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Abstract Hops are a major component of beer that is added during brewing. In addition to its wide range of bioactivity, it exhibits neuroactive properties as a sedative and sleeping aid. The compounds responsible for this activity are yet to be revealed and understood in terms of their pharmacological properties. Here we evaluated the potential of several hops flavonoids in modulating the GABAergic activity and assessed their selectivity to GABA A receptors subtypes. GABA-potentiating effects were measured using [3H]ethynylbicycloorthobenzoate (EBOB) radioligand binding assay in native and recombinant α1β3γ2, α2β3γ2 and α6β3δ receptors expressed in HEK293 cells. Flumazenil sensitivity of GABA-potentiating effects and [3H]Ro 15-4513 binding assay were used to examine the flavonoids binding to benzodiazepine site. The prenylflavonoids xanthohumol (XN), isoxanthohumol (IXN) and 8-prenylnaringenin (8PN) potentiated GABA-induced displacement of [3H]EBOB binding in a concentration-dependent manner. The IC 50 for this potentiation in native GABA A receptors were 29.7 µM, 11.6 µM, 7.3 µM, respectively. In recombinant receptors, the sensitivity to prenylflavonoid potentiation of GABA-induced displacement of [3H]EBOB binding followed the order α6β3δ > α2β3γ2 > α1β3γ2 with the strongest inhibition observed by 8PN in α6β3δ (IC 50 = 3.6 μM). Flumazenil had no significant effect on the prenylflavonoid-induced displacement of [3H]EBOB binding and [3H]Ro 15-4513 displacement from native GABA A receptors was only detected at high micromolar concentrations (100 µM). We identified potent prenylflavonoids in hops that positively modulate GABA-induced responses in native and αβγ/δ recombinant GABA A receptors at low micromolar concentrations. These GABAergic modulatory effects were not mediated via the high-affinity benzodiazepine binding site. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association between fertility history and cognition in older men and women. Method: We analyzed associations between number of children (parity) and timing of births with level and change in cog- nition among 11,233 men and women aged 50+ in England using latent growth curve models. Models were adjusted for age, socioeconomic position, health, depressive symptoms, control, social contacts, activities, and isolation. Results: Low (0-1 child) and high parity (3+ children) compared to medium parity (2 children) were associated with poorer cognitive functioning, as was an early age at entry to parenthood (<20 women/23 men). Many of these associations disappeared when socioeconomic position and health were controlled. For women, however, adjusting for socioeconomic position and social contacts strengthened the association between childlessness and poor cognition. Late motherhood (>35) was associated with better cognitive function. Conclusion: Associations between fertility history and cognition were to large extent accounted for socioeconomic position, partly because this influenced health and social engagement. Poorer cognition in childless people and better cognition among mothers experiencing child birth at higher ages suggest factors related to childbearing/rearing that are beneficial for later cognitive functioning, although further research into possible earlier selection factors is needed. [ABSTRACT FROM AUTHOR]

Dynamic combinatorial chemistry has emerged as a promising tool for the discovery of complex receptors in supramolecular chemistry. At the heart of dynamic combinatorial chemistry are the reversible reactions that enable the exchange of building blocks between library members in dynamic combinatorial libraries (DCLs) ensuring thermodynamic control over the system. If more than one reversible reaction operates in a single dynamic combinatorial library, the complexity of the system increases dramatically, and so does its possible applications. One can imagine two reversible reactions that operate simultaneously or two reversible reactions that operate independently. Both these scenarios have advantages and disadvantages. In this contribution, we show how disulfide exchange and boronic ester transesterification can function simultaneous in dynamic combinatorial libraries under appropriate conditions. We describe the detailed studies necessary to establish suitable reaction conditions and highlight the analytical techniques appropriate to study this type of system. [ABSTRACT FROM AUTHOR]

The efficacy of the Neuman systems model as a guiding framework for curriculum development of a baccalaureate program is examined. Insights from lessons learned provide directions for nursing theory-based curriculum change and program development. Challenges and opportunities during curriculum development are explored. Recommendations and strategies that contribute to consensus building are reported. [ABSTRACT FROM AUTHOR]

Abstract: The preparation of hippocampal slices results in loss of input neurons to dentate granule cells, which leads to the reorganization of their axons, the mossy fibers, and alters their functional properties in long-term cultures, but its temporal aspects in the immature hippocampus are not known. In this study, we have focused on the early phase of this plastic reorganization process by analyzing granule cell function with field potential and whole cell recordings during the in vitro maturation of hippocampal slices (from 1 to 17 days in vitro, prepared from 6 to 7-day-old rats), and their morphology using extracellular biocytin labelling technique. Acute slices from postnatal 14–22-day-old rats were analyzed to detect any differences in the functional properties of granule cells in these two preparations. In field potential recordings, small synaptically-evoked responses were detected at 2 days in vitro, and their amplitude increased during the culture time. Whole cell voltage clamp recordings revealed intensive spontaneous excitatory postsynaptic currents, and the susceptibility to stimulus-evoked bursting increased with culture time. In acutely prepared slices, neither synaptically-evoked responses in field potential recordings nor any bursting in whole cell recordings were detected. The excitatory activity was under the inhibitory control of γ-aminobutyric acid type A receptor. Extracellularily applied biocytin labelled dentate granule cells, and revealed sprouting and aberrant targeting of mossy fibers in cultured slices. Our results suggest that reorganization of granule cell axons takes place during the early in vitro maturation of hippocampal slices, and contributes to their increased excitatory activity resembling that in the epileptic hippocampus. Cultured immature hippocampal slices could thus serve as an additional in vitro model to elucidate mechanisms of synaptic plasticity and cellular reactivity in response to external damage in the developing hippocampus. [Copyright &y& Elsevier]

It has been suggested that opioid peptides play a role in the reinforcing effects of alcohol. The present study was designed to examine the function of the μ-opioid receptor system in rat lines selectively bred for alcohol preference (AA [Alko, Alcohol] rat line) and alcohol avoidance (ANA [Alko, Non-Alcohol] rat line). The functional coupling of μ-opioid receptors to G proteins was determined autoradiographically using Tyr-d-Ala-Gly-N(Me)Phe-Gly-ol-enkephalin-stimulated [35S]GTPγS binding in brain cryostat sections. The binding was significantly increased in the striatal patches and substantia nigra reticulata of the AA rats in comparison with that of the ANA rats. Within the AA rat line, there was a significant positive correlation between 3 mg/kg morphine-induced locomotor activity and activation of G-proteins in the substantia nigra compacta and nucleus accumbens core. These results of the selective breeding experiment suggest that brain region-specific differences in μ-opioid receptor function may correlate with innate differences in alcohol preference. [Copyright &y& Elsevier]

The unique pharmacological properties of δ-containing γ-aminobutyric acid type A receptors (δ-GABAARs) make them an attractive target for selective and persistent modulation of neuronal excitability. However, the availability of selective modulators targeting δ-GABAARs remains limited. AA29504 ([2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester), an analog of K+ channel opener retigabine, acts as an agonist and a positive allosteric modulator (Ago-PAM) of δ-GABAARs. Based on electrophysiological studies using recombinant receptors, AA29504 was found to be a more potent and effective agonist in δ-GABAARs than in γ2-GABAARs. In comparison, AA29504 positively modulated the activity of recombinant δ-GABAARs more effectively than γ2-GABAARs, with no significant differences in potency. The impact of AA29504's efficacy- and potency-associated GABAAR subtype selectivity on radioligand binding properties remain unexplored. Using [3H]4'-ethynyl-4-n-propylbicycloorthobenzoate ([3H]EBOB) binding assay, we found no difference in the modulatory potency of AA29504 on GABA- and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol)-induced responses between native forebrain GABAARs of wild type and δ knock-out mice. In recombinant receptors expressed in HEK293 cells, AA29504 showed higher efficacy on δ- than γ2-GABAARs in the GABA-independent displacement of [3H]EBOB binding. Interestingly, AA29504 showed a concentration-dependent stimulation of [3H]muscimol binding to γ2-GABAARs, which was absent in δ-GABAARs. This was explained by AA29504 shifting the low-affinity γ2-GABAAR towards a higher affinity desensitized state, thereby rising new sites capable of binding GABAAR agonists with low nanomolar affinity. Hence, the potential of AA29504 to act as a desensitization-modifying allosteric modulator of γ2-GABAARs deserves further investigation for its promising influence on shaping efficacy, duration and plasticity of GABAAR synaptic responses. [ABSTRACT FROM AUTHOR]

Drunkorexia, limiting food intake before alcohol consumption, increases teenagers and young adults’ risk for negative alcohol-related health consequences. The purpose of the present study is to explore gender and age differences regarding weight management behaviors and alcohol consumption among 3004 students aged 13 to 24 years. The following questionnaires were administered: Eating Disorder Inventory-3 (EDI-3), Alcohol Use Disorders Identification Test (AUDIT) and Compensatory Eating and Behaviors in Response to Alcohol Consumption Scale (CEBRACS). EDI-3 showed that 11.3% of the sample met the threshold on the “Drive for Thinness” (DT) scale, 28.9% on the “Bulimia” (B) scale, 17.2% on the “Body Dissatisfaction” (BD) scale. Females presented a higher risk at DT, B and BD scales ( P < 0.001), and the risk of bulimia was higher in those aged ≤ 16 years ( P = 0.028). AUDIT revealed a greater clinical risk of alcohol-related problems in males ( P < 0.001) and in those aged > 16 years ( P < 0.001). Drunkorexia was found in 44% of the sample, without significant difference in relation to gender and age. Girls and younger students have more weight concerns, while boys and older students are at greater risk of alcohol use disorders. Therefore, no specific group should be considered risk-free with respect to drunkorexia. [ABSTRACT FROM AUTHOR]

Abstract: Prenatal stress has been associated with a variety of alterations in the offspring. The presented observations suggest that rather than causing changes in the offspring per se, prenatal stress may increase the organism''s vulnerability to aversive life events. Offspring of rat dams stressed gestationally by chronic mild stress (CMS, a variable schedule of different stressors) or dexamethasone (DEX, a synthetic glucocorticoid, i.e., a pharmacological stressor) was tested for reactivity by testing their acoustic startle response (ASR). Two subsets of offspring were tested. One was experimentally naïve at the time of ASR testing, whereas the other had been through blood sampling for assessment of the hormonal stress response to restraint, 3 months previously. Both prenatal CMS and dexamethasone increased ASR in the offspring compared to controls, but only in prenatally stressed offspring that had been blood sampled 3 months previously. In conclusion, similarity of the effects of maternal gestational exposure to a regular stress schedule and of exposure to a synthetic glucocorticoid suggests that maternal glucocorticoids may be a determining factor for changes in the regulatory mechanisms of the acoustic startle response. Further, a single aversive life event showed capable of changing the reactivity of prenatally stressed offspring, whereas offspring of dams going through a less stressful gestation was largely unaffected by this event. This suggests that circumstances dating back to the very beginning of life affect the individual''s sensitivity towards experiences in life after birth. The prenatal environment may thus form part of the explanation of the considerable individual variation in the development of psychopathology. [Copyright &y& Elsevier]

Muscimol, the major psychoactive ingredient in the mushroom Amanita muscaria, has been regarded as a universal non‐selective GABA‐site agonist. Deletion of the GABAA receptor (GABAAR) δ subunit in mice (δKO) leads to a drastic reduction in high‐affinity muscimol binding in brain sections and to a lower behavioral sensitivity to muscimol than their wild type counterparts. Here, we use forebrain and cerebellar brain homogenates from WT and δKO mice to show that deletion of the δ subunit leads to a > 50% loss of high‐affinity 5 nM [3H]muscimol‐binding sites despite the relatively low abundance of δ‐containing GABAARs (δ‐GABAAR) in the brain. By subtracting residual high‐affinity binding in δKO mice and measuring the slow association and dissociation rates we show that native δ‐GABAARs in WT mice exhibit high‐affinity [3H]muscimol‐binding sites (KD ~1.6 nM on α4βδ receptors in the forebrain and ~1 nM on α6βδ receptors in the cerebellum at 22°C). Co‐expression of the δ subunit with α6 and β2 or β3 in recombinant (HEK 293) expression leads to the appearance of a slowly dissociating [3H]muscimol component. In addition, we compared muscimol currents in recombinant α4β3δ and α4β3 receptors and show that δ subunit co‐expression leads to highly muscimol‐sensitive currents with an estimated EC50 of around 1–2 nM and slow deactivation kinetics. These data indicate that δ subunit incorporation leads to a dramatic increase in GABAAR muscimol sensitivity. We conclude that biochemical and behavioral low‐dose muscimol selectivity for δ‐subunit‐containing receptors is a result of low nanomolar‐binding affinity on δ‐GABAARs. Muscimol has been regarded as a universal non‐selective GABA‐site agonist. Here, we show that δ subunit incorporation leads to a dramatic increase in GABAA receptor (GABAAR) muscimol sensitivity. The biochemical and behavioral low‐dose muscimol selectivity for δ subunit‐containing receptors was because of low nanomolar‐binding affinity on α4/6βδ GABAARs. This paints a consistent picture in which extrasynaptic δ‐GABAARs are not only exquisitely sensitive to GABA, but also the GABA analogs gaboxadol and muscimol. [ABSTRACT FROM AUTHOR]

Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with improved pharmacological properties in vivo . Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used for this purpose. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties. [ABSTRACT FROM AUTHOR]

The reliability of a post-IR elevated temperature IRSL (290 °C; pIRIR 290 ) is tested on wind-blown, sand-sized (180–250 μm) K-rich feldspar grains. The pIRIR 290 ages were compared with quartz SAR-OSL data, other independent age controls and historical information. Three study areas along the coast of Sardinia (Italy) were selected: the south Alghero coast, the Bue Marino cave (E Sardinia) and the Alghero bay (NW Sardinia). Along the south Alghero coastline a thick dunefield system is widely recognised in the literature to represent the beginning of the last glacial phase ( post 80 ka). From a single block sand-sized grains for quartz SAR-OSL and K-feldspar pIRIR dating were collected. The natural quartz SAR-OSL sample lies below the saturation limit of the dose response curve (D e < 2xD 0 ) giving a reliable age of 76 ± 6 ka. The fading-uncorrected pIRIR 290 age of 73 ± 5 ka is in good agreement with the quartz result. A further test on older samples was carried out on the sedimentary succession at Bue Marino cave, which includes a sandy wind-blown unit, enclosed between two calcareous crusts. U-series dates of crusts constrain the aeolianite formation between ∼130 and ∼86 ka. The quartz SAR-OSL signals for aeolianite samples lies close to saturation and the resulting ages underestimate the independent age control. Instead, uncorrected pIRIR 290 ages on K-feldspar extracts point to a formation of the wind-blown unit between ∼100 and ∼80 ka, in good agreement with the U-series data. The bleachability of the pIRIR 290 signal was further investigated using samples from a modern coastal barrier system backing the Alghero bay. The dunefield was stabilized by plantation during the 1950s. The quartz SAR-OSL ages span from 2450 ± 170 years to 60 ± 13 years ago, consistent with the known coastal barrier stabilization. The pIRIR 290 ages indicate an offset up to ∼1000 years. We can conclude that the pIRIR 290 method on sand-sized K-feldspar grains shows great promise for samples at or beyond the quartz OSL age limit but should not be applied to Late Holocene or modern deposits. [ABSTRACT FROM AUTHOR]

Introduction: As many studies suggest, schizophrenic spectrum disorders outcome is linked with the duration of untreated first-episode psychosis; the longer is the gap between the onset of the disease and the first medical treatement the worst is the outcome. Cognitive impairment is one of the major predictor of poor outcome. Objective: We study if there is a correlation between a long duration of untreated first-episode psychosis and cognitive impairment in the long term outcome. Methods: Our sample consisted of 41 subjects (27M and 14 F) with a mean age of 48.6 years (SD=11.91) with a mean age of onset of 23.4 years (SD=7.68) and a mean duration of illness of 22.1 years (SD=14.8) who has been diagnosed schizophrenic according to DSM-IV TR through the SCID-I and evaluated with the Wechsler Adult Intelligence Scale (WAIS) to study neuro-cognitive profile. Results: A long duration of untreated psychosis is associated with redution in the performance scale of association symbols to number (p=0.04) and performance IQ (p=0.04) regardless of the duration of illness. Conclusion: This study confirms an association between long duration of untreated psychosis and cognitive deterioration. The reduced performance suggest a deficit in memory, attention and concentration, speed of performance, coordination,skill and non verbal ability in the sample with the longer DUI. [ABSTRACT FROM AUTHOR]

Introduction: The duration of untreated psychosis (DUP) is the time between the onset of symptoms and first psychiatric drug treatment. A large number of studies show that this time stretch is largely variable and often very long, lasting several months or even years and is associated with a worse outcome. Materials and methods: This retrospective study is based on an analysis of medical records, standardized format AMDP, used at the Psychiatric Clinic of the University of Cagliari. The sample consisted of 184 patients (M=57.1%, F=42.4%) with an history of a psychotic onset regardless of the diagnosis made. We have collected data on the duration of untreated psychosis (DUP), number of relapse, number of hospitalizations, number of suicide attempts, disease duration, have been considered as course and outcome variables. Conclusions: The duration of untreated psychosis is associated with an increased number of hospitalizations during the course of the disease (p=0.04) regardless the disease duration. Our study gives a further confirmation of the fact that early intervention in first psychotic episode is necessary to improve the course of psychiatric illness. [ABSTRACT FROM AUTHOR]

Introduction: A number of studies of a possible relationship between duration of untreated illness (DUI) and various psychiatric disorders shown the possible role of DUI as negative prognostic factor in schizophrenia and psychotic disorders. On the other hand few data evaluate the role of DUI in the clinical outcome of major depressive disorder. Objectives: Analyze the duration of untreated illness and evaluate long-term outcomes in major depressive disorder. Method: Sample of 73 subjects (53F and 20M) with major depressive disorder according to DSM-IV-TR. We collected demographic, clinical and outcome data: age, sex, family history, age at onset of illness, age of first antidepressant treatment and dosage, possible comorbidity with other diagnoses and substance abuse, number of depressive episodes before and after treatment, number of hospitalizations and suicide attempts. Results: Results show that the DUI is longer in the male than in the female sample (p=0.049) and long DUI is related to an onset disorder at a younger age (p=0.040) and with a longer duration of illness (p=0.006). It was also demonstrated that the number of depressive episodes prior to the first antidepressant treatment is higher in the sample of patients with a longer DUI (p=0.006). Discussion: These results show that the duration of untreated illness is longer in the male sample; other results are consistent with previous studies and show a better outcome of depression in patients with a short duration of untreated illness. [ABSTRACT FROM AUTHOR]

OBJECTIVES: A prospective study was undertaken to compare the efficacy of everolimus versus azathioprine or placebo in maintaining steroid-induced remission in active Crohn's disease (CD) and assess the safety and pharmacokinetics of everolimus. METHODS: This was a randomized, double-blind, placebo-controlled, proof-of-concept study in adults with moderate-to-severe active CD. The patients received oral steroids for a rapid induction of remission plus everolimus 6 mg/day, azathioprine 2.5 mg/kg/day, or placebo as maintenance treatment. The main outcome measure was the treatment success, defined as a steroid-free remission by the end of month 3 and maintained until study cutoff without the use of prohibited efficacy treatments. RESULTS: Following an interim analysis, the study was terminated before enrollment was completed due to the lack of efficacy. The full intent-to-treat population comprised 138 patients. Only 96 patients who entered the study ≥7 months prior to data cutoff were included in the primary efficacy population. The treatment success was achieved in 13 of 38 everolimus patients, 22 of 36 azathioprine patients, and 8 of 22 placebo patients. Using the Kaplan–Meier estimates at month 7, the incidence of treatment success was 22.0% with everolimus group (95% confidence interval [CI] 6.7–37.3%, P= 0.610 vs placebo), 38.3% with azathioprine group (95% CI 20.6–55.9%, P= 0.500 vs placebo), and 28.8% with placebo group (95% CI 7.7–49.9%). The type and incidence of adverse events in the everolimus cohort were similar to those reported in the approved transplantation indications. CONCLUSIONS: The safety and tolerability of everolimus (6 mg/day) in patients with active CD were comparable to azathioprine. At this dose, everolimus is not more efficacious in achieving a steroid-free remission in active CD than the comparators. [ABSTRACT FROM AUTHOR]

In a 5-year study involving 119 postmenopausal women, zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. BMD increased significantly. Bone turnover markers decreased from baseline and were maintained within premenopausal reference ranges. After completion of the core study, two consecutive, 2-year, open-label extensions investigated the efficacy and safety of zoledronic acid 4 mg over 5 years in postmenopausal osteoporosis. In the core study, patients received 1 to 4 mg zoledronic acid or placebo. In the first extension, most patients received 4 mg per year and then patients entered the second extension and received 4 mg per year or calcium only. Patients were divided into three subgroups according to years of active treatment received (2, 3 or 5 years). Changes in BMD and bone turnover markers (bone ALP and CTX-I) were assessed. All subgroups showed substantial increases in BMD and decreases in bone markers. By the end of the core study, 37.5% of patients revealed a suboptimal reduction (< 30%) of bone ALP levels. After subsequent study drug administration during the extensions, there was no evidence of progressive reduction of bone turnover markers. Furthermore, increased marker levels after treatment discontinuation demonstrates preservation of bone remodelling capacity. This study showed that zoledronic acid 4 mg once-yearly was well tolerated and effective in reducing biomarkers over 5 years. Detailed analysis of bone marker changes, however, suggests that this drug regimen causes insufficient reduction of remodelling activity in one third of patients. [ABSTRACT FROM AUTHOR]

[18F]FDG has been used as an inflammation marker and shown to accumulate in inflammatory atherosclerotic plaques. The aim of this study was to investigate the uptake and location of [18F]FDG in atherosclerotic plaque compartments. The biodistribution of intravenously administered [18F]FDG was analysed in atherosclerotic LDLR/ApoB48 mice ( n=11) and control mice ( n=9). Digital autoradiography was used to detect the ex vivo distribution in frozen aortic sections. In vitro binding of [18F]FDG in human atherosclerotic arteries was also examined. The uptake of [18F]FDG was significantly higher in the aorta of atherosclerotic mice as compared with the control mice. Autoradiography of excised arteries showed higher [18F]FDG uptake in the plaques than in the healthy vessel wall (mean ratio ±SD 2.7±1.1). The uptake of [18F]FDG in the necrotic, calcified sites of the advanced atherosclerotic lesions was 6.2±3.2 times higher than that in the healthy vessel wall. The in vitro studies of human arterial sections showed marked binding of [18F]FDG to the calcifications but not to other structures of the artery wall. In agreement with previous studies, we observed [18F]FDG uptake in atherosclerotic plaques. However, prominent non-specific binding to calcified structures was found. This finding warrants further studies to clarify the significance of this non-specific binding in human plaques in vivo. [ABSTRACT FROM AUTHOR]

Changes in the structure and function of inhibitory GABAA receptors may contribute to epileptogenesis. We have used the in situ hybridization technique to study GABAA receptor α2, α4, β3 and γ2 subunit mRNA expression in the hippocampus of spontaneously seizing rats with chronic temporal lobe epilepsy. In control rats, all four subunit mRNAs were expressed in the hippocampal subregions but the intensity of expression varied significantly between the subfields. In epileptic rats, α2 expression was decreased in CA3c, and α4 in CA1, but β3 was increased in all subregions, in particular in the granule cell layer. Our results suggest that GABAA receptor undergoes region selective subunit changes during epileptogenesis in the hippocampus of rats with chronic temporal lobe epilepsy. [Copyright &y& Elsevier]

This study attempted to address limitations in the understanding of optimism and pessimism among middle-aged adults. Specifically, a model of affectivity as a mediator of the link between outcome expectancies and psychological adjustment (life satisfaction and depressive symptoms) was presented and examined in a sample of 237 middle-aged adults. Consistent with a mediation model, results of path analyses indicated that optimism and pessimism (particularly the former) had significant direct and indirect links (by means of positive and negative affectivity) with depressive symptoms and life satisfaction. These results add to the small but growing literature identifying optimism and pessimism as important concomitants of psychological adjustment in more mature adults. [ABSTRACT FROM AUTHOR]

Hops (Humulus lupulus L.), a major component of beer, contain potentially neuroactive compounds that made it useful in traditional medicine as a sleeping aid. The present study aims to investigate the individual components in hops acting as allosteric modulators in GABA A receptors and bring further insight into the mode of action behind the sedative properties of hops. GABA-potentiating effects were measured using [3H]ethynylbicycloorthobenzoate (EBOB) radioligand binding assay in native GABA A receptors. Flumazenil sensitivity of GABA-potentiating effects, [3H]Ro 15–4513, and [3H]flunitrazepam binding assays were used to examine the binding to the classical benzodiazepines site. Humulone (alpha acid) and 6-prenylnaringenin (prenylflavonoid) were the most potent compounds displaying a modulatory activity at low micromolar concentrations. Humulone and 6-prenylnaringenin potentiated GABA-induced displacement of [3H]EBOB binding in a concentration-dependent manner where the IC 50 values for this potentiation in native GABA A receptors were 3.2 μM and 3.7 μM, respectively. Flumazenil had no significant effects on humulone- or 6-prenylnaringenin-induced displacement of [3H]EBOB binding. [3H]Ro 15–4513 and [3H]flunitrazepam displacements were only minor with humulone but surprisingly prominent with 6-prenylnaringenin despite its flumazenil-insensitive modulatory activity. Thus, we applied molecular docking methods to investigate putative binding sites and poses of 6-prenylnaringenin at the GABA A receptor α1β2γ2 isoform. Radioligand binding and docking results suggest a dual mode of action by 6-prenylnaringenin on GABA A receptors where it may act as a positive allosteric modulator at α+β- binding interface as well as a null modulator at the flumazenil-sensitive α+γ2- binding interface. [ABSTRACT FROM AUTHOR]