Use of immediate release melatonin in psychiatry: BMI impacts the daily-dose.

OBJECTIVE: There is a growing interest in psychiatry regarding melatonin use both for its soporific and chronobiotic effects. This study aimed to evaluate factors impacting the daily-dose. METHODS: In a university department of psychiatry in Paris (France), we conducted a posteriori naturalistic observational study from April 03, 2017 to January 31, 2018. We assessed links between sociodemographic and clinical characteristics and daily dose of melatonin (the daily-dose of melatonin initiation and the daily-dose at Hospital discharge). A survey of drug interactions was performed regarding metabolic inducers and inhibitors of the cytochrome P450 1A2. RESULTS: Forty patients were included and treated with immediate-release melatonin. For patients with no history of melatonin use, the initiation dose of was 2 or 4mg, with no effects of age, weight, BMI, melatonin indication, cause of hospitalization. We found that higher discharge dose was associated with higher BMI (P=0.036) and more reevaluations of melatonin dose (P=0.00019). All patients with a moderate inducer (n=3, here lansoprazole) were significantly more associated with the discontinuation melatonin group (P=0.002). CONCLUSION: The BMI and the number of reevaluations impact the daily dose of melatonin. Two mechanisms may explain that BMI may need higher doses: (i) melatonin diffuses into the fat mass, (ii) the variant 24E on melatonin receptor MT2, more frequent in obese patients, leads to a decrease of the receptor signal.

[Securing the distribution of patient-specific unit dose medication following the installation of a unit dose dispensing system: Cartography of risks a priori within a hospital pharmacy]. / Sécurisation de la dispensation individuelle et nominative suite à l'implantation d'un automate de dispensation nominative : cartographie des risques a priori au sein d'une pharmacie à usage intérieur.

INTRODUCTION: With a view to reinforcing the security of the drug distribution process, the hospital pharmacy has decided to automate the patient-specific unit dose distribution system which, up to now was performed manually, through the acquisition of a unit dose dispensing system: the ACCED S 300 (ECODEX®). The aim of this work is to realize a cartography of risks, focused on the dispensing stage, prior to the implementation of the automated system. MATERIALS AND METHOD: A multidisciplinary group applied the preliminary risk analysis (PRA) technique. The study was limited to the dispensing stage of unit doses within the hospital pharmacy. RESULTS: This analysis revealed 122 accident scenarii, including 18 with an initial unacceptable criticality (14.8 % of scenarii). In total, 140 risk management actions were proposed. These actions include: acquisition of equipment, communication and training of pharmacy staff, communication with services, human resources management and organization of working hours, writing and updating quality documents, programming the software and interfaces linked with the robot. CONCLUSION: The implementation of risk management actions should reduce the risk and contribute to avoiding the most critical scenarii. This will require the availability of human and financial resources and the implication of management.

[Stable iodine as a prophylaxis therapy following exposure to radioactive iodines: pharmacological and pharmaceutical characteristics]. / Iode stable et prévention de la contamination par les iodes radioactifs : données pharmacologiques et pharmaceutiques.

More or less rapid radio-induction of thyroidian cancers is the main pathological consequence of an accidental exposure to ingested or inhaled radioactive iodines following a nuclear power plant accident. The prophylactic administration of potassium iodine in a single oral dose has to be practiced as soon as possible after the nuclear accident. The efficacy of this therapy depends on pharmacokinetics of radioidines. Iodines are rapidly and completely absorbed as iodides. The radioactive iodines, mainly iodine 131, concentrate in the thyroid gland because of a carrier-mediated transport by the Na-I symporter. Administration of stable iodine results in the symporter blockade, which limits the uptake of radioactive iodines by the thyroid and the duration of the internal irradiation. This irradiation will never exceed 3days if the therapy is started between 6h before the accidental exposure and 1h after. The pharmacist asked to dispense the tablets of stable iodine has a important place because, besides his advices on the optimal modalities of taking stable iodine and the risks of unwanted effects, he extend these advices to information on the radioactive risk and on measures of civil and sanitary protection.

[Cannabis withdrawal syndrome in patients with cannabis dependence only, and in patients with cannabis and opioid dependence]. / Syndrome de sevrage au cannabis dans une population de patients mono- et polydépendants (cannabis et opiacés).

BACKGROUND: The cannabis withdrawal syndrome occurs after cannabis cessation in more than 50% of dependent smokers. But although opioid-dependent patients are more frequently cannabis users and cannabis-dependent than the general population, the frequency and phenomenology of cannabis withdrawal symptoms in this specific population is unknown. Our hypothesis was that cannabis-dependent patients with current opioid dependence would experience the same withdrawal syndrome after cannabis cessation. OBJECTIVE: To describe cannabis withdrawal symptoms in cannabis-only dependent patients and in cannabis-dependent patients with current opioid dependence. METHODS: Using retrospective interviews, we evaluated the number and duration of six cannabis withdrawal symptoms in two groups: 56 cannabis-dependent patients without and 43 cannabis dependent patients with current opioid dependence. Cannabis and opioid dependence diagnoses were defined with DSM IV criteria using the MINI structured interview. RESULTS: The two groups were not different in terms of age of onset of cannabis use, and number of cannabis joints smoked at the time of the cannabis cessation attempt. The frequency of a cannabis withdrawal syndrome (defined as at least two different symptoms) did not differ in the two groups (65%). Neither was the proportion of subjects with the following symptoms: appetite or weight loss (30.8%), irritability (45.1%), anxiety (56%), aggression (36.3%) and restlessness (45.1%). Patients with cannabis dependence and current opioid dependence were more likely to report sleep disturbances (79.1 vs. 53.6%, chi(2)=6.91, P=0.007). The median duration of this cannabis withdrawal syndrome was 20 days post-cessation. CONCLUSION: This is, to our knowledge, the first study describing cannabis withdrawal syndrome in cannabis-dependent patients with current opioid dependence. These patients experience a cannabis withdrawal syndrome as often as cannabis-only dependent subjects, but describe more frequently sleep disturbances. This high rate of sleep disturbances may cause relapse to cannabis use.

Design a system for measuring individual cow feed intake in commercial dairies.

Monitoring individual cow feed intake is necessary for calculating the cow individual feed efficiency. The cost and maintenance time necessary for research systems make them impractical for most of the commercial producers. We developed a measurement system with producer convenience and low investment as key design criteria. The goal of this study was to design the system and validate its ability to rank cows by their feed conversion efficiency in commercial farms. The new system consisted of three principal parts: (a) a hanging weighing system, (b) a visual cow identification system and (c) an automatic cleaning system. The weighing system consisted of hanging a single load cell to provide feed mass measurements. The image-based cow identification system (replacing Radio-Frequency Identification) entailed cameras installed above the feeding area and an image processing algorithm that recognized cows by their collar numbers. The new system worked within normal farm routines: the feed supplying truck distributed the animal feed, and a tractor cleaned feed residual. To validate the accuracy and convenience of the system and to rank the cows by their efficiency, an experiment with six scales and 12 cows was conducted in a research barn, succeeded by eight-scale system in a commercial farm with 16 cows. The feed intake of each cow participating in the experiments was monitored for one month. The validation experiment showed that the system had the following specification: scales were accurate within 120 g; the visual cow identification rate was greater than 96%; feeding duration was accurate to 52 s; and routine farm practices (feed distribution, pushing, and residual removal) continued as usual. The cost for a feeding station (utilized consequently for a number of cows) was about 1 500 USD. An example of application of the system to rank cows by their efficiency under commercial conditions was shown. The system can potentially be used for ranking cows by their efficiency in commercial facilities.

Dynamic cooling strategy based on individual animal response mitigated heat stress in dairy cows.

Technological progress enables individual cow's temperatures to be measured in real time, using a bolus sensor inserted into the rumen (reticulorumen). However, current cooling systems often work at a constant schedule based on the ambient temperature and not on monitoring the animal itself. This study hypothesized that tailoring the cooling management to the cow's thermal reaction can mitigate heat stress. We propose a dynamic cooling system based on in vivo temperature sensors (boluses). Thus, cooling can be activated as needed and is thus most efficacious. A total of 30 lactating cows were randomly assigned to one of two groups; the groups received two different evaporative cooling regimes. A control group received cooling sessions on a preset time-based schedule, the method commonly used in farms; and an experimental group, which received the sensor-based (SB) cooling regime. Sensor-based was changed weekly according to the cow's reaction, as reflected in the changes in body temperatures from the previous week, as measured by reticulorumen boluses. The two treatment groups of cows had similar milk yields (44.7 kg/d), but those in the experimental group had higher milk fat (3.65 vs 3.43%), higher milk protein (3.23 vs 3.13%), higher energy corrected milk (ECM, 42.84 vs 41.48 kg/d), higher fat corrected milk 4%; (42.76 vs 41.34 kg/d), and shorter heat stress duration (5.03 vs 9.46 h/day) comparing to the control. Dry matter intake was higher in the experimental group. Daily visits to the feed trough were less frequent, with each visit lasting longer. The sensor-based cooling regime may be an effective tool to detect and ease heat stress in high-producing dairy cows during transitional seasons when heat load can become severe in arid and semi-arid zones.

HOPE, an open platform for medical data management on the grid.

The paper describes a platform developed for the secure management and analysis of medical data and images in a grid environment. Designed for telemedicine and built upon the EGEE gLite middleware and particularly the metadata catalogue AMGA as well as the GridSphere web portal, the platform provides to healthcare professionals the capacity to upload and query medical information stored over distributed servers. A job submission environment is also available for data analysis. Security features include authentication and authorization by grid certificates, anonymization of medical data and image encryption. The platform is currently deployed on several sites in Europe and Asia and is being customized for applications in the field of telemedicine and medical physics.

Gender-specific study of recurrent suicide attempts in outpatients with multiple substance use disorders.

BACKGROUND: people suffering from substance use disorders (SUD) often die by suicide, so that the prevention of suicide attempts (SA) remains a top priority in this population. SA recurrence is common and is associated with suicide death, but this phenotype has been overlooked in SUD populations. Thus, we aimed at identifying the risk factors of SA recurrence in SUD, controlling for both gender and levels of exposure to addictive substances, including tobacco. METHODS: we consecutively recruited 433 treatment-seeking outpatients with either opiate or cocaine use disorder and assessed their lifetime history of addictive and suicidal symptoms by standardized questionnaires. They were reliably classified as never, single or recurrent (≥ 2) suicide attempters, whose characteristics were identified by multinomial regression, stratified by gender; and compared to our previous work on serious SA in order to identify common or different risk profiles. RESULTS: 86/140 (61%) suicide attempters reported recurrence. The mean number of SA was 3.1. Recurrence was independently associated with psychiatric hospitalization in both genders, with nicotine dependence in men and with sedative use disorders in women. LIMITATIONS: psychiatric diagnoses were derived from the current medication regimen. CONCLUSION: specific and possibly avoidable/treatable risk factors for the recurrence of SA in SUD have been identified for the first time, opening new avenues for research and prevention in this high-risk population. Apart from nicotine dependence, these risk factors were very similar to those of serious SA. Although this comparison is indirect for now, it suggests a common liability towards suicidal behavior.

Serious suicide attempts in outpatients with multiple substance use disorders.

BACKGROUND: Suicide is a major public health concern and suicide attempts (SA) are frequent and burdensome in people suffering from substance use disorders (SUDs). In particular, serious SAs are a preoccupying form of attempt, which remain largely overlooked in these populations, especially regarding basic risk factors such as gender, addictive comorbidity and substance use patterns. Thus, we undertook a gender-specific approach to identify the risk factors for serious SAs in outpatients with multiple SUDs. MATERIAL AND METHODS: 433 Treatment-seeking outpatients were consecutively recruited in specialized care centers and reliably classified as serious, non-serious and non-suicide attempters. We also characterized lifetime exposure to SUDs, including tobacco smoking, with standardized instruments. Current medication, including psychotropic treatments were collected, which informed psychiatric diagnoses. Multinomial regression identified independent factors specifically associated with serious SAs in each gender, separately. RESULTS: 32% Participants (N=139, 47% Women and 27% Men) reported lifetime SA. There were 82 serious attempters (59% of attempters), without significant gender difference. Sedative dependence was an independent risk factor for serious SA compared to non-SA in Women and compared to non-serious SA in Men, respectively. Other risk factors included later onset of daily tobacco smoking in Men and history of psychiatric hospitalizations in Women, whose serious SA risk was conversely lower when reporting opiate use disorder or mood disorder, probably because of treatment issues. CONCLUSIONS: Despite several study limitations, we identified subgroups for a better-tailored prevention of serious SAs among individuals with SUDs, notably highlighting the need to better prevent and treat sedative dependence.

Linear relation between the magnitude of long-term potentiation in the dentate gyrus and associative learning in the rat. A demonstration using commissural inhibition and local infusion of an N-methyl-D-aspartate receptor antagonist.

Field potentials were recorded in the dentate gyrus of freely-moving rats in a classical conditioning paradigm in which high-frequency stimulation of the perforant path served as a conditioned stimulus. Paired or unpaired perforant path stimulus-footshock presentations were given to animals engaged in a previously acquired food-motivated lever-pressing task. Conditioned suppression of lever-pressing was the behavioural measure of conditioning. Perforant path stimulus trains at an intensity above spike threshold induced long-term potentiation of synaptic transmission in the dentate gyrus. In this condition, animals learned the perforant path stimulus-shock association. Three strategies were employed to block the induction or reduce the magnitude of long-term potentiation induced by the conditioned stimulus: (1) reduction of the intensity of the stimulus below the spike threshold resulted in no long-term potentiation and a failure by the animals to learn the perforant path stimulus-shock association; (2) inhibitory modulation of long-term potentiation by high-frequency activation of commissural input to the dentate gyrus resulted in learning deficits; (3) chronic infusion of DL-2-amino-5-phosphonovalerate, a selective antagonist of the N-methyl-D-aspartate subtype of glutamate receptor, blocked the induction of long-term potentiation and prevented associative learning. A highly significant linear relation emerged from a correlational analysis between the magnitude of the change in synaptic efficacy at the activated synapses and the amount the animals learned about the perforant path stimulus-shock association. The results presented in this paper are consistent with the hypothesis that associative learning depends on the development of lasting changes in synaptic function. We propose that the activation of N-methyl-D-aspartate receptors in the dentate gyrus is involved in this process and that the more change in synaptic efficacy is produced in the activated network, the more the animals learn.

Conditioning of hippocampal cells: its acceleration and long-term facilitation by post-trial reticular stimulation.

Neuronal activity, recorded in the dorsal hippocampus (CA3) during classical conditioning, was studied in rats receiving mild post-trial stimulation of the mesencephalic reticular formation. Hippocampal multi-unit activity increased in response to an auditory signal (conditioned stimulus) after pairing of the signal with a footshock (unconditioned stimulus), while the auditory signal alone, presented before conditioning, did not change the rate of hippocampal cell discharges. Trial-by-trial analysis of hippocampal multi-unit responses to the conditioned stimulus, both during acquisition and during a test of long-term retention, indicated that post-trial mesencephalic reticular stimulation hastened the onset of cellular conditioning and facilitated conversion to long-term storage. A study of evoked potentials recorded in the hippocampal formation to stimulation of the perforant path in awake rats, suggested that these effects could be mediated through a modulation of synaptic efficiency within hippocampal neuronal networks. These data are discussed in relation to the concept of neural perseveration in memory consolidation.

Post-trial reticular facilitation of associative changes in multiunit activity; comparison between dentate gyrus and entorhinal cortex.

Multiunit activity recorded in both the dentate gyrus and the entorhinal cortex during classical conditioning was studied in freely moving rats receiving a mild post-trial stimulation of the mesencephalic reticular formation. Dentate multiunit activity progressively increased in response to an auditory signal (conditioned stimulus) after pairing the signal with a footshock (unconditioned stimulus). No such increase was seen in the entorhinal cortex of the same animals during conditioning. Post-trial reticular stimulation facilitated the development of associative changes in dentate multiunit activity, while having no effect in the entorhinal cortex. The results were interpreted as indicating a possible specificity of action of post-trial reticular stimulation on learning-induced plasticity and are discussed in relation to the concept of neural perseverance in memory consolidation.

Processing of learned information in paradoxical sleep: relevance for memory.

After a short review of the post-learning paradoxical sleep (PS) deprivation effects and of the PS changes induced by learning, we present a set of electrophysiological and behavioural experiments showing that: (1) processing of relevant information is possible during PS; (2) new associations can be formed during PS; (3) previously learned information can be reprocessed during PS; and (4) the effects of information processed during PS can be transferred to the awake state and be expressed in behaviour. Altogether, these results support the idea that dynamic processes occurring during post-learning PS can contribute to the effectiveness of memory processing and facilitate memory retrieval in wakefulness.

Responses of hippocampal cells can be conditioned during paradoxical sleep.

To test the hypothesis that new associations can be acquired during sleep, we developed a conditioning paradigm in which both conditioned (CS) and unconditioned (US) stimuli were non-awakening intra-cerebral stimulations. The CS was a stimulation of the Medical Geniculate body and the US a stimulation of the Central Grey. An increase in hippocampal multiunit activity to CS was taken as the conditioned response. CS-US pairings were presented across 14 sessions, with 15 trials per session and a 24-h inter-session interval. Three groups were studied: in a group the CS-US pairings were given during the awake state (group W), and in two groups pairings were presented during sleep, either slow-wave sleep (group SWS) or paradoxical sleep (group PS). In the last group, to test the possibility of transfer to the awake state of the hippocampal response acquired in PS, the CS alone were presented interspersed with periods of wakefulness. Results showed that, before pairing, CS presentation induced no change in hippocampal multiunit activity in the three groups. After pairing, no hippocampal response to CS presentation occurred in SWS. In contrast, in the W group and in the PS group, a marked increase in hippocampal activity appeared to CS. The hippocampal response in the PS group developed progressively across sessions; it occurred only two sessions later than in the W group. Moreover, when the CS-evoked response reached the asymptotic level in PS, the presentation of CS alone in awake animals elicited the hippocampal response. These results suggest that a cellular conditioning can be established during PS and that the cellular conditioned response developed in PS can be transferred to the awake state.

Facilitation of generalization performances in spatial learning problems by posttrial stimulation of the mesencephalic reticular formation.

The effects of low posttrial stimulation of the mesenphalic reticular formation (MRF) on spatial learning problems were studied in two consecutive stages. First, the performances of stimulated (S) and no-stimulated (NS) subjects were assessed in a reconvergent three-arm maze. Secondly, the same animals were tested in a generalization paradigm, since they had to solve a similar task in a radial four-arm maze, each group being divided into newly stimulated (S-S, NS-S) or no-stimulated (S-NS, NS-NS) subjects. In the first experiment, no differences were found between the acquisition processes of groups S and NS. Conversely, in the second experiment, previously stimulated animals (S-S and S-NS) showed better generalization of the experimental rule. The results are discussed in terms of preservation of the neural activity after the early MRF stimulation. From a functional point of view, our data indicate that an enhancement of the neural activity during acquisition facilitates not only a high accessibility of memories concerning the experimental rule in a subsequent similar situation but also the capability to apply a previously elaborated response system in a more complex situation.

A life-threatening dichlorophen poisoning case: clinical features and kinetics study.

BACKGROUND: Human dichlorophen poisoning is rare. We aim to report a case of dichlorophen poisoning resulting in complete recovery despite life-threatening multiorgan failure and huge serum dichlorophen concentrations. METHODS: Description of features and management in one dichlorophen-poisoned patient. After liquid-liquid extraction, dichlorophen concentrations in the urine and the serum were measured using liquid chromatography-heated electrospray ionization-tandem mass spectrometry (LC-HESI-MS/MS). CASE REPORT: A 74-year-old female self-ingested an anti-moss dichlorophen solution (360 g/L) in a suicidal attempt. She rapidly developed caustic esophageal and gastric mucosal injuries, confusion, profuse diarrhea, and electrolyte disturbances. Initial elevation in serum aminotransferase and γ-glutamyltransferase concentrations resolved over 6 days. Serum dichlorophen concentration measured was 708.1 µg/L on admission, and its elimination was prolonged (serum apparent elimination half-life: 35.5 h), peaking in urine on day 2. Mild elevation in serum creatine phosphokinase concentration (peaking 48 h post-ingestion) and acute renal failure (requiring hemodialysis on day 8) occurred. The final outcome was favorable with supportive management. CONCLUSION: Dichlorophen ingestion results in life-threatening multiorgan dysfunction including rapid onset of caustic digestive lesions, diarrhea, liver enzyme disturbances, as well as acute kidney injury and rhabdomyolysis. Recovery can be complete if prompt supportive management is provided.

Could the inter-individual variability in cocaine-induced psychotic effects influence the development of cocaine addiction? Towards a new pharmacogenetic approach to addictions.

Cocaine addiction is a chronic disease marked by relapses, co-morbidities and the importance of psychosocial consequences. The etiology of cocaine addiction is complex and involves three types of factors: environmental factors, factors linked to the specific effects of cocaine and genetic factors. The latter could explain 40-60% of the risk for developing an addiction. Several studies have looked for a link between cocaine addiction and the genes of the dopaminergic system: the genes DRD2, COMT, SLC6A3 (coding for the dopamine transporter DAT) and DBH (coding for the dopamine beta hydroxylase) but unfortunately very few well established results. Pharmacogenetic approach could be an interesting opportunity for the future. The gene DBH has particularly been linked with the psychotic effects caused by cocaine. This so-called cocaine-induced psychosis (CIP) or cocaine-induced paranoia may influence the development of cocaine addiction. Indeed, these psychotic symptoms during cocaine exposure could cause an aversive effect limiting the development of an addiction. Several functional alterations caused by different mutations of the genes involved in dopaminergic transmission (principally-1021C>T of the gene DBH, but also Val158Met of the gene COMT, TaqI A of the gene DRD2 and VNTR 9 repeat of the DAT) could result in a cocaine-induced psychosis prone phenotype. We are hypothesising that the appearance of CIP during the first contact with cocaine is associated with a lower risk of developing cocaine addiction. This protective effect could be associated with the presence of one or more polymorphisms associated with CIP. A pharmacogenetic approach studying combination of polymorphism could isolate a sub-group of patients at risk for CIPs but more favorably protected from developing an addiction. This theory could enable a better understanding of the protective factors against cocaine addiction and offer new therapeutic or preventive targets in vulnerable sub-groups exposed to cocaine.