Intermittent Intake Research Articles

Intermittent nicotine access is as effective as continuous access in promoting nicotine seeking and taking in rats.

Nicotine is a principal psychoactive agent in tobacco, contributing to tobacco's addictive potential. Preclinical studies on the effects of voluntary nicotine intake typically use self-administration procedures that provide continuous nicotine access during each self-administration session. However, many smokers consume cigarettes intermittently rather than continuously throughout each day. For drugs including cocaine and opioids, research in laboratory rats shows that intermittent intake can be more effective than continuous intake in producing patterns of drug use relevant to addiction. We determined how intermittent versus continuous nicotine self-administration influences nicotine seeking and taking behaviours. Female and male rats had continuous (i.e., Long Access; LgA, 6h/day) or intermittent (IntA; 12min ON, 60min OFF, for 6h/day) access to intravenous nicotine (15µg/kg/infusion), for 12 daily sessions. We then assessed intake, responding for nicotine under a progressive ratio schedule of drug reinforcement and cue- and nicotine-induced reinstatement of drug seeking. We also estimated nicotine pharmacokinetic parameters during LgA and IntA self-administration. Overall, LgA rats took twice more nicotine than did IntA rats, yielding more sustained increases in estimated brain concentrations of the drug. However, the two groups showed similar motivation to seek and take nicotine, as measured using reinstatement and progressive ratio procedures, respectively. Intermittent nicotine use is just as effective as continuous use in producing addiction-relevant behaviours, despite significantly less nicotine exposure. This has implications for modeling nicotine self-administration patterns in human smokers and resulting effects on brain and behaviour.

If Mediterranean Diet Could Slow Atherosclerosis Progression, Could Specific Herbal Supplement Achieve the Same?

Dietary Control has been emphasized as an important means to prevent the development of atherosclerosis. It is a form belief without scientific evidence until the early report of the Study on Coronary Diet Intervention with olive oil and Cardiovascular Prevention (CODIOPREV Study on Mediterranean Diet). The current study is using Surrogate market IMT as the objective indicator, to compare the CORDIOPREV volunteers with known cardiovascular disease, which have demonstrated objective reduction in IMT thickness after 5 to 7 years of Mediterranean diet consumption. A study done in Hong Kong since 2003 using a simple twin herb formula for the prevention of progress of atherosclerosis in 4 different groups of patients with cardiovascular diseases, and using the same surrogate marker IMT as the objective indicator, showed comparable results within a much shorter period of 6-12 months. Extensive laboratory tests have also been completed to verify the bioactivities of the twin herb formula on anti-inflammation, anti-oxidation, endothelial protection and regenerative capacity related to atherosclerosis. It is suggested that before more potent therapeutic measures become available to slow atherosclerosis progression are available. The purpose of the paper is to compare the Mediterranean Diet for long term consumption and selective herbal preparations for shorter term or intermittent scheduled intake, and recommend to high-risk individuals.

P.0294 Lysergic acid diethylamide acutely reduces intermittent ethanol intake without observable effects on sucrose consumption of intracranial stimulation reward in mice

P.0294 Lysergic acid diethylamide acutely reduces intermittent ethanol intake without observable effects on sucrose consumption of intracranial stimulation reward in mice

Limited cheese intake reduces HPA axis and behavioral stress responses in male rats

Eating palatable foods reduces behavioral and hypothalamic-pituitary-adrenocortical (HPA) axis responses to stress – an idea referred to by the colloquial term “comfort” food. To study the underlying stress-relieving mechanisms of palatable foods, we previously developed a paradigm of limited sucrose feeding in which male rats are given twice-daily access to a small amount of sucrose drink and subsequently have reduced stress responses. Prior research in humans and rodents implicates high dietary sugars/carbohydrates with reduced stress responsivity. However, it is not clear whether the stress-relieving effects of the limited sucrose paradigm depend upon its macronutrient content. To test this idea, the current work measures stress responses in male rats following the limited intermittent intake of cheese – a highly palatable food that is low in sugar and other carbohydrates. The data show that a history of limited cheese intake (LCI) reduced HPA axis responses to acute psychological (restraint) and physiological (hypoxia) stressors. LCI also reduced behavioral struggling during restraint, increased sociability during a social interaction test, and increased open arm activity in the elevated plus-maze test. Z-score analyses evaluated the extent to which these behavioral effects extended within and across assays, and indicated that there was an overall reduction in stress-related behaviors following LCI. Finally, LCI increased immunolabeling for FosB/deltaFosB (a protein associated with repeated or chronic neuronal activation) in the nucleus accumbens. These results indicate that palatable foods can provide stress blunting regardless of their sugar/carbohydrate composition, and support the idea that food reward per se contributes to stress relief.

Effect of an Intermittent Meat Protein Diet on Colon Homeostasis

Abstract Objectives The level of dietary protein is a major factor determining gut health. The level of dietary protein is fluctuated in real life, which may affect colon homeostasis. However, it is still less known about it. Here, we investigated how an intermittent protein diet affected inflammatory, gut barrier and microbiota. Methods Six-week-old male C57BL/6J mice received either a casein or pork protein with (i) 20% protein (C), (ii) 5% protein, (iii) 40% protein, or intermittent diet, a diet alternating weekly between 5% protein and 40% protein ((iv) ending on 40% protein or (v) ending on 5% protein)) for up to 16 weeks. The gene expression of inflammatory cytokines, tight junction protein and gut microbiota composition were measured. Results The intermittent intake of casein decreased body weight, but intermittent pork protein diet didn't affect body weight. In casein group, the proinflammatory factors were highly upregulated in intermittent group ending on 5% protein, but the proinflammatory cytokines of intermittent group ending on 40% protein were not significantly affected. However, the two intermittent pork protein groups reduced the expression of proinflammatory cytokines. Additionally, intermittent diet altered gut microbiota composition. Intermittent casein group ending on 40% protein increased richness of gut microbiota, but intermittent pork protein group ending on 5% protein decreased richness and microbial diversity. Conclusions Intermittent diet indeed altered microbiota structure and colon health. In addition to protein level and source, dietary pattern is also an important parameter for host health. Funding Sources This work was funded by Ministry of Science and Technology (10000 Talent Project).

Taking Rapid and Intermittent Cocaine Infusions Enhances Both Incentive Motivation for the Drug and Cocaine-induced Gene Regulation in Corticostriatal Regions

A goal in addiction research is to distinguish forms of neuroplasticity that are involved in the transition to addiction from those involved in mere drug taking. Animal models of drug self-administration are essential in this context. Here, we compared in male rats two cocaine self-administration procedures that differ in the extent to which they evoke addiction-like behaviours. We measured both incentive motivation for cocaine using progressive ratio procedures, and cocaine-induced c-fos mRNA expression, a marker of neuronal activity. Rats self-administered intravenous cocaine (0.25 mg/kg/infusion) for seven daily 6-hour sessions. One group had intermittent access (IntA; 6 minutes ON, 26 min OFF × 12) to rapid infusions (delivered over 5 s). This models the temporal kinetics of human cocaine use and produces robust addiction-like behaviour. The other group had Long access (LgA) to slower infusions (90 s). This produces high levels of intake without promoting robust addiction-like behaviour. LgA-90 s rats took twice as much cocaine as IntA-5 s rats did, but IntA-5 s rats showed greater incentive motivation for the drug. Following a final self-administration session, we quantified c-fos mRNA expression in corticostriatal regions. Compared to LgA-90 s rats, IntA-5 s rats had more cocaine-induced c-fos mRNA in the orbitofrontal and prelimbic cortices and the caudate-putamen. Thus, a cocaine self-administration procedure (intermittent intake of rapid infusions) that promotes increased incentive motivation for the drug also enhances cocaine-induced gene regulation in corticostriatal regions. This suggests that increased drug-induced recruitment of these regions could contribute to the neural and behavioural plasticity underlying the transition to addiction.

Factors Associated with Frequency of Peanut Consumption in Korea: A National Population-Based Study.

Household peanut exposure via skin in infants with impaired skin barrier function is a risk factor for peanut allergy development. The aim of this study is to investigate the peanut consumption of Koreans using national representative data. We used data from the Korean National Health and Nutrition Examination Survey 2012–2016, consisting of data from 17,625 adults who complete the survey. Peanut intake was assessed using a 24-h recall method. Of the study population, 10,552 (59.9%), 6726 (38.2%), and 347 (1.9%) subjects were categorized into non-intake, intermittent intake, and frequent intake group, respectively. Ordered logistic regression models were used to examine the association between sociodemographic and dietary factors and the frequency of peanut intake. After adjusting for confounders, increasing age (adjusted odds ratio (aOR) 1.03; 95% confidence interval (CI) 1.03–1.04), higher education (high school graduates: aOR 1.75, 95 CI 1.39–2.19; higher than college: aOR 2.11, 95% CI 1.65–2.70), and prudent dietary scores in the second (aOR 1.71; 95% CI 1.47–1.99), third (aOR 2.53; 95% CI 2.16–2.97) and the fourth quartiles (aOR 3.72; 95%CI 3.16–4.40) were associated with a high frequency of peanut consumption. This information may be helpful not only in public health research for nutrition but also in personal management for the prevention of peanut allergy in Korea.

Effects of Daily and Intermittent Intake of New Zealand Blackcurrant Extract on Cardiovascular Responses During Moderate Intensity Exercise in Males (P23-011-19)

ObjectivesSeven-day intake of anthocyanin-rich New Zealand blackcurrant extract affected exercise-induced cardiovascular responses by vasodilation. It is not known whether daily intake of NZBC extract is required for effectiveness. Effects of daily and intermittent NZBC extract intake on cardiovascular responses were examined during brisk walking. MethodsFifteen healthy men (mean ± SD age: 24 ± 6 yr, body mass: 79 ± 16 kg, height: 178 ± 6 cm, BMI: 24.7 ± 4.3 kg·m−2, IPAQ score: 4534 ± 1576 MET·week−1) volunteered. Resting metabolic equivalent (1-MET) was measured using Douglas bags (1-MET: 3.97 ± 0.66 ml·kg−1·min−1) and an incremental walking test to determine the relationship between walking speed and MET. A randomised, cross-over (14-day washout) experimental design was used for baseline, 14-day intermittent (14I, every other day), and 14-day continuous (14C, daily) intake. Participants consumed 2 capsules of NZBC extract (600 mg and containing 210 mg of anthocyanins, CurraNZ™ Health Currancy Ltd., Surrey, UK) with breakfast. On the morning of testing, the final 2 capsules were ingested 2-hr before the 30-min brisk walk at 4 (n = 3) or 5 (n = 12) METs (walking speed: 5.68 ± 0.67 km·hr−1). Cardiovascular responses were measured at 7–10, 17–20 and 27–30 min during the walk by Portapres Model 2, averaged and analysed (ANOVA and post-hoc t-tests). ResultsThere were no changes in heart rate (e.g., baseline: 102 ± 18 beats·min-1), systolic blood pressure (e.g., baseline: 158 ± 18 mm Hg) and ejection time (e.g., baseline: 0.28 ± 0.03 s). Cardiac output (baseline: 11.7 ± 2.0, 14I: 12.5 ± 2.0, 14C: 12.7 ± 2.1 L·min-1, P = 0.009) and stroke volume (baseline: 114 ± 13, 14I: 123 ± 17, 14C: 126 ± 21 mL·min-1, P = 0.004) were higher, and total peripheral resistance (baseline 0.51 ± 0.11, 14I: 0.45 ± 0.09, 14C: 0.44 ± 0.12 mmHg·L-1·min-1, P = 0.001), diastolic blood pressure (baseline: 71 ± 9, 14I: 66 ± 9, 14C: 63 ± 11 mm Hg, P < 0.001) and mean arterial pressure (baseline 93 ± 10, 14I: 88 ± 9, 14C: 87 ± 11 mm Hg P = 0.006) were lower for 14I and 14C intake. ConclusionsDaily intake of anthocyanin-rich NZBC extract is not required to obtain beneficial cardiovascular responses during walking. Funding SourcesHealth Currancy (UK) Ltd and CurraNZ (NZ) Ltd provided supplements and support for conference attendance with Blackcurrant New Zealand Inc. (NZ).

Intermittent intake of rapid cocaine injections promotes the risk of relapse and increases mesocorticolimbic BDNF levels during abstinence.

Cocaine is thought to be more addictive when it reaches the brain rapidly. We predicted that variation in the speed of cocaine delivery influences the likelihood of addiction in part by determining the risk of relapse after abstinence. Under an intermittent-access schedule, rats pressed a lever for rapid (injected over 5 s) or slower (90 s) intravenous cocaine injections (0.5 mg/kg/injection). Control rats self-administered food pellets. A tone-light cue accompanied each self-administered reward. The 5s- and 90s-rats took a similar average amount of cocaine. Oneor 45 days after withdrawalfrom cocaine/forced abstinence, lever-pressing behaviour was extinguished during a 6-h session. Immediately thereafter, cue- or cocaine (10 mg/kg, i.p.)-induced reinstatement was assessed for 1 h. Oneor 45 days after withdrawal, only 5s-rats showed significant cocaine-induced reinstatement of reward-seeking behaviour. Inboth cocaine groups, cue-induced reinstatement behaviourwas more pronounced after 45daysthan after 1day of withdrawal from cocaine, indicating incubation of conditioned drug craving. However, cue-induced reinstatement after extended abstinence was greatest in the 5s-rats. Brain-derived neurotrophic factor (BDNF) activity in the brain regulates reinstatement behaviour. Thus, 24 h after reinstatement tests, we measured BDNF protein concentrations in mesocorticolimbic regions. Only 5s-rats showed time-dependent increases in BDNF concentrations in the prelimbic cortex, nucleus accumbens core and ventral tegmental area after withdrawalfrom cocaine (day 45 > day 1). Thus, rapidly rising brain cocaine levels might facilitate addiction by evoking changes in the brain that intensify drug craving after abstinence, and these changes persist long after the last bout of cocaine use.

Revisiting long-access versus short-access cocaine self-administration in rats: intermittent intake promotes addiction symptoms independent of session length.

In rats, continuous cocaine access during long self-administration sessions (6 versus 1-2hours) promotes the development of behavioral symptoms of addiction. This has led to the assumption that taking large amounts of drug during extended daily bouts is necessary to develop an addiction phenotype. Recent work shows that within-session intermittent access (IntA) to cocaine produces much less drug intake than continuous-access procedures (i.e. long-access sessions) but evokes addiction symptoms more effectively. IntA-sessions are also long, typically lasting 6hours. It is not known whether IntA-sessions must be extended to promote addiction-relevant changes in drug use over time. Here, we determined the influence of IntA-session length on patterns of cocaine use relevant to addiction. Two groups of male Wistar rats self-administered cocaine (0.25mg/kg/injection, injected over 5seconds) during 18 daily IntA-sessions. One group had long 6-hour sessions (Long-IntA), the other group had shorter, 2-hour sessions (Short-IntA). Only Long-IntA rats escalated their cocaine intake over sessions, but both groups developed a burst-like pattern of drug use over time and similar levels of psychomotor sensitization. The two groups also showed robust and similar levels of both responding for cocaine under a progressive ratio schedule of reinforcement and cocaine-induced reinstatement of extinguished drug-seeking behavior. In summary, long IntA-sessions lead to greater cocaine intake than shorter IntA-sessions, but the two conditions are equally effective in evoking the patterns of drug-taking and drug-seeking that define addiction. This suggests that chronic intermittent cocaine use, even during short daily bouts, is sufficient to promote addiction symptoms.

The Efficacy of One-time and Intermittent Intake of Coffee as a Countermeasure to Sleepiness on Partially Sleep-deprived Drivers

The Efficacy of One-time and Intermittent Intake of Coffee as a Countermeasure to Sleepiness on Partially Sleep-deprived Drivers

The rewarding effects of ethanol are modulated by binge eating of a high-fat diet during adolescence

Binge-eating is considered a specific form of overeating characterized by intermittent and high caloric food intake in a short period of time. Epidemiologic studies support a positive relation between the ingestion of fat and ethanol (EtOH), specifically among adolescent subjects.The aim of this work was to clarify the role of the compulsive, limited and intermittent intake of a high-fat food during adolescence on the rewarding effects of EtOH. After binge-eating for 2 h, three days a week from postnatal day (PND) 29, the reinforcing effects of EtOH were tested with EtOH self-administration (SA), conditioned place preference (CPP) and ethanol locomotor sensitization procedures in young adult mice.Animals in the high fat binge (HFB) group that underwent the EtOH SA procedure presented greater EtOH consumption and a higher motivation to obtain the drug. HFB mice also developed preference for the paired compartment in the CPP with a subthreshold dose of EtOH. Independently of the diet, mice developed EtOH-induced locomotor sensitization. After the SA procedure, HFB mice exhibited reduced levels of the mu opioid receptor (MOr) and increased cannabinoid 1 receptor (CB1r) gene expression in the nucleus accumbens (N Acc), and decreased of tyrosine hydroxylase (TH) gene expression in the ventral tegmental area (VTA).Taken together the results suggest that bingeing on fat may represent a vulnerability factor to an escalation of EtOH consumption.

Intermittent intake of rapid cocaine injections promotes robust psychomotor sensitization, increased incentive motivation for the drug and mGlu2/3 receptor dysregulation

The choice between smoking, injecting or swallowing a drug influences the risk of addiction, as this determines both how much drug gets into the brain and how fast. Most animal studies on addiction focus on how much drug it takes to produce pathological drug use. How fast drugs get to the brain is generally ignored. A few studies have examined the influence of the speed of drug onset, but speed varied along with cumulative intake. Here we held average cumulative intake constant and determined whether variation in the speed of cocaine onset alone predicts outcome. Two groups of rats self-administered intravenous cocaine (0.25 mg/kg/injection) during daily sessions. Cocaine was available intermittently during each session. This produces the spikes and troughs in brain levels of cocaine thought to model how addicts take the drug. To vary the speed of cocaine onset, each injection was delivered over 5 s to one group, and over 90 s to the other. Average cumulative cocaine intake was the same in the two groups. However, rapid injections promoted robust psychomotor sensitization and potentiated incentive motivation for cocaine (0.063–0.25 mg/kg/injection). This addiction-relevant phenotype was accompanied by enhanced functional activity of metabotropic glutamate group II receptors (mGluR2/3s) in the prelimbic cortex and nucleus accumbens. Pharmacological activation of mGluR2/3s with LY379268 also preferentially decreased the motivation to take cocaine in rats previously exposed to rapid drug injections. Thus, varying the speed of drug onset can be used to parse the neurobiology of addiction from that of mere drug taking.

Behavioural sensitisation during dopamine replacement therapy in Parkinson's disease is reminiscent of the addicted brain.

The intermittent oral intake of the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA) is the classic therapy of Parkinson's disease (PD). In this way, the drug precursor can be metabolised into the active neurotransmitter DA. Although this occurs throughout the brain, the therapeutic relief is believed to be due to restoring extracellular DA levels within the dorsal striatum (more in the putamen than the caudate nucleus) which lacks endogenous DA as a consequence of the disease process. However, differing from physiological DA transmission, this therapeutic pattern leads to abnormal peaks of non-synaptic DA, which are supposed to trigger behavioural sensitisation expressed as abnormal involuntary movements. A similar pattern of abnormal DA stimulation occurs during methamphetamine (METH) intake. In the present review we will provide evidence showing the similarities between METH- and L-DOPA-induced DA stimulation with an intact and denervated striatum respectively. This comparison will encompass various features; the timing, the areas and the amount of extracellular DA levels which reveal surprising homologies. Such an overlapping between L-DOPA in PD and METH will be further analysed to critically assess the commonalities concerning the following points: abnormal receptor stimulation, recruitment of altered transduction pathways, abnormal gene expression, alterations in the phenotype of striatal neurons, and the establishment of behavioural sensitisation which appear as distinct phenomena (i.e. abnormal involuntary movements in PD and drug addiction in METH abuse); nonetheless, this may also lead to common behavioural alterations (METH-like addictive behaviours in PD patients during the course of DA replacement therapy in subsets of PD patients).

Abstract P1-12-11: Prospective study of aromatase inhibitor-induced bone loss and lipid levels in early hormone sensitive breast cancer treated with AI during 8 years

Abstract Introduction: AI’s are the preferred adjuvant hormonal treatment for postmenopausal(PM) estrogen receptor positive (ER+) disease because of the improved efficacy over tamoxifen in terms of disease free survival and reduction in distant recurrence. AI’s have been associated with increased bone loss by blocking peripheral tissue estrogen synthesis, arthralgia and a negative effect on lipid metabolism. In this prospective study we wanted to assess the amount of bone loss and the changes in lipid levels in early breast cancer(EBC) patients (pts) treated with 3yrs of extended letrozole as part of the SOLE study after 5 yrs of adjuvant AI. Objectives: the primary objective of the study is to calculate the mean percentage change in bone mineral density(BMD)(g/cm2) after 8 yrs of letrozole and to compare between the continuous(C) and intermittent(I) intake of letrozole. The secondary objectives are to correlate the mean change in BMD with the initial value, BMI and to describe the evolution of the lipid levels in both groups. Patients and methods: BMD was measured at the lumbar spine (L2-4) and hip by dual energy X-ray absorptiometry (DEXA) in PM pts. with ER+ EBC. We also measured the fasting lipid levels baseline and after 8 yrs of an AI. Differences between the two groups were assessed by the independent samples T-test and the correlation by the linear regression analysis. Results: Fifty four pts were included in the study with a mean age of 62.5 yrs(+/-8.6 yrs). Seventeen pts are too early to be evaluable, 8 pts stopped letrozole due to adverse events and 2 pts had no baseline DEXA values. Two pts received tamoxifen 2 to 5 yrs before inclusion in the SOLE study. The remaining 25 pts showed a mean change in BMD for the lumbar spine of -1.1 (10.6SD) and for the hip -4.4 (7.04SD). Currently 13 pts in the C arm demonstrated a mean decrease in BMD for the (LS) of -2.7(10.2SD), and for the hip of -2.7(5.5SD). Twelve pts included in the I arm experienced a mean increase in BMD for the LS of 0.65(SD11.2) and a mean decrease in BMD for the hip of -4.9(9.1SD). The difference between the two treatment groups was not significant for the LS measurements after 8yrs (p=0.4) nor for the hip (p=0.23) neither was it at baseline (p=0.9; 0.1). Only three pts had fractures due to trauma. The overall fracture rate was only 0.05%.There was no correlation with the BMI, but there was a significant correlation with baseline BMD.(p=0.002)The mean fasting cholesterol levels at 8yrs in the C arm was 214mg/dl(41.3SD) and in the I arm was 218mg/dl(35.6SD)and was not significantly different(p=0.8), nor was it at baseline(p=0.5). Conclusion: This first prospective long term BMD and lipid follow-up study in PM EBC pts taking adjuvant letrozole beyond 5 yrs shows a decline in BMD. Until now no significant differences were observed between continuous and intermittent letrozole. An updated and detailed follow-up on more patients will be presented. Citation Format: Christel Fontaine, Lore Decoster, Denis Schallier, Leen Vanacker, Jacques De Grève, Marian Vanhoeij, Guy Verfaillie, Jan Lamote. Prospective study of aromatase inhibitor-induced bone loss and lipid levels in early hormone sensitive breast cancer treated with AI during 8 years [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-11.

Acceptability of PrEP among HIV negative Portuguese men who have sex with men that attended 2014 Lisbon pride fair.

IntroductionConsistent use of PrEP reduces HIV transmission from sexual practices amongst men who have sex with men (MSM) up to 92% [1]. Lisbon MSM cohort study estimates point that 59.3% of their participants at entrance (1593 HIV negative MSM enrolled between April 2011 and May 2013) were eligible for PrEP [2], according to the 2014 USA PrEP guidelines [3]. Studies about PrEP acceptability and implementation support policies aimed at increasing and rolling out its use. Hence, the exploratory study about PrEP acceptability in MSM at Lisbon.Materials and MethodsA street-based intercept survey, adapted from Mantell et al. study [4], was the one used on MSM attending the 2014 Lisbon pride fair. The survey included socio-demographic data, PrEP awareness and readiness to use it, probability of MSM's social network to also use it, promptness to join PrEP-related studies, type of PrEP warranted and condomless anal sex practice in the last six months.ResultsA total of 110 HIV negative Portuguese MSM responded, with a median age of 33% and 84% of them identified themselves as gay. A majority of MSM were unaware of PrEP (59%); those that were aware, had heard of it trough CheckpointLx (31%), internet (22%) or health professionals (20%). 66% were likely or very likely to participate in PrEP-related studies. 57% of MSM were likely or very likely to use PrEP if available and reported that some, if not almost all of their social network, will do it too (70%). Type of PrEP preferred was oral, a pill a day (43%), followed by oral, intermittent intake (32%). Overall 41% of MSM had condomless anal sex practice in the last six months.ConclusionsIn this MSM Portuguese sample, a general willingness to adopt PrEP was predominant, specially the oral daily intake. Forty-one percent of participants had had condomless anal sex practice in the last six months and therefore fitted within the criteria to be on Pre-Exposure Prophylaxis (PrEP), according to MSM Risk Index in 2014 USA PrEP guidelines. PrEP, when available in Portugal, should be a powerful tool for HIV prevention in this key population.

Direct Thrombin Inhibitors—A Case Indicating Benefit From ‘Plasmapheresis’ in Toxicity

Patient presented with passage of fresh blood mixed with clots per rectum. In the ER, she was found to have bright red blood per rectum with clots, with frank blood on nasogastric tube. She was on dabigatran for atrial fibrillation and aspirin, with intermittent intake of ibuprofen. Vitals were positive for orthostatic hypotension. The pertinent findings in the physical examination were altered mental status with orientation*1, weak peripheral pulses, irregularly irregular heart rate, and bilateral pitting edema 2+ in bilateral lower extremities. Patient was intubated and put on mechanical ventilation. A massive transfusion protocol was followed. Laboratories and imaging: hemoglobin/hematocrit, 7.2/22.1; white blood cells, 7.7, platelet, 210; international normalized ratio, 2.5; prothrombin time, 19.2; activated partial thromboplastin time, 88.2; CMP was WNL; BNP, 621; fibrinogen, 500 mg/dL. Electrocardiogram showed atrial fibrillation with inferolateral ischemia. Ultrasonography of the liver and gallbladder showed no acute pathology. Echocardiogram showed an EF of 70% with hyperdynamic LV. Patient was transferred to the intensive care unit. Dabigatran, aspirin, and nonsteroidal anti-inflammatory drugs were discontinued, and antihypertensives were held. She was given blood and FFPs. Hemoglobin, hematocrit, and coagulation profile was monitored every 6 hours. Gastroenterology, general surgery, interventional radiology, and hematology services were called stat. IR placed a double-lumen, power central venous catheter. In gastroenterology, EGD and colonoscopy was performed, which showed active bleed at distal esophagus, stopped with local epinephrine. No active bleed seen on colonoscopy. The patient was put on Nexium drip. Hematology service recommended thrombin time (>200) and factors 2, 5, 7, 9, 10-41(l), 80, 68, 48(l), 61. Prothrombin time and activated partial thromboplastin time mixing studies were done, which indicated the presence of thrombin inhibition. Prothrombin complex concentrate at 50 U/kg was started to reverse the effect of dabigatran, and platelets were transfused to reverse the effect of aspirin. They also discussed that the half-life of dabigatran being 17 hours, and the drug would not be toxic at this point, as the patient was already 24-hour inpatient by now. The hemoglobin trend: 7.4→6.4→8.2→7.5→6.6. At this point, the need for further intervention in form of hemodialysis or plasmapheresis was considered. The patient was given plasmapheresis and hemoglobin and hematocrit stabilized. The patient was kept on continued mechanical ventilator support for the night and extubated next day. The hemodynamics stabilized and the patient was transferred to the general medical floors after 1 day of observation, after extubation.

The dark side of food addiction

In drug addiction, the transition from casual drug use to dependence has been linked to a shift away from positive reinforcement and toward negative reinforcement. That is, drugs ultimately are relied on to prevent or relieve negative states that otherwise result from abstinence (e.g., withdrawal) or from adverse environmental circumstances (e.g., stress). Recent work has suggested that this “dark side” shift also is a key in the development of food addiction. Initially, palatable food consumption has both positively reinforcing, pleasurable effects and negatively reinforcing, “comforting” effects that can acutely normalize organism responses to stress. Repeated, intermittent intake of palatable food may instead amplify brain stress circuitry and downregulate brain reward pathways such that continued intake becomes obligatory to prevent negative emotional states via negative reinforcement. Stress, anxiety and depressed mood have shown high comorbidity with and the potential to trigger bouts of addiction-like eating behavior in humans. Animal models indicate that repeated, intermittent access to palatable foods can lead to emotional and somatic signs of withdrawal when the food is no longer available, tolerance and dampening of brain reward circuitry, compulsive seeking of palatable food despite potentially aversive consequences, and relapse to palatable food-seeking in response to anxiogenic-like stimuli. The neurocircuitry identified to date in the “dark” side of food addiction qualitatively resembles that associated with drug and alcohol dependence. The present review summarizes Bart Hoebel's groundbreaking conceptual and empirical contributions to understanding the role of the “dark side” in food addiction along with related work of those that have followed him.

“Snacking” causes long term attenuation of HPA axis stress responses and enhancement of brain FosB/deltaFosB expression in rats

A history of limited, intermittent intake of palatable food (sucrose drink) attenuates hypothalamic-pituitary-adrenal (HPA) axis stress responses and induces markers of neuronal plasticity in stress- and reward-regulatory brain regions. Synaptic plasticity could provide a mechanism for long-term changes in neuronal function, implying that sucrose stress-dampening may endure over long periods of time. The present study tests the persistence of HPA axis dampening and plasticity after cessation of palatable drinking. Adult, male Long-Evans rats (n=10-13) with free access to water and chow were given additional twice-daily access to 4ml sucrose (30%) or water for 14days. Rats were subsequently tested for HPA responsiveness to an acute (20min) restraint stress at 1, 6 and 21days after the cessation of sucrose. Brains were collected for immunohistochemical analysis of FosB/deltaFosB, a marker of long-term neuronal plasticity, in the basolateral amygdala (BLA) and nucleus accumbens (NuAc). Prior sucrose consumption significantly decreased the plasma corticosterone response to restraint at 1day after the last palatable drink presentation, and also increased FosB/deltaFosB-positive cells in the BLA and in the NuAc core. This HPA-dampening persisted through 21days after the termination of the palatable drink, as did the increased FosB/deltaFosB immunoreactivity in both the BLA and the NuAc core. These data suggest that chronic palatable food intake causes lasting changes in stress/reward-modulatory circuitry and that the suppressed hormonal response to stress that can persist well beyond periods of palatable drink exposure.

Repeated transient sulforaphane stimulation in astrocytes leads to prolonged Nrf2-mediated gene expression and protection from superoxide-induced damage

Oxidative stress is a major contributor to slowly developing diseases like Parkinson’s disease, Alzheimer’s disease and cancer and one of the main causes of tissue damage following ischemic insults in the brain. Nrf2 is a transcription factor responsible for much of the inducible cellular defense against oxidative stress. Nrf2 can also be activated by xenobiotics like sulforaphane, a component highly enriched in cruciferous vegetables such as broccoli. Ingestion of broccoli or sulforaphane results in long-term protection against radical damage, although absorbed sulforaphane is cleared from the body within a few hours. Here we have examined whether the prolonged protection induced by sulforaphane is explained by a slow down regulation of the Nrf2 response. Furthermore, to simulate daily ingestion of sulforaphane, we examined the hypothesis that repeated transient sulforaphane stimulation results in an accumulation of Nrf2-mediated gene expression and an increased protection against oxidative damage. The kinetics of sulforaphane-induced Nrf2 response was studied in astrocytes, a cell type known to be highly involved in the defense against oxidative stress in the brain. Sulforaphane stimulation for 4 h induced an Nrf2-dependent increase of Nqo1 and Hmox1 mRNA that remained elevated for 24 h, and the corresponding proteins remained elevated for over 48 h. In addition, peroxide-clearing activity and the levels of glutathione were elevated for more than 20 h after stimulation for 4 h with sulforaphane, resulting in an increased resistance to superoxide-induced cell damage. Repeated sulforaphane stimulation resulted in an accumulation of mRNA and protein levels of Nqo1 and a persistent cell protection against oxidative damage. These findings indicate that brief stimulation of the Nrf2 pathway by sulforaphane results in long-lasting elevation of endogenous antioxidants in astrocytes. The findings also demonstrate that part of this response can be built up by repeated transient stimulation, possibly explaining how intermittent intake of sulforaphane can result in long-term protection from radical-induced disease.