COMT polymorphism modulates the resting-state EEG alpha oscillatory response to acute nicotine in male non-smokers.

Performance improvements in cognitive tasks requiring executive functions are evident with nicotinic acetylcholine receptor (nAChR) agonists, and activation of the underlying neural circuitry supporting these cognitive effects is thought to involve dopamine neurotransmission. As individual difference in response to nicotine may be related to a functional polymorphism in the gene encoding catechol-O-methyltransferase (COMT), an enzyme that strongly influences cortical dopamine metabolism, this study examined the modulatory effects of the COMT Val158Met polymorphism on the neural response to acute nicotine as measured with resting-state electroencephalographic (EEG) oscillations. In a sample of 62 healthy non-smoking adult males, a single dose (6 mg) of nicotine gum administered in a randomized, double-blind, placebo-controlled design was shown to affect α oscillatory activity, increasing power of upper α oscillations in frontocentral regions of Met/Met homozygotes and in parietal/occipital regions of Val/Met heterozygotes. Peak α frequency was also found to be faster with nicotine (vs. placebo) treatment in Val/Met heterozygotes, who exhibited a slower α frequency compared to Val/Val homozygotes. The data tentatively suggest that interindividual differences in brain α oscillations and their response to nicotinic agonist treatment are influenced by genetic mechanisms involving COMT.

Pharmacologic regimens for knee osteoarthritis prevention: can they be cost-effective?

OBJECTIVE: We sought to determine the target populations and drug efficacy, toxicity, cost, and initiation age thresholds under which a pharmacologic regimen for knee osteoarthritis (OA) prevention could be cost-effective. DESIGN: We used the Osteoarthritis Policy (OAPol) Model, a validated state-transition simulation model of knee OA, to evaluate the cost-effectiveness of using disease-modifying OA drugs (DMOADs) as prophylaxis for the disease. We assessed four cohorts at varying risk for developing OA: (1) no risk factors, (2) obese, (3) history of knee injury, and (4) high-risk (obese with history of knee injury). The base case DMOAD was initiated at age 50 with 40% efficacy in the first year, 5% failure per subsequent year, 0.22% major toxicity, and annual cost of $1,000. Outcomes included costs, quality-adjusted life expectancy (QALE), and incremental cost-effectiveness ratios (ICERs). Key parameters were varied in sensitivity analyses. RESULTS: For the high-risk cohort, base case prophylaxis increased quality-adjusted life-years (QALYs) by 0.04 and lifetime costs by $4,600, and produced an ICER of $118,000 per QALY gained. ICERs >$150,000/QALY were observed when comparing the base case DMOAD to the standard of care in the knee injury only cohort; for the obese only and no risk factors cohorts, the base case DMOAD was less cost-effective than the standard of care. Regimens priced at $3,000 per year and higher demonstrated ICERs above cost-effectiveness thresholds consistent with current US standards. CONCLUSIONS: The cost-effectiveness of DMOADs for OA prevention for persons at high risk for incident OA may be comparable to other accepted preventive therapies.

Studies of pain management in osteoarthritis: bedside to policy.

OBJECTIVE: Osteoarthritis (OA) is a debilitating chronic condition requiring long-term treatment of pain and functional impairment. Our objective was to characterize studies addressing management of OA-related pain with respect to the breadth of interventions, trial duration and size, outcome measures, and funding sources. DESIGN: We identified studies focused on 'pain' and 'osteoarthritis' from ClinicalTrals.gov and abstracted data on study status, sample size, design, funding source, duration, outcomes measured, and interventions evaluated. We examined associations among intervention type, funding source, sample size, duration, and outcomes measured. RESULTS: We identified 287 registered studies, of which 69% investigated pharmacologic interventions, 11% behavioral interventions, and 5% surgical procedures or devices, while the remainder examined other types of interventions. Eighty-seven percent evaluated knee OA. The average sample size was 290 subjects and average study duration was 7.4 months, with 52% using durations ≤3 months and 21% ≥12 months. Industry funded 64% of studies, either fully or partially. Of 180 completed studies, 139 were pharmacologic studies. Of these, 34 (24%) posted results to the registry. Among the studies funded by industry, 60% had durations ≤3 months as compared with 36% among non-industry funded studies (P < 0.0001). Behavioral intervention trials tended to be of longer duration than pharmacologic trials and were less likely to be funded by industry. CONCLUSION: Over half of OA pain studies and >80% of those funded by industry used trial durations of less than 6 months. Future studies should take into consideration the need for long-term pain management for OA when designing trial protocols.

Disease-modifying drugs for knee osteoarthritis: can they be cost-effective?

OBJECTIVE: Disease-modifying osteoarthritis drugs (DMOADs) are under development. Our goal was to determine efficacy, toxicity, and cost thresholds under which DMOADs would be a cost-effective knee OA treatment. DESIGN: We used the Osteoarthritis Policy Model, a validated computer simulation of knee OA, to compare guideline-concordant care to strategies that insert DMOADs into the care sequence. The guideline-concordant care sequence included conservative pain management, corticosteroid injections, total knee replacement (TKR), and revision TKR. Base case DMOAD characteristics included: 50% chance of suspending progression in the first year (resumption rate of 10% thereafter) and 30% pain relief among those with suspended progression; 0.5%/year risk of major toxicity; and costs of $1,000/year. In sensitivity analyses, we varied suspended progression (20-100%), pain relief (10-100%), major toxicity (0.1-2%), and cost ($1,000-$7,000). Outcomes included costs, quality-adjusted life expectancy, incremental cost-effectiveness ratios (ICERs), and TKR utilization. RESULTS: Base case DMOADs added 4.00 quality-adjusted life years (QALYs) and $230,000 per 100 persons, with an ICER of $57,500/QALY. DMOADs reduced need for TKR by 15%. Cost-effectiveness was most sensitive to likelihoods of suspended progression and pain relief. DMOADs costing $3,000/year achieved ICERs below $100,000/QALY if the likelihoods of suspended progression and pain relief were 20% and 70%. At a cost of $5,000, these ICERs were attained if the likelihoods of suspended progression and pain relief were both 60%. CONCLUSIONS: Cost, suspended progression, and pain relief are key drivers of value for DMOADs. Plausible combinations of these factors could reduce need for TKR and satisfy commonly cited cost-effectiveness criteria.

Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease.

OBJECTIVE: To assess serum brain derived neurotrophic factor (BDNF) concentrations as a correlate of cardiopulmonary fitness and as a predictor of cognitive performance in subjects with coronary artery disease (CAD). METHODS: Serum BDNF concentrations were assayed by ELISA and fitness was assessed using a standardized exercise stress test. The Mini Mental Status Examination (MMSE), California Verbal Learning Test 2nd Ed., Stroop, Trail Making Test B and the Digit Symbol-Coding task were administered. The val66met BDNF genotype and serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations were determined as potential confounders. RESULTS: In subjects with CAD (n=88; 85.2% male, mean age 62.8±10.5 yr), cardiopulmonary fitness was associated with higher serum BDNF concentrations (ß=.305, p=.013). Higher serum BDNF concentrations were associated with higher MMSE scores (F(1,87)=15.406, p<.0005) and better performance on the Digit Symbol-Coding task (F(1,87)=9.620, p=.003). IL-6, TNF-α and the val66met genotype did not influence these results. CONCLUSION: Serum BDNF concentrations were associated with cardiopulmonary fitness, psychomotor processing speed and overall cognition in subjects with CAD.

[Mobilizing community around the lack of preventive measures against crime among 10- and 11-year-old children]. / Mobiliser sa communauté autour du défi de prévention de la criminalité chez les enfants de 10 et 11 ans.

Originality and relevance are not the only factors in the success of innovative programs. Community consensus, expertise and credibility of staff, and evaluative approaches are important as well. Virgule ("Comma"), a program aimed at helping 10- and 11-year-olds who are first offenders, has these characteristics. The temporary hitch in the youth's life is viewed not as a definitive failure but as an opportunity for change. This is Virgule's philosophy: "Changing a period into a comma means changing a difficulty into a reason for progress."

Reaction of essentially free benzyl cations with acetonitrile; synthesis of ethanimidic carboxylic anhydrides and unsymmetrical diacylamines

Benzyl cations were generated via the thermal decomposition of N-benzyl-N-nitrosopivalamide in acetonitrile and acetonitrile-water mixtures at 25 degrees C. The first-formed (primary) benzylating agent, the benzyl cation, was scavenged competitively by pivalate (trimethyl acetate) ion to yield benzyl pivalate, by acetonitrile to yield the corresponding N-benzylnitrilium ion, and by water (when present) to yield benzyl alcohol. The nitrilium ion underwent a cascade of reactions to yield an array of products whose identities and relative yields as a function of time were used to elucidate the mechanistic paths involved. Thus, the N-benzylnitrilium ion reacted with pivalate ion to yield the Z-isomer of N-benzylethanimidic pivalic anhydride, followed by its conversion into the E-isomer. This article appears to be the first to document compounds of this type. The E-isomer is labile under the reaction conditions, rearranging into N-acetyl-N-pivalylbenzylamine. In the presence of water as a diluent, a significant fraction of the nitrosoamide was hydrolyzed to benzyl alcohol; hydrolysis of the nitrilium ion yielded N-benzyl acetamide. The yield of hydrosylates was directly proportional to the mole fraction of water in the medium.

Support and coping of male hemodialysis-dependent patients.

The purpose of this descriptive-correlational study was to describe coping strategies used by males with chronic renal failure who are dependent on hemodialysis; to describe their social networks; to describe the perceived support, conflict, and reciprocity within their interpersonal relationships; and to examine the relationships among the variables support, conflict, reciprocity, social networks, and coping strategies. Social support was conceptualized as a coping resource or source of assistance in coping with the renal illness- or hemodialysis-related stressor. The Ways of Coping questionnaire and the Interpersonal Relationship Inventory were administered to 30 participants while in hospital. Although, both problem-focused and emotion-focused forms of coping were used, participants primarily used problem-focused coping, in particular, "seeking social support". Overall, the participants perceived relatively high levels of support and moderate to high levels of reciprocity with members of their social networks. Participants experienced a moderate level of conflict in their interpersonal relationships. Both escape-avoidance and conflict were positively associated with the number of people in the household. Positive reappraisal was negatively associated with the number of close relatives. The small sample size prohibits generalizability of the results. Longitudinal studies with a larger randomly selected sample would yield insights into the long-term psychological outcomes of different coping strategies and into the bi-directional relationship of support from social network and coping in this population. Implications for nurses are discussed.

Effects of different telephone intervention styles with suicidal callers at two suicide prevention centers: an empirical investigation.

To determine the relative effectiveness of telephone intervention styles with suicidal callers, researchers listened unobtrusively to 617 calls by suicidal persons at two suicide prevention centers and categorized all 66,953 responses by the 110 volunteer helpers according to a reliable 20-category checklist. Outcome measures showed observer evaluations of decreased depressive mood from the beginning to the end in 14% of calls, decreased suicidal urgency ratings from the beginning to the end in 27% of calls, and reaching a contract in 68% of calls, of which 54% of contracts were upheld according to follow-up data. Within the context of relatively directive interventions, a greater proportion of "Rogerian" nondirective responses was related to significantly more decreases in depression. Reduction in urgency and reaching a contract were related to greater use of Rogerian response categories only with nonchronic callers.

Intervention styles with suicidal callers at two suicide prevention centers.

Callers to suicide prevention centers are mainly helped by volunteers trained to face these crisis situations. This study evaluated this process of intervention in order to better understand the nature of the interventions and their determinants. A total of 617 calls with suicidal clients were classified with a 20-category rating instrument, the Helper's Response List. Cluster analysis determined that the 617 intervention profiles could match one of two styles: nondirective ("Rogerian" -391 calls) or directive (226 calls). Further analyses indicated that the particular style of intervention was related more to the characteristics of the callers themselves than to characteristics of volunteers.

Isolation and characterization of S. cerevisiae mutants defective in somatostatin expression: cloning and functional role of a yeast gene encoding an aspartyl protease in precursor processing at monobasic cleavage sites.

The peptide somatostatin exists as two different molecular species. In addition to the most common form, somatostatin-14, there is also a fourteen amino acid N-terminally extended form of the tetradecapeptide, somatostatin-28. Both peptides are synthesized as larger precursors containing paired basic and monobasic amino acids at their processing sites, which upon cleavage generate either somatostatin-14 or -28, respectively. In some species of fish two distinct, but homologous, precursors (prosomatostatin-I and -II) give rise to somatostatin-14 and -28, respectively. Whereas anglerfish prosomatostatin-II was previously shown to release exclusively somatostatin-28, the yeast Saccharomyces cerevisiae proteolytically matures the homologous prosomatostatin-I precursor to somatostatin-28 and -14 as well as to a lysine-extended form of somatostatin-14. The Kex2 endoprotease appears to be essential for the formation of lysine somatostatin-14 and is involved either directly or indirectly in the release of mature somatostatin-14. The isolation of yeast mutants defective in somatostatin-28 expression (sex mutant) allowed the cloning of a non-essential gene, which encodes an aspartyl protease, whose disruption severely affects the cleavage of mature somatostatin-28 from both somatostatin precursors. We conclude that two distinct endoproteases, which demonstrate some cross specificity in vivo, are involved in the proteolytic maturation of prosomatostatin at mono- and dibasic processing sites in yeast.

Retinal dopamine sensitivity to MPP+ toxicity: electrophysiological and biochemical evaluation.

This study concerns the effect of intravitreal injection of 1-methyl-4-phenylpyridinium ion (MPP+) on the electroretinograms (ERG) and on the levels of retinal dopamine (DA) in rabbits. The right eye was injected intravitreously with MPP+ while the other received only the vehicle and served as control. The administration of 7, 40, 70 or 700 micrograms MPP+ resulted in a dose-related decrease of the amplitude of the a and b-waves as well as the oscillatory potentials (OPs) of the ERG, down to extinction. In contrast, the retinal DA content was decreased only with the 700 micrograms MPP+ dose. Fluorescein angiography demonstrated abnormalities in the retinal circulation of all MPP+-treated eyes. These observations indicate that MPP+ causes lesions to the retinal vessels at doses non-toxic to the retinal dopaminergic neurons. These data suggest that intravitreal injection of MPP+ cannot be used to study the physiological role of retinal DA.

Attitudes towards child sexuality.

The way in which North American attitudes contribute to child sexual abuse, so inhibiting abuse prevention education, is examined. A comprehensive literature review identifies sources of materials available to North Americans and determines whether the material includes the identification and anatomical labelling of genitalia. A tendency to avoid doing so is discerned.

Assay of dopamine and its metabolites in human and rat retina.

Human and rat retina dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured after various delays in enucleation and freezing of the eyes. Human eyes were enucleated 45 min to 4 h after death, kept at 4 degrees C and frozen at -70 degrees C from 1.5 to 15 h after enucleation. In human retina, maximal DA concentration (4.85 ng/mg prot.) was obtained from eyes enucleated with a delay of 1 h and frozen with a delay of 2 h. After longer delays, DA concentrations decreased. Retinas of humans who died during the night had lower DA retina concentrations compared to those who died during daytime. Rats were decapitated and the eyes enucleated within 5 min or with a delay up to 8 h before freezing at -70 degrees C or kept at 4 degrees C for 5 min to 12 h before being frozen at -70 degrees C. Delays in enucleation of the rat eyes markedly decreased DA retinal concentrations with a minimal value reached as soon as 2 h after death. However, when the rat eyes were kept at 4 degrees C the minimal value was obtained after a longer period of time (about 7 h). Our results thus show that time of death and delays in enucleation and freezing significantly influence DA and its metabolite concentrations in retinas of rats and humans.

Treatment assessment of learning disabled children: is there a role for frequently repeated neuropsychological testing?

Test/retest practice effects among learning disabled (LD) and non-learning disabled (NLD) children were examined using the Halstead Category Test. Two experimental paradigms were performed. The first compared subjects on successive trials. The second paradigm used a control group to compare second trial performance of the experimental group with first trial performance of the controls. Both paradigms provide evidence of the relative inability of LD children to profit from practice. It is suggested that neuropsychological data can be used for short term test/retest as one indication of the efficacy of treatment intervention for learning disabled children without the practice effect being a significantly confounding variable.

Long-term effects of MPTP on central and peripheral catecholamine and indoleamine concentrations in monkeys.

5 Macaca fascicularis monkeys developed a severe parkinsonian syndrome in the days following intravenous administration of the toxin MPTP. One monkey remained untreated while two groups of two animals were treated daily for 5 months with supramaximal oral doses of either Sinemet or bromocriptine. Both drugs relieved the parkinsonian symptoms. Plasma prolactin concentrations were elevated in MPTP-treated monkeys compared to intact monkeys. MPTP caused a rapid decrease of homovanillic acid (HVA) concentrations in the CSF of these monkeys within days of the toxin injection and these values remained low until sacrifice of the animals 5 months later. By contrast, CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations were elevated a few days after the start of MPTP treatment and these values returned to control levels by 5 months. Five months after the start of MPTP treatment, epinephrine (E) and dopamine (DA) levels were decreased in the adrenal medulla while the norepinephrine (NE) concentration remained unchanged. Catecholamines were assayed in the caudate putamen, nucleus accumbens, amygdala and frontal cortex of these monkeys. NE concentrations were decreased in the frontal cortex of MPTP-treated monkeys while a decrease of E concentrations after MPTP was only observed in the n. accumbens. Dopamine and its metabolites dihydroxyphenylacetic acid (DOPAC) and HVA were reduced in the caudate, putamen, n. accumbens and frontal cortex. Our results show that MPTP treatment in the long-term (5 months) not only affects the dopaminergic system of the caudate-putamen but also has effects on dopaminergic systems in other regions as well as on noradrenergic and adrenergic systems in the brain and the periphery.

A physiological dose of progesterone affects rat striatum biogenic amine metabolism.

Ovariectomized rats injected with progesterone (50 micrograms s.c.) showed a peak in striatum dopamine (DA) concentration after 15 min followed by a decrease at 60-75 min and a return to control values 90 min after the steroid injection. The DA metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased after the progesterone injection, with a peak at 45 min and a return to control values after about 2 h. Striatum serotonin (5-HT) concentrations remained unchanged after the progesterone injection while its metabolite 5-hydroxyindoleacetic acid (5-HIAA) was increased at 45 min and returned to control values after 2 h. The peak plasma progesterone concentration occurred 15-30 min after the steroid injection while estradiol concentrations were unchanged indicating no significant conversion of progesterone into estradiol. A similar experiment was performed in male rats. As with female rats, a progesterone injection led to a progesterone peak at 30 min while plasma estradiol levels remained unchanged. Male rats responded to the progesterone injection with a maximal increase of DA, DOPAC and HVA concentrations as soon as after 15 min and these amines remained elevated up to 75 min after the steroid injection. 5-HT and 5-HIAA remained unchanged after the progesterone injection. Thus, very small physiological doses of progesterone can increase striatum dopaminergic activity in rats of both sexes while serotonergic activity is influenced only in female rats. This effect is seen within minutes and is relatively short. It is probably non-genomic, presynaptic and similar to the effect of a small dose of a DA releasing agent.

Physiological doses of estradiol can increase lingual dyskinesia and cerebrospinal fluid homovanillic acid in monkeys.

In 4 ovariectomized monkeys bearing a dopamine-sensitive lingual dyskinesia due to a previous mid-brain lesion, 30 ng of 17 beta-estradiol injected subcutaneously, caused a 4-fold increase in the dyskinesia in the hour following the injection. In a separate experiment done on 7 anesthetized monkeys, the same dose of estradiol caused a significant increase of homovanillic acid in the cerebrospinal fluid obtained by cisternal puncture. The above findings suggest that very small doses of estradiol in the physiological range can increase dopaminergic transmission in the striatum via increased release.

Decreased tuberoinfundibular and pituitary dopamine and dihydroxyphenylacetic acid concentrations in rats with estrogen-induced pituitary tumors.

The majority of pituitary adenomas are prolactin (PRL)-secreting, but it is still uncertain whether their pathogenesis results from a central nervous system (CNS) disturbance or autonomous lactotroph growth and function. We have measured dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) concentrations in rats bearing estradiol-induced PRL-secreting pituitary tumors. Female rats, injected at 3-week intervals with 2 mg estradiol valerate (EV), had increased plasma prolactin concentrations, up to 3 micrograms/ml, at 31 weeks. Inversely, there was a reduction of DA and DOPAC in the median eminence and arcuate nucleus as well as a decreased DOPAC/DA ratio in the arcuate nucleus. DA-containing nuclei in the other parts of the brain were not affected. Anterior pituitary weight increased while its DA concentration decreased during estradiol treatment. In the neurohypophysis, DA concentrations were unchanged while DOPAC and the ratio DOPAC/DA decreased following the estrogen treatment. Our data suggest that rats with primary estrogen-induced PRL-secreting tumors have a defect in the CNS-DA neurotransmission.