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.

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.

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.

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.

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.

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.

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.

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.

Posttraumatic stress disorder and dementia in Holocaust survivors.

The incidence of mental and somatic sequelae has been shown to be very high in the group of people damaged by the Holocaust. Within the context of internal research, 93 Holocaust survivors suffering from posttraumatic stress disorder have been examined. Patients suffered on average from 4.5 (standard deviation ± 1.8) somatic diagnoses as well as 1.8 (standard deviation ± 0.5) psychiatric diagnoses. A diagnosis of dementia was ascertained according to ICD-10 criteria in 14%. Vascular dementia (66%) dominated over Alzheimer's dementia (23%) and other subtypes (11%).

Non-right-handedness and free serum testosterone levels in detoxified patients with alcohol dependence.

AIMS: The influence of testosterone on the extent of hemispheric dominance has been discussed not just during the first two trimesters of pregnancy but also later in life. An increase in free serum testosterone levels has been found during and after the detoxification phase of patients with alcohol dependence. METHODS: In 250 participants (125 men and 125 women) with alcohol dependence immediately after the direct withdrawal phase (Day 21) and in 250 healthy age- and gender-matched participants, free testosterone in the serum was determined and handedness was assessed as a peripheral marker of central hemispheric dominance. RESULTS: Patients with alcohol dependence were 2.7-fold (odds ratio, OR: 2.66; 95% confidence interval, CI: 1.62-4.38) and men 4.1-fold (OR: 4.12; 95% CI: 2.44-6.98) more likely to be non-right-handed (NRH). In addition to male gender, non-right-handedness and alcohol dependence contributed statistically significantly to higher serum testosterone levels. Testosterone values of patients with alcohol dependence differed significantly between the four different Lesch subtypes; in particular, participants with alcohol dependence classified according to Lesch subtype IV were found to have significantly higher serum testosterone levels (F = 20.5; P < 0.001) when compared to participants classified according to Lesch subtypes I-III. CONCLUSIONS: An alteration of hemispheric dominance and thus an exogenously modifiable neuronal plasticity may be demonstrated directly on a population at risk.

Statistical methods for detecting and comparing periodic data and their application to the nycthemeral rhythm of bodily harm: A population based study.

BACKGROUND: Animals, including humans, exhibit a variety of biological rhythms. This article describes a method for the detection and simultaneous comparison of multiple nycthemeral rhythms. METHODS: A statistical method for detecting periodic patterns in time-related data via harmonic regression is described. The method is particularly capable of detecting nycthemeral rhythms in medical data. Additionally a method for simultaneously comparing two or more periodic patterns is described, which derives from the analysis of variance (ANOVA). This method statistically confirms or rejects equality of periodic patterns. Mathematical descriptions of the detecting method and the comparing method are displayed. RESULTS: Nycthemeral rhythms of incidents of bodily harm in Middle Franconia are analyzed in order to demonstrate both methods. Every day of the week showed a significant nycthemeral rhythm of bodily harm. These seven patterns of the week were compared to each other revealing only two different nycthemeral rhythms, one for Friday and Saturday and one for the other weekdays.

N-methyl-D-aspartate 2b receptor subtype (NR2B) promoter methylation in patients during alcohol withdrawal.

NMDA receptors and especially the NR2B receptor subtype play a crucial role during chronic ethanol consumption and alcohol withdrawal. Therefore, the NR2B receptor subtype expression in peripheral blood cells of 32 male patients suffering from alcohol dependency were assessed through quantitative RT-PCR and to explore regulating epigenetic mechanisms, a methylation analysis was conducted using bisulfite sequencing of a fragment of the NR2B promoter region. The expression of the NR2B receptor increased significantly during the first 24 h of withdrawal treatment (day 1; t = 4.1, P = 0.001), and also on and day 3 (t = 2.4; P = 0.029). The severity of alcohol drinking pattern, measured by lifetime drinking and daily ethanol intake, was negatively correlated with the methylation of a defined cluster of five CPG-sites within the NR2B promoter (lifetime drinking: Spearman's rho = -0.55; P = 0.013; daily ethanol intake: rho = -0.46; P = 0.043). These findings might explain the observation of an impact of alcohol consumption patterns on the gravity of withdrawal symptoms.

Relationship between lunar phases and serious crimes of battery: a population-based study.

OBJECTIVE: The hypothesis of a lunar influence on human abnormal behavior is still widespread, although research has led to conflicting findings. Therefore, a population-based study to assess the influence of lunar phases on violent crimes was conducted. METHODS: The study included all serious crimes of battery (aggravated assaults) committed in Middle Franconia (Bavaria, Germany) between 1999 and 2005 (n = 23 142). Data were analyzed regarding lunar phase, sex, and place of crime scene (outdoor vs indoor). RESULTS: No significant associations between full, absent, and the moon's interphases and serious crimes of battery could be detected. Furthermore, a Fourier analysis was conducted that failed to produce an association between violence and the moon's phases. DISCUSSION: Several possible explanations for the presented results are discussed including biological and social mechanisms. CONCLUSIONS: The present study fails to find a significant association between lunar phases and crimes of battery.

The hypothesis of an impact of ozone on the occurrence of completed and attempted suicides.

Air pollution and its impact on human health are of growing concern throughout the world. Recent studies have mainly focussed on respiratory and vascular mortality. The existence of seasonality of ozone distribution and also of the occurrence of suicides as well as suicide attempts is generally accepted, though an interconnection of both phenomena has not yet been established. This hypothesis of an influence of ozone on the occurrence of suicidality was tested on preliminary data (1008 suicides and 917 suicide attempts from a larger epidemiological sample in Middle-Franconia from 2004 to 2007). A higher suicide rate than expected could be observed from July to September, whereas the rates of the suicide attempts did not show a seasonality in relation to ozone levels. To further strengthen the hypothesis, ozone levels differed significantly (T = -2.5; p = 0.014) between days where one or no suicide were observed (mean ozone: 79.8 microg/m(3); SD: 36.3) and days with two or more suicides (mean ozone: 86.4 microg/m(3); SD: 39.4). This phenomenon might be explained including sociological, biological as well as psychological effects. Sociologically, behaviour precipitating suicide might be influenced by climatic variables such as the weather or air pollution causing fatigue or cardio-respiratory symptoms influencing individual well-being in general thereby possibly leading to the decision to end one's life. Biologically, ozone is able to influence the immune system, is a strong trigeminal irritant and might influence neurotransmitter systems such as serotonin, which are known to vary with season and play a major role in impulsivity, aggression, depression and thereby suicidality. Putative psychological explanations for the suicide peak in summer include the influence of a higher ambient temperature leading individuals to a more disinhibited, aggressive and violent behaviour possibly resulting in an increased proneness for suicidal acts that is influenced by ozone. This might lead one to speculate whether ozone is able to account - at least amongst others - for the seasonal distribution of suicides or might even be a causative agent in the multifactorial genesis of a suicide. If this hypothesis is found to be true, further research should focus on the underlying mechanisms. Furthermore, this might be a strong argument to further encourage environment protection.

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.

Managing an effective treatment for neuroleptic malignant syndrome.

INTRODUCTION: Neuroleptic malignant syndrome (NMS) is a rare, but sometimes fatal, adverse reaction to neuroleptics characterized principally by fever and rigor. The aim of this study was to prove the efficacy of different NMS treatment strategies, focusing on the efficacy of dantrolene. METHODS: Altogether, 271 case reports were included. These cases were categorized into four treatment groups and compared to each other according to effectiveness of therapy within 24 hours, mortality, complete time of remission in days, effectiveness due to increase of dosage, relapse on the basis of decrease of dosage, and improvement of symptoms. RESULTS: Between the four treatment groups, the complete time of remission was significantly different (analysis of variance, F = 4.02; degrees of freedom = 3; p = 0.008). In a logistic regression with adjustment for age, gender, and severity code, no significant predictor of the treatment for the complete time of remission (dichotomized by median) could be found. However, if the premedication was a monotherapy with neuroleptics, the complete time of remission was significantly shorter with dantrolene monotherapy (t = -2.97; p = 0.004). CONCLUSION: The treatment of NMS with drugs that are combined with dantrolene is associated with a prolongation of clinical recovery. Furthermore, treatment of NMS with dantrolene as monotherapy seems to be associated with a higher overall mortality. Therefore, dantrolene does not seem to be the evidence-based treatment of choice in cases of NMS but might be useful if premedication consisted of a neuroleptic monotherapy.

[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.

Influence of lunar phases on suicide: the end of a myth? A population-based study.

The hypothesis of lunar influence on suicide remains widespread, despite the fact that little scientific evidence to substantiate it. We conducted a population-based study to assess the influence of the lunar phases on suicides according to age, sex, and chosen method. The study included all suicides in Middle Franconia between 1998 and 2003. From a population-based sample of 3351 events, the files of 3054 suicides (1949 males and 1105 females) were complete for the study variables. Data were categorized by lunar phase, sex, age, and chosen method-"violent" vs. "non-violent" acts. No significant relationship was detected between the full, absent, and moon's interphases and suicide incidence. Nevertheless, there was a weak association between the absent moon and choice of a non-violent suicide method in men aged less than the median of 40.2 yrs. There was no evidence of a relationship between suicide and lunar phase. Some explanations for this phenomenon are discussed.

Influence of lung fixation technique on the state of alveolar expansion-a histomorphometrical study.

Lungs removed at necropsy normally collapse due to the loss of negative pleural pressure leading to a quite unnatural appearance of both gross and histological specimens. In order to demonstrate the influence of post-mortem lung retraction on the degree of alveolar expansion, a histomorphometrical analysis was performed in lungs from a 9-month-old healthy infant. Tissue specimens from the right lung were obtained at autopsy and routinely fixed after retraction ('routinely fixed lung'), whereas the left lung was fixed in situ before opening the thoracic cage ('in situ fixed lung'). The size of the alveoli as well as the thickness of the alveolar walls were measured using an automatic image processing and analysis system (Leica QWIN) in both lungs. The mean alveolar size was 8.7 x 10(3) microm(2) in the routinely fixed lung (alveoli, n=1.1576) and 10.9 x 10(3) microm(2) in the in situ fixed lung (alveoli, n = 841). In contrast, the diameter of the alveolar walls showed no significant difference in both lungs. The average thickness of the alveolar walls was 7.9 microm (measuring sites, n = 1.190) in the routinely fixed lung and 8.1 microm in the in situ fixed lung (measuring sites, n = 1.027), respectively. The results provide evidence of significantly reduced aeration in the retracted and routinely fixed lung which could be of special forensic interest in cases of suspicious infanticide, stillbirth or infant death by drowning or suffocation.