Association of CamK2A genetic variants with transition time from occasional to regular heroin use in a sample of heroin-dependent individuals.

OBJECTIVES: Susceptibility to heroin dependence is strongly influenced by genetic factors with heritability estimates as high as 0.7. A number of genes, as well as environmental factors, are likely to contribute to its etiology. Not all individuals who have ever tried heroin at some stage during their lifetime become dependent on heroin. It has been suggested that genetic factors might be more important in the transition stage to heroin dependence rather than in environmental exposures and experimenting with heroin. As the features of substance dependence and memory formation have been found to be strikingly similar, we have focused on a key enzyme involved in long-term potentiation and synaptic plasticity, namely the calcium-dependent/calmodulin-dependent protein kinase IIα (CAMKIIa). We hypothesized, that CamK2A genetic variation may play a role in the transition from occasional to regular heroin use. MATERIALS AND METHODS: Using quantitative trait association analysis, we addressed this hypothesis by correlating the self-reported time interval between occasional and regular heroin use with the frequency of 12 single nucleotide polymorphisms located within the genomic region of the CamK2A gene. A sample of 570 Caucasian patients was available for analysis. RESULTS: Single marker association analysis (rs10066581, P=0.007), as well as haplotype analysis (global P=0.005), suggested an association with the quantitative trait 'time interval from occasional to regular heroin use.' CONCLUSION: Our results propose that genetic variants located in the genomic region of the CamK2A gene may be involved in transition time from occasional to regular heroin use.

[Mental Disorder and Partnership: the Influence and Potential Burden of Affective Disorders on the Quality of Partnerships]. / Psychische Störung und Partnerschaft: Auswirkungen und Belastungen affektiver Störungen auf die Partnerschaft.

AIM: The aim of the present study was to explore the connection between affective disorders and various aspects of the quality of relationships and their impact on partnerships. METHODS: In a multi-centric study, we used questionnaires to compare three groups of couples: 23 patients suffering from major depression and their partners, 32 patients with a bipolar disorder and their partners, and 49 healthy couples serving as controls. RESULTS: Regardless of the type of affective disorders, stability of the relationship, felt happiness and other measures of quality of partnership were significantly impaired in couples with an affected partner. Partners of patients experience a higher emotional strain in every day life compared to healthy controls. There was a trend showing that bipolar disorder leads to a greater burden and a higher conflict potential than depression. DISCUSSION: The present study deals with stabile partnerships in daily life, including severely disabled patients needing in-patient treatment. Taking into account the health status of their partners, we discuss various aspects of happiness, conflict potentials as well as impact on the quality of relationships.

Rasgrf2 controls dopaminergic adaptations to alcohol in mice.

Alcohol abuse leads to serious health problems with no effective treatment available. Recent evidence suggests a role for ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) in alcoholism. Rasgrf2 is a calcium sensor and MAPK/ERK activating protein, which has been linked to neurotransmitter release and monoaminergic receptor adaptations. Rasgrf2 knock out (KO) mice do not develop a dopamine response in the nucleus accumbens after an alcohol challenge and show a reduced consumption of alcohol. The present study aims to further characterise the role of Rasgrf2 in dopaminergic activation beyond the nucleus accumbens following alcohol treatment. Using in vivo microdialysis we found that alcohol induces alterations in dopamine levels in the dorsal striatum between wildtype (WT) and Rasgrf2 KO mice. There was no difference in the expression of dopamine transporter (DAT), dopamine receptor regulating factor (DRRF), or dopamine D2 receptor (DRD2) mRNA in the brain between Rasgrf2 KO and WT mice. After sub-chronic alcohol treatment, DAT and DRRF, but not DRD2 mRNA expression differed between WT and Rasgrf2 KO mice. Brain adaptations were positively correlated with splenic expression levels. These data suggest that Rasgrf2 controls dopaminergic signalling and adaptations to alcohol also in other brain regions, beyond the nucleus accumbens.

Sex-dependent decrease of sphingomyelinase activity during alcohol withdrawal treatment.

BACKGROUND: In vitro and in vivo studies have demonstrated the role of the acid sphingomyelinase (ASM) in pathophysiological processes and alterations in response to ethanol exposure. Cellular and plasmatic ASM activities are increased in male alcohol dependent patients and decrease during physical withdrawal. METHODS: Here, we analyzed the time course of ASM in male and also female acutely intoxicated patients during alcohol withdrawal and compared the activity levels to those under long-term maintenance treatment. Craving and further psychometric parameters were assessed by questionnaires. RESULTS: The gradual decrease of serum ASM was confirmed in males (p<0.001) and continued to lower activities in long-term patients (p=0.001). The trend was similar in females (p=0.178), although the initial enzyme activities were significantly lower (p=0.035). ASM activity strongly correlated with the body mass index in males. The initial ASM activity and its decline during the first two days were associated with the improvement in scores for the Beck depression inventory, the obsessive compulsive drinking and the withdrawal syndrome scales. CONCLUSION: These data support the potential of ASM as a biomarker for the course of withdrawal therapy in males and provide the first associations of this enzyme with psychological variables such as craving and depression.

Rasgrf2 controls noradrenergic involvement in the acute and subchronic effects of alcohol in the brain.

RATIONALE: Alcohol addiction is a major psychiatric disease, and yet, the underlying molecular adaptations in the brain remain unclear. Recent evidence suggests a functional role for the ras-specific guanine-nucleotide releasing factor 2 (Rasgrf2) in alcoholism. Rasgrf2(-/-) mice consume less alcohol and show entirely absent dopamine responses to an alcohol challenge compared to wild types (WT). OBJECTIVE: In order to further investigate how Rasgrf2 modifies the acute and subchronic effects of alcohol in the brain, we investigated its effects on the noradrenergic and serotonergic systems. METHODS: We measured noradrenaline and serotonin activity in the brain by in vivo microdialysis and RNA expression by chip analysis and RT-PCR after acute and sub-chronic alcohol exposure in Rasgrf2(-/-) and WT mice. RESULTS: In vivo microdialysis showed a significantly reduced noradrenergic response and an absent serotonergic response in the nucleus accumbens (NAcc) and caudate putamen (CPu) after an alcohol challenge in Rasgrf2(-/-) mice. A co-expression analysis showed that there is a high correlation between Rasgrf2 and α2 adrenoceptor RNA expression in the ventral striatum in naïve animals. Accordingly, we further assessed the role of Rasgrf2 in the response of the noradrenergic system to subchronic alcohol exposure. A decrease in ß1 adrenoceptor gene expression was seen in Rasgrf2(+/+), but not Rasgrf2(-/-) mice following alcohol exposure. Conversely, alcohol resulted in a decrease in both ß2 and α2 adrenoceptor gene expression in knockout but not WT Rasgrf2 mice. CONCLUSIONS: These findings suggest that adaptations in the noradrenergic system contribute to the Rasgrf2 enhanced risk of alcoholism.

Somnography using unobtrusive motion sensors and Android-based mobile phones.

Sleep plays a fundamental role in the life of every human. The prevalence of sleep disorders has increased significantly, now affecting up to 50% of the general population. Sleep is usually analyzed by extracting a hypnogram containing sleep stages. The gold standard method polysomnography (PSG) requires subjects to stay overnight in a sleep laboratory and to wear a series of obtrusive devices. This work presents an easy to use method to perform somnography at home using unobtrusive motion sensors. Ten healthy male subjects were recorded during two consecutive nights. Sensors from the Shimmer platform were placed in the bed to record accelerometer data, while reference hypnograms were collected using a SOMNOwatch system. A series of filters were used to extract a motion feature in 30 second epochs from the accelerometer signals. The feature was used together with the ground truth information to train a Naive Bayes classifiers that distinguished wakefulness, REM and non-REM sleep. Additionally the algorithm was implemented on an Android mobile phone. Averaged over all subjects, the classifier had a mean accuracy of 79.0 % (SD 9.2%) for the three classes. The mobile phone implementation was able to run in realtime during all experiments. In future this will lead to a method for simple and unobtrusive somnography using mobile phones.

Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism.

Impaired learning and memory performance is often found in aging as an early sign of dementia. It is associated with neuronal loss and reduced functioning of cholinergic networks. Here we present evidence that the neurokinin3 receptors (NK3-R) and their influence on acetylcholine (ACh) release may represent a crucial mechanism that underlies age-related deficits in learning and memory. Repeated pharmacological stimulation of NK3-R in aged rats was found to improve learning in the water maze and in object-place recognition. This treatment also enhanced in vivo acetylcholinergic activity in the frontal cortex, hippocampus, and amygdala but reduced NK3-R mRNA expression in the hippocampus. Furthermore, NK3-R agonism incurred a significantly higher increase in ACh levels in aged animals that showed superior learning than in those that were most deficient in learning. Our findings suggest that the induced activation of ACh, rather than basal ACh activity, is associated with superior learning in the aged. To test whether natural variation in NK3-R function also determines learning and memory performance in aged humans, we investigated 209 elderly patients with cognitive impairments. We found that of the 15 analyzed single single-nucleotide ploymorphism (SNPs) of the NK3-R-coding gene, TACR3, the rs2765 SNP predicted the degree of impairment of learning and memory in these patients. This relationship could be partially explained by a reduced right hippocampus volume in a subsample of 111 tested dementia patients. These data indicate the NK3-R as an important target to predict and improve learning and memory performance in the aged organism.

iPad-assisted measurements of duration estimation in psychiatric patients and healthy control subjects.

Handheld devices with touchscreen controls have become widespread in the general population. In this study, we examined the duration estimates (explicit timing) made by patients in a major general hospital and healthy control subjects using a custom iPad application. We methodically assessed duration estimates using this novel device. We found that both psychiatric and non-psychiatric patients significantly overestimated time periods compared with healthy control subjects, who estimated elapsed time very precisely. The use of touchscreen-based methodologies can provide valuable information about patients.

Changes of cytokine profiles during electroconvulsive therapy in patients with major depression.

OBJECTIVES: Electroconvulsive therapy (ECT) is an effective treatment of depression, but its mechanism of action still remains unknown. Some studies emphasize that epileptic seizures result in cerebral production of cytokines, including the cytokine network in association with the pathophysiology of depression. We hypothesized that depressed patients would show a dysregulated profile of peripheral cytokines before and after ECT treatment. METHODS: Fifteen hospitalized subjects with major depressive disorder were recruited. Human cytokine array IV was used to determine the profile of cytokines in the serum during the course of ECT. Positive results of the cytokine assay were verified by reverse transcriptase-polymerase chain reaction. Depressive symptoms were evaluated before and after ECT series. RESULTS: The signal intensity of eotaxin-3 and interleukin (IL)-5 changed statistically significantly between the first ECT and 24 hours after the last ECT. Furthermore, there were significant correlations between the signal intensities of eotaxin-3, bone morphogenetic protein 6, IL-5, and transforming growth factor-ß and the severity of depression. The results of Cytoray assays were confirmed partly by reverse transcriptase-polymerase chain reaction. The changes of tumor necrosis factor ß in pre-post comparison of ECT and the correlation of the Montgomery-Asberg Depression Scale score with tumor necrosis factor ß, IL-5, and bone morphogenetic protein 6 expression could be verified. Only the relative signal intensity of IL-16 correlated significantly with the clinically as well as electroencephalographically measurable seizure duration. CONCLUSION: Electroconvulsive therapy treatment seems to change the expression of various cytokines in relation to changes of affective states such as mood. Therefore, cytokines might play a specific role within the treatment and pathogenesis of affective disorders.

CB1 and CB2 receptor expression and promoter methylation in patients with cannabis dependence.

CB1 and CB2 receptors are influenced via exogenous and endogenous cannabinoids. To date, little is known regarding changes in receptor expression and methylation in THC (tetrahydrocannabinol) dependence. Therefore, the CB1 and CB2 receptor mRNA expression levels and promoter methylation status in the peripheral blood cells of 77 subjects (36 with THC dependence, 21 cigarette smokers and 20 nonsmokers) were assessed by quantitative real-time PCR and methylation-specific PCR. There was a significant difference in CB1 receptor expression levels between the three groups (ANOVA, p < 0.001, d.f. = 2, F = 71.3). The mean promoter methylation (%) was significantly negatively correlated with CB1 receptor mRNA expression levels (Spearman's rho: r = -0.37; p = 0.002). Using a mixed general linear model, it was demonstrated that the CB1 mRNA expression (as the dependent variable) was associated with the satisfaction with life scale (SWLS) (r = 0.101; T = 2.8; p = 0.007), craving (as measured with the VAS; r = -0.023; T = -2.3; p = 0.023) and the WHO-Assist Subscale for Cannabis consumption (r = -0.068; T = -2.4; p = 0.02). CB1 receptor expression levels and methylation status appear to be altered in subjects with THC dependence.

Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study.

Invasive vagus nerve stimulation has been demonstrated to be an effective treatment in major depressive episodes. Recently, a novel non-invasive method of stimulating the vagus nerve on the outer canal of the ear has been proposed. In healthy subjects, a prominent fMRI BOLD signal deactivation in the limbic system was found. The present pilot study investigates the effects of this novel technique of auricular transcutaneous electric nerve stimulation in depressed patients for the first time. A total of 37 patients suffering from major depression were included in two randomized sham controlled add-on studies. Patients were stimulated five times a week on a daily basis for the duration of 2 weeks. On days 0 and 14, the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI) were assessed. In contrast to sham-treated patients, electrically stimulated persons showed a significantly better outcome in the BDI. Mean decrease in the active treatment group was 12.6 (SD 6.0) points compared to 4.4 (SD 9.9) points in the sham group. HAMD score did not change significantly in the two groups. An antidepressant effect of a new transcutaneous auricular nerve stimulation technique has been shown for the first time in this controlled pilot study. Regarding the limitations of psychometric testing, the risk of unblinding for technical reasons, and the small sample size, further studies are necessary to confirm the present results and verify the practicability of tVNS in clinical fields.

Peer review versus editorial review and their role in innovative science.

Peer review is a widely accepted instrument for raising the quality of science. Peer review limits the enormous unstructured influx of information and the sheer amount of dubious data, which in its absence would plunge science into chaos. In particular, peer review offers the benefit of eliminating papers that suffer from poor craftsmanship or methodological shortcomings, especially in the experimental sciences. However, we believe that peer review is not always appropriate for the evaluation of controversial hypothetical science. We argue that the process of peer review can be prone to bias towards ideas that affirm the prior convictions of reviewers and against innovation and radical new ideas. Innovative hypotheses are thus highly vulnerable to being "filtered out" or made to accord with conventional wisdom by the peer review process. Consequently, having introduced peer review, the Elsevier journal Medical Hypotheses may be unable to continue its tradition as a radical journal allowing discussion of improbable or unconventional ideas. Hence we conclude by asking the publisher to consider re-introducing the system of editorial review to Medical Hypotheses.

Chronic calcium pyrophosphate crystal inflammatory arthritis induced by extreme hypomagnesemia in short bowel syndrome.

BACKGROUND: Short bowel syndrome (SBS) may induce a plethora of clinical symptoms ranging from underweight to nutrient-, vitamin- and electrolyte deficiencies. The objective of this case report is to illustrate how demanding the management of a 60 year old patient with SBS and recurrent joint attacks was for different medical disciplines. CASE PRESENTATION: The patient with SBS presented with a body mass index of 16.5 kg/m2 after partial jejunoileal resection of the small intestine with a six year long history of recurrent pain attacks in multiple peripheral joints, chronic diarrhoea and food intolerances. Pain attacks occurred 4-5 times a week with a median consumption of 15 mg prednisone per day. The interdisciplinary workup after several gastroenterologic, rheumatologic, radiologic, psychiatric and orthopedic consultations is shown including successful treatment steps.Clinical diagnosis revealed no systemic inflammatory disease, but confirmed extreme hypomagnesemia (0.2 mmol/l) after reproducible pathological magnesium resorption tests as causative for chronic calcium pyrophosphate crystal inflammatory arthritis (pseudogout, chondrocalcinosis).Multidisciplinary treatment included application of colchicines, parenteral nutrition and magnesium substitution, antiperistaltic agents and avoidance of intolerant foods. Normalization of magnesium levels and a marked remission of joint attacks were achieved after six months with significant reduction of prednisone to 1.5 mg/day. CONCLUSION: Despite the rarity of this condition, it is important to know that hypomagnesaemia may be associated with calcium pyrophosphate crystal inflammatory arthritis (chondrocalcinosis) and that SBS patients may be prone to develop extreme hypomagnesaemia causing recurrent joint attacks without systemic inflammation.

Orexin A expression and promoter methylation in patients with cannabis dependence in comparison to nicotine-dependent cigarette smokers and nonsmokers.

BACKGROUND: The orexins (hypocretins) are neuropeptides with an origin in the lateral hypothalamus. They have been found to be crucial within the context of drug craving, withdrawal und relapse. METHODS: Therefore, orexin A gene expression and promoter methylation in peripheral blood cells of 77 subjects [36 with tetrahydrocannabinol (THC) dependence, 20 nicotine-dependent cigarette smokers and 21 nonsmokers] were assessed by quantitative real-time PCR and methylation-specific digestion PCR. RESULTS: There was a statistically significant difference in orexin A expression between the three groups [p = 0.000, F = 131.4, d.f. = 2, analysis of variance (ANOVA)]. Orexin A gene expression was statistically significantly correlated with the Satisfaction with Life Scale (r = -0.28, p = 0.018), a visual analogue scale of craving (r = 0.734, p = 0.000) and three subscales of the World Health Organization Alcohol, Smoking and Substance Involvement Screening Test, i.e. nicotine consumption (r = 0.388, p = 0.001), alcohol consumption (r = 0.354, p = 0.002) and cannabis consumption (r = 0.783, p = 0.000). The mean promoter methylation (as a percentage) was not statistically related to orexin gene expression. However, there was a statistically significant difference in promoter methylation with regard to body mass index in general (F = 2.37, d.f. = 54, p = 0.016, ANOVA). CONCLUSIONS: Orexin might be a possible target in THC as well as nicotine dependence, taking into account the effect of THC on energy homeostasis in the circuit of reward and motivation and its impact on appetite and body weight.

The schizoictal syndrome.

There are several common denominators of schizophrenia and epilepsy including models of pathogenesis as well as their clinical occurrence mainly referring to schizophrenia-like syndrome in epilepsy or similar clinical entities [1]. Up to now it has not been emphasized that a process of synchronization or desynchronization of neuronal cell structures within the context of neuronal plasticity might be a plausible pathogenetic mechanism of epilepsy as well as schizophrenia. Clinical as well as therapeutical implications of this hypothesis on the basis of scientific evidence are discussed.

Somatic diseases in child survivors of the Holocaust with posttraumatic stress disorder: a comparative study.

The incidence of mental and somatic sequelae has been shown to be very high in people who survived the Holocaust. In the current study, 80 Holocaust survivors with posttraumatic stress disorder were examined based on evaluation of their complete record (medical reports, clinical history, medical statements, and handwritten declarations of patients under oath). These survivors were compared with subjects with posttraumatic stress disorder caused by traumata other than the Holocaust. The data were analyzed for the presence of cardiovascular, gastrointestinal, and orthopedic diseases that developed in the time between the earliest medical report (expert opinion) and the latest expert opinion. Analysis revealed an increase in myocardial infarction, chronic degenerative diseases, and cancerous changes in the second expert opinion. No differences between the groups were seen with regard to sex, age at traumatization, or age at examination. Several implications of the data are discussed, including the implication that the survivors examined in this study may comprise a highly resilient group, inasmuch as they had reached an advanced age.

Sex hormone activity in alcohol addiction: integrating organizational and activational effects.

There are well-known sex differences in the epidemiology and etiopathology of alcohol dependence. Male gender is a crucial risk factor for the onset of alcohol addiction. A directly modifying role of testosterone in alcohol addiction-related behavior is well established. Sex hormones exert both permanent (organizational) and transient (activational) effects on the human brain. The sensitive period for these effects lasts throughout life. In this article, we present a novel early sex hormone activity model of alcohol addiction. We propose that early exposure to sex hormones triggers structural (organizational) neuroadaptations. These neuroadaptations affect cellular and behavioral responses to adult sex hormones, sensitize the brain's reward system to the reinforcing properties of alcohol and modulate alcohol addictive behavior later in life. This review outlines clinical findings related to the early sex hormone activity model of alcohol addiction (handedness, the second-to-fourth-finger length ratio, and the androgen receptor and aromatase) and includes clinical and preclinical literature regarding the activational effects of sex hormones in alcohol drinking behavior. Furthermore, we discuss the role of the hypothalamic-pituitary-adrenal and -gonadal axes and the opioid system in mediating the relationship between sex hormone activity and alcohol dependence. We conclude that a combination of exposure to sex hormones in utero and during early development contributes to the risk of alcohol addiction later in life. The early sex hormone activity model of alcohol addiction may prove to be a valuable tool in the development of preventive and therapeutic strategies.

Higher environmental temperature and global radiation are correlated with increasing suicidality--a localized data analysis.

Suicide rate follows a seasonal pattern that is related to rising air temperature and global radiation. These findings are reproducible within different climatic regions. Numerous studies have attempted to explain this peak in relation to weather. However, many of these studies did not use meteorological data representative of the site of the suicide or attempted suicide, resulting in limitations of the findings. Previous studies also suffered from limitations in the methods of data analysis. The current study examined the relationship between weather, i.e., solar radiation, air temperature, and the rate of suicides and suicidality in the area of Mittelfranken, Germany, using regional meteorological data. Statistical risk estimation revealed associations between higher global radiation and air temperatures on the day of and day before suicide acts. The results could be of interest for general suicide prevention strategies. Future studies should examine additional possible factors of influence and concentrate on a strict standardized study design. The aim is to obtain reproducible data of the seasonal influences on suicide behavior, allowing for the comparison of data from different meteorological regions and patient subgroups.

Orexin A expression and promoter methylation in patients with alcohol dependence comparing acute and protracted withdrawal.

The orexins (hypocretins) are neuropeptides deriving from the lateral hypothalamus and may be of importance within the context of drug craving, withdrawal, and relapse. Therefore, the orexin A expression and promoter methylation in peripheral blood cells of 68 patients (41 male and 27 female patients at three different time points during withdrawal and 27 patients during stationary dehabituation therapy) suffering from alcohol dependence were assessed by quantitative reverse transcription-polymerase chain reaction and bisulfite sequencing. There was a statistically significant difference of orexin A expression between the three time points of withdrawal and long-term (LT) abstinence (F=4.16, P=.011). This difference was most prominent in comparison with LT abstinence (t=-3.08, P=.0032). Expression was significantly associated with the severity of withdrawal symptoms measured with the Withdrawal Syndrome Scale for Alcohol and Related Psychoactive Drugs (WSA) (t=2.17, P=.0356). The stronger the withdrawal symptoms, the lower the orexin A expression (F=4.69, P=.036). Body mass index (t=2.15, P=.041), the severity of withdrawal measured with the WSA (t=2.595, P=.0133), craving measured either by the Obsessive Compulsive Drinking Scale (t=2.77, P=.0085) or the Lübecker Craving Questionnaire (t=-2.23, P=.0314) had a significant influence on orexin A expression taking into account mean methylation of the CpG island of the orexin A promoter during withdrawal. Orexin A may be a possible candidate to further elucidate mechanisms of alcohol withdrawal taking into account energy homoeostasis in the circuit of reward and motivation.

Low digit ratio 2D:4D in alcohol dependent patients.

The ratio of the lengths of the second and fourth finger (2D∶4D) has been described as reflecting the degree of prenatal androgen exposure in humans. 2D∶4D is smaller for males than females and is associated with traits such as left-handedness, physical aggression, attention-deficit-hyperactivity disorder and a genetic polymorphism of the androgen receptor. All of these traits are known to be correlated to the vulnerability for alcohol dependency. We therefore hypothesized low 2D∶4D in patients with alcohol dependency. In the present study on 131 patients suffering from alcohol dependency and 185 healthy volunteers, we found that alcohol dependent patients had smaller 2D∶4D ratios compared to controls with preserved sexual dimorphism but with reduced right-left differences. The detection of alcohol dependency based on 2D∶4D ratios was most accurate using the right hand of males (ROC-analysis: AUC 0.725, sensitivity 0.667, specificity 0.723). These findings provide novel insights into the role of prenatal androgen exposure in the development of alcohol dependency and for the use of 2D∶4D as a possible trait marker in identifying patients with alcohol dependency.