Genetic-based interactions among tree neighbors: identification of the most influential neighbors, and estimation of correlations among direct and indirect genetic effects for leaf disease and growth in Eucalyptus globulus.

An individual's genes may influence the phenotype of neighboring conspecifics. Such indirect genetic effects (IGEs) are important as they can affect the apparent total heritable variance in a population, and thus the response to selection. We studied these effects in a large, pedigreed population of Eucalyptus globulus using variance component analyses of Mycosphearella leaf disease, diameter growth at age 2 years, and post-infection diameter growth at ages 4 and 8 years. In a novel approach, we initially modeled IGEs using a factor analytic (FA) structure to identify the most influential neighbor positions, with the FA loadings being position-specific regressions on the IGEs. This involved sequentially comparing FA models for the variance-covariance matrices of the direct and indirect effects of each neighbor. We then modeled IGEs as a distance-based, combined effect of the most influential neighbors. This often increased the magnitude and significance of indirect genetic variance estimates relative to using all neighbors. The extension of a univariate IGEs model to bivariate analyses also provided insights into the genetic architecture of this population, revealing that: (1) IGEs arising from increased probability of neighbor infection were not associated with reduced growth of neighbors, despite adverse fitness effects being evident at the direct genetic level; and (2) the strong, genetic-based competitive interactions for growth, established early in stand development, were highly positively correlated over time. Our results highlight the complexities of genetic-based interactions at the multi-trait level due to (co)variances associated with IGEs, and the marked discrepancy occurring between direct and total heritable variances.

Electric and magnetic field effects on the excitonic properties of elliptic core-multishell quantum wires.

The effect of eccentricity distortions of core-multishell quantum wires on their electron, hole and exciton states is theoretically investigated. Within the effective mass approximation, the Schrödinger equation is numerically solved for electrons and holes in systems with single and double radial heterostructures, and the exciton binding energy is calculated by means of a variational approach. We show that the energy spectrum of a core-multishell heterostructure with eccentricity distortions, as well as its magnetic field dependence, are very sensitive to the direction of an externally applied electric field, an effect that can be used to identify the eccentricity of the system. For a double heterostructure, the eccentricities of the inner and outer shells play an important role on the excitonic binding energy, especially in the presence of external magnetic fields, and lead to drastic modifications in the oscillator strength.

The effects of age and environment on the expression of inbreeding depression in Eucalyptus globulus.

Inbreeding adversely affects fitness traits in many plant and animal species, and the magnitude, stability and genetic basis of inbreeding depression (ID) will have short- and long-term evolutionary consequences. The effects of four degrees of inbreeding (selfing, f=50%; full- and half-sib matings, f=25 and 12.5%; and unrelated outcrosses, f=0%) on survival and growth of an island population of Eucalyptus globulus were studied at two sites for over 14 years. For selfs, ID in survival increased over time, reaching a maximum of 49% by age 14 years. However, their inbreeding depression for stem diameter remained relatively stable with age, and ranged from 28 to 36% across years and sites. ID for survival was markedly greater on the more productive site, possibly due to greater and earlier onset of inter-tree competition, but was similar on both sites for the diameter of survivors. The deleterious trait response to increasing inbreeding coefficients was linear for survival and diameter. Non-significant quadratic effects suggested that epistasis did not contribute considerably to the observed ID at the population level. Among- and within-family coefficients of variation for diameter increased with inbreeding degree, and the variance among the outcrossed families was significant only on the more productive site. The performance of self-families for diameter was highly stable between sites. This suggests that, for species with mixed mating systems, environmentally stable inbreeding effects in open-pollinated progenies may tend to mask the additive genotype-by-environment interaction for fitness traits and the adaptive response to the environment.

Medicines and the drug control treaties: is buprenorphine for opioid addiction at risk of being lost?

Over the past century, a worldwide system for the control of drugs with abuse potential has developed through the adoption of a series of international treaties. The important multilateral conventions currently in force are the United Nations Single Convention on Narcotic Drugs, 1961 (Single Convention), the United Nations Convention on Psychotropic Substances, 1971 (Psychotropic Convention) and the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988. From the beginning, the aim of these drug control treaties has been to control the abuse and trafficking of substances with abuse potential while assuring that the availability of these drugs for medical and scientific purposes is not unduly restricted. There is activity in the World Health Organization and the International Narcotics Control Board to determine whether the international control of buprenorphine, a partial mu-opioid agonist used as an analgesic and for the treatment of opioid addiction, should be changed from the Psychotropic Convention to the Single Convention. This change would result in the classification and regulation of buprenorphine as a narcotic drug rather than a psychotropic substance. Such a move is unwarranted medically and scientifically and would provoke increased controls on buprenorphine that would fundamentally disrupt the medical practice of pain management and opioid replacement therapy around the world. The negative impact of inappropriate regulatory controls when licensed medicines come under such scrutiny are described.

Evidence-based analysis of the worldwide abuse of licit and illicit drugs.

In order to place the issues of drug abuse in a proper perspective and to allow rational, evidence-based decision-making, an analysis of the international data on the use of illicit drugs and the misuse of legally prescribed psychotropic drugs was undertaken. The data show that by far the most widely abused drug is cannabis, followed, according to region, by amphetamine-type stimulants or cocaine. While opiate abuse is far less widespread, it accounts for a disproportionately large proportion of medical and social problems. The illicit use of licit medicines is a very small, and declining, problem. The implications of these data for physicians, politicians, regulators and administrators are discussed.

Olanzapine as alternative therapy for patients with haloperidol-induced extrapyramidal symptoms: results of a multicenter, collaborative trial in Latin America.

Conventional antipsychotic agents can induce extrapyramidal symptoms (EPS) that may be alleviated by switching patients to novel agents such as olanzapine. Patients with schizophrenia and related disorders (ICD-10) who were taking haloperidol (N = 94; mean dose = 12.7 mg/day) and had EPS (Simpson-Angus Scale [SAS] > 3) were directly switched to 6 weeks of open-label olanzapine treatment (mean dose = 11.4 mg/day). There were significant mean improvements (p <0.001 for all measurements) from baseline to endpoint on the SAS (-9.69+/-5.33; percentage change, 87.2%), the Barnes Akathisia Scale (-1.00+/-1.19; percentage change, 82.5%), and the Abnormal Involuntary Movement Scale (-1.48+/-2.89; percentage change, 81.1%), and anticholinergic use decreased from 47.9% to 12.8% (mean baseline to endpoint change: -1.52+/-1.91-mg equivalents of benztropine; p < 0.001). Significant mean baseline to endpoint improvements (p < 0.001 for all measurements) were observed on the Positive and Negative Syndrome Scale (PANSS; -25.28+/-18.67; percentage change, 30.3%), the PANSS-extracted Brief Psychiatric Rating Scale (0-6 scale, -13.41+/-10.16; percentage change, 54.4%), and the Clinical Global Impressions Severity scale (-1.16+/-1.19; percentage change, 26.4%). Spontaneously reported treatment- emergent adverse events with a greater than 5% incidence were somnolence (16.0%), increased appetite (14.9%), weight gain (11.7%), headache (8.5%), anxiety (7.4%), dizziness (6.4%), and insomnia (5.3%). Criteria for a successful switch were met by 90.5% of patients. Psychotic symptom exacerbation was experienced by 30.9% of patients at any time during the study and by 11.7% of patients at endpoint. Results suggest that a direct switch to olanzapine is a therapeutic option when patients with haloperidol-induced EPS are unable to tolerate a more gradual switch.

Efficacy and safety of tianeptine in the treatment of depressive disorders in comparison with fluoxetine*

Depression is treated by a great variety of antidepressant treatments. SSRIs (such as fluoxetine) are well known: it is, however, sure that further progress is needed and the search for antidepressants with other mechanisms of action (such as tianeptine) or different efficacy is still of interest. A multinational study compared tianeptine with fluoxetine in 387 patients with Depressive Episode, or Recurrent Depressive Disorder, or Bipolar Affective Disorder (ICD-10), in a double-blind parallel group design. They were treated for six weeks. At inclusion, no significant difference between groups was shown. Final MADRS scores were 15.7 and 15.8 with tianeptine and fluoxetine, respectively (ITT population) (p = 0.944). MADRS responders were 58% and 56% with tianeptine and fluoxetine, respectively (p = 0.710). No statistical difference was observed for the other efficacy parameters. Thirty-six withdrawals occurred in each group, without any difference for the reasons of discontinuation. There was no major difference between groups for the other safety parameters. In this study, both tianeptine and fluoxetine exhibited a good efficacy and safety. Copyright 1999 Elsevier Science B. V. All rights reserved.

Sleep and cognitive (memory) function: research and clinical perspectives.

The field of memory and sleep is controversial and extremely interesting, and the relationships between thought processes, i.e. cognition and sleep, have recently been examined in a variety of clinical and basic research settings, as well as being the object of intense interest by the general public. For example, there are data which demonstrate that insomnia, as well as specific sleep disorders, can have a negative impact on sleep cognition as well as affect daytime patterns of cognitive functioning. Thus, sleep, disturbed sleep and the lack of sleep appear to affect cognitive and memory functions. An International Workshop dealing with Sleep and Cognitive Function: Research and Clinical Perspectives was convened in Cancún, Mexico, 1-4 March 1999 under the auspices of the World Health Organization Worldwide Project on Sleep and Health and the World Federation of Sleep Research Societies. A great number of areas of intersection between sleep and cognitive function were examined during the course of the Workshop, such as aging, cognition and sleep and the dream process and sleep. The results of these discussions are included in a WHO publication (WHO Doc.: MSD/MBD/00.8). In the present report we concentrate on presenting a summary of a coherent set of data which examine memory consolidation during sleep and the impact of insomnia on cognitive functions. Based upon these data, a review of memory and drug effects that are sleep-related, and an examination of the relationship between hypnotics and cognitive function are included. Finally, a summary of recommendations of the Workshop participants is presented.

Sleep and health: research and clinical perspectives.

Overall, the Workshop covered most of the principal areas which will be the focus of the Worldwide Project on Sleep and Health. Presentations ranged from the basic science of melatonin receptors to the epidemiology of untreated insomnia, and finally, to the education of primary care physicians. It was emphasized that there is a need for more data, and new experimental paradigms are necessary for successful public health initiatives dealing with sleep disorders.

Experimental treatment with sodium stibogluconate of hamsters infected with Leishmania (Leishmania) chagasi and Leishmania (Leishmania) amazonensis.

The present paper reports the experimental treatment of hamsters infected with Leishmania chagasi and Leishmania amazonensis with sodium stibogluconate (20 mg/kg/day x 20 days). Only with L. chagasi did the treatment result in the complete elimination of parasites from the spleen. However, no parasitological cure was achieved in hamsters infected with L. amazonensis.

The public health impact of anxiety disorders: a WHO perspective.

Anxiety disorders, which may constitute anywhere from one quarter to one half of all mental illnesses in the community, are most commonly seen in the primary care sector. Despite their significant impact on the functioning of individual patients, the plethora of unnecessary medical procedures to which these sufferers are subjected, and the large indirect economic burden, these disorders continue to be grossly underdiagnosed and undertreated in this sector. Effective treatments for anxiety disorders have been available for at least two decades. Concerted efforts by the World Health Organization (WHO), the World Psychiatric Association and similar organizations are needed to change this picture.

Randomized, double-blind comparison of venlafaxine and fluoxetine in outpatients with major depression.

BACKGROUND: This was an 8-week, multicenter, randomized, double-blind, parallel-group study of the efficacy and tolerability of venlafaxine and fluoxetine. METHOD: Outpatients with DSM-III-R major depression, a minimum score of 20 on the 21-item Hamilton Rating Scale for Depression (HAM-D), and depressive symptoms for at least 1 month were eligible. Patients were randomly assigned to treatment with venlafaxine, 37.5 mg twice daily, or fluoxetine, 20 mg once daily. The dose could be increased to venlafaxine, 75 mg twice daily, or fluoxetine, 20 mg twice daily, after 3 weeks for a poor response. The primary efficacy variables were the final on-therapy scores on the HAM-D, Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impressions Severity of Illness (CGI-S) and Improvement (CGI-I) scales. RESULTS: Three hundred eighty-two patients were randomly assigned to therapy and included in the intent-to-treat analysis. Both venlafaxine and fluoxetine produced significant reductions from baseline to day 56 in mean HAM-D, MADRS, and CGI-S scores, but no significant differences were noted between groups. Among patients who increased their dose at 3 weeks, significantly (p < .05) more patients taking venlafaxine than taking fluoxetine had a CGI-I score of 1 (very much improved) at the final evaluation. The most frequent adverse events were nausea, headache, and dizziness with venlafaxine and nausea, headache, and insomnia with fluoxetine. CONCLUSION: These results support the efficacy and tolerability of venlafaxine in comparison with fluoxetine for treating outpatients with major depression.

Placebo-controlled study of tianeptine in major depressive episodes.

The efficacy and safety of tianeptine were compared, in the course of a multicentre randomised, double-blind, parallel group study, to those of placebo in the treatment of Major Depressions and Bipolar Disorder, Depressed with or without melancholia, without psychotic features. After a 1-week run-in placebo period, 126 depressed out-patients presenting DSM-III-R Major Depression or Bipolar Disorder, Depressed, with a total MADRS score of at least 25, were treated for 42 days with either tianeptine (25-50 mg/day) or placebo. Efficacy assessments were MADRS, CGI, HARS, Zung Depression Self Rating Scale and a VAS. Better efficacy of tianeptine was shown, and confirmed by covariance analyses, in final MADRS scores of the intention-to-treat population, of patients treated for at least 14 days and of completers; also in CGI items 1 and 2, MADRS item 10, and VAS. The results confirmed the efficacy of tianeptine (mean dosage: 37.5 mg/day) in the treatment of Major Depression and Bipolar Disorder, Depressed, with or without melancholia, compared to placebo. Tianeptine's acceptability did not differ from that of placebo. For adverse events, a higher incidence of headaches was found with tianeptine.

The World Health Organization's global initiative on neurology and public health.

In 1993, the World Health Organization launched a global initiative aimed at increasing public and professional awareness of the public health aspects of neurological disorders. The initial phase of this project has been carried out through the organization of a series of symposia on prevalence, severity and costs of neurological disorders including dementia, stroke, epilepsy and headache. The main objective of the next phase of the project is to develop an international educational programme on neurology and public health and to establish a network of training centres in different regions of the world.

Dysthymia in neurological disorders.

Dysthymia is characterized by long-lasting periods of lowered mood. Epidemiological studies in the USA and Europe have demonstrated that the prevalence of dysthymia is at least 3% of the general population. Its pervasive occurrence makes dysthymia a public health problem worldwide. One feature of this disorder is its co-occurrence with medical and neurological disorders. A World Health Organization meeting on dysthymia in neurological disorders was held in Geneva, 1-3 July 1996 to address this topic. Some of the major goals of this meeting were to clarify the definition of dysthymia in the presence of neurological disorders and to evaluate current research in the field, to point out new areas for investigation, and to discuss current psychological and pharmacological treatments for dysthymia in neurological disorders. The potential roles of neuroendocrine and molecular mechanisms in dysthymia were identified through specific problems related to dysthymia occurring in disorders such as Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis and epilepsy. This meeting provided direction and opportunity for future studies in the under-recognized and under-investigated relationship between dysthymia and neurological disorders.