Comparison of the effects of zolpidem and zopiclone on nocturnal sleep and sleep latency in the morning: a cross-over study in healthy young volunteers

Zolpidem (ZOL) and zopiclone (ZPC) are non-benzodiazepine hypnotics, with unique effects on sleep architecture compared with conventional benzodiazepines. The two compounds have different profiles in action to two major subtypes of the GABA-A receptors, therefore different effects on sleep structure may be expected. In the present study, the effects of ZOL (10mg) and ZPC (7.5mg) were compared in nine healthy young male subjects during nine-night sessions, employing a crossover design. Time courses during the sessions were significantly different between the compounds in the ratio (%) of S2 and S1. Compared to the baseline, an increase of S2 and a decrease of S1 and SR were caused by ZPC, not by ZOL. SWS was increased by both ZPC and ZOL. Significant changes by ZOL were found during the first 150-min, while changes by ZPC were mostly observed during the second 150-min. This might be related to their half-lives. ZOL did not affect sleep latency in the morning, while ZPC caused a significant decrease. Subjective sleepiness, however, was not increased in the ZPC or ZOL mornings. It was speculated that difference in the action to the GABA-A receptor subtypes might be related to the differences in the effects on the sleep architecture between the compounds.     

Brainstem structures responsible for paradoxical sleep onset and maintenance

This paper is dedicated to our mentor, Michel Jouvet who inspired our career and transmitted to us his passion for the study of the mechanisms responsible for paradoxical sleep genesis and also that of its still mysterious functions. We expose in the following the progresses in the knowledge in this field brought during 40 years by Michel Jouvet and his team and more recently by the members of a new CNRS laboratory in which we aim to pursue in the path opened by Michel Jouvet.     

Tolerance rendered by neonatal treatment with anti-idiotypic antibodies: induction and maintenance in athymic mice

Congenitally athymic (nude) mice of BALB/c background and their littermates were rendered unresponsive to the phosphorylcholine (PC) determinant by neonatal injection of anti-idiotypic antibodies. The kinetics of recovery from unresponsiveness were found to be similar for both groups when measured over a 20-week period. Spleen cells from suppressed, athymic mice did not respond to PC and were able to inhibit the response of normal cells to PC when tested in vitro. These results indicated that a population of specific suppressor cells, which may be responsible for induction and/or maintenance of unresponsiveness, can be generated in the absence of a thymic environment.     

Trypanosoma cruzi: requirements for induction and maintenance of protective immunity conferred by immunization

Immunization with CL-14-trypomastigotes generates efficient humoral and cellular responses against infective challenge. Herein, we investigated the relevance of these mechanisms in vivo. Immunization with live CL-14-trypomastigotes protected only part of beta2m(-/-) mice but efficiently protected perforin-knockout mice. Fixed CL-14-trypomastigotes could successfully immunize BALB/c, though live trypomastigotes lowered the requirements for doses and time intervals. Post-immune depletion of CD4 or CD8 subsets did not affect protection conferred by immunization, but switched the production of anti-Trypanosoma cruzi antibodies to IgG2a. Sublethal irradiation partially broke the resistance of immune mice, leading to development of late parasitemia. Passive serum transfer from immune mice conferred protection to nai;ve mice. Our results indicate that presentation of cytosolic antigens by MHC class I molecules is involved in the generation of immunity and suggest that the humoral response contributes to a great extent to keep CL-14-immunized mice protected against infective challenge.     

Comparison of escitalopram alone and combined with zolpidem in treating major depression and related sleep impairments

Escitalopram has been shown to be effective for treating major depression (MDD); however, research is lacking regarding its effect on treating MDD-related sleep impairments. The purpose of this study was to assess the efficacy of escitalopram monotherapy and investigate changes in insomnia, depressive symptoms, and quality of life (QOL). Participants were 14 patients with MDD who enrolled in a clinical trial at Jikei University Katsushika Medical Center. Escitalopram monotherapy was used, and hypnotics were administered three times per week for individuals suffering from sleep impairments. The following variables were assessed: (1) sleep quality [Pittsburgh sleep quality index (PSQI)], (2) depression [Zung self-rating depression scale (ZSRDS)], and (3) quality of life (QOL) as determined by the Sheehan disability scale (SDISS) and short form (36) health survey (SF-36). These assessments were conducted prior to any treatment (pre-test) and again 8–12 weeks after treatment (post-test). Monotherapy (E = escitalopram alone; n = 6) and combination therapy (E+ = escitalopram + zolpidem; n = 8) groups were compared. All participants completed the full protocol (average 9.4 ± 1.8 weeks). Regardless of treatment group, participants improved on all assessments (including sleep impairment). However, groups did not differ in their level of improvement. A two-factor ANOVA revealed that the E+ group showed particular improvements in QOL. In treating MDD and associated sleep impairments, zolpidem did not confer additional benefits. Thus, clinicians should consider E monotherapy for patients with MDD-related sleep impairments before prescribing combination therapies.

     

Callus induction and maintenance of Zea mays kernels

Summary Totipotent tissue cultures of maize (Zea mays L.) have previously been initiated from various explant tissues. In this paper, we present an alternative source of callus induction.A callus of maize (G 204 hybrid) was obtained from intact kernels grown on Linsmair and Skoog RM medium supplemented with 20 mg 2,4-dichlorphenoxyacetic acid (2,4-D) per litre. The callus growth was greatest from the first node of the seedling shoot. Occasionally, callus growth was observed from the radicle and coleopticle regions. The callus was easily transferred and maintained on a medium with 2 mg/L 2,4-D. This callus formed numerous roots and leaf-like structures when grown on a medium containing 800 mg/L yeast extract, 30 g/L sucrose and 10 g/L agar.     

Autophagy induction for the treatment of cancer

Cancer can be viewed in 2 rather distinct ways, namely (i) as a cell-autonomous disease in which malignant cells have escaped control from cell-intrinsic barriers against proliferation and dissemination or (ii) as a systemic disease that involves failing immune control of aberrant cells. Since macroautophagy/autophagy generally increases the fitness of cells as well as their resistance against endogenous or iatrogenic (i.e., relating to illness due to medical intervention) stress, it has been widely proposed that inhibition of autophagy would constitute a valid strategy for sensitizing cancer cells to chemotherapy or radiotherapy. Colliding with this cell-autonomous vision, however, we found that immunosurveillance against transplantable, carcinogen-induced or genetically engineered cancers can be improved by pharmacologically inducing autophagy with caloric restriction mimetics. This positive effect depends on autophagy induction in cancer cells and is mediated by alterations in extracellular ATP metabolism, namely increased release of immunostimulatory ATP and reduced adenosine-dependent recruitment of immunosuppressive regulatory T cells into the tumor bed. The combination of autophagy inducers and chemotherapeutic agents is particularly efficient in reducing cancer growth through the stimulation of CD8⁺ T lymphocyte-dependent anticancer immune responses.     

Transcriptional activation by Oct4 is sufficient for the maintenance and induction of pluripotency

Oct4 is an essential regulator of pluripotency in vivo and in vitro in embryonic stem cells, as well as a key mediator of the reprogramming of somatic cells into induced pluripotent stem cells. It is not known whether activation and/or repression of specific genes by Oct4 is relevant to these functions. Here, we show that fusion proteins containing the coding sequence of Oct4 or Xlpou91 (the Xenopus homolog of Oct4) fused to activating regions, but not those fused to repressing regions, behave as Oct4, suppressing differentiation and promoting maintenance of undifferentiated phenotypes in vivo and in vitro. An Oct4 activation domain fusion supported embryonic stem cell self-renewal in vitro at lower concentrations than that required for Oct4 while alleviating the ordinary requirement for the cytokine LIF. At still lower levels of the fusion, LIF dependence was restored. We conclude that the necessary and sufficient function of Oct4 in promoting pluripotency is to activate specific target genes.     

Shift work and depressive symptoms: the mediating effect of vitamin D and sleep quality

Shift work is associated with vitamin D level, sleep quality, and depressive symptoms. Vitamin D and sleep quality are also associated with depressive symptoms. The purpose of this study was to compare vitamin D level, sleep quality, and depressive symptoms between shift workers and daytime workers and analyze the mediating effect of vitamin D and sleep quality between shift work and depressive symptoms. Among those who participated in the Kangbuk Samsung Health Study in 2012 and 2014, 82,078 cases of full-time workers were analyzed. We evaluated their shift work, vitamin D level, sleep quality, and depressive symptoms with blood samples and questionnaires. Chi-square tests, t-tests, and path statistical analysis were performed. More depressive symptoms, lower vitamin D levels, and poorer sleep quality were associated with shift work. According to a path analysis, shift work had both a direct effect and an indirect effect on depressive symptoms, each mediated by sleep quality and vitamin D level. When a multigroup analysis was conducted for each sex, paths containing sleep quality were more significant in female shift workers than male shift workers; paths involving vitamin D did not differ between sexes. To assess depression risk in shift workers, evaluating vitamin D level and sleep quality is essential. Also, sleep problems are more prevalent in female compared to male shift workers with respect depression prevalence.     

Nocturnal profile of growth hormone secretion during sleep induced by zolpidem: a double-blind study in young adults and children

Overnight blood sampling for repeated growth hormone (GH) assays, regarded as the most physiological assessment of GH status, may induce some disturbances in patients' sleep and then in the evaluation of GH secretion. We studied the influence of a hypnotic drug, zolpidem (10 mg), on nocturnal GH profiles (GH peak, time to first and maximum GH peak, area under the curve, mean integrated concentration) over two nights at a 7-day interval, in a double-blind cross-over design in a group of 12 young adult volunteers (27.9 +/- 4.3 years), and in a group of 12 children (10.8 +/- 2.3 years) with short stature, in a parallel double-blind study. Mean GH profiles showed no difference between zolpidem-treated subjects and placebo-treated controls, either in adults or in children. Although in these experimental conditions, sleep onset latency was significantly reduced with zolpidem in the adult volunteers, the mean time to first GH peak remained unchanged. Furthermore, GH profile did not relate with sleep duration, sleep onset latency or number of awakenings. A hypnotic drug, such as zolpidem, given at bedtime, is therefore devoided of effect on nocturnal GH profile and may be used in young children for overnight blood sampling when needed.     

Flexible induction dose regimen for warfarin and prediction of maintenance dose.

Fifty patients with venous thromboembolic disease being treated by heparin infusion received a three day warfarin induction regimen tailored according to the prothrombin time (British comparative ratio) measured on days 2 and 3. A prediction of the final maintenance dose of warfarin was made on the basis of a prothrombin time measured on day 4. All patients were safely anticoagulated by day 6, and the prediction was accurate to within 1 mg in 46 patients. Predicted and actual maintenance doses were closely related (r = 0.867; n = 50; p less than 0.001). This scheme should prove helpful in the control of anticoagulation, particularly in patients likely to be sensitive to warfarin, and should shorten hospital stay.     

Mechanisms underlying induction and maintenance of long-term potentiation in the hippocampus

Long-term potentiation (LTP) in the hippocampus is accompanied by a number of changes on both sides of the synapse. It is now generally considered that the trigger for initiating LTP is the entry of calcium into the postsynaptic area through the NMDA-associated channel while the mechanism(s) underlying the maintenance of LTP are less well understood and probably involve contributions from both sides of the synapse.     

Self-guided psychological treatment for depressive symptoms: a meta-analysis

Background

A number of trials have examined the effects of self-guided psychological intervention, without any contact between the participants and a therapist or coach. The results and sizes of these trials have been mixed. This is the first quantitative meta-analysis, aimed at organizing and evaluating the literature, and estimating effect size.

Method

We conducted systematic literature searches in PubMed, PsycINFO and Embase up to January 2010, and identified additional studies through earlier meta-analyses, and the references of included studies. We identified seven randomized controlled trials that met our inclusion criteria, with a total of 1,362 respondents. The overall quality of the studies was high. A post-hoc power calculation showed that the studies had sufficient statistical power to detect an effect size of d = 0.19.

Results

The overall mean effect size indicating the difference between self-guided psychological treatment and control groups at post-test was d = 0.28 (p<0.001), which corresponds to a NNT of 6.41. At 4 to 12 months follow-up the effect size was d = 0.23. There was no indication for significant publication bias.

Conclusions

We found evidence that self-guided psychological treatment has a small but significant effect on participants with increased levels of depressive symptomatology.     

Sleep and dreaming: induction and mediation of REM sleep by cholinergic mechanisms

The most important recent work on the neurobiology of sleep has focused on the precise cellular and biochemical mechanisms of rapid eye movement sleep mediation. Direct and indirect evidence implicates acetylcholine-containing neurons in the peribrachial pons as critical in the triggering and maintenance of rapid eye movement sleep. Other new studies provide support for the hypothesis that the cholinergic generator system is gated during waking by serotonergic and noradrenergic influences. A growing consensus regarding the basic neurobiology has stimulated new thinking about the brain basis of consciousness during waking and dreaming.     

amnesiac regulates sleep onset and maintenance in Drosophila melanogaster

The adenylate cyclase/cAMP signaling pathway and adult mushroom bodies (MBs) have been shown to play an important role in sleep regulation in Drosophila. The amnesiac (amn) gene, encodes a neuropeptide that is homologous with vertebrate pituitary adenylate cyclase-activating peptide (PACAP), is expressed in dorsal paired medial (DPM) neurons and is required for the middle-term memory (MTM) in flies. However, the role of amn on regulation of sleep is as yet unknown. Here we provide evidence that amn plays a major role on sleep maintenance and onset in Drosophila. Flies with the amnesiac allele, loss-of-function amn^X8 mutation, showed a fragmented sleep pattern and short sleep latency. Moreover, homeostatic regulation was disrupted in amn^X8 mutants after sleep deprivation. Sleep maintenance was also influenced by disruption of neurotransmission in DPM neurons with increased sleep bout number and decreased sleep bout length. Furthermore, age-related sleep fragmentation and initiation were inhibited in amn^X8 mutant flies. These data suggest that amn is required in initiation and maintenance of sleep.