Teresa Biermann

Evidence of Increased Homocysteine Levels in Alcoholism: The Franconian Alcoholism Research Studies (FARS)

BACKGROUND A limited number of investigations have studied clearly defined patients with alcoholism and blood alcohol concentrations with their correlation to plasma homocysteine values and differentiated actively drinking patients from those with early abstinence. Therefore, this power analysis-based study was undertaken to determine whether plasma homocysteine levels are evidently altered in actively drinking alcoholic patients and patients with early abstinence. METHODS Two groups of patients with an established diagnosis of alcohol dependence. For both groups, a power of 90% (alpha = 0.05) was applied. Group A comprised 144 consecutively admitted actively drinking patients with alcoholism. Group B consisted of 56 patients with alcoholism who had abstained from alcohol for 24 to 72 hr before admission to the hospital. RESULTS Plasma homocysteine levels were significantly (t test: df = 198, t = -8.6, p < 0.0001) higher at admission when comparing group A with group B. The highly increased homocysteine levels in actively drinking patients with alcoholism were based on a strong significant positive correlation with the blood alcohol concentration (multiple regression analysis, p < 0.0001). CONCLUSIONS Plasma homocysteine levels are evidently altered in actively drinking patients with alcoholism. Even though it has been described, the authors found no evidence for an increase of homocysteine levels in alcoholic patients with early abstinence. The current results emphasize the proposed pathogenetic role of increased plasma homocysteine levels in alcohol-related disorders (i.e., brain atrophy, alcohol withdrawal seizures).

Managing an effective treatment for neuroleptic malignant syndrome

IntroductionNeuroleptic 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.MethodsAltogether, 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.ResultsBetween 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).ConclusionThe 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.

α‐Synuclein Protein Levels Are Increased in Alcoholic Patients and Are Linked to Craving

BACKGROUND Alpha synuclein has been found to be increased in dopamine neurones of cocaine abusers and in rats whose alcohol preference is inbred. Furthermore, increased alpha-synuclein messenger RNA expression has been linked to craving in patients with alcoholism. The aim of the current study was to investigate whether protein levels of alpha synuclein in alcoholics are changed and possibly influence alcohol craving. METHODS The alpha-synuclein protein expression level was measured by enzyme-linked immunosorbent assay in the serum of 49 male alcoholics and 50 nondrinking healthy controls. Alcohol craving was assessed by the Obsessive-Compulsive Drinking Scale total score, including subscales for obsessive and compulsive craving. RESULTS Alpha-synuclein protein expression in patients with alcoholism (14.33 ng/ml; SD, 13.01 ng/ml) was significantly higher (t test, T = 3.66, p < 0.0001) when compared with that of healthy controls (5.92 ng/ml; SD, 9.72 ng/ml). Using a multivariate analysis, all craving scores (Obsessive-Compulsive Drinking Scale total score and obsessive and compulsive subscale scores) in alcoholics were significantly associated with their alpha-synuclein protein levels (multiple linear regression, p < 0.014). CONCLUSIONS To our knowledge, this is the first study evaluating alpha-synuclein protein expression in alcoholics. The current study provides further evidence of altered alpha-synuclein levels in patients with alcoholism and their linkage to alcohol craving. Because alpha synuclein is involved in the modulation of dopaminergic neurotransmission, these results deliver further pathophysiological explanations of craving mechanisms.

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 brains 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.

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.

Orexin expression and promoter-methylation in peripheral blood of patients suffering from major depressive disorder

Orexins are endogenous neuropeptides synthesized in hypothalamic neurones; they play a major role in the regulation of feeding, drinking, endocrine function and sleep/wakefulness that is often disturbed in major depression. The aim of this study was to explore Orexin A expression and promotermethylation in peripheral blood cells of 29 patients (14 male and 15 female patients at three different time points during antidepressive treatment) suffering from major depressive disorder (MDD) by quantitative RT-PCR and bisulfite sequencing. There was a measurable difference between Orexin A expression on admission in comparison to the Orexin mRNA expression in the healthy control group (T=1.53; df=39; p=0.135) that failed to reach statistical significance. An inverse correlation between Orexin A mRNA expression on admission and the HAMD scores at all measurement dates each week over 6 weeks could be detected. A cluster of methylated CPG sites within the promoter region of the Orexin A gene could be identified that was positively correlated with Delta CT values of the mRNA expression 14 days after hospital admission (r=0.625; p=0.072) and 4 weeks afterwards (r=0.582; p=0.1). Considering only the methylation of the 7 CPGs within the CPG island in the promoter 4 weeks after treatment onset a statistically significant relation between the cluster of CPG sites within the island and body weight (r=0.55; p=0.034) as well as BMI (r=0.474; p=0.074) could be detected. Furthermore, this methylation pattern 4 weeks after treatment onset was positively associated with mRNA expression on admission, 2 and 4 weeks afterwards. In sum, these results are an indicator of a link between social stresses, disruptions in energy homeostasis and changes in body weight in relation to depressive disorders that are possibly linked to Orexin dysregulation.

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.

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 moons 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.

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

Significance Cognitive decline during aging impairs life quality and may lead to dementia. It is associated with a dysfunction of the brain acetylcholinergic system. Here we demonstrate that pharmacological stimulation of neurokinin3 receptors improves learning and memory in aged rats by enhancing acetylcholinergic function in the brain. In a human association study we show that a single-nucleotide polymorphism in the neurokinin3-receptor–coding gene TACR3 can predict learning and memory in elderly patients with cognitive impairments and their hippocampus volume. These findings suggest the neurokinin3 receptor as a potential biomarker and treatment target for cognitive enhancement in the elderly. 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.

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 ones 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.