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The postpartum period is crucial in dairy cows and is marked by major physiological and metabolic changes that affect milk production, immune response and fertility. Nutrition remains the most important lever for limiting the negative energy balance and its consequences on general health status in highly selected dairy cows. In order to analyze the effect of a commercial micronutrient on intrinsic parameters, performances and the epigenome of dairy cows, 2 groups of 12 Holstein cows were used: 1 fed a standard diet (mainly composed of corn silage, soybean meal and non-mineral supplement) and the other 1 fed the same diet supplemented with the commercial micronutrient (µ-nutrient supplementation) for 4 weeks before calving and 8 weeks thereafter. Milk production and composition, BW, body condition score (BCS), DM intake (DMI) and health (calving score, metritis and mastitis) were recorded over the study period. Milk samples were collected on D15 and D60 post-calving for analyses of casein, Na+ and K+ contents and metalloprotease activity. Milk leukocytes and milk mammary epithelial cells (mMECs) were purified and counted. The viability of mMECs was assessed, together with their activity, through an analysis of gene expression. At the same time points, peripheral blood mononuclear cells (PBMCs) were purified and counted. Using genomic DNA extracted from PBMCs, mMECs and milk leukocytes, we assessed global DNA methylation (Me-CCGG) to evaluate the epigenetic imprinting associated with the µ-nutrient-supplemented diet. The µ-nutrient supplementation increased BCS and BW without modifying DMI or milk yield and composition. It also improved calving condition, reducing the time interval between calving and first service. Each easily collectable cell type displayed a specific pattern of Me-CCGG with only subtle changes associated with lactation stages in PBMCs. In conclusion, the response to the µ-nutrient supplementation improved the body condition without alteration of global epigenetic status in dairy cows.
Genetic and environmental influences are both known to be causal factors in the development and maintenance of obesity. Stress related chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and resulting increased glucocorticoid exposure is known to be an important pathophysiological mechanism in the development of obesity. We show that the natriuretic peptide system, that mediates endocrine and behavioural responses to stress, plays a role in the control of long-term body weight in chronically ethanol drinking mice. In mice lacking functional NPR-A receptors, physical, and in particular psychological stress leads to enhanced and continuous increase in body weight in homozygote NPR-A mice. The effect of repeated stress on body weight appeared rapidly and persisted throughout life. Over a longer period of time without stress, body weights do not differ between the different genotypes. Moreover, we could demonstrate that NPR-A homozygote mice show significant higher corticosterone levels following stress. Heterozygote animals show an intermediate phenotype concerning body weights and corticosterone levels following stress. Alterations in the NPR-A receptor gene may constitute a genetic risk factor for stress-induced eating and obesity.
The selective alpha4-beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline has been shown to be effective in the treatment of tobacco dependence by counteracting withdrawal symptoms and reducing smoking reward. However, the need to test safety, especially in smokers with varying co-morbidities and risk patterns is highlighted. There are some publications reporting exacerbation of psychiatric symptoms in subjects with pre-existing psychiatric disorders associated with varenicline treatment.
This case-report describes a patient whose several smoking cessation attempts led to enduring nicotine-related symptoms such as depression and suicidal tendencies. All further cessation attempts under medical control with nicotine patches, bupropion and psychotherapy failed. At lest reducing her daily dose by one cigarette already led to suicidal thoughts. We took her into inpatient treatment and started an uptitration with varenicline. Unlike earlier attempts there were no complications during the detoxication and depressive symptoms improved clearly.
Affective symptoms like depression are known to develop during nicotine cessation. The improving of affective symptoms in this case might be a result of the partial agonistic effects of varenicline.
Schizophrenia is frequently complicated by depressive or negative symptoms that respond only moderately to treatment with antipsychotic drugs. Reboxetine is a novel antidepressant, which inhibits the reuptake of norepinephrine. We sought to study the efficacy and tolerability of the adjunctive use of reboxetine in a cohort of schizophrenic patients with prominent depressive or negative symptoms.
Sixteen schizophrenic inpatients were recruited for this study. All subjects received 4–8 mg of reboxetine/day while the antipsychotic medication (typical antipsychotics = 4; atypical antipsychotics = 12) was continued. All subjects underwent a standardized assessment including PANSS, CGI, HAMD, and CDSS before and after treatment with reboxetine (mean 26 ± 17 d).
All subjects tolerated treatment with reboxetine. Adverse effects were mild and did not require discontinuation of reboxetine. All clinical scores (PANSS 93.1 vs. 63.1; CGI 5.4 vs. 4.1; HAMD 20.4 vs. 8.1; CDSS 12.5 vs. 4.6) improved significantly under adjunctive treatment with reboxetine (all P < 0.01).
The adjunctive use of reboxetine in schizophrenic patients was safe and well-tolerated. Our results suggest that the adjunctive use of reboxetine may be an effective treatment for depressive and negative symptoms in schizophrenia.
Dysregulation in the neuroendocrine stress system has been attributed repeatedly to the stressful and anxiogenic state observed during alcohol withdrawal. Activity of the atrial natriuretic peptide (ANP) has been shown to inhibit the release of corticotrophin releasing hormone (CRH) and corticotrophin (ACTH) and opioid neurotransmission also plays a role in counteracting effects of sustained stress by facilitating the termination of the hypothalamo-pituitary-adrenocortical (HPA) axis stress response. Thus ANP and ß-endorphin may be involved in modulating the HPA axis activity in alcohol withdrawal. Aim of the study was to evaluate the anxiolytic activity of ANP and ß-endorphin during alcohol withdrawal in mice habitated to chronic alcohol intake.
24 male mice (C57/Bl6J) were studied following 21 days of free-choice and forced alcohol intake. Anxiety related behavior (elevated plus maze, open field) was tested during acute ethanol withdrawal (12 hours after last ethanol consumption). 30 minutes before testing, randomized groups of mice were given i.p. injections of ANP (60 μg/kg), ß-endorphin (2 μg/kg) or saline.
Acute alcohol withdrawal in alcohol habituated mice was associated with increased anxiety related behavior. Application of both, ß-endorphin and ANP, was significantly associated with reduced anxiety related behavior.
Taking into consideration data from studies in humans, where decreased levels of ß-endorphin and ANP were associated with anxiety during acute and protracted alcohol withdrawal, our results suggest a causal relationship between ANP, ß-endorphin and withdrawal-induced anxiety in alcohol related disorders.
Recent results suggest that the endocrine system can affect as well as modulate ethanol drinking behavior. In mice and humans a correlation has been found between ANP plasma concentration and craving, anxiety as well as the severity of the withdrawal symptoms. To further elucidate the involvement of the natriuretic peptide system in neurobehavioral effects of alcohol, we examined ethanol drinking behavior in mice lacking a functional natriuretic peptide-A (NPR-A) receptor.
NPR-A heterozygote, -knockout and wild-type mice were given a free choice between water and increasing concentrations of ethanol. Once a stable baseline of 16% ethanol consumption was established, access to ethanol was withdrawn for 2 weeks and then reinstated to measure the alcohol deprivation effect (ADE). A forced swim stress was performed thereafter on 3 consecutive days.
Data analysis revealed a higher ethanol preference and voluntary ethanol intake in NPR-A-transgenic mice. Throughout the experiments the ethanol intake was highest in heterozygote animals. Stress-induced drinking led to an immediate increase in ethanol consumption in the homozygote subgroup. Deprivation from alcohol resulted in a classical ADE in wild-type and heterozygote animals. The homozygote mice do not show an increase in alcohol intake during the ADE.
We demonstrated that the NPR-A receptor gene is involved in free choice ethanol consumption, preference and ethanol consumption following stress. Mice lacking a functional NPR-A receptor represent a useful animal model to adress the question of whether a dysfunctonal natriuretic peptide receptor system influences longterm alcohol self-administration and stress induced alcohol drinking.
In the phase 3 programme on nalmefene for reduction of alcohol consumption in alcohol dependent patients, an as-needed dosing regimen was used. Patients were instructed to take one tablet on each day they perceived a risk of drinking alcohol, preferably 1 to 2 hours prior to the anticipated time of drinking. Tablets could be taken up to once daily. As-needed use is a patient-centered approach engaging patients in active and responsible management of their illness. It should be seen as an integral part of disease management, increasing awareness of drinking amount and patterns, facilitating identification of at-risk situations.
Explore the feasibility of as-needed use of nalmefene in alcohol dependence.
The Timeline Follow-back was used to obtain estimates of daily drinking and to record daily medication intake. Pooled data (treated patients: nalmefene=643; placebo=633) from the two randomised controlled 6 month studies (ESENSE 1 [NCT00811720] and ESENSE 2 [NCT00812461]) was used. Adherence was defined as medication intake and alcohol consumption, or no alcohol consumption (with or without medication intake).
Nalmefene was taken on approximately half of the study days; placebo was taken more often than nalmefene. In each treatment group, medication intake varied according to patients’ needs as intake correlated with baseline drinking pattern. 68% of the nalmefene treated patients (78% of the study completers) adhered to the as-needed treatment regimen on at least 80% of the study days.
These results demonstrate that patients understand, accept, and adhered to the as-needed treatment regimen.
Pathological gambling and comorbide alcohol dependence are common occuring diseases. Disulfiram is one of the proven drugs for alcohol dependence. It was shown recently, that Disulfiram is also effective in relapse prevention of cocaine addiction. In addition to its inhibiting effect of the acetaldehyde dehydrogenase (ADH), disulfiram inhibits the dopamine β-hydroxylase (DBH) and thereby augments dopamine and depletes norepinephrine concentrations in the CNS. Inhibition of the DBH is suggested to be the responsible mechanism of Disulfiram acting in cocaine addiction. Previous research indicates common neurochemical substrates for pathological gambling and cocaine addiction. This suggests that dopamine substrates may directly govern the reinforcement process in pathological gambling.
In this report we now present the clinical data of a patient who was treated with disulfiram in our outpatient unit for addiction treatment due to existing alcohol dependence. The patient suffered also from severe pathological gambling.
Initialy we started to treat the patient with supervised disulfiram because of his alcohol dependence. During the treatment with disulfiram the patient’ desire for gambling disappeared entirely and he has not gambled anymore since then.
However, the exact mechnism of action by which disulfiram reduces urge to gamble is not fully unterstood, yet. Because craving is a key contributor to relapse, strategies aimed at modulate dopamine increases are likely to be therapeutically beneficial in gambling. Although uncontrolled case observations can only be interpreted with caution disulfiram seems to deserve further investigation and may hold the potential for preventing relapse in gamblers suffering from additional alcohol dependence.
Among abstinent alcohol-dependent patients, sleep disorders are a wide-spread and persistent problem and have been associated with the risk of alcohol relapse. The melatonin-agonist agomelatine has been shown to improve overall sleep quality without daytime sedation.
To examine the effect of agomelatine on sleep quality in abstinent alcohol-dependet patients suffering from chronic sleep disorders.
9 alcohol-dependet patients suffering from chronic sleep disorders received nightly doses between 25 and 50 mg of agomelatine. Sleep quality was assesed using the Pittsburgh Sleep Quality Index prior and following 6 weeks of treatment with agomelatine. Prior and during treatment with agomelatine all patients were monitored for serum levels of liver enzymes.
After 6 weeks of agomelatine treatment, the Pittsburgh Sleep Quality Index global score for all patients had decreased significantly.
The present data suggest that agomelatine may improve the sleep quality of alcohol-dependent patients suffering from chronic sleep disorders.
Pregabalin is a novel GABA-analogue approved for the treatment of partial onset seizures, neuropathic pain, and general anxiety disorder. Pregabalin has been classified as a Schedule V drug with a low risk of inflicting abuse or addiction. However, some publications have indicated that pregabalin may have a potential for abuse among patients with past or current opiate addiction.
We hypothesized that pregabalin might be abused my patients who were undergoing an opiate replacement therapy and never had an indication for taking pregabalin on medical grounds.
Urine specimens from 124 patients with opiate dependency syndrome and from 111 patients with other addiction disorders (alcohol, benzodiazepines, cannabis, amphetamines) were screened for pregabalin by means of a mass spectrometer analysis.
We found 12.1% of all urine specimens from patients with opiate addiction to be positive for pregabalin. None of the patients concerned had a medical indication for using pregabalin. In the control group, 2.7% of the patients were tested positively for pregabalin, due to their taking it regularly for chronic pain or general anxiety.
Our data suggest that pregabalin is liable to be abused among patients with opiate dependency syndrome. Thus, vigilance and caution are called for when patients with a past or current opiate dependency are exposed to treatment with pregabalin.
The development and maintenance of an alcohol addiction is a complex interaction between genetic and environmental factors. Genetic effects seem to contribute substantially to the risk of developing an addiction, but also to its course and patients’ responses to different treatments. Recent studies identified associations between polymorphisms in the genes of glutamate and μ-opioid receptors and addiction risk. Those receptors are of special interest, because they are targets of therapeutic agents, such as acamprosate and topiramate.
Objectives and aims
Several studies were conducted, in order to further determine the effects of genetic polymorphisms in glutamate and opioid receptor genes on addictive behavior, neural response to alcohol cues and relapse risk.
Genetic effects were investigated in samples of alcohol-dependent patients using functional imaging techniques, neuropsychological tests and follow-up investigation after standard clinical treatment. Data on clinical parameters, neuronal response to alcohol cues, functional neuronal connectivity and relapse risk were collected and analyzed.
Results demonstrate effects of genetic polymorphisms in glutamate and opioid receptors on neuronal response to alcohol cues in frontal and mesolimbic brain areas, subjective craving and time to first relapse. Current findings will be discussed in the light of existing evidence on the contribution of genetic effects to treatment outcome and patient stratification.
The investigation of genetic risk factors and mechanisms by which they affect addiction related phenotypes seems to be a promising tool to identify molecular treatment targets and predictors for successful treatment strategies.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence.
Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence.
No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value = 6.63 × 10−3); 5′-adenosine monophosphate-activated protein kinase signalling (P-value = 9.57 × 10−3); and apoptosis (P-value = 1.75 × 10−2) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status.
The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies.
Internet gaming disorder appears to be associated with self-concept deficits and increased identification with one's avatar. For increased social network use, the few existing studies suggest striatal-related positive social feedback as an underlying factor. Furthermore, few study findings indicate that internet addicts generally have problems in emotional inhibitory control processing.
Pathological and addicted internet gamers as well as social network users were compared with healthy controls regarding psychometric and neurobiological measures of self-concept-related characteristics, avatar identification and emotional inhibitory control processing.
Results and conclusion
Psychometric results indicated that both subgroups showed higher self-concept deficits compared to healthy controls. Neurobiologically, different brain activation patterns were observed in the subgroups during self-knowledge retrieval and inhibition of emotional stimuli. Furthermore, addicted internet gamers showed a higher identification with the own avatar, mirrored in an increased left angular gyrus activation, a region functionally associated with identification processing and feelings of empathy.
These findings provide a starting point for the deduction of specific psychotherapeutic treatment approaches for addicted internet gamers and social network users.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Light sheet fluorescence microscopy (LSFM) allows for high-resolution three-dimensional imaging with minimal photo-damage. By viewing the sample from different directions, different regions of large specimens can be imaged optimally. Moreover, owing to their good spatial resolution and high signal-to-noise ratio, LSFM data are well suited for image deconvolution. Here we present the Huygens Fusion and Deconvolution Wizard, a unique integrated solution for restoring LSFM images, and show that improvements in signal and resolution of 1.5 times and higher are feasible.
The properties of the acoustic modes are sensitive to magnetic activity. The unprecedented long-term Kepler photometry, thus, allows stellar magnetic cycles to be studied through asteroseismology. We search for signatures of magnetic cycles in the seismic data of Kepler solar-type stars. We find evidence for periodic variations in the acoustic properties of about half of the 87 analysed stars. In these proceedings, we highlight the results obtained for two such stars, namely KIC 8006161 and KIC 5184732.
The crystal structure of the mineral koninckite was solved from synchrotron powder X-ray diffraction (XRD) data and refined using density-functional theory (DFT) calculations. Koninckite is tetragonal, with the space group P41212, a = 11.9800(5) Å, c = 14.618(1) Å, V = 2097.9(2) Å3, Z = 8. Its structure is a heteropolyhedral framework with zeolite-like tunnels along . Owing to the severe peak overlap in the powder XRD data and the probable intergrowth of enantiomorphic domains in koninckite, the DFT calculations were applied to provide precise atomic positions (including hydrogen). Additionally, the DFT calculations suggest strongly that koninckite is an antiferromagnetic semiconductor, at least at low temperatures. The DFT computations were used to locate H2O molecules in the channels and to complete the structural description. Thermogravimetric analysis and powder XRD data at variable temperatures show that the structure of koninckite dehydrates and eventually collapses between 160–180°C. Negative thermal expansion was observed between 80 and 150°C. A list of the known occurrences of koninckite suggests that this mineral is not as rare as assumed previously; koninckite is often fine-grained, inconspicuous, and thereby easy to overlook. Koninckite is yet another natural example of an Fe-phosphate zeolitic material.