Home-Cage Sipper Devices Reveal Age and Sex Differences in Ethanol Consumption Patterns.

Free-choice paradigms such as two-bottle choice (2BC) are commonly used to characterize ethanol consumption and preference of rodent models used to study alcohol use disorder (AUD). However, these assays are limited by low temporal resolution that misses finer patterns of drinking behavior, including circadian drinking patterns that are known to vary with age and sex and are affected in AUD pathogenesis. Modern, cost-effective tools are becoming widely available that could elucidate these patterns, including open-source, Arduino-based home-cage sipper devices. We hypothesized that adaptation of these home-cage sipper devices would uncover distinct age- and sex-related differences in temporal drinking patterns. To test this hypothesis, we used the sipper devices in a continuous 2BC paradigm using water and ethanol (10%; v/v) for 14 days to measure drinking patterns of male and female adolescent (3-week), young adult (6-week), and mature adult (18-week) C57BL/6J mice. Daily grams of fluid consumption were manually recorded at the beginning of the dark cycle, while home-cage sipper devices continuously recorded the number of sips. Consistent with prior studies, females consumed more ethanol than males, and adolescent mice consumed the most out of any age group. Correlation analyses of manually recorded fluid consumption versus home-cage sipper activity revealed a statistically significant prediction of fluid consumption across all experimental groups. Sipper activity was able to capture subtle circadian differences between experimental groups, as well as distinct individual variation in drinking behavior among animals. Blood ethanol concentrations were significantly correlated with sipper data, suggesting that home-cage sipper devices can accurately determine individual timing of ethanol consumption. Overall, our studies show that augmenting the 2BC drinking paradigm with automated home-cage sipper devices can accurately measure ethanol consumption across sexes and age groups, revealing individual differences and temporal patterns of ethanol drinking behavior. Future studies utilizing these home-cage sipper devices will further dissect circadian patterns for age and sex relevant to the pathogenesis of AUD, as well as underlying molecular mechanisms for patterns in ethanol consumption. Highlights: Female mice consume more ethanol than males in a continuous access paradigmAdolescent male and female mice consume more ethanol than young or mature adult miceAutomated home-cage sipper devices accurately measure ethanol consumptionDevices reveal sex- and age-dependent differences in circadian drinking patternsDevices reveal distinct individual variation in circadian drinking patterns.

Hippocampal ceRNA networks from chronic intermittent ethanol vapor-exposed male mice and functional analysis of top-ranked lncRNA genes for ethanol drinking phenotypes.

The molecular mechanisms regulating the development and progression of alcohol use disorder (AUD) are largely unknown. While noncoding RNAs have previously been implicated as playing key roles in AUD, long-noncoding RNA (lncRNA) remains understudied in relation to AUD. In this study, we first identified ethanol-responsive lncRNAs in the mouse hippocampus that are transcriptional network hub genes. Microarray analysis of lncRNA, miRNA, circular RNA, and protein coding gene expression in the hippocampus from chronic intermittent ethanol vapor- or air- (control) exposed mice was used to identify ethanol-responsive competing endogenous RNA (ceRNA) networks. Highly interconnected lncRNAs (genes that had the strongest overall correlation to all other dysregulated genes identified) were ranked. The top four lncRNAs were novel, previously uncharacterized genes named Gm42575, 4930413E15Rik, Gm15767, and Gm33447, hereafter referred to as Pitt1, Pitt2, Pitt3, and Pitt4, respectively. We subsequently tested the hypothesis that CRISPR/Cas9 mutagenesis of the putative promoter and first exon of these lncRNAs in C57BL/6J mice would alter ethanol drinking behavior. The Drinking in the Dark (DID) assay was used to examine binge-like drinking behavior, and the Every-Other-Day Two-Bottle Choice (EOD-2BC) assay was used to examine intermittent ethanol consumption and preference. No significant differences between control and mutant mice were observed in the DID assay. Female-specific reductions in ethanol consumption were observed in the EOD-2BC assay for Pitt1, Pitt3, and Pitt4 mutant mice compared to controls. Male-specific alterations in ethanol preference were observed for Pitt1 and Pitt2. Female-specific increases in ethanol preference were observed for Pitt3 and Pitt4. Total fluid consumption was reduced in Pitt1 and Pitt2 mutants at 15% v/v ethanol and in Pitt3 and Pitt4 at 20% v/v ethanol in females only. We conclude that all lncRNAs targeted altered ethanol drinking behavior, and that lncRNAs Pitt1, Pitt3, and Pitt4 influenced ethanol consumption in a sex-specific manner. Further research is necessary to elucidate the biological mechanisms for these effects. These findings add to the literature implicating noncoding RNAs in AUD and suggest lncRNAs also play an important regulatory role in the disease.

Plasma metabolomics indicates metabolic perturbations in low birth weight piglets supplemented with arginine.

Large profit losses in the swine industry can be attributed to morbidity and mortality of piglets before weaning, especially in the low birth weight (LBW) piglet. Recent evidence suggests sow's milk contains insufficient concentrations of Arg to support optimal growth and health of piglets. Therefore, our objective was to assess global metabolomic profiles and the potential for Arg supplementation to promote growth of LBW (≤0.9 kg BW) and average birth weight (ABW; 1.3 to 1.5 kg BW) piglets. Piglets were selected in littermate pairs at processing to receive either Arg or an isonitrogenous control (Ala) and weighed daily to assess growth rate, and blood was collected at approximately 16 d of age for metabolomics analysis. In terms of growth, LBW and ABW piglets supplemented with Arg weighed 22.3 and 12.7% less, respectively, at d 16 compared with Ala-supplemented piglets of the same birth weight group. Overall, differences ( < 0.05) were observed among treatments for metabolic pathways involving energy (i.e., tricarboxylic acid cycle intermediates), AA, nucleotides, and fatty acids. Increased nucleotide turnover, indicative of an increase in DNA damage and cell death, was particularly noted in the LBW piglet. However, Arg supplementation reduced these effects to levels comparable to those observed in ABW piglets. Moreover, changes in glucose metabolism suggested a compromised ability to extract energy from dietary sources may have occurred in the LBW piglet, but these effects were partially recovered by Arg supplementation. We conclude that a reduction in the growth potential of LBW piglets may be associated with alterations in multiple metabolic pathways, and further reduction due to Arg supplementation may have resulted from perturbations in multiple metabolic pathways.

[Injunction to care. Results of a study carried out in the regions of Alsace and Lorraine]. / L'injonction de soins. À propos d'une étude réalisée sur les régions Alsace et Lorraine.

INTRODUCTION: The act of June 17, 1998 created a new form of compulsory treatment: the injunction to care. This is a legal measure intended to fight against recidivism of offenders and sex offenders through medical measures. The only therapies that have demonstrated partial efficacy are cognitive behavioural therapy and treatment with anti-hormone. In France, psychodynamic therapies are paramount in the treatment of perpetrators of sexual violence, although such treatments have not demonstrated effectiveness in reducing sexual recidivism. Very few studies are available regarding the implementation of court-ordered treatment in France. The recent report by the General Inspectorate of Social Affairs (IGAS) in 2011 confirms the absence of medical statistics on the implementation of court-ordered care. OBJECTIVE: We conducted a study on the procedure of the injunction to care in the regions of Alsace and Lorraine. The aim of the study is to develop an inventory coordinator for practitioners (number, type of exercise) and the profile of patients undergoing the injunction of care (type of offense convicted for, psychiatric comorbidity identified for example). METHODS: We first identified the practicing coordinator doctors by contacting the High Courts in the geographic area studied. We then sent out a questionnaire by post to coordinator doctors to profile their patients on care injunctions. RESULTS: We identified 16 practicing coordinator doctors in two study areas: 13 are state hospital doctors and three are private practice. Of the 16 doctors contacted, six returned the completed questionnaires (38% of the sample). This allows characterizing a sample of 50 patients on care injunctions. The majority of convicted crimes are of a sexual nature (92% of cases). This is mostly for crimes or sexual offenses involving minors aged under 15 (83% of cases). Psychiatric comorbidity is the most frequently identified paedophile primary (38%) followed by mental retardation (14%), dissocial personality disorder (6%) and a borderline personality, and emotional liability (6%). Other comorbidities are divided between paranoid schizophrenia, chronic alcoholism, or other personality disorder. The follow-up is monitored by a physician in 82% of cases, while it is provided by a psychologist in 18% of cases. The management consists of a simple psychotherapy in 66% of cases. Pharmacological treatment is most often prescribed with antipsychotics (26% of cases), followed by anti-depressants (4%) and the anti-hormone (4%). CONCLUSION: Our study confirms that the majority of patients on care injunctions are sexual offenders involving minors under the age of 15. The most implemented treatment is a simple psychotherapy. The pharmacological option is infrequent and generally involves the use of inappropriate treatment (neuroleptics). Suppressive libido treatment (antidepressants and anti hormone) remains an exception in France.

[Acute psychotic disorders related to bupropion: review of the literature]. / Troubles psychotiques aigus liés au bupropion: revue de la littérature.

RATIONALE AND OBJECTIVES: Bupropion, or amfebutamone, is an atypical antidepressant also used during tobacco cessation. From a structural standpoint, it resembles amphetamine drugs with psychostimulant effects, and endogenous monoamines. From a pharmacological standpoint, bupropion, and two of its most important active metabolites, inhibit dopamine and norepinephrine reuptake. It has recently been discovered that bupropion may act as a non-competitive cholinergic nicotinic receptor antagonist, and that it may inhibit the activation of reward systems triggered by nicotine. Buproprion's efficacy as a smoking cessation aid has been demonstrated by numerous clinical trials that have compared its effects with those of placebo and other nicotinic substitutes. In 2001, buproprion SR received marketing authorization in France as a smoking cessation aid, under the name ZYBAN®. Tobacco addiction indeed remains a major public health issue. Among patients with psychiatric conditions, chronic tobacco consumption is frequent. The development of non-nicotinic drugs may therefore enhance therapeutic possibilities. However, the psychotropic effects of these molecules should be taken into account. We have recently reported the case of a patient with schizoaffective disorder, who presented two acute bupropion-induced psychotic episodes. We have also undertaken an exhaustive bibliographical research on this subject. The aim of the present study is to present the information available to us, in order to suggest aetiopathogenic hypotheses and therapeutic proposals. DATA SOURCES: The following databases were consulted on a regular basis, with no date restriction: Medline, Cochrane and Elsevier. The present study identified 22 cases of psychotic conditions associated with buproprion, as well as randomized and pharmacovigilance studies published in English, from December 1985 to November 2008. Since 2002, there have been three published case-reports on patients who underwent a tobacco cessation program. DATA SYNTHESIS: Psychotic disorders associated with buproprion appear after an average of 10 days of 300 mg/d bupropion intake. In about two third of cases, the patients have no history of psychiatric conditions. In one third of cases, they have a history of thymic disorders. In our review, auditory, visual or cenaesthetic hallucinations frequently occur (85% of the reported cases), and are sometimes characterized by single episodes and/or are rationalized. Some of them occur along with delusional episodes (mystical, paranoid, etc.). The patients are restless, confused, but seldom exhibit dissociative and thymic symptoms. DISCUSSION AND CONCLUSIONS: From an aetiopathogenic, clinical and evolutive standpoint, buproprion-induced psychotic episodes share many similarities with acute organic or toxic psychosis (notably induced by amphetamines). The hypothesis of a dopaminergic hyper-reactivity should be analyzed. Moreover, most of these patients were taking other medication, and the possibility of a dopaminergic potentialization prior to buproprion intake could be suggested. In such cases, bupropion should be discontinued and complete remission is expected within an average of 10 days. Even though neuroleptic drugs are still frequently used in these cases, benzodiazepines could become a valid alternative, according to the model of amphetamine-induced acute psychosis.

New frontiers of cognitive rehabilitation in geriatric age: the Mozart Effect (ME).

The ME was described for the first time in 1993. Subsequently other studies with similar designs were performed. The present study, therefore, proposes: (i) to verify the existence of the benefits of exposure to music in elderly subjects with mild cognitive impairment (MCI), (ii) to explore whether it is possible to find any lasting improvement after training, conducted for a long period of time, with such musical pieces, in the measurable cognitive performances. The study we conducted showed that the ME is present in geriatric patients with MCI; the influence on spatial-temporal abilities remains constant in time if the stimulation is maintained. The continuation of our study will consist of increasing the number of individuals examined and in having them listen to music during the study of ECG rhythms and during the acquisition of cerebral functional magnetic resonance imaging (fMRI), and, at the same time, testing them by neuropsychometric methods.

Exaggerated morning blood pressure surge and cardiovascular events. A 5-year longitudinal study in normotensive and well-controlled hypertensive elderly.

Cardiovascular events (CE) occur most frequently in the morning hours in hypertensive subjects. We studied the association between the morning blood pressure (BP) surge and CE in prognosis of 10 normotensive and 32 well-controlled hypertensive elderly, in whom ambulatory BP monitoring was performed and who were followed prospectively for 5 years. The morning surge (MS) of BP was calculated as mean systolic BP during 2h after awakening--mean systolic BP during 1h that included the lowest sleep BP. During an average of 60 months, five CE occurred. When the patients were divided into two groups according to MS, those in the top terzile (MS group; MS> or =34 mmHg, n=14) had a higher prevalence of CE (5 versus 0, p=0.001) during the follow-up period, than the others (non-MS group; MS<34 mmHg, n=28). The logistic regression analysis showed the MS sleep-trough surge as predictive variable of CE (odds ratio, OR=0.794, p=0.022). In conclusion, in older normotensives and well-controlled hypertensives, a higher BP MS is associated with vascular risk independently of clinical and ambulatory BP. Reduction of the MS could thus be a therapeutic target for preventing vascular events also in non-hypertensive patients.

The Marigliano-Cacciafesta polypathology scale (MCPS): a tool for predicting the risk of developing disability.

The purpose of the work was to verify whether our MCPS can be a tool for predicting the risk of developing disabilities. We considered 45 elderly subjects divided into three groups of 15 subjects each. Group 1 consisted of cases with a "moderate-severe" degree of polypathology, with no associated condition of disability evaluated by means of the activities of daily living (ADL). Group 2 contained cases with a "moderate" degree of polypathology (with no associated condition of ADL disability). The Group 3 was the control group with a "mild" degree of polypathology (with no disability associated with ADL). All subjects were re-evaluated after 6 and 12 months. Both Groups 1 and 2 of cases over time developed greater disabilities, compared to the control Group 3; in particular, the subjects with "moderate-severe" polypathology were more disabled after 12 months.

The Marigliano-Cacciafesta polypathological scale: a tool for assessing fragility.

The aim of our studies was to establish a standard method of assessment that allows an early identification of frailty in the elderly, i.e., to predict who are at risk of developing disabilities, in order to be able to intervene with preventive global and individualized measures. A new multidimensional scale called Marigliano-Cacciafesta polypathological scale (MCPS) was used on 180 elderly people, together with the Barthel index (BI), the global evaluation functional index (GEFI), the geriatric depression scale (GDS), the mini mental state examination (MMSE), the mini nutritional assessment (MNA), and the Tinetti test. A strongly significant statistical correlation was found between the MCPS and the nutritional state, mood level, motor functionality, level of disability and global functionality. As the fragile patients are at a risk to develop disabilities, we think that our scale can be a significant contribution to the multidimensional geriatric assessment (MGA), aimed at identifying and quantifying the parameter of fragility of each patient, an information which should be known, if we intend to introduce preventive measures.

Sleep quality of centenarians: cognitive and survival implications.

Sleep is an active nervous process, which is structured in phases characterized by subsequent cycles of various psycho-physiological phenomena. It performs vital, yet mysterious functions and is in all likelihood involved in many processes, including cognitive processes. In old age the internal structure of sleep changes, but these physiological variations allow, in healthy subjects, a satisfactory quantity and quality of sleep. Until now there have been no literature reports of studies regarding sleep quality in extreme old age. Our work describes the investigation of the quality of sleep in a sample of 180 centenarians selected from the registered residents of Rome. We have studied sleep disorders, related pathologies and pharmacological treatments. The results of the study show good sleep quality for 57.4% of the sample group; 35.2% complain of medium intensity problems, significantly related to angina pectoris and to chronic obstructive bronchopneumopathy. Only 7.4% of the subjects showed severe problems, significantly related with cognitive deficiency and lower survival rate. The results of our study confirm, in centenarians as in the elderly, the existence of a positive correlation between sleep quality, survival and successful aging.

Smoking and longevity: an incompatible binomial?

In Western countries data from clinical and epidemiological studies have induced the public health offices to promote a great deal of advertising and informative campaigning for smoking reduction. Cigarette smoking has been clearly linked to the most common causes of death in the elderly and contributes to the higher death rate and disability rate associated with many chronic illnesses that are common in this age group. The combination of smoking along with other risk factors like hypertension and diabetes increase high frequency diseases, disability as well as adding to an increase in mortality rate. In order to verify if a healthy lifestyle really favors longevity and how much smoking is incompatible with extreme longevity we investigated the prevalence of smokers and the total smoking exposure of a sample of centenarians in relation with residual survival and health conditions. Our sample consists of 157 centenarians living in Rome, 39 males and 118 females (ratio m/f =1:3),mean age being 101.59 +/- 1.8 years (+/-SD), 83.8% of the centenarians have never smoked,13.5 % are former smokers, and 2.7% are active smokers. The average starting age of smoking is 21.2 years, while the average age of quitting is 65.7 years with an average of 44.7 +/- 17.1 smoking years. The average number of smoked cigarettes per day is quite low,less than 10 cigarettes, so that the total average number of smoked cigarettes is 158,045,well under 280,000 which is considered the cut-off point in many studies of when tumors are noticed. There seemed to be a significant difference (p < 0.001) in gender results in smokers: among male centenarians smokers reached 46%, while female smoker centenarians reached only 8.1%. Statistically significant chronic illnesses were noted among centenarian smokers over the age of 65 (p < 0.02). Moreover, Cox's regression has shown in centenarians a lower survival rate (p < 0.05) in smokers (20.7 +/- 11.2 months) than in non-smokers (27.0 +/- 19.0 months). In conclusion, our study evidences that smoking is for all but some exceptional subjects, incompatible with successful aging and compromises life expectancy even in extreme longevity.

The development and testing of a prototype on-line radioiodine monitor for nuclear power stations.

A prototype on-line monitor has been developed which is capable of detecting radioiodine in the presence of as much as 1 X 10(6) higher concentration of noble gases. The system contains two identical radiation monitoring chambers through which the monitored air and a purging gas alternately cycle. Each chamber contains a silver zeolite filter which has a high retention of the various forms of airborne radioiodine but low retention of noble gases. During the purging cycle the radioactive noble gases are quickly purged from the filter and chamber and the lower levels of radioiodine accumulated on the filter are detected. This system has been successfully tested using short-lived radionuclides simulating vented reactor gases resulting from an abnormal condition.

Evaluation of radiation monitor effectiveness for the detection of 85Kr.

As part of the preparations for the purging of TMI Unit-2, the 85Kr sensitivity of 12 radiation detector systems or system combinations was determined. Eleven of these were evaluated using a cube-shaped polyethylene-walled room containing a volume of 5.6 m3 (200 ft3). Krypton-85 gas was added to produce a concentration of 6.7 x 10(-6) muCi/ml in the test room. It was found that none of the ion chambers and scintillation detector systems were able to detect this concentration of 85Kr. Detectors employing thin window GM pancake probes were found to be sensitive enough to monitor this gas down to the unrestrictive area maximum permissible concentration level (MPC) of 3 x 10(-5) muCi/ml, while a large window gas flow proportional counter was found to be sensitive enough to monitor down to about 09.1 MPC. At the end of this experiment, 2.3 m3 (80 ft3) of the gas in the test room was pumped into a compressed air cylinder (scuba bottle) and was used to calibrate The Pennsylvania State University (PSU) Noble Gas Monitor. The sensitivity of this system, which employs gas compression and Ge(Li) spectroscopy, was demonstrated to be between 0.1 and 0.03 times MPC, depending on the counting time employed.