7, days after cessation of drug pretreatment. Thus, the persistence of the sensitized response was very brief. Test day treatment with U-50,488 stimulated Fos IR in various brain regions of the preweanling rat, including the medial striatum, nucleus accumbens, lateral habenula, and septal area. Chronic treatment with U-50,488 depressed Fos expression in a number of brain regions (relative to acutely treated rats); however, these changes in Fos IR did not necessarily coincide with the occurrence of behavioral sensitization. Repeated treatment with U-50,488 did not produce locomotor sensitization in adult rats, so Fos IR was not assessed in this age group. Therefore, while acute treatment with U-50,488 both increased locomotor activity and stimulated Fos IR in preweanling rats, chronic U-50,488 treatment produced behavioral changes that did not correspond with Fos expression.

Establishment of an oocyte donor program. Donor screening and selection.

IVF with donated oocytes, followed by embryo placement in the uterus of a recipient who has been primed with exogenous steroids, is a successful treatment for special cases of infertility. Preliminary results indicate that the success rate in this situation is even greater than that usually seen with normal IVF (with placement of the embryos back into the uteri of the women from whom the oocytes were recovered). Although different sources for donated oocytes have been identified, the use of "excess" oocytes from IVF cycles and the attempted collection of oocytes at the time of otherwise indicated pelvic surgery have ethical and practical problems associated with their use. We have herein described the establishment of a successful program relying on anonymous volunteers who go through ovarian stimulation, monitoring, and oocyte recovery procedures solely to donate oocytes. The potential donors go through an exhaustive screening and education process before they are accepted in the program. Psychological evaluation of our potential donors indicated a great degree of turmoil in their backgrounds and a wide variety of motivations for actually participating. Despite the extensive educational and screening process, a substantial percentage of the donors did not complete a donation cycle, having either voluntarily withdrawn or been dropped because of lack of compliance. Further investigation of the psychological aspects of participating in such a program is certainly warranted. The use of donated oocytes to alleviate specific types of infertility is quite successful, but the application of this treatment is likely to be limited by the relative unavailability of suitable oocyte donors.

The effects of early experience on callosal development and functional lateralization in pigmented BALB/c mice.

A proportion of animals of the BALB/c inbred mouse strain have an unusually small (sometimes absent) midsagittal area of the corpus callosum (CC). In this study, we used a large sample of both males and females (total n = 198) from a pigmented congenic BALB/c line to investigate the relations among preweaning handling, area of CC, and direction and degree of lateralization as measured by Collins' paw preference task. Twenty litters were handled daily from the day after birth until day 25 (weaning) according to Denenberg's procedure and 18 litters were left undisturbed until weaning. All animals were tested for degree and direction of paw preference in a modification of Collins' apparatus at about 60 days and measures taken on CNS structures at 100 days of age. There were no handling or sex effects on degree or direction of paw preference or on the extent of CC defects, but for animals in the normal range (CC > or = 0.7 mm2), those which had been handled had significantly smaller callosa. No significant differences were detected between right and left hemisphere weights, and these measures did not appear to be related to the behavioural measures. There was no significant correlation between CC area and degree of paw preference nor was there any relationship between total agenesis and degree of handedness. This last result is particularly interesting in light of recent evidence that ILn/J mice, all acallosal, are exclusively ambilateral.