Objective Physiological Measurements but Not Subjective Reports Moderate the Effect of Hunger on Choice Behavior.

Hunger is a powerful driver of human behavior, and is therefore of great interest to the study of psychology, economics, and consumer behavior. Assessing hunger levels in experiments is often biased, when using self-report methods, or complex, when using blood tests. We propose a novel way of objectively measuring subjects' levels of hunger by identifying levels of alpha-amylase (AA) enzyme in their saliva samples. We used this measure to uncover the effect of hunger on different types of choice behaviors. We found that hunger increases risk-seeking behavior in a lottery-choice task, modifies levels of vindictiveness in a social decision-making task, but does not have a detectible effect on economic inconsistency in a budget-set choice task. Importantly, these findings were moderated by AA levels and not by self-report measures. We demonstrate the effects hunger has on choice behavior and the problematic nature of subjective measures of physiological states, and propose to use reliable and valid biologically based methods to overcome these problems.

Perioperative COX-2 and ß-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial.

Purpose: Translational studies suggest that excess perioperative release of catecholamines and prostaglandins may facilitate metastasis and reduce disease-free survival. This trial tested the combined perioperative blockade of these pathways in breast cancer patients.Experimental Design: In a randomized placebo-controlled biomarker trial, 38 early-stage breast cancer patients received 11 days of perioperative treatment with a ß-adrenergic antagonist (propranolol) and a COX-2 inhibitor (etodolac), beginning 5 days before surgery. Excised tumors and sequential blood samples were assessed for prometastatic biomarkers.Results: Drugs were well tolerated with adverse event rates comparable with placebo. Transcriptome profiling of the primary tumor tested a priori hypotheses and indicated that drug treatment significantly (i) decreased epithelial-to-mesenchymal transition, (ii) reduced activity of prometastatic/proinflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and (iii) decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells. Drug treatment also significantly abrogated presurgical increases in serum IL6 and C-reactive protein levels, abrogated perioperative declines in stimulated IL12 and IFNγ production, abrogated postoperative mobilization of CD16- "classical" monocytes, and enhanced expression of CD11a on circulating natural killer cells.Conclusions: Perioperative inhibition of COX-2 and ß-adrenergic signaling provides a safe and effective strategy for inhibiting multiple cellular and molecular pathways related to metastasis and disease recurrence in early-stage breast cancer. Clin Cancer Res; 23(16); 4651-61. ©2017 AACR.

Leishmania major infection in a dog with cutaneous manifestations.

BACKGROUND: Leishmania major is a main cause of cutaneous leishmaniasis in humans in an area that stretches from India through Central Asia, the Middle East, to North and West Africa. In Israel, it is a common infection of humans with rodents as the reservoir hosts and Phlebotomus papatasi as its sand fly vector. FINDINGS: A 6 months old spayed female mixed breed dog was referred to the Hebrew University Veterinary Teaching Hospital with a large ulcerative dermal lesion on the muzzle, and lesions in the foot pads and left hind leg. Histopathology of a skin biopsy found chronic lymphohistiocytic dermatitis with the presence of Leishmania spp. amastigotes in the muzzle. Physical examination indicated that the dog was overall in a good clinical condition and the main findings were the skin lesions and enlarged prescapular lymph nodes. Complete blood count and serum biochemistry profile were within reference ranges. Serology by ELISA was positive for Leishmania spp. and PCR of the prescapular lymph node was positive by an ITS1 region PCR-high resolution melt analysis. However, the melt curve and subsequent DNA sequencing indicated that infection was caused by L. major and not L. infantum, which is the main causative agent of canine leishmaniosis in the Mediterranean region. DNA was extracted from the paraffin embedded muzzle biopsy and PCR with sequencing also indicated L. major. The dog's young age and the absence of hyperglobulinemia and anemia were not typical of L. infantum infection. The dog was treated with allopurinol and the skin lesions improved and later disappeared when the dog was re-evaluated. CONCLUSIONS: This is the first molecularly-confirmed case of L. major infection in a dog. Two previous reports of L. major in dogs originated from Saudi-Arabia and Egypt in 1985 and 1987 were confirmed by enzymatic biochemical techniques. Serology for L. infantum was positive probably due to the well documented serological cross-reactivity between Leishmania spp. Although dogs and wild carnivores are not considered main reservoirs for L. major, the possibility of clinical canine disease and their potential as secondary hosts should be investigated in areas endemic for human L. major infection.

Soluble Syndecan-1 Levels Are Elevated in Patients with Inflammatory Bowel Disease.

BACKGROUND: Syndecan-1 plays a central role in maintaining normal intestinal barrier function. Shedding of syndecan-1, reflected by soluble syndecan-1 serum concentrations, is highly regulated by inflammation. AIM: To determine soluble syndecan-1 levels in inflammatory bowel disease patients and its relationship with other inflammatory markers, disease activity, and medical treatment. METHODS: Cross-sectional, pilot study in which serum concentrations of soluble syndecan-1 were analyzed by ELISA in a cohort of 41 inflammatory bowel disease patients (22 Crohn's disease, 19 ulcerative colitis) and 16 healthy controls. Disease activity was estimated by the Crohn's disease activity index, partial Mayo score, and C-reactive protein. RESULTS: Soluble syndecan-1 levels were significantly higher in inflammatory bowel disease patients compared to healthy controls (29.5 ± 13.4 vs. 21.1 ± 10.4 ng/ml, respectively, P = 0.03). Soluble syndecan-1 displayed a reliable ability to discriminate inflammatory bowel disease patients from healthy controls with a sensitivity of 95 %, specificity of 50 %, and positive predictive value of 83 %. Patients treated with anti-inflammatory medications demonstrated significantly lower soluble syndecan-1 levels compared to untreated patients (26.45 ± 9.75 vs. 38 ± 18.43 ng/ml, respectively, P = 0.008). CONCLUSIONS: Our results suggest that soluble syndecan-1 is potentially a novel diagnostic marker in the management of inflammatory bowel disease patients. Its applicability as a surrogate, prognostic biomarker remains to be determined.

Beneficial effect of glatiramer acetate treatment on syndecan-1 expression in dextran sodium sulfate colitis.

Syndecan-1, the most abundant heparan sulfate proteoglycan in the gastrointestinal tract, is reduced in the regenerative epithelium in inflammatory bowel disease (IBD). This study explored the effects of the immunomodulator glatiramer acetate (GA; Copaxone) treatment on syndecan-1 expression in dextran sodium sulfate (DSS)-induced colitis. Acute and chronic colitis was induced in C57BL/6 mice by 2 and 1.5% DSS in tap water, respectively. GA was applied subcutaneously, 2 mg per mouse per day, starting on the day of DSS induction until the mice were sacrificed. Syndecan-1 expression was assessed by immunohistochemistry. The effect of adoptive transfer of GA-specific T cells as an organ-specific therapy also was evaluated. Syndecan-1 expression was significantly lower in both colitis groups compared with that in naive mice (p < 0.0001). GA attenuated clinical scores and pathological manifestations of colitis and led to the reinstatement of normal levels of syndecan-1. After adoptive transfer, GA-specific cells homed to the surface epithelium of the distal colon, accompanied by the augmentation of syndecan-1 staining in their vicinity. We concluded that syndecan-1 expression is reduced in DSS-induced colitis and could be a potential prognostic factor in IBD. Treatment with GA exerts not only an anti-inflammatory effect but also a possible beneficial effect in stabilizing the intestinal epithelium barrier and tissue repair in DSS colitis. GA may be applied as a novel drug for IBD, shifting treatment from immunosuppression toward immunomodulation.

Vaccination as a novel approach for treating depressive behavior.

BACKGROUND: Depressive behavior in animals is often associated with reduced levels of brain-derived neurotrophic factor (BDNF) and impaired neurogenesis in the hippocampus. Recent studies showed that T cells recognizing central nervous system (CNS)-specific antigens can regulate adult hippocampal neurogenesis and expression of BDNF. On the basis of these findings, we hypothesized that controlling CNS specific immune activity by immunization with a myelin-related peptide may have an antidepressant effect. METHODS: We investigated the impact of immunization with a CNS related peptide, on the behavioral and cellular outcomes of chronic mild stress (CMS; an animal model for depression) in rats. RESULTS: Immunization with a weak agonist of a myelin-derived peptide ameliorated depressive behavior such as anhedonia (measured by sucrose preference), induced by CMS in rats. The behavioral outcome was accompanied by restoration of hippocampal BDNF levels and neurogenesis. CONCLUSIONS: The results of this study introduce a novel approach of immunization with CNS-related antigens as a therapeutic means for fighting depression. Vaccination, as an antidepressant therapy, may invoke several molecular and cellular pathways that are known to be regulated by antidepressant drugs. Therefore, we suggest that immune-based therapies should be considered for treatment of depression.

Dissociation between rewarding and psychomotor effects of opiates: differential roles for glutamate receptors within anterior and posterior portions of the ventral tegmental area.

The rewarding effects of drugs of abuse are thought to be dependent on the mesocorticolimbic dopamine system, which originates in the ventral tegmental area (VTA) and projects into the nucleus accumbens (NAC) and other forebrain regions. Heroin, by inhibiting GABAergic interneurons in the VTA, induces local dopaminergic activation and release in the NAC terminals. The role of other basic neurotransmitter systems, such as glutamate in the VTA, in mediating the rewarding effect of addictive drugs, is less established. We explored whether blockade of glutamate receptors in subregions of the VTA modulate the rewarding properties and/or the development of psychomotor changes induced by opiates. Administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; an AMPA/kainate receptor antagonist) into the anterior VTA blocked the rewarding effects of opiates in both the conditioned place preference and the self-administration paradigms without affecting the gradual increase of the psychomotor response to opiates. In contrast, administration of CNQX into the posterior VTA did not affect the rewarding properties of opiates, but blocked the initial sedative effect of opiates and the gradual increase of the psychomotor response to the drug. These findings suggest a critical role for glutamate receptors in the VTA in opiate reward, as well as behavioral and anatomical dissociation between the rewarding and psychomotor effects of opiates.

Repeated electrical stimulation of reward-related brain regions affects cocaine but not "natural" reinforcement.

Drug addiction is associated with long-lasting neuronal adaptations including alterations in dopamine and glutamate receptors in the brain reward system. Treatment strategies for cocaine addiction and especially the prevention of craving and relapse are limited, and their effectiveness is still questionable. We hypothesized that repeated stimulation of the brain reward system can induce localized neuronal adaptations that may either potentiate or reduce addictive behaviors. The present study was designed to test how repeated interference with the brain reward system using localized electrical stimulation of the medial forebrain bundle at the lateral hypothalamus (LH) or the prefrontal cortex (PFC) affects cocaine addiction-associated behaviors and some of the neuronal adaptations induced by repeated exposure to cocaine. Repeated high-frequency stimulation in either site influenced cocaine, but not sucrose reward-related behaviors. Stimulation of the LH reduced cue-induced seeking behavior, whereas stimulation of the PFC reduced both cocaine-seeking behavior and the motivation for its consumption. The behavioral findings were accompanied by glutamate receptor subtype alterations in the nucleus accumbens and the ventral tegmental area, both key structures of the reward system. It is therefore suggested that repeated electrical stimulation of the PFC can become a novel strategy for treating addiction.

Chronic exposure to Delta9-tetrahydrocannabinol downregulates oxytocin and oxytocin-associated neurophysin in specific brain areas.

Cannabinoids are widely abused drugs. Our goal was to identify genes modulated by Delta9-tetrahydrocannabinol (Delta9-THC) treatment. We found that chronic administration of Delta9-THC (1.5 mg/kg/day, i.p.; 7 days) to rats, downregulates the expression of oxytocin-neurophysin (OT-NP) mRNA and of OT and oxytocin-associated NP (NPOT) immunoreactivity in nucleus accumbens (NAc) and ventral tegmental area (VTA), brain areas involved in reward and addiction. Real-time PCR revealed a 60% and 53% reduction of OT-NP mRNA in NAc and VTA, respectively, under chronic treatment, while no changes were observed in NAc after 24 h. Immunohistochemistry showed a large decrease in number of OT and NPOT-stained fibers in NAc (by 59% and 52%, respectively) and VTA (by 50% and 56%, respectively). No changes in cell staining were observed in the paraventricular nucleus and supraoptic nucleus. As OT is known to inhibit development of drug tolerance and attenuate withdrawal symptoms, we suggest that OT downregulation could play a role during the establishment of the chronic effects of Delta9-THC.

Dehydroepiandrosterone (DHEA) attenuates cocaine-seeking behavior in the self-administration model in rats.

The aim of this study was to determine the possible involvement of the neurosteroid dehydroepiandrosterone (DHEA) in cocaine-seeking behavior in a self-administration model in rats. DHEA pretreatment (continued thereafter concomitantly with cocaine self-administration) attenuated cocaine-seeking behavior and elevated the levels of dopamine and serotonin in several brain regions relevant to cocaine addiction. Chronic cocaine self-administration induced elevation in brain DHEA, its sulfate ester, DHEAS, and pregnenolone. The increased brain DHEA following cocaine self-administration may serve as a compensatory protective mechanism geared to attenuate the craving for cocaine. Such anti-craving activity is further enhanced by DHEA treatment before and during cocaine self-administration.

Behavioral analysis during the forced swimming test using a joystick device.

The behavioral test described by Porsolt in 1977 for screening potential antidepressant drugs is extensively used both in basic research and in the pharmaceutical industry. The measured behavior is the immobility time during the swimming test (preformed in rodents), which decreases upon acute antidepressant treatment. Several research groups have suggested some modifications on the original Porsolt paradigm and its analysis. Nevertheless, there are still inaccuracies resulting from either undefined intermediate behaviors or from considering the movement of the whole body as one unit without analyzing the motion of the limbs. Herein, we propose a novel and simple scoring method, based on continuous measurement of the limbs motion, using a joystick, a computer screen and simple software. We validated the method, using antidepressant drugs and studied examples of false positives and false negatives of the traditional Porsolt paradigm. The proposed method is easy to use, it accounts for all range of movements and the analysis is relatively fast. Moreover, the results obtained using this analysis method show a normal Gaussian distribution in a population of rats (while the traditional Porsolt analysis does not) which allows selective breeding of 'motivated' and 'depressed' lines of animals.