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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.
Although the majority of studies associated the function of orexin neurons with arousal and sleep and leptin with balancing energy expenditure and food craving these neuropeptides were also shown to directly affect dopaminergic transmission in mesolimbic reward pathways. This indicates a possible role for orexin and leptin in reward function and motivation and thus in addictive diseases. Aim of our study was to test whether both peptides are involved in nicotine craving in a standardized setting. We studied orexin and leptin plasma concentrations (RIA) in tobacco smokers (n = 60) compared to healthy controls (n = 64). In smoking subjects we assessed craving for nicotine applying the Questionnaire of Smoking Urges (QSU) after three hours of withdrawal from nicotine. As main results we found a significant negative correlation between orexin plasma concentration and nicotine craving (r = -0.28; p < .05) and a positive association between nicotine craving and leptin (r = 0.29; p < .05). Our results show a bidirectional association between craving for nicotine and plasma concentrations of orexin and leptin suggesting that both neuropeptides may be regulators for the dopaminergic transmission in nicotine withdrawal and, thus, modulators for craving for nicotine.
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.
A synopsis of current treatment options shows only moderate effect sizes. They could be improved considerably if individual predictors were available.
Previous attempts to identify predictors for the treatment response in alcoholism have mainly concentrated on social and personality variables. Project MATCH was such an attempt which finally failed. The same holds true for similar attempts in pharmacotherapy. Therefore, we set out for a large oligocentre trial “Project PREDICT”. 432 patients are randomly assigned to treatment with acamprosate, naltrexone or placebo. At baseline patients are assessed with a battery of interviews, questionnaires and biological examinations (e.g. genetics). Specific emphasis is put on patients’ individual pathways into relapse. It is determined whether relapse drinking respresented a positive reinforcer (“reward craving”) or a negative reinforcer (“relief craving”). This is assessed with questionnaires, the startle reflex and fMRI. We hypothesize, that patients who are a priori identified as “positive reinforcers” better respond to naltrexone. Negative reinforcers should benefit most from acamprosate.
All patients have been included by now. Preliminary analyses suggest that it is possible to distinguish between the two craving types. The equivalent of positive reinforcement in the startle reflex correlates with fMRI responses to cues with a positive valence of about 0.7. These methods might offer a platform for a targeted pharmacotherapy in alcoholism.
Mechanisms contributing to the development and maintenance of obesity remain to be elucidated especially regarding the interaction between appetite regulating hormones and mesolimbic reward circuits. Leptin was recently suggested to attenuate dopamine release in mesolimbic reward pathways. We now test the functional relevance assessing whether leptin plasma concentration affects the BOLD-response following the presentation of food cues.
21 obese and 23 normal weight subjects were investigated. Visual food cues and neutral stimuli were presented in a block design during fMRI. Blood-samples were collected immediately prior to the scan to assess plasma leptin concentration. Using linear regression analyses, the association between BOLD response to food cues and the body mass index (BMI) as well as plasma leptin concentration was examined.
Food-cues elicited activation of large cortical and subcortical networks, whereas only in obese patients food cues activated the left ventral and right dorsal striatum. Mean plasma concentration of leptin was significantly increased in obese subjects compared to normal weight controls. We found a significant positive correlation between the food cue-induced BOLD signal change in the ventral striatum and leptin plasma concentration. Furthermore, ventral and dorsal striatum BOLD response to food cues was significantly positive associated with the body mass index (BMI).
These findings suggest a physiological role of the satiety factor leptin in modulating responsivity of reward pathways towards food cues. Altered homeostatic feedback regulation of the mesolimbic brain reward circuit might explain the inability of obese patients to adapt their food intake according to physiologically needs.
The orexins (hypocretins) are neuropeptides recently identified as neurotransmitters in lateral hypothalamus neurons. Although the majority of studies associated the function of orexin neurons with arousal and sleep, these neurons also project to reward-associated brain regions, including the nucleus accumbens and ventral tegmental area. This indicates a possible role for orexins in reward function and motivation and thus in addictive diseases. Additionally, there is growing evidence from preclinical studies for an involvement of orexins in the regulation of stress, affectivity and drug seeking behavior.
We investigated orexin plasma concentrations and psychological symptoms in a sample of 34 alcohol dependent subjects on day 1 and day 14 of detoxification. For this purpose we used the Brief Symptom Inventory (BSI) as well as the Obsessive-Compulsive Drinking Scale to identify self-reported clinically relevant psychological symptoms including alcohol craving.
As a main result a significant positive correlation between orexin plasma concentration and depression as well as global distress indicies of the BSI was detected during early withdrawal (day 1), which is not shown after detoxification on day 14. No association with subjective craving for alcohol was found.
Our data indicate that orexins may be directly involved in affective dysregulation in alcohol dependent patients; moreover the effects of orexins on reinstatement of drug seeking behaviors might be mediated by impaired brain stress systems.
Ghrelin plays an orexigenic role in regulating appetite and energy balance. Preclinical studies also provided support for an important role of ghrelin in the neurobiology of addiction-related reward pathways. In contrast, clinical data have failed to support an association between ghrelin and alcohol craving, possibly due to analysing the pharmacologically inactive, preprohormone ghrelin instead of ghrelin in its active, acetylated form.
Materials and methods
In a sample of 61 alcohol-dependent male inpatients we assessed plasma concentrations of both active and total ghrelin, using blood samples taken at the onset of withdrawal and then again after 14 days of controlled abstinence. During this time, we also assessed the patients' alcohol cravings (applying the obsessive compulsive drinking scale, OCDS), symptoms of depression (Beck Depression Inventory; BDI) and anxiety (State Trait Anxiety Inventory; STAI). The severity of alcohol dependence was assessed using the alcohol dependence scale (ADS).
We found a significant positive correlation between the plasma concentration of active ghrelin and alcohol craving in both blood samples. In a linear regression model, the plasma concentration of active ghrelin on day one, the scores of the ADS, and the BDI explained 36% of the variance in OCDS sum score (p < 0.0001). By day 14, these same factors accounted for 54% (p < 0.0001). We did not detect any association between the plasma concentration of total ghrelin and patients' alcohol cravings.
Our results suggest that biologically active, acetylated ghrelin is involved in reward-associated craving during alcohol withdrawal and early abstinence in alcohol-dependent patients.
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.
The reclassification of PG as an addictive disorder is under debate for ICD-11. Data on psychiatric comorbidity and family history might provide the basis for a well-informed decision.
We compared 515 male pathological gamblers from inpatient treatment units with 269 matched controls. Patients were diagnosed by experienced clinicians. In a random sample of 58 patients clinical diagnoses were validated through SKID 1 interviews .
88% had a comorbid diagnosis of substance dependence (nicotine dependence 80%, alcohol dependence 28%). Only 1% of the gamblers had an impulse control disorder diagnosis. Compared with controls first degree relatives were more likely to suffer from alcohol dependence (27.0% vs. 7.4%), PG (8.3% vs. 0.7%) and suicide attempts (2.7% vs. 0.4%).
In addition to recent papers on the neurobiology (Fauth-Bühler et al., 2016) and genetics of gambling [2,3], our findings support the classification of PG as behavioural addiction in the ICD-11 .
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Alcohol relapse is often occurring to regulate negative affect during withdrawal. On the neurobiological level, alcoholism is associated with gray matter (GM) abnormalities in regions that regulate emotional experience such as the orbitofrontal cortex (OFC). However, no study to our knowledge has investigated the neurobiological unpinning of affect in alcoholism at early withdrawal and the associations of OFC volume with long-term relapse risk.
One hundred and eighty-two participants were included, 95 recently detoxified alcohol dependent patients (ADP) and 87 healthy controls (HC). We measured affective states using the positive and negative affect schedule (PANAS). We collected T1-weighted brain structural images and performed Voxel-based morphometry (VBM).
Findings revealed GM volume decrease in alcoholics in the prefrontal cortex (including medial OFC), anterior cingulate gyrus, and insula. GM volume in the medial OFC was positively associated with NA in the ADP group. Cox regression analysis predicted that risk to heavy relapse at 6 months increases with decreased GM volume in the medial OFC.
Negative affect during alcohol withdrawal was positively associated with OFC volume. What is more, increased GM volume in the OFC also moderated risk to heavy relapse at 6 months. Reduced GM in the OFC poses as risk to recovery from alcohol dependence and provides valuable insights into transient negative affect states during withdrawal that can trigger relapse. Implications exist for therapeutic interventions signifying the OFC as a neurobiological marker to relapse and could explain the inability of ADP to regulate internal negative affective states.
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.
While DSM-5 classified pathological gambling as an addictive disorder, there is debate as to whether ICD-11 should follow suit. The debate hinges on scientific evidence such as neurobiological findings, family history of psychiatric disorders, psychiatric comorbidity, and personality variables.
In the “Baden-Württemberg Study of Pathological Gambling”, we compared a group of 515 male pathological gamblers receiving treatment with 269 matched healthy controls. We studied differences in sociodemographic characteristics, gambling-related variables, psychiatric comorbidity (lifetime), family history of psychiatric conditions, as well as personality traits such as impulsivity (Barratt Impulsiveness Scale), sensation seeking (Zuckerman's Sensation Seeking Scale) and the NEO-FFI big five. Personality traits were validated in an age- and ethnicity-matched subsample of “pure” gamblers without any psychiatric comorbidity (including nicotine dependence). Data were analyzed using two-sample t-tests, Chi2 analyses, Fisher's exact test and Pearson correlation analysis, as appropriate. Bonferroni correction was applied to correct for multiple comparisons.
Only 1% of the gamblers had been diagnosed with an impulse control disorder other than gambling (ICD-10). Notably, 88% of the gamblers in our sample had a comorbid diagnosis of substance dependence. The highest axis I comorbidity rate was for nicotine dependence (80%), followed by alcohol dependence (28%). Early age of first gambling experience was correlated with gambling severity. Compared to first-degree relatives of controls, first-degree relatives of pathological gamblers were more likely to suffer from alcohol dependence (27.0% vs. 7.4%), pathological gambling (8.3% vs. 0.7%) and suicide attempts (2.7% vs. 0.4%). Significant group differences were observed for the NEO-FFI factors neuroticism, agreeableness and conscientiousness. Gamblers were also more impulsive than controls, but did not differ from controls in terms of sensation seeking.
Our findings support classifying pathological gambling as a behavioural addiction in the ICD-11. This decision will have a significant impact on the approaches available for prevention (e.g. age limits) and treatment.
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.
We tested Szidat's rule (the more primitive the host, the more primitive the parasites it harbours) by analysing the relationships between phylogenetic clade ranks of fleas and their small mammalian hosts in four biogeographic realms (Afrotropics, Neotropics, Nearctic and Palearctic). From the host perspective, we tested the association between host clade rank and the mean clade rank of all fleas collected from this host. From the flea perspective, we tested the relationships between flea clade rank and the mean clade rank of hosts on which this flea was recorded. First, we tested whether the analysis of the relationships between host and flea clade ranks should be controlled for phylogenetic dependence among either host or flea species. Then, we tested for the associations between host and flea clade ranks separately for each realm using either a phylogenetic general least-squares analysis or an ordinary least-squares analysis. In all realms, the mean clade rank of fleas parasitic on a given host increased with an increase of this host's clade rank, and the mean clade rank of hosts recorded on a given flea increased with an increase of this flea's clade rank, suggesting that Szidat's rule, at least to some extent, holds for fleas.
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.