Can the Dose of Belimumab be Reduced in Patients with Systemic Lupus Erythematosus?

OBJECTIVES: The aims of this study were to investigate the prevalence of dose reduction in patients with SLE treated with belimumab (BEL) in Spain, analyze treatment modalities, and determine impact on control of disease activity. METHODS: Retrospective longitudinal and multicentre study of SLE patients treated with BEL. Data on disease activity, treatments and outcomes were recorded before and after reduction (6-12 months), and they were compared. RESULTS: A total of 324 patients were included. The dose was reduced in 29 patients (8.9%). The dosing interval was increased in 9 patients receiving subcutaneous BEL and in 6 patients receiving intravenous BEL. The dose per administration was reduced in 16 patients.Pre-reduction status was remission (2021 DORIS) in 15/26 patients (57.7%) and LLDAS in 23/26 patients (88.5%). After reduction, 2/24 patients (8.3%) and 3/22 patients (13.6%) lost remission at 6 months and 12 months, respectively (not statistically significant [NS]). As for LLDAS, 2/23 patients (8.7%) and 2/21 patients (9.5%) lost their status at 6 and 12 months, respectively (NS). Significantly fewer patients were taking glucocorticoids (GCs) at their 12-month visit, although the median dose of GCs was higher at the 12-month visit (5 [0.62-8.75] vs 2.5 [0-5] at baseline). CONCLUSION: Doses of BEL can be reduced with no relevant changes in disease activity-at least in the short term-in a significant percentage of patients, and most maintain the reduced dose. However, increased clinical or serologic activity may be observed in some patients. Consequently, tighter post-reduction follow-up is advisable.

Annular erythema in primary Sjogren's syndrome: description of 43 non-Asian cases.

OBJECTIVE: The objective of this paper is to evaluate the prevalence and characterize the main epidemiological, clinical and immunological features of annular erythema (AE) in non-Asian patients with primary Sjögren's syndrome (SS). METHODS: We carried out a retrospective study searching for AE in 377 Spanish patients with primary SS fulfilling the 2002 American-European criteria. In addition, we searched PubMed (1994-2012) using the MeSH terms "annular erythema" and "primary Sjögren's syndrome" for additional cases. All cases with AE reported in patients with SS associated with systemic lupus erythematosus were excluded. RESULTS: In our Spanish cohort, we found 35 (9%) patients diagnosed with AE. All were white females, with a mean age of 47 years at diagnosis of AE. AE preceded diagnosis of SS in 27 (77%) patients. Cutaneous AE lesions involved principally the face and upper extremities. All patients reported photosensitivity, with cutaneous flares being reported during the warmest months in 93% of patients. Immunological markers consisted of anti-Ro/La antibodies in 31 (89%) patients. In the literature search, we identified eight additional non-Asian patients with primary SS diagnosed with AE. In comparison with 52 Asian patients, the 43 non-Asian patients with AE related to primary SS were more frequently women (100% vs 78%, p=0.008), and cutaneous lesions were less frequently reported in the face (55% vs 81%, p=0.045) and more frequently in the neck (40% vs 14%, p=0.041). Immunologically, non-Asian patients had a lower frequency of anti-Ro antibodies and a higher frequency of negative Ro/La antibodies, although the differences were not statistically significant. CONCLUSION: AE is not an exclusive cutaneous feature of Asian patients with primary SS. In addition to the characteristic cutaneous expression, AE has a very specific clinical and immunological profile: often presenting before the fulfillment of SS criteria, overwhelmingly associated with anti-Ro antibodies but weakly associated with other immunological markers and the main systemic SS-related features.

Improving echographic monitoring of hemodynamics in critically ill patients: Validation of right cardiac output measurements through the modified subcostal window.

OBJECTIVE: We aimed to assess the usefulness of using the right ventricle outflow tract (RVOT) velocity-time integral (VTI) for echocardiographic monitoring of cardiac output compared to the gold standard, the VTI along the left ventricle outflow tract (LVOT). DESIGN: Prospective observational study. SETTING: A tertiary intensive care unit. PATIENTS: 100 consecutive patients. INTERVENTIONS: echocardiographic monitoring in critically ill patients. MAIN VARIABLES OF INTEREST: We used intraclass correlation coefficients (ICC) to compare echocardiographic measurements of LVOT VTI through apical window with RVOT VTI through the parasternal and modified subcostal windows and to assess interobserver reproducibility. Preplanned post hoc analyses compared the ICC between ventilated and nonventilated patients. RESULTS: At the time of echocardiography, 44 (44%) patients were mechanically ventilated and 28 (28%) were receiving vasoactive drugs. Good-quality measurements were obtained through the parasternal short-axis and/or apical views in 81 (81%) patients and in 100 (100%) patients through the subcostal window. Consistency with LVOT VTI was moderate for RVOT VTI measured from the modified subcostal view (ICC 0.727; 95%CI: 0.62-0.808) and for RVOT VTI measured from the transthoracic view (0.715; 95%CI: 0.59-0.807). CONCLUSIONS: Measurements of RVOT VTI are moderately consistent with measurements of LVOT VTI. Adding the modified subcostal window allows monitoring RVOT VTI in all the patients of this selected cohort, even those under mechanical ventilation.

Mortality and long term survival prognostic factors of patients with systemic autoimmune diseases admitted to an intensive care unit: a retrospective study.

OBJECTIVES: To determine mortality and long-term survival factors in patients with systemic autoimmune diseases (SAD) admitted to the intensive care unit (ICU). METHODS: Retrospective observational study including all consecutive patients with a diagnosis of any systemic autoimmune disease admitted to the medical ICU in a tertiary hospital between 1999 and 2007. Factors associated with reduced survival were identified by means of log rank test and backward stepwise Cox regression. RESULTS: Thirty-seven patients (26 females) were included with median age being 44.3 years (interquartilic range [IQR]: 31.3). Sixteen (43.2%) patients had systemic lupus erythematosus, 9 (24.3%) had systemic vasculitis, 4 (10.8%) had systemic sclerosis and 4 (10.8%) had primary antiphospholipid syndrome. The main reason for ICU admission was autoimmune disease flare-up in 20 (54.0%) patients, followed by infections in 12 (32.4%). Median APACHE II at admission was 17 (IQR 7). At the end of follow-up, 15 (40.5%) patients died, 10 (27%) during hospitalisation (7 in the ICU) and 5 after hospital discharge. Factors associated with reduced long-term survival were: APACHE II score ≥18 (HR 6.02, 95% CI 1.76-20.62), age <45 years (HR 6.54, 95% CI 1.84-23.29), presence of any previous chronic disease (HR 18.20, 95% CI 3.72-88.96), and increase of corticosteroid therapy during ICU stay (HR 22.87, 95% CI 4.31-121.30). CONCLUSIONS: The long-term survival of patients with systemic autoimmune diseases admitted to the ICU was related with age, higher APACHE II score, previous chronic diseases, and an increase in corticosteroids dose when comparing with previous ICU admissions.

Cognitive profile of male mice exposed to a Ketogenic Diet.

In recent years, nutritional interventions for different psychiatric diseases have gained increasing attention, such as the ketogenic diet (KD). This has led to positive effects in neurological disorders such as Parkinson's disease, addiction, autism or epilepsy. The neurobiological mechanisms through which these effects are induced and the effects in cognition still warrant investigation, and considering that other high-fat diets (HFD) can lead to cognitive disturbances that may affect the results achieved, the main aim of the present work was to evaluate the effects of a KD to determine whether it can induce such cognitive effects. A total of 30 OF1 male mice were employed to establish the behavioral profile of mice fed a KD by testing anxiety behavior (Elevated Plus Maze), locomotor activity (Open Field), learning (Hebb Williams Maze), and memory (Passive Avoidance Test). The results revealed that the KD did not affect locomotor activity, memory or hippocampal-dependent learning, as similar results were obtained with mice on a standard diet, albeit with increased anxiety behavior. We conclude that a KD is a promising nutritional approach to apply in research studies, given that it does not cause cognitive alterations.

Effects of ketosis on cocaine-induced reinstatement in male mice.

In recent years, the benefits of the ketogenic diet (KD) on different psychiatric disorders have been gaining attention, but the substance abuse field is still unexplored. Some studies have reported that palatable food can modulate the rewarding effects of cocaine, but the negative metabolic consequences rule out the recommendation of using it as a complementary treatment. Thus, the main aim of this study was to evaluate the effects of the KD on cocaine conditioned place preference (CPP) during acquisition, extinction, and reinstatement. 41 OF1 male mice were employed to assess the effects of the KD on a 10 mg/kg cocaine-induced CPP. Animals were divided into three groups: SD, KD, and KD after the Post-Conditioning test. The results revealed that, while access to the KD did not block CPP acquisition, it did significantly reduce the number of sessions required to extinguish the drug-associated memories and it blocked the priming-induced reinstatement.

Reduced salivary oxytocin after an empathic induction task in Intimate Partner Violence perpetrators: Importance of socio-affective functions and its impact on prosocial behavior.

Intimate Partner Violence (IPV) has been linked to difficulties in socio-affective functions. Nevertheless, the underlying psychobiological mechanisms that might be responsible for them remain unclear. Oxytocin (OXT) stands out as an important hormone that may favor the salience of social information, due to its relevance in empathy and prosocial behavior. Thus, the study of salivary OXT (sOXT) may provide further information about potential impairments in social cognition in IPV perpetrators. This study analyzed the effects of an empathic induction task, performed through negative emotion-eliciting videos, on endogenous sOXT levels, mood state, and emotional perception in 30 IPV perpetrators compared to 32 controls. Additionally, we explored their performance on prosocial behavior after the empathic induction task, using Hare's donation procedure. Lower sOXT levels were found in IPV perpetrators after the task compared to controls, along with a general decreasing tendency in their sOXT levels. Additionally, IPV perpetrators exhibited no change in their mood state and perceived others' emotions as more positive and less intense. Moreover, the mood state response and alexithymia traits, respectively, positively and negatively predicted the sOXT levels after the empathic induction task in the entire sample. Finally, we did not observe a lower appearance of prosocial behaviors in IPV perpetrators; however, higher sOXT levels after the empathic induction task were found in subjects who donated when considering the whole sample. In sum, IPV perpetrators exhibited differences in their sOXT levels when empathizing, compared to controls, with alexithymia and the emotional response potentially explaining the sOXT levels after the task. Furthermore, prosocial behavior was more related to these sOXT levels than to IPV. As our knowledge about the emotional processing of IPV perpetrators increases, we will be better able to develop and include coadjutant treatments in current psychotherapeutic programs, in order to focus on their emotional needs, which, in turn, would reduce the future risk of recidivism.

Binge eating and psychostimulant addiction.

Many of the various factors, characteristics, and variables involved in the addictive process can determine an individual's vulnerability to develop drug addiction. Hedonic eating, based on pleasure rather than energy needs, modulates the same reward circuits, as do drugs of abuse. According to the last report of the World Health Organization, the worldwide obesity rate has more than doubled since 1980, reaching especially critical levels in children and young people, who are overexposed to high-fat, high-sugar, energy-dense foods. Over the past few decades, there has been an increase in the number of studies focused on how eating disorders can lead to the development of drug addiction and on the comorbidity that exists between the two disorders. Herein, we review the most recent research on the subject, focusing especially on animal models of binge eating disorders and drug addiction. The complex profile of patients with substance use and binge eating disorders requires an integrated response to dually diagnosed patients. Nutritional patterns should be considered an important variable in the treatment of substance use disorders, and future studies need to focus on specific treatments and interventions in individuals who show a special vulnerability to shift from one addiction to the other.

Critical role of TLR4 in uncovering the increased rewarding effects of cocaine and ethanol induced by social defeat in male mice.

BACKGROUND: Substance use disorders and social stress are currently associated with changes in the immune system response by which they induce a proinflammatory state in neurons and glial cells that eventually modulates the reward system. AIMS: The aim of the present work was to assess the role of the immune TLR4 (Toll-like receptors 4) and its signaling response in the increased contextual reinforcing effects of cocaine and reinforcing effects of ethanol (EtOH) induced by social defeat (SD) stress. METHODS: Adult male C57BL/6 J wild-type (WT) mice and mice deficient in TLR4 (TLR4-KO) were assigned to experimental groups according to stress condition (exploration or SD). Three weeks after the last SD, conditioned place preference (CPP) was induced by a subthreshold cocaine dose (1 mg/kg), while another set underwent EtOH 6% operant self-administration (SA). Several inflammatory molecules were analyzed in the hippocampus and the striatum. RESULTS: SD induced higher vulnerability to the conditioned rewarding effects of cocaine only in defeated WT mice. Similarly, defeated WT mice exhibited higher 6% EtOH consumption, an effect that was not observed in the defeated TLR4-KO group. However, the motivation to obtain the drug was observed in both genotypes of defeated animals. Notably, a significant upregulation of the protein proinflammatory markers NFkBp-p65, IL-1ß, IL-17 A and COX-2 were observed only in the defeated WT mice, but not in their defeated TLR4-KO counterparts. CONCLUSIONS: These results suggest that TLR4 receptors mediate the neuroinflammatory response underlying the increase in the rewarding effects of cocaine and EtOH induced by social stress.

Targeting Alzheimer's disease with multimodal polypeptide-based nanoconjugates.

Alzheimer's disease (AD), the most prevalent form of dementia, remains incurable mainly due to our failings in the search for effective pharmacological strategies. Here, we describe the development of targeted multimodal polypeptide-based nanoconjugates as potential AD treatments. Treatment with polypeptide nanoconjugates bearing propargylamine moieties and bisdemethoxycurcumin or genistein afforded neuroprotection and displayed neurotrophic effects, as evidenced by an increase in dendritic density of pyramidal neurons in organotypic hippocampal culture. The additional conjugation of the Angiopep-2 targeting moiety enhanced nanoconjugate passage through the blood-brain barrier and modulated brain distribution with nanoconjugate accumulation in neurogenic areas, including the olfactory bulb. Nanoconjugate treatment effectively reduced neurotoxic ß amyloid aggregate levels and rescued impairments to olfactory memory and object recognition in APP/PS1 transgenic AD model mice. Overall, this study provides a description of a targeted multimodal polyglutamate-based nanoconjugate with neuroprotective and neurotrophic potential for AD treatment.

Bronchiectasis in primary Sjögren's syndrome: prevalence and clinical significance.

OBJECTIVES: To analyse the prevalence and clinical significance of bronchiectasis in a large series of patients with primary Sjögren's syndrome (SS) and evaluate its impact on disease expression and outcomes. METHODS: The study cohort included 507 patients with primary SS. Bronchiectasis were diagnosed according to pulmonary computed tomography (CT). As a control group, we included 37 consecutive SS patients evaluated by pulmonary CT during the same study period without pulmonary involvement. RESULTS: Fifty primary SS patients had bronchiectasis according to the pulmonary CT. Nine patients were excluded due to non-autoimmune processes and 41 were classified as bronchiectasis associated with primary SS (40 women, mean age of 64 years). All cases of bronchiectasis were of the cylindrical type and were located in the inferior lobes in 29 cases (71%). Patients with bronchiectasis were older at diagnosis of SS (60.39 vs. 52.54 years, p=0.022) and had a higher frequency of hiatus hernia (41% vs. 16%, p=0.024) in comparison with controls. Immunologically, patients with bronchiectasis had a lower frequency of anti-Ro/SS-A antibodies (27% vs. 54%, p=0.022) but a higher frequency of anti-smooth muscle--SMAantibodies (82% vs. 60%, p=0.043). During follow-up, patients with bronchiectasis had a higher frequency of respiratory infections (56% vs. 3%, p<0.001) and pneumonia (29% vs. 3%, p=0.002) in comparison with those without. CONCLUSIONS: Patients with primary SS and bronchiectasis are characterised by an older age, a high frequency of hiatus hernia, a specific immunologic pattern (low frequency of anti-Ro/SS-A and high frequency of anti-SMA) and during follow-up a much higher frequency of respiratory infections and pneumonia.

Cross-reinstatement between 3,4-methylenedioxypyrovalerone (MDPV) and cocaine using conditioned place preference.

3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) considered to be a cocaine-like psychostimulant. The substitution of an established illicit drug as cocaine with an NPS is a pattern of use reported among drug users. The aim of this study was to investigate the relationship between cocaine and MDPV in the reinstatement of the conditioned place preference (CPP) paradigm, in order to establish whether there is cross-reinstatement between the two psychostimulants. Four experimental groups of male OF1 mice were subjected to the CPP paradigm: MDPV-MDPV, Cocaine-Cocaine, Cocaine-MDPV, and MDPV-Cocaine. The first drug refers to the substance with which the animals were conditioned (cocaine 10 mg/kg or MDPV 2 mg/kg) and the s to the substance with which preference was reinstated. In parallel, G9a, ΔFosB, CB1 receptor, CDK5, Arc and c-Fos were determined in ventral striatum. MDPV induced CPP at doses from 1 to 4 mg/kg. Although 2 mg/kg MDPV induced a stronger psychostimulant effect than 10 mg/kg cocaine, both doses seemed to be equivalent in their rewarding properties. However, memories associated with MDPV required more time to be extinguished. MDPV and cocaine restore drug-seeking behavior with respect to each other, although relapse into drug-taking is always more pronounced with the conditioning drug. The fact that MDPV-treated mice show increased ΔFosB protein levels correlates with its longer extinction time and points to the activation of neuroplasticity mechanisms that persist for at least 12 days. Moreover, in these animals, a priming-dose of cocaine can trigger significant neuroplasticity, implying a high vulnerability to cocaine abuse.

Social defeat-induced increase in the conditioned rewarding effects of cocaine: Role of CX3CL1.

Social stress is associated with higher vulnerability to drug use, as it enhances the reinforcing effects of psychostimulants in rodents. Furthermore, continued or severe stress induces a proinflammatory state of microglial activation and augmented cytokine production. The aim of the present work was to evaluate the role of fractalkine [C-X3-C motif ligand 1 (CX3CL1)], an inflammatory chemokine, in the increased conditioned rewarding effects of cocaine in animals exposed to social defeat stress. In addition, we measured the signaling cascade pathway of CX3CL1 in the hippocampus (HPC) (including p-ERK/ERK, p-p38/p38 MAPK, p-p65/p65 NFκB and p-CREB/CREB ratios). The glutamate receptor subunits NR1, NR2B and GluA1 were also assessed. A total of 102 adult male C57BL/6 J wild-type (WT) and Cx3cr1 knockout (KO) mice were divided into different experimental groups according to stress condition (exploration or social defeat). Three weeks after the last social defeat, conditioned place preference (CPP) was induced by a subthreshold dose of cocaine (1 mg/kg). Brain tissue samples were taken 24 h after the CPP procedure to determine the levels of the proteins and transcription factors. Our results showed that, in WT animals, repeated social defeat (RSD) decreased CX3CL1 striatal levels without producing changes in the HPC. In addition, RSD induced an increase in the conditioned rewarding effects of cocaine, regardless of the genotype. After CPP induced by cocaine, defeated Cx3cr1-deficient mice showed a decrease in the p-p65/p65 NFκB and pCREB/CREB ratio in the HPC, and an increase in the hippocampal levels of CX3CL1 and p-p38/p38 MAPK relation. In all defeated mice, there was a decrease in the ionotropic glutamate receptor subunit NR1. In conclusion, these results suggest that the lack of CX3CL1/Cx3cr1 signaling under stress conditions induces changes in protein and transcription factors, indicating that CX3CL1 is needed to shield the response to social defeat.

Behavioral profile of intermittent vs continuous access to a high fat diet during adolescence.

Over the past few years, the effects of a high-fat diet (HFD) on cognitive functions have been broadly studied as a model of obesity, although no studies have evaluated whether these effects are maintained after the cessation of this diet. In addition, the behavioral effects of having a limited access to an HFD (binge-eating pattern) are mostly unknown, although they dramatically increase the vulnerability to drug use in contrast to having continuous access. Thus, the aim of the present study was to compare the effects of an intermittent versus a continuous exposure to an HFD during adolescence on cognition and anxiety-like behaviors, as well as to study the changes observed after the interruption of this diet. Adolescent male mice received for 40 days a standard diet, an HFD with continuous access or an HFD with sporadic limited access (2 h, three days a week). Two additional groups were fed with intermittent or continuous access to the HFD and withdrawn from this diet 15 days before the behavioral tests. Only the animals with a continuous access to the HFD showed higher circulating leptin levels, increased bodyweight, marked memory and spatial learning deficits, symptoms that disappeared after 15 days of HFD abstinence. Mice that binged on fat only showed hyperlocomotion, which normalized after 15 days of HFD cessation. However, discontinuation of fat, either in a binge or a continuous pattern, led to an increase in anxiety-like behavior. These results highlight that exposure to a high-fat diet during adolescence induces alterations in brain functions, although the way in which this diet is ingested determines the extent of these behavioral changes.

Differential Impact of Ad Libitum or Intermittent High-Fat Diets on Bingeing Ethanol-Mediated Behaviors.

BACKGROUND: Dietary factors have significant effects on the brain, modulating mood, anxiety, motivation and cognition. To date, no attention has been paid to the consequences that the combination of ethanol (EtOH) and a high-fat diet (HFD) have on learning and mood disorders during adolescence. The aim of the present work was to evaluate the biochemical and behavioral consequences of ethanol binge drinking and an HFD consumption in adolescent mice. METHODS: Animals received either a standard diet or an HFD (ad libitum vs. binge pattern) in combination with ethanol binge drinking and were evaluated in anxiety and memory. The metabolic profile and gene expression of leptin receptors and clock genes were also evaluated. RESULTS: Excessive white adipose tissue and an increase in plasma insulin and leptin levels were mainly observed in ad libitum HFD + EtOH mice. An upregulation of the Lepr gene expression in the prefrontal cortex and the hippocampus was also observed in ad libitum HFD groups. EtOH-induced impairment on spatial memory retrieval was absent in mice exposed to an HFD, although the aversive memory deficits persisted. Mice bingeing on an HFD only showed an anxiolytic profile, without other alterations. We also observed a mismatch between Clock and Bmal1 expression in ad libitum HFD animals, which were mostly independent of EtOH bingeing. CONCLUSIONS: Our results confirm the bidirectional influence that occurs between the composition and intake pattern of a HFD and ethanol consumption during adolescence, even when the metabolic, behavioral and chronobiological effects of this interaction are dissociated.

Pharmacological modulation of the behavioral effects of social defeat in memory and learning in male mice.

RATIONALE: Previous studies have demonstrated that repeated social defeat (RSD) stress only induces cognitive deficits when experienced during adulthood. However, RSD increases cocaine-rewarding effects in adult and adolescent mice, inducing different expressions of proBDNF in the ventral tegmental area. OBJECTIVE: The aim of the present study was to evaluate the effect of cocaine administration in socially defeated adult or adolescent mice on learning, memory, and anxiety. Additionally, the role of BDNF was also studied. METHODS: Adolescent and young adult mice were exposed to four episodes of social defeat or exploration (control), being treated with a daily injection of four doses of saline or 1 mg/kg of cocaine 3 weeks after the last social defeat. Other groups were treated with the TrkB receptor antagonist ANA-12 during this 21-day period. After this treatment, their cognitive and anxiogenic profiles were evaluated, along with the expression of BDNF, pCREB, and pERK1/2 in the dentate gyrus (DG) and basolateral amygdala (BLA). RESULTS: Cocaine induced an increased expression of pCREB and BDNF in the DG and BLA only in defeated animals. Although RSD did not affect memory, the administration of cocaine induced memory impairments only in defeated animals. Defeated adult mice needed more time to complete the mazes, and this effect was counteracted by cocaine administration. RSD induced anxiogenic effects only when experienced during adulthood and cocaine induced a general anxiolytic effect. Blockade of Trkb decreased memory retention without affecting spatial learning and modified anxiety on non-stressed mice depending on their age. CONCLUSION: Our results demonstrate that the long-lasting effects of social defeat on anxiety and cognition are modulated by cocaine administration. Our results highlight that the BDNF signaling pathway could be a target to counteract the effects of cocaine on socially stressed subjects.

Pharmacological treatments for opiate and alcohol addiction: A historical perspective of the last 50 years.

Addiction pharmacotherapy aims to prevent drug abstinence symptoms, reduce drug craving and relapse, and normalize physiologic functions disrupted by chronic use of the drug. During the last 50 years, there has been an enormous revolution in pharmacotherapy for drug addiction. From abstinence as practically the only treatment option available, there are now multiple drugs on the market that have proved their efficacy in treating opiate and alcohol disorders. The present review will focus on the pharmacological treatments of the drugs whose consumption most affects individuals and society: alcohol and opiates. We will review the drugs most widely prescribed to prevent relapse and maintain abstinence, as well as those designed to reduce the consumption of short-acting drugs (e.g. maintenance therapies) since the 1960s. Methadone and buprenorphine are the most widely used maintenance therapies for opiate addicts, although new pharmacological depot systems of naltrexone are showing promising results. For alcohol use disorders, acamprosate, nalmefene and naltrexone are replacing disulfiram prescriptions, and a wide variety of new products are currently under study. The number of new pharmacological targets already on clinical trials and the advanced new ways to administer classic therapies can improve the success rate of the pharmacotherapy for opioid and alcohol addiction.

Reinstatement of Drug-seeking in Mice Using the Conditioned Place Preference Paradigm.

The present protocol describes the Conditioned Place Preference (CPP) as a model of relapse in drug addiction. In this model, animals are first trained to acquire a conditioned place preference in a drug-paired compartment, and after the post-conditioning test, they perform several sessions to extinguish the established preference. The CPP permits the evaluation of the conditioned rewarding effects of drugs related to environmental cues. Then, the extinguished CPP can be robustly reinstated by the non-contingent administration of a priming dose of the drug, and by exposure to stressful stimuli. Both methods will be explained here. When the animal reinitiates the behavioral response, a reinstatement of the conditioned reward is considered to have taken place. The main advantages of this protocol are that it is non-invasive, inexpensive, and simple with good validity criteria. In addition, it allows the study of different environmental manipulations, such as stress or diet, which can modulate relapse into drug seeking behaviors. However, one limitation is that if the researcher aims to explore the motivation and primary reinforcing effects of the drug, it should be complemented with self-administration procedures, as they involve operant responses of animals.

Increased ethanol consumption after interruption of fat bingeing.

There is a marked comorbidity between alcohol abuse and eating disorders, especially in the young population. We have previously reported that bingeing on fat during adolescence increases the rewarding effects of ethanol (EtOH). The aim of the present work was to study if vulnerability to EtOH persists after cessation of binge eating. OF1 mice binged on fat (HFB: high-fat binge) during adolescence (PND 25-43) and were tested for 15 days after the last access to HFB (on PND 59) using the self-administration paradigm, the conditioned place preference (CPP) and locomotor sensitization to ethanol. Our results showed that after 15 days of cessation of fat ingestion, mice increased their consumption of ethanol and showed greater motivation to obtain ethanol. On the other hand, no effects were observed in the CPP, while an increased locomotor response to ethanol was detected. The present results confirm and extend our previous study demonstrating that the compulsive intake of fat induces long-lasting effects on the reward system that lead to an increased consumption of EtOH.

Short-term Results of Liver Transplantation With Octogenarian Donors.

BACKGROUND: There are increasingly more patients awaiting liver transplantation while the number of donors has remained stable. It has been proven that grafts from donors older than 60 years have comparable results with those from younger donors. It is unclear whether this is so with donors older than 80 years old. MATERIAL AND METHODS: This was a retrospective study of all adult liver transplantations at our institution between March 2011 and December 2015. We compared 1-, 3-, 6-, and 12-month graft survival rates from donors <80 years and ≥80 years. We also compared postoperative complications: infections, acute kidney injury, need for readmission in the intensive care unit, length of stay, mechanical ventilation, and specific graft complications. We considered differences in each age group regarding the presence of hepatitis C virus (HCV). RESULTS: Of 177 recipients, 38 received grafts from octogenarian donors (21.5%). Survival rates were very similar in the groups (97%, 93%, 91%, and 87% for donors <80 years and 95%, 92%, 87%, and 76% for donors ≥80 years). Although for younger grafts, 1-year survival rates were slightly lower for HCV+ patients (80% vs 89%; log-rank 0.205), this difference does not exist for elderly donors. The incidence of postoperative complications was similar in both groups. CONCLUSIONS: Livers from octogenarian donors are acceptable for liver transplantation provided that thorough assessment and selection is made by avoiding other known poor prognosis factors. The presence of HCV did not affect survival rates.