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Background: The National Institute on Aging (NIA)/Alzheimer’s Association (AA) 2018 framework conceptualizes Alzheimer’s disease (AD) biologically. Evidence of brain amyloid by biomarkers defines AD pathologic change and the Alzheimer’s continuum. The presence of tau or neurodegeneration in the absence of amyloid defines non-AD pathologic change. Objective: To examine the relation of in vivo amyloid and neurodegeneration with verbal learning, one of the cognitive abilities affected early in AD, in late middle age. Methods: This was a cross-sectional study of amyloid and neurodegeneration biomarkers in a community-based cohort of 350 late-middle aged Hispanics without dementia (mean age: 64.15±3.34; 72.0%women). Amyloid (A) was measured as global standardized uptake value ratio (SUVR) with 18F-Florbetaben positron emission tomography (PET). Neurodegeneration (N) was ascertained as cortical thickness (CT) in AD signature areas using brain magnetic resonance imaging. We examined A/N continuously, categorically, by A/N profiles, and profile categories. The amyloid threshold for positivity was defined using the K means method. The CT threshold was defined as 2 standard deviations below the mean CT. Verbal learning was ascertained using total recall and delayed recall in the Buschke Selective Reminding test (SRT). Results: Higher cortical thickness was associated with higher performance in SRT delayed recall. Amyloid SUVR was not related to SRT performance. The low CT category was associated with lower performance in SRT delayed recall, while Amyloid categories were not related to any SRT score. The non-AD pathologic change group (A-N+) performed worse in SRT delayed recall compared to the Normal A/N profile group (A-N-). Conclusion: In late middle-aged Hispanics without dementia, non-AD pathologic change, but not the Alzheimer’s continuum, was related to verbal learning.

The likely involvement of inflammation and oxidative stress (IOS) in mental disease has led to advocate anti-oxidant and anti-inflammatory drugs as therapeutic strategies in the treatment of schizophrenia. Since omega-3 fatty acids (ω-3) show anti-inflammatory/neuroprotective properties, we aim to evaluate whether ω-3 treatment during adolescence in the maternal immune stimulation (MIS) animal model of schizophrenia could prevent the brain and behavioural deficits described in adulthood. At gestational day 15, PolyI:C (4 mg/kg) or saline (VH) were injected to pregnant Wistar rats. Male offspring received ω-3 (800 mg/kg) or saline (Sal) daily from postnatal day (PND) 35-49, defining 4 groups: MIS-ω-3; MIS-Sal; VH-ω-3 and VH-Sal. At PND70, rats were submitted to prepulse inhibition test (PPI). FDG-PET and T2-weighted MRI brain studies were performed in adulthood and analyzed by means of SPM12. IOS markers were measured in selected brain areas. MIS-offspring showed a PPI deficit compared with VH-offspring and ω-3 treatment prevented this deficit. Also, ω-3 reduced the brain metabolism in the deep mesencephalic area and prevented the volumetric abnormalities in the hippocampus but not in the ventricles in MIS-offspring. Besides, ω-3 reduced the expression of iNOS and Keap1 and increased the activity/concentration of HO1, NQO1 and GPX. Our study demonstrates that administration of ω-3 during adolescence prevents PPI behavioural deficits and hippocampal volumetric abnormalities, and partially counteracts IOS deficits via iNOS and Nrf2-ARE pathways in the MIS model. This study highlights the need for novel strategies based on anti-inflammatory/anti-oxidant compounds to alter the disease course in high-risk populations at early stages.

Deep brain stimulation (DBS) is a powerful neurostimulation therapy proposed for the treatment of several neuropsychiatric disorders. However, DBS mechanism of action remains unclear, being its effects on brain dynamics of particular interest. Specifically, DBS reversibility is a major point of debate. Preclinical studies in obesity showed that the stimulation of the lateral hypothalamus (LH) and nucleus accumbens (NAcc), brain centers involved in satiety and reward circuits, are able to modulate the activity of brain structures impaired in this pathology. Nevertheless, the long-term persistence of this modulation after DBS withdrawal was unexplored. Here we examine the in vivo presence of such changes 1 month after LH- and NAcc-DBS, along with differences in synaptic plasticity, following an exploratory approach. Thus, both stimulated and non-stimulated animals with electrodes in the NAcc showed a common pattern of brain metabolism modulation, presumably derived from the electrodes’ presence. In contrast, animals stimulated in the LH showed a relative metabolic invariance, and a reduction of neuroplasticity molecules, evidencing long-lasting neural changes. Our findings suggest that the reversibility or persistence of DBS modulation in the long-term depends on the selected DBS target. Therefore, the DBS footprint would be influenced by the stability achieved in the neural network involved during the stimulation. This research was supported by the Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III (projects PI14/00860 and PI17/01766, and grant CPII14/00005), co-financed by European Regional Development Fund (ERDF), “A way of making Europe”, CIBERSAM, Delegación del Gobierno para el Plan Nacional sobre Drogas (2017/085), Fundación Mapfre and Fundación Alicia Koplowitz. MCV was supported by Fundación Tatiana Pérez de Guzmán el Bueno as scholarship holder of this institution. DRM was supported by Consejería de Educación e Investigación, Comunidad de Madrid, co-funded by European Social Fund “Investing in your future” (grant, PEJD-2018-PRE/BMD- 7899). NLR was supported by Instituto de Investigación Sanitaria Gregorio Marañón, "Programa Intramural de Impulso a la I+D+I 2019”. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV‐2015‐0505). Support for Nacher’s lab came from Ministry of Economy and Competitiveness (SAF2015- 68436-R), Generalitat Valenciana (PROMETEO2013/069) and Fundación Alicia Koplowitz (FAK2012/01).

BACKGROUND AND PURPOSE Minocycline is a broad-spectrum antibiotic, effective as a chronic treatment for recurrent bacterial infections. Beyond its antibiotic action, minocycline also has important anti-inflammatory, antioxidant and antiapoptotic properties. Its efficacy has therefore been evaluated in many neurodegenerative and psychiatric diseases that have an inflammatory basis. Our aim was to review preclinical and clinical studies performed in neurological and psychiatric diseases whose treatment involved the use of minocycline and thereby to discern the possible beneficial effect of minocycline in these disorders. METHODS Completed and ongoing preclinical studies and clinical trials of minocycline for both neurodegenerative diseases and psychiatric disorders, published from January 1995 to January 2020, were identified through searching relevant databases (https://www.ncbi.nlm.nih.gov/pubmed/, https://clinicaltrials.gov/). A total of 74 preclinical studies and 44 clinical trials and open-label studies were selected. RESULTS The results of the nearly 20 years of research identified are diverse. While minocycline mostly proved to be effective in animal models, clinical results showed divergent outcomes, with positive results in some studies counterbalanced by a number of cases with no significant improvements. Specific data for each disease are further individually described in this review. CONCLUSIONS Despite minocycline demonstrating antioxidant and anti-inflammatory effects, discrepancies between preclinical and clinical data indicate that we should be cautious in analyzing the outcomes. Improving and standardizing protocols and refining animal models could help us to determine if minocycline really is a useful drug in the treatment of these pathologies.

Substance use disorders are more prevalent in schizophrenia, worsening its course and prognosis. Here, we used a double-hit rat model, combining maternal immune activation (MIA) and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to 5 episodes of unpredictable stress every other day during adolescence (from postnatal day 28 to 38). When rats reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, conditioning processes and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration while PUS reduced cocaine intake, an effect that was reversed by MIA. MIA increased motivation for cocaine and reversed the effects of PUS during extended access. Incubation of seeking was unaffected. Neither hit alone nor their combination impacted Pavlovian or instrumental conditioning or impulsiveness. At the brain level, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum. MIA+PUS altered the structure and function of the dorsal striatum increasing its volume and interfering with glutamatergic dynamics. MIA did not affect the gene expression of the nucleus accumbens but, when combined with PUS, modulated specific genes that could account for the restored cocaine intake. PUS had a profound effect on the dorsal striatal transcriptome however, this was obliterated when PUS occurred in animals with MIA. These results describe a complex interplay between MIA and stress on neurodevelopment and in the susceptibility to develop cocaine addiction.

Background: Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model. Methods: On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue. Results: MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen). Conclusions: MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains., M.L.S. was supported by the Ministerio de Ciencia, Innovacion y Universidades, Instituto de Salud Carlos III (projects PI14/00860 and PI17/01766, and grant CPII14/00005), co-financed by European Regional Development Fund (ERDF), "A way of making Europe", CIBER of Mental Health (CIBERSAM), Delegacion del Gobierno para el Plan Nacional sobre Drogas (2017/085), Fundacion Mapfre and Fundacion Alicia Koplowitz. M.C.-V. was supported by Fundacion Tatiana Perez de Guzman el Bueno. D.R.-M. was supported by Consejeria de Educacion e Investigacion, Comunidad de Madrid, co-funded by European Social Fund "Investing in your future" (grant, PEJD-2018-PRE/BMD-7899). N.L.-R. was supported by Instituto de investigacion Sanitaria Gregorio Maranon. A.R.-M. was supported by Consejeria de Educacion e Investigacion, Comunidad de Madrid, co-funded by European Social Fund "Investing in your future" (grant, PEJ15/BIO/TL-0216). The CNIC was supported by the Spanish Ministerio de Ciencia, Innovacion y Universidades (MCIU) and the Pro-CNIC Foundation. J.C.L. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECOEU-FEDER) SAF2016-75500-R and CIBERSAM. E.B.D., S.T.-S., and J.A.G.-P. were supported by grants: co-financed by the "Fondo Europeo de Desarrollo Regional" (FEDER)-UE "A way to build Europe" from the "Ministerio de Economia y Competitividad" (MINECO: RTI2018-099778-B-I00) and the "Ministerio de SaludInstituto de Salud Carlos III (PI18/01691); from the "Plan Nacional sobre Drogas, Ministerio de Sanidad, Consumo y Bienestar Social" (2019I041); from the "Programa Operativo de Andalucia FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejeria Salud, Junta de Andalucia" (PI-0080-2017 and PI-0009-2017); from the Consejeria de Salud de la Junta de Andalucia (PI-0134-2018); from the University of Cadiz (PR2019-046); from the "Instituto de Investigacion e Innovacion en Ciencias Biomedicas de Cadiz-INiBICA" (IN-C22; LI19/06IN-CO22); from the "Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia" (CTS-510); from the "CIBERSAM" (CB/07/09/0033).

Inflammation and oxidative stress (IOS) are considered key pathophysiological elements in the development of mental disorders. Recent studies demonstrated that the antipsychotic risperidone elicits an antiinflammatory effect in the brain. We administered risperidone for 2-weeks at adolescence to assess its role in preventing brain-related IOS changes in the maternal immune stimulation (MIS) model at adulthood. We also investigated the development of volumetric and neurotrophic abnormalities in areas related to the HPA-axis. Poly I:C (MIS) or saline (Sal) were injected into pregnant Wistar rats on GD15. Male offspring received risperidone or vehicle daily from PND35-PND49. We studied 4 groups (8-15 animals/group): Sal-vehicle, MIS-vehicle, Sal-risperidone and MIS-risperidone. [18F]FDG-PET and MRI studies were performed at adulthood and analyzed using SPM12 software. IOS and neurotrophic markers were measured using WB and ELISA assays in brain tissue. Risperidone elicited a protective function of schizophrenia-related IOS deficits. In particular, risperidone elicited the following effects: reduced volume in the ventricles and the pituitary gland; reduced glucose metabolism in the cerebellum, periaqueductal gray matter, and parietal cortex; higher FDG uptake in the cingulate cortex, hippocampus, thalamus, and brainstem; reduced NFκB activity and iNOS expression; and increased enzymatic activity of CAT and SOD in some brain areas. Our study suggests that some schizophrenia-related IOS changes can be prevented in the MIS model. It also stresses the need to search for novel strategies based on anti-inflammatory compounds in risk populations at early stages in order to alter the course of the disease.

Cannabis is widely consumed by adolescents, and is also a potential prior step leading to the use of other drugs later in life (Gateway Hypothesis); however, the evidence for this hypothesis is controversial. This work aimed to increase our understanding of the long-term consequences of adolescent exposure to Δ9-tetrahydrocannabinol (THC) and to test the Gateway Hypothesis, experimentally. We exposed rats of both sexes to THC and studied its effects on reward-related processes, brain morphology (MRI), metabolism (1H-MRS), function (PET) and the transcriptomic profiles of the nucleus accumbens (RNASeq). Lastly, we studied cocaine-induced cellular activation (c-Fos) and cocaine addiction-like behaviours. THC exposure increased Pavlovian to instrumental transfer in males, goal-tracking (regardless of the sex) and impulsivity, but did not affect habit formation. Adolescent THC reduced striatal volume (in females), commissural integrity and ventricular volume. Also, there were lower levels of choline compounds in the cortex of THC-exposed rats and cerebellar hypoactivation in THC-females. THC also modified some of the gene expression programs of the nucleus accumbens, which could contribute to the behavioural features observed. Lastly, THC exposure increased cocaine-induced c-Fos levels in cortical and hypothalamic areas and increased the motivation for cocaine, followed by a higher rebound of use in THC-females after reestablishing low-effort conditions. Critically, acquisition of cocaine self-administration, compulsive seeking, intake under extended access or the incubation of seeking were unaltered. These results suggest that adolescent THC exposure alters psychological and brain development and that the Gateway Hypothesis does not entirely pass the test of preclinical enquiry.

Non-linear relations of brain amyloid beta (Aβ) with task- based functional connectivity (tbFC) measured with functional magnetic resonance imaging (fMRI) have been reported in late middle age. Our objective was to examine the association between brain Aβ and resting-state functional connectivity (rsFC) in late middle-aged adults. Global brain Aβ burden was ascertained with 18F-Florbetaben Positron Emission Tomography (PET); rsFC was ascertained on 3T Magnetic Resonance Imaging (MRI) among 333 late middle-aged Hispanics adults without dementia in four major brain functional connectivity networks: default mode network (DMN), fronto-parietal control network (FPC), salience network (SAL) and dorsal attention network (DAN). We examined the relationship of global brain Aβ with rsFC using multivariable linear regression adjusted for age, sex, education, and APOE-ε4 genotype. We quantified the non-linear associations both with quadratic terms and by categorizing Aβ into three groups: low Aβ, intermediate Aβ, and positive Aβ. We found no significant linear or non-linear associations between Aβ, measured either continuously or categorically, with rsFC in the examined networks. Our null findings may be explained by the younger age of our participants in whom amyloid burden is relatively low. It is also possible that the recently reported non-linear relationship is exclusive to task fMRI and not rsfMRI.

Metabolic syndrome (MetS) is associated with dementia, but it is unclear whether MetS is related to Alzheimer's disease (AD). We investigated the association of MetS with brain amyloid, a key AD feature, and neurodegeneration. A community-based sample of 350 middle-aged Hispanics in New York City had cerebral amyloid β (Aβ) burden ascertained with 18F-Florbetaben positron emission tomography. Neurodegeneration was ascertained as cortical thickness in AD signature regions from 3T brain MRI. MetS and its components (glucose, blood pressure, triglycerides, high-density lipoprotein, adiposity) were defined using the National Institutes of Health criteria. Neither the presence of MetS nor the MetS score was associated with Aβ or neurodegeneration. Among the MetS components, elevated glucose was associated with lower Aβ burden, and this association was not explained by diabetes treatment. Glucose and triglycerides were related to smaller cortical thickness. Our findings suggest that MetS as an arbitrary measure of aggregate metabolic and vascular risk does not capture the risk of AD neuropathology in late middle age and that other approaches to measure the aggregate risk should be examined.

BACKGROUND: Females may have a higher risk of dementia than males. It is not clear if sex differences in Alzheimer’s disease (AD) neuropathology explain the higher risk of dementia in females. Sex differences in AD neuropathology might begin in middle age, decades before the sex differences in dementia are apparent. OBJECTIVE: To examine sex differences in in-vivo AD neuropathology in late middle age. METHODS: We conducted a cross-sectional comparison of AD biomarkers among 266 Hispanic males and females (mean age: 64.0; 71.8% females) without dementia. Amyloid burden was measured as global standardized uptake value ratio (SUVR) with (18)F-Florbetaben Positron Emission Tomography (PET). Neurodegeneration was ascertained as cortical thickness in AD signature areas using brain magnetic resonance imaging. Tau burden was measured as tau SUVR in the middle/inferior temporal gyri and medial temporal cortex with (18)F-MK-6240 in 75 of the 266 participants. RESULTS: Females had higher amyloid SUVR and tau SUVR in the middle/inferior temporal gyri than males. However, females had higher cortical thickness than males and performed better in a test of verbal memory despite having higher AD neuropathology burden. CONCLUSION: Higher amyloid and tau in females compared to males in late middle-age may explain the reported higher dementia risk in elderly females compared to males. Longitudinal follow-up is necessary to examine whether higher amyloid and tau burden in late middle age is followed by increased neurodegeneration and cognitive decline in females as compared with males.

Background An initial antidepressant effect when using deep brain stimulation (DBS) of the subcallosal area of the cingulate cortex (Cg25) to treat resistant depression that could be the result of electrode insertion has been described. We previously showed that electrode insertion into the infralimbic cortex (ILC; the Cg25 rodent correlate) provokes a temporally limited antidepressant-like effect that is counteracted by non-steroidal anti-inflammatory drugs, such as those routinely used for pain relief. Objective We characterized the effect of electrode insertion using functional neuroimaging and evaluated the impact of different analgesics on this effect. Methods The effect of electrode insertion into the ILC was evaluated by positron emission tomography. The effect of analgesics (ibuprofen, tramadol and morphine) on the behavioral effect induced by electrode insertion were evaluated through the forced swimming test and the novelty suppressed feeding test. Furthermore, glial fibrillary acidic protein (GFAP) and p11 expression were measured. Results Electrode implantation produces an antidepressant- and anxiolytic-like effect, a local decrease in glucose metabolism, and changes in several brain regions commonly related to depression and the antidepressant response. Ibuprofen counteracted the behavioral and molecular changes produced by electrode insertion (changes in GFAP and p11 protein expression). However, analgesics with no anti-inflammatory properties (e.g., tramadol) neither counteract the behavioral effects of electrode implantation nor the molecular mechanisms triggered. Conclusions Analgesics without anti-inflammatory properties may not limit the transient benefit produced by electrode insertion reducing the time required to achieve remission in depressive DBS patients.

Alzheimer's disease (AD) is a progressive and debilitating degenerative disorder for which there are currently no effective therapeutic options. Non-invasive neuromodulation, including transcranial direct current stimulation (tDCS), has been investigated for the treatment of cognitive symptoms in AD. Results from clinical and preclinical studies, however, have been somewhat controversial. We investigate whether tDCS delivered to triple transgenic (3xTg) AD mice improves memory deficits and mitigates the development of AD-type neuropathology. 3xTg AD mice and controls were implanted with paddle electrodes over the skull. The cathode was anterior to bregma and the anode anterior to lamda. tDCS was delivered for 20 min/day, 5 days/week over three weeks at 50 μA. Though this amplitude was lower than the one used in the preclinical literature, it generated a high current density compared to the clinical scenario. Memory testing was conducted during treatment weeks 2 and 3. Post-mortem pathological AD markers were studied. Our results show that performance of 3xTg mice in the novel object recognition and Morris water maze tests was significantly impaired compared to that of controls. In addition, AD transgenics had an increased expression of tau, phosphorylated-tau and amyloid precursor protein in the hippocampus. tDCS did not improve behavioural deficits or mitigated the development of AD neuropathology in 3xTg animals. In summary, we found that tDCS at the settings selected in our study was largely ineffective in improving memory performance or altering the expression of AD pathological hallmarks in a validated mouse model.

Purpose The nucleus accumbens (NAcc) has been suggested as a possible target for deep brain stimulation (DBS) in the treatment of obesity. Our hypothesis was that NAcc-DBS would modulate brain regions related to reward and food intake regulation, consequently reducing the food intake and, finally, the weight gain. Therefore, we examined changes in brain glucose metabolism, weight gain and food intake after NAcc-DBS in a rat model of obesity. Procedures Electrodes were bilaterally implanted in 2 groups of obese Zucker rats targeting the NAcc. One group received stimulation one hour daily during 15 days, while the other remained as control. Weight and daily consumption of food and water were everyday registered the days of stimulation, and twice per week during the following month. Positron emission tomography (PET) studies with 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) were performed 1 day after the end of DBS. PET data was assessed by statistical parametric mapping (SPM12) software and region of interest (ROI) analyses. Results NAcc-DBS lead to increased metabolism in the cingulate-retrosplenial-parietal association cortices, and decreased metabolism in the NAcc, thalamic and pretectal nuclei. Furthermore, ROIs analyses confirmed these results by showing a significant striatal and thalamic hypometabolism, and a cortical hypermetabolic region. However, NAcc-DBS did not induce a decrease in either weight gain or food intake. Conclusions NAcc-DBS led to changes in the metabolism of regions associated with cognitive and reward systems, whose impairment has been described in obesity. This research was supported by the Ministry of Economy and Competitiveness ISCIII grants (PI14/00860, CPII14/00005), Ministry of Economy, Industry and Competitiveness (PI17/01766), cofunded by ERDF (FEDER) Funds from the European Commission ``A way of making Europe´´, Fundacion Mapfre, Fundacion Alicia Koplowitz (FAK2016/01), `Delegacion de Gobierno para el Plan Nacional sobre Drogas' (PNSD 2017/085), Comunidad de Madrid (BRADE-CM S2013/ICE-2958) and Fundacion Tatiana Perez de Guzman el Bueno. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

The objective of this study was to evaluate the potential use of some vegetal raw materials in personal-care products. Four ethanolic extracts (grape pomace, Pinus pinaster wood chips, Acacia dealbata flowers, and Lentinus edodes) were prepared and total phenolics, monomeric sugars, and antioxidant capacity were determined on alcoholic extracts. Six of the most important groups of cosmetics products (hand cream, body oil, shampoo, clay mask, body exfoliating cream, and skin cleanser) were formulated. Participants evaluated some sensory attributes and overall acceptance by a 10-point scale; the results showed differences among age-intervals, but not between males and females. The results confirmed that all extracts presented characteristics appropriate for their use in cosmetic formulations and their good acceptability by consumers into all cosmetic products. Texture/appearance, spreadability, and skin feeling are important attributes among consumer expectations, but odor and color were the primary drivers and helped differentiate the natural extracts added into all personal-care products.

Image quality of positron emission tomography (PET) tracers that emits high-energy positrons, such as Ga-68, Rb-82, or I-124, is significantly affected by positron range (PR) effects. PR effects are especially important in small animal PET studies, since they can limit spatial resolution and quantitative accuracy of the images. Since generators accessibility has made Ga-68 tracers wide available, the aim of this study is to show how the quantitative results of [Ga-68]DOTA-labeled PET/X-ray computed tomography (CT) imaging of neuroendocrine tumors in mice can be improved using positron range correction (PRC). Eighteen scans in 12 mice were evaluated, with three different models of tumors: PC12, AR42J, and meningiomas. In addition, three different [Ga-68]DOTA-labeled radiotracers were used to evaluate the PRC with different tracer distributions: [Ga-68]DOTANOC, [Ga-68]DOTATOC, and [Ga-68]DOTATATE. Two PRC methods were evaluated: a tissue-dependent (TD-PRC) and a tissue-dependent spatially-variant correction (TDSV-PRC). Taking a region in the liver as reference, the tissue-to-liver ratio values for tumor tissue (TLRtumor), lung (TLRlung), and necrotic areas within the tumors (TLRnecrotic) and their respective relative variations (Delta TLR) were evaluated. All TLR values in the PRC images were significantly different (p < 0.05) than the ones from non-PRC images. The relative differences of the tumor TLR values, respect to the case with no PRC, were Delta TLRtumor 87 +/- 41 \% (TD-PRC) and 85 +/- 46 \% (TDSV-PRC). TLRlung decreased when applying PRC, being this effect more remarkable for the TDSV-PRC method, with relative differences respect to no PRC: Delta TLRlung = - 45 +/- 24 (TD-PRC), - 55 +/- 18 (TDSV-PRC). TLRnecrotic values also decreased when using PRC, with more noticeable differences for TD-PRC: Delta TLRnecrotic = - 52 +/- 6 (TD-PRC), - 48 +/- 8 (TDSV-PRC). The PRC methods proposed provide a significant quantitative improvement in [Ga-68]DOTA-labeled PET/CT imaging of mice with neuroendocrine tumors, hence demonstrating that these techniques could also ameliorate the deleterious effect of the positron range in clinical PET imaging. This work was partially funded by the projects RTC-2015-3772-1, TEC2014-56600-R, and TEC2016-78052-R from the Spanish Ministry of Science and Innovation, Spanish Government, Spanish Ministry of Economy and Competitiveness grants (FIS PI11/00616, FIS PI14/00860, CP08/00017, and CPII14/00005) co-financed by European Regional Development Fund (ERDF), Alicia Koplowitz Foundation and TOPUS S2013/MIT-3024 project from the regional government of Madrid. The research leading to these results has received funding from the Innovative Medicines Initiative (www.imi.europa.eu) Joint Undertaking under grant agreement no 115337, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. Part of the calculations were performed in the ``Cluster de Calculo de Alta Capacidad para Tecnicas Fisicas´´ funded by UCM and by UE under the FEDER programme. Sí

Deep brain stimulation (DBS) is a neurosurgery technique widely used in movement disorders, although its mechanism of action remains unclear. In fact, apart from the stimulation itself, the mechanical insertion of the electrode may play a crucial role. Here we aimed to distinguish between the insertional and the DBS effects on brain glucose metabolism. To this end, electrodes were implanted targeting the medial prefrontal cortex in five adult male Wistar rats. Positron Emission Tomography (PET) studies were performed before surgery (D0) and seven (D7) and nine days (D9) after that. DBS was applied during the (18)FDG uptake of the D9 study. PET data were analysed with statistical parametric mapping. We found an electrode insertional effect in cortical areas, while DBS resulted in a more widespread metabolic pattern. The consequences of simultaneous electrode and DBS factors revealed a combination of both effects. Therefore, the insertion metabolic effects differed from the stimulation ones, which should be considered when assessing DBS protocols. The authors thank Kenia Martinez for her help in performing the statistical analyses and the interpretation of the results; Alexandra de Francisco and Yolanda Sierra for their support in stereotaxic surgery, animal handling, and acquisition of imaging studies. This research was supported by Fundacion Mapfre, Alicia Koplowitz [FAK16/01], CIBER de Salud Mental (CIBERSAM), the Ministry of Economy and Competitiveness ISCIII-FIS Grants [PI14/00860, CPII14/00005, and PI17/01766], and Delegacion del Gobierno para el Plan Nacional sobre Drogas [PNSD 2017/085] and cofinanced by ERDF (FEDER) Funds from the European Commission, ``A way of Making Europe,´´ and Comunidad de Madrid [BRADE-CMS2013/ICE-2958]. Sí

Introduction The main therapeutic intervention for sickle cell disease (SCD) is hydroxyurea (HU). The effect of HU is largely through dose-dependent induction of fetal hemoglobin (HbF). Poor HU adherence is common among adolescents. Methods Our 6-month, two-site pilot intervention trial, “HABIT,” was led by culturally aligned community health workers (CHWs). CHWs performed support primarily through home visits, augmented by tailored text message reminders. Dyads of youth with SCD ages 10–18 years and a parent were enrolled. A customized HbF biomarker, the percentage decrease from each patients’ highest historical HU-induced HbF, “Personal best,” was used to qualify for enrollment and assess HU adherence. Two primary outcomes were as follows: (1) intervention feasibility and acceptability and (2) HU adherence measured in three ways: monthly percentage improvement toward HbF Personal best, proportion of days covered (PDC) by HU, and self-report. Results Twenty-eight dyads were enrolled, of which 89% were retained. Feasibility and acceptability were excellent. Controlling for group assignment and month of intervention, the intervention group improved percentage decrease from Personal best by 2.3% per month during months 0–4 (P = 0.30), with similar improvement in adherence demonstrated using pharmacy records. Self-reported adherence did not correlate. Dyads viewed CHWs as supportive for learning about SCD and HU, living with SCD and making progress in coordinated self-management responsibility to support a daily HU habit. Most parents and youth appreciated text message HU reminders. Conclusions The HABIT pilot intervention demonstrated feasibility and acceptability with promising effect toward improved medication adherence. Testing in a larger multisite intervention trial is warranted.

Background and aims Left ventricular hypertrophy (LVH) in hypertension is associated with a greater risk of sustained supraventricular/atrial arrhythmias. Dronedarone is an antiarrhythmic agent that was recently approved for the treatment of atrial fibrillation. However, its effect on early regression of LVH has not been reported. We tested the hypothesis that short-term administration of dronedarone induces early regression of LVH in spontaneously hypertensive rats (SHRs). Methods Ten-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where animals received dronedarone treatment (100 mg/kg) for a period of 14 days, or to a control group (SHR) where rats were given vehicle. A third group with normotensive control rats (WKY) was also added. At the end of the treatment with dronedarone we studied the cardiac anatomy and function in all the rats using transthoracic echocardiogram, cardiac metabolism using the PET/CT study (2-deoxy-2[18F]fluoro-D-glucose) and cardiac structure by histological analysis of myocyte size and collagen content. Results The hypertensive vehicle treated SHR rats developed the classic cardiac pattern of hypertensive cardiomyopathy as expected for the experimental model, with increases in left ventricular wall thickness, a metabolic shift towards an increase in glucose use and increases in myocyte and collagen content. However, the SHR-D rats showed statistically significant lower values in comparison to SHR group for septal wall thickness, posterior wall thickness, ventricular mass, glucose myocardial uptake, size of left ventricular cardiomyocytes and collagen content. All these values obtained in SHR-D rats were similar to the values measured in the normotensive WKY control group. Conclusion The results suggest by three alternative and complementary ways (analysis of anatomy and cardiac function, metabolism and histological structure) that dronedarone has the potential to reverse the LVH induced by arterial hypertension in the SHR model of compensated ventricular hypertrophy.

OBJECTIVE To investigate metabolic changes in brain networks by deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC), nucleus accumbens (NAcc) and dorsomedial thalamus (DM) using positron emission tomography (PET) in naive rats. METHODS 43 male Wistar rats underwent stereotactic surgery and concentric bipolar platinum-iridium electrodes were bilaterally implanted into one of the three brain sites. [18F]-fluoro-2-deoxy-glucose-PET (18FDG-PET) and computed tomography (CT) scans were performed at the 7th (without DBS) and 9th day (with DBS) after surgery. Stimulation period matched tracer uptake period. Images were acquired with a small-animal PET-CT scanner. Differences in glucose uptake between groups were assessed with Statistical Parametric Mapping. RESULTS DBS induced site-specific metabolic changes, although a common increased metabolic activity in the piriform cortex was found for the three brain targets. mPFC-DBS increased metabolic activity in the striatum, temporal and amygdala, and reduced it in the cerebellum, brainstem (BS) and periaqueductal gray matter (PAG). NAcc-DBS increased metabolic activity in the subiculum and olfactory bulb, and decreased it in the BS, PAG, septum and hypothalamus. DM-DBS increased metabolic activity in the striatum, NAcc and thalamus and decreased it in the temporal and cingulate cortex. CONCLUSIONS DBS induced significant changes in 18FDG uptake in brain regions associated with the basal ganglia-thalamo-cortical circuitry. Stimulation of mPFC, NAcc and DM induced different patterns of 18FDG uptake despite interacting with the same circuitries. This may have important implications to DBS research suggesting individualized target selection according to specific neural modulatory requirements.

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia’s neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy. We thank Renate Winter, Doris Zschaber and Roselies Pickert for excellent technical assistance. This research was conducted under the EraNet Neuron framework (DBS_F20rat) and supported by the BMBF, Germany (B01EW1103, 01EE1403A), Fundación Mapfre, Comunidad de Madrid and the Ministry of Economy and Competitiveness ISCIII-FIS grants (PI14/00860, CPII/00005) co-financed by ERDF (FEDER) Funds from the European Commission, ‘A way of making Europe’, Spain (PI14/00860, CPII/00005, MV1500002), the CSO-MOH, Israel (3-8580) and the Canadian Institutes of Health Research, Canada (CIHR, 110068), and co-financed by the DFG, Germany (WI 2140/1-1/2; WI 2140/2-1). Publicado

Background: Rationalization of antiangiogenics requires biomarkers. Vascular re‐normalization is one widely accepted mechanism of action for this drug class. The interstitium of tumors with abnormal vasculature is hypoxic. We sought to track vascular normalization with 18F‐misonidazole ([18F]‐FMISO, a probe that detects hypoxia) PET, in response to window‐of‐opportunity (WoO) treatment with the antiangiogenic dovitinib. Methods: Two patient‐derived pancreas xenografts (PDXs; Panc215 and Panc286) and the spontaneous breast cancer model MMTV‐PyMT were used. Animals were treated during 1 week of WoO treatment with vehicle or dovitinib, preceded and followed by [18F]‐FMISO‐PET, [18F]‐FDG‐PET, and histologic assessment (dextran extravasation, hypoxia and microvessel staining, and necrosis, cleaved caspase‐3 and Ki67 measurements). After WoO treatment, gemcitabine (pancreas)/adriamycin (breast) or vehicle was added and animals were treated until the humane endpoint. Tumor growth inhibition (TGI) and survival were the parameters studied. Results: [18F]‐FMISO SUV did not change after dovitinib‐WoO treatment compared to vehicle‐WoO (0.54 vs. 0.6) treatment in Panc215, but it decreased significantly in Panc286 (0.58 vs. 1.18; P, Highlights We describe a new technique to monitor the efficacy of antiangiogenics.This drug class currently lacks biomarkers.Antiangiogenics exert their positive effect by inducing stromal normalization.18F‐fluoromisonidazole PET is able to monitor stromal normalization.Tumors showing stromal normalization by PET experience benefit from antiangiogenics.

Grape and wine byproducts have been extensively studied for the recovery of phenolic compounds with antioxidant activity and a variety of biological actions. The selective recovery and concentration of the phenolic compounds from the liquid phase separated from further diluted winery wastes has been proposed. Adsorption onto non ionic polymeric resins and further desorption with ethanolic solutions was studied. Several commercial food grade resins were screened with the aim of selecting the most suited for the practical recovery of phenolic compounds with radical scavenging activity. Under the optimized desorption conditions (using Sepabeads SP207 or Diaion HP20 as adsorbents and eluting with 96% ethanol at 50 °C) a powdered yellow-light brown product with 50% phenolic content, expressed as gallic acid equivalents, was obtained. The radical scavenging capacity of one gram of product was equivalent to 2–3 g of Trolox The authors are grateful to grateful to the Spanish Ministry of Education and Science (Research Project reference ALG2006-05387, which had partial financial support from the FEDER funds of the European Union), and to Xunta de Galicia (Research Project Ref. PGIDIT06 TAM38301PR) for the financial support of this work. The authors thank Miguel Estévez for his excellent technical support. EC thanks the Spanish MEC (PTA-2003-02-00194) and AM thanks the MEC (PTA-2003-01-00194) and the Isidro Parga Pondal Program (Xunta de Galicia) SI

Food intake is regulated by factors that modulate caloric requirements as well as food's reinforcing properties. In this study, we measured brain glucose utilization to an olfactory stimulus (bacon scent), and we examined the role of food restriction and genetic predisposition to obesity on such brain metabolic activity.Zucker obese (Ob) and lean (Le) rats were divided into four groups: (1) Ob ad-libitum fed, (2) Ob food restricted (70% of ad libitum), (3) Le ad-libitum fed and (4) Le food restricted. Rats were scanned using micro-positron emission tomography and 2-[(18)F]-fluoro-2-deoxy-D-glucose under two conditions: (1) baseline scan (no stimulation) and (2) challenge scan (food stimulation, FS).FS resulted in deactivation of the right and left hippocampus. Ob rats showed greater changes with FS than Le rats (deactivation of hippocampus and activation of the medial thalamus) and Ob but not Le animals deactivated the frontal cortex and activated the superior colliculus. Access to food resulted in an opposite pattern of metabolic changes to the food stimuli in olfactory nucleus (deactivated in unrestricted and activated in restricted) and in right insular/parietal cortex (activated in unrestricted and deactivated in restricted). In addition, restricted but not unrestricted animals activated the medial thalamus.The greater changes in the Ob rats suggest that leptin modulates the regional brain responses to a familiar food stimulus. Similarly, the differences in the pattern of responses with food restriction suggest that FS is influenced by access to food conditions. The main changes with FS occurred in the hippocampus, a region involved in memory, the insular cortex, a region involved with interoception (perception of internal sensations), the medial thalamus (region involved in alertness) and in regions involved with sensory perception (olfactory bulb, olfactory nucleus, occipital cortex, superior colliculus and parietal cortex), which corroborates their relevance in the perception of food.

Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Deep brain stimulation (DBS) is a surgical technique currently investigated for medically-refractory psychiatric disorders. Here, we use the poly I:C rat model of schizophrenia to study the effects of medial prefrontal cortex (mPFC) and nucleus accumbens (Nacc) DBS on two behavioral schizophrenia-like deficits, i.e. sensorimotor gating, as reflected by disrupted prepulse inhibition (PPI), and attentional selectivity, as reflected by disrupted latent inhibition (LI). In addition, the neurocircuitry influenced by DBS was studied using FDG PET. We found that mPFC- and Nacc-DBS alleviated PPI and LI abnormalities in poly I:C offspring, whereas Nacc- but not mPFC-DBS disrupted PPI and LI in saline offspring. In saline offspring, mPFC-DBS increased metabolism in the parietal cortex, striatum, ventral hippocampus and Nacc, while reducing it in the brainstem, cerebellum, hypothalamus and periaqueductal gray. Nacc-DBS, on the other hand, increased activity in the ventral hippocampus and olfactory bulb and reduced it in the septal area, brainstem, periaqueductal gray and hypothalamus. In poly I:C offspring changes in metabolism following mPFC-DBS were similar to those recorded in saline offspring, except for a reduced activity in the brainstem and hypothalamus. In contrast, Nacc-DBS did not induce any statistical changes in brain metabolism in poly I:C offspring. Our study shows that mPFC- or Nacc-DBS delivered to the adult progeny of poly I:C treated dams improves deficits in PPI and LI. Despite common behavioral responses, stimulation in the two targets induced different metabolic effects.

Marijuana consumption during adolescence has been proposed to be a stepping stone for adult cocaine addiction. However, experimental evidence for this hypothesis is missing. In this work we chronically injected male and female Wistar rats with either the cannabinoid agonist CP 55,940 (CP; 0.4 mg/kg) or its corresponding vehicle. Adult acquisition (seven 30 min daily sessions) and maintenance (fourteen 2 h daily sessions) of cocaine self administration (1 mg/kg), food reinforced operant learning under conditions of normal (ad libitum access to food), and high motivation (food restriction schedule) were measured. Additionally, brain metabolic activity was analyzed by means of [18F] fluorodeoxyglucose positron emission tomography. During the acquisition phase, female CP treated rats showed a higher rate of cocaine self administration as compared to vehicle treated females and males; no differences were found between both male groups. This effect disappeared in the maintenance phase. Moreover, no differences among groups were evident in the food reinforced operant task, pointing to the cocaine specific nature of the effect seen in self administration rather than a general change in reward processing. Basal brain metabolic activity also changed in CP treated females when compared to their vehicle treated counterparts with no differences being found in the males; more specifically we observed a hyper activation of the frontal cortex and a hypo activation of the amygdalo entorhinal cortex. Our results suggest that a chronic exposure to cannabinoids during adolescence alters the susceptibility to acquire cocaine self administration, in a sex specific fashion. This increased susceptibility could be related to thechanges in brain metabolic activity induced by cannabinoids during adolescence This work was supported by Grants FIS G03/05 (Red de Trastornos Adictivos), BSO2001-1099, FIS 01-05-01, Plan Nacional sobre Drogas (PNSD) 2001–2003, PNSD 2004–2007, GR-SAL/0260/2004 to EA and Grants INT/2012/ 2002, CB06/01/0079, and CENIT (2006–2009) to MD Publicado

We have reported, previously, some effect of allogenic hepatic cells for islet tolerance when they are injected mixed (hepatic cells and islets) in different proportions via portal vein, in diabetic Wistar rats. Now we have studied the role of allogenic hepatic cells injected sequentially 15 min before islets, comparing via the portal vein (A and B groups) and via the cava vein (C and D groups) with a control group of islets alone. The allogenic islets were always injected via portal vein, in similar conditions, while the ratio of hepatic cells/islets was 100:1 (A, C groups) or 200:1 (B, D groups). Islets and hepatic cells were obtained from several different rats. The transplanted rats were observed during 30 days and results compared among the different rat groups: porta-porta (P/P), cava-porta (C/P), and control group. Statistically, a significant interaction between type of transplant and proportion of hepatic cells was observed. Also, C plus D groups showed statistical difference with the control group (p < 0.017) and also all the groups together (p < 0.047). These results suggest that hepatic cells can induce, in some cases, islet graft prolongation in Wistar rats. Better results were obtained when hepatic cells were injected via the cava vein than via the portal vein. Because we used a liver cell suspension integrated for several kinds of cells, the study does not clarify if this effect can be related to some specific hepatic cell subpopulation. To confirm the results and to determine if the hypothetical mechanism can be attributed to a block of the immune system or to some factor secreted by hepatic cells, more studies must be performed.

[Background]: Monosodium glutamate (MSG) is a flavor-enhancer widely used as a food additive. However, its safe dietary concentration and its toxicity, including its possible implication in the recent metabolic syndrome pandemia, is still a controversial issue. Therefore, a deep knowledge of its effects upon regular dietary use is needed. Our aim was to evaluate the effects of chronic exposure to MSG on feeding behavior, abdominal fat, gastrointestinal motility, and cardiovascular function in rats. [Methods]: Two groups of adult male Wistar rats were used: control and treated with MSG (4 g/L in drinking water) for 6 weeks. Different functional parameters were determined and the histological structure was analyzed in tissues of interest. [Key Results]: Compared to control animals, chronic MSG increased water intake but did not modify food ingestion or body weight gain. Neither the abdominal fat volume nor the fat fraction, measured by magnetic resonance imaging, was modified by MSG. Monosodium glutamate did not alter general gastrointestinal motility, but significantly increased the colonic response to mechanical stimulation. It slightly reduced endothelium-dependent relaxation in aorta, without significantly modifying any other cardiovascular parameters. No significant histological alterations were detected in salivary glands, intestinal wall, aorta, heart, and kidney. [Conclusions & Inferences]: Chronic treatment with MSG in the adult rat increased water intake. This supports its potential to improve acceptance of low-fat regimens and to increase hydration in the elderly and sportspeople, often at risk of dehydration. Changes in colonic contractility and cardiovascular function could have some long-term repercussions warranting further research., This work was supported by Fundacion Mapfre (Ayudas a la Investigacion-Promocion de la Salud 2011 and 2012); Ministerio de Educacion y Ciencia y Ministerio de Ciencia e Innovacion (SAF2009-12422-C02-01, SAF2012-40075-C02-01, PI11/00616, PI14/00860, CPII14/00005, and PI10/02986); and CIBERSAM.

Purpose The goal of this study was to compare the tumor uptake kinetics and diagnostic value of three 68Ga-DOTA-labeled somatostatin analogues (68Ga-DOTATOC, 68Ga-DOTANOC, and 68Ga-DOTATATE) using PET/CT in a murine model with subcutaneous meningioma xenografts. Methods The experiment was performed with 16 male NUDE NU/NU mice bearing xenografts of a human meningioma cell line (CH-157MN). 68Ga-DOTATOC, 68Ga-DOTANOC, and 68Ga-DOTATATE were produced in a FASTLab automated platform. Imaging was performed on an Argus small-animal PET/CT scanner. The SUVmax of the liver and muscle, and the tumor-to-liver (T/L) and tumor-to-muscle (T/M) SUV ratios were computed. Kinetic analysis was performed using Logan graphical analysis for a two-tissue reversible compartmental model, and the volume of distribution (Vt) was determined. Results Hepatic SUVmax and Vt were significantly higher with 68Ga-DOTANOC than with 68Ga-DOTATOC and 68Ga-DOTATATE. No significant differences between tracers were found for SUVmax in tumor or muscle. No differences were found in the T/L SUV ratio between 68Ga-DOTATATE and 68Ga-DOTATOC, both of which had a higher fraction than 68Ga-DOTANOC. The T/M SUV ratio was significantly higher with 68Ga-DOTATATE than with 68Ga-DOTATOC and 68Ga-DOTANOC. The Vt for tumor was higher with 68Ga-DOTATATE than with 68Ga-DOTANOC and relatively similar to that of 68Ga-DOTATOC. Conclusions This study demonstrates, for the first time, the ability of the three radiolabeled somatostatin analogues tested to image a human meningioma cell line. Although Vt was relatively similar with 68Ga-DOTATATE and 68Ga-DOTATOC, uptake was higher with 68Ga-DOTATATE in the tumor than with 68Ga-DOTANOC and 68Ga-DOTATOC, suggesting a higher diagnostic value of 68Ga-DOTATATE for detecting meningiomas.

Amphetamine-induced neurotoxic effects have traditionally been studied using immunohistochemistry and other post-mortem techniques, which have proven invaluable for the definition of amphetamine-induced dopaminergic damage in the nigrostriatal pathway. However, these approaches are limited in that they require large numbers of animals and do not provide the temporal data that can be collected in longitudinal studies using functional neuroimaging techniques. Unfortunately, functional imaging studies in rodent models of drug-induced neurotoxicity are lacking. The aim of this study was to evaluate in vivo the changes in brain glucose metabolism caused by amphetamine in the pleiotrophin knockout mouse (PTN-/-), a genetic model with increased vulnerability to amphetamine-induced neurotoxic effects. We showed that administration of amphetamine causes a significantly greater loss of striatal tyrosine hydroxylase content in PTN-/- mice than in wild-type (WT) mice. In addition, [ 18 F]-FDG-PET shows that amphetamine produces a significant decrease in glucose metabolism in the striatum and prefrontal cortex in the PTN-/- mice, compared to WT mice. These findings suggest that [ 18 F]-FDG uptake measured by PET is useful for detecting amphetamine-induced changes in glucose metabolism in vivo in specific brain areas, including the striatum, a key feature of amphetamine-induced neurotoxicity.

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.-- et al., Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D(1) receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia. The animal could provide valuable insights into phenotypic aspects of this psychiatric disorder., The study was supported by an intramural Grant from Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM), Spanish MICINN and FEDER (SAF2009-08460 to JJM; SAF2010-21948 to JLMMM; AGL2009-11358 to AG-A, SAF2011-29918 to JAGS; PI10/02986, CP08/00017 and CEN-20101014 to MD), Basque Government (S-PR10UN01 to JEO and IT-199/07 to JJM), University of the Basque Country (UPV/EHU) and Complutense University of Madrid (UCM GR42/10-962075 to JLMM).

RASopathies are a class of developmental syndromes that result from congenital mutations in key elements of the RAS/RAF/MEK signaling pathway. A well-recognized RASopathy is the cardio-facio-cutaneous (CFC) syndrome characterized by a distinctive facial appearance, heart defects, and mental retardation. Clinically diagnosed CFC patients carry germ-line mutations in four different genes, B-RAF, MEK1, MEK2, and K-RAS. B-RAF is by far the most commonly mutated locus, displaying mutations that most often result in constitutive activation of the B-RAF kinase. Here, we describe a mouse model for CFC generated by germ-line expression of a B-RafLSLV600E allele. This targeted allele allows low levels of expression of B-RafV600E, a constitutively active B-Raf kinase first identified in human melanoma. B-Raf+/LSLV600E mice are viable and display several of the characteristic features observed in CFC patients, including reduced life span, small size, facial dysmorphism, cardiomegaly, and epileptic seizures. These mice also show up-regulation of specific catecholamines and cataracts, two features detected in a low percentage of CFC patients. In addition, B-Raf +/LSLV600E mice develop neuroendocrine tumors, a pathology not observed in CFC patients. These mice may provide a means of better understanding the pathophysiology of at least some of the clinical features present in CFC patients. Moreover, they may serve as a tool to evaluate the potential therapeutic efficacy of B-RAF inhibitors and establish the precise window at which they could be effective against this congenital syndrome., Work in the laboratory of M.D. was funded by Consorcios Estratégicos Nacionales en Investigación Técnica Program (CDTEAM) Grant TEC2008-06715-C02-01, Centro de Investigación Biomédica en Red Program Grants CB06/01/0079 and PNSD 2007-2010, Fondo de Investigación Sanitaria (FIS) Grant CP08/00017, and Fundación de la Mutua Madrileña del Automovil (FMMA). E.M.B.W. was the holder of a United Kingdom National Institute for Health Research Academic Clinical Fellowship and was supported by the Manchester Biomedical Research Centre. Work in the laboratory of X.R.B. was funded by National Institutes of Health Grant R01CA073735, Spanish Ministry of Science and Innovation (MICINN) Grants SAF2009-07172 and RD06/0020/0001, Autonomous Government of Castilla y León (GR97), and Asociación Española contra el Cáncer. Work in the laboratory of M.B. was supported by European Union- Framework Programme Grants LSHG-CT-2006-037188 and LSHG-CT-2007-037665 (to M.B.), European Research Council Grant ERC-AG/250297-RAS AHEAD (to M.B.), MICINN Grants SAF2006-11773 and CSD2007-00017 (to M.B.), FMMA (to M.B.), FIS Grant PI042124, and Autonomous Community of Madrid Grant GR/SAL/0349/2004.

We developed a cost-effective SPECT scanner prototype (rSPECT) for in vivo imaging of rodents based on small-area gamma cameras. Each detector consists of a position-sensitive photomultiplier tube (PS-PMT) coupled to a 30 30 NaI(Tl) scintillator array and electronics attached to the PS-PMT sockets for adapting the detector signals to an in-house developed data acquisition system. The detector components are enclosed in a leadshielded case with a receptacle to insert the collimators. System performance was assessed using 􀀀􀀀 􀀀 for a high-resolution parallel- hole collimator, and for a 0.75-mm pinhole collimator with a 60 aperture angle and a 42-mm collimator length. The energy resolution is about 10.7% of the photopeak energy. The overall system sensitivity is about and planar spatial resolution ranges from 2.4 mm at 1 cm source-to-collimator distance to 4.1 mm at 4.5 cm with parallel-hole collimators. With pinhole collimators planar spatial resolution ranges from 1.2 mm at 1 cm source-to-collimator distance to 2.4 mm at 4.5 cm; sensitivity at these distances ranges from 2.8 to . Tomographic hot-rod phantom images are presented together with images of bone, myocardium and brain of living rodents to demonstrate the feasibility of preclinical small-animal studies with the rSPECT. This work was supported in part by the CD-TEAM project, CENIT program, Spanish Ministerio de Industria and with grants from the Ministerio de Educación y Ciencia, Projects TEC2007-64731/TCM, TEC2008-06715-C02-01, SAF2009-08076, program ARTEMIS S2009/DPI-1802, Comunidad de Madrid, and the RECAVA-RETIC Network Publicado

The establishment of new therapeutic indications for deep brain stimulation (DBS) is ambitiously promoted though the underlying mechanisms remain contested. Here, we report that PET-imaging and subsequent c-Fos-immunostaining in rats constitute a new translational approach to further understand DBS-mechanisms and -effectiveness.

Purpose: To analyze brain metabolic response to acute cocaine in male and female Wistar rats with or without a history of cannabinoid exposure during periadolescence. Procedures: The synthetic cannabinoid agonist CP 55,940 (CP) or its vehicle (VH), were administered to male and female rats during periadolescence. When these animals reached adulthood, saline and cocaine-induced changes in 2-deoxy-2-[18F]fluoro D glucose (FDG) uptake were studied by positron emission tomography. Results: The baseline (post-saline) metabolism in the septal nuclei was higher in CP-females than in VH-females, although septal metabolism was lower in CP-females after cocaine, reaching similar values to those of VH-females at baseline. Cocaine did not affect metabolism in VH-females. Periadolescent cannabinoid treatment did not influence baseline metabolism in males although cocaine reduced the FDG uptake in the dorsal striatum of males that received the VH but not CP. Conclusions: These results suggest that cannabinoids during periadolescence modify baseline and cocaine-evoked brain metabolism in a sex-dependent manner. In the case of CP-females, the involvement of septal metabolic alterations in their susceptibility to the rewarding effects of cocaine should be further investigated. This work was supported by grants from the Ministerio de Educación y Ciencia (Grants nº SAF2004-08148 and SAF2007-064890); Ministerio de Sanidad y Consumo (Grants RD06/ 00170029 of Instituto de Salud Carlos III, PNSD 2004 2007 and 2008 2010); Dirección General de Investigación de la Comunidad de Madrid (Grant S-SAL/0261/2006, I+D CANNAB-CM Consortium); and UNED (Plan de Promoción de la Investigación) to EA, and grants from the “Ministerio de Ciencia y Tecnología” (TEC2004-07052-C02-01/TCM), “Ministerio de Sanidad y Consumo” (CIBER CB06/01/0079, PNSD 2007 2010, FIS CP08/00017), “Ministerio de Industria” (CENIT program) and “Fundación de Investigación Médica Mutua Madrileña” (2007 2010 and 2008 2011) to MD. Publicado

We propose and compare different registration approaches to align small-animal PET studies and a procedure to validate the results by means of objective registration consistency measurements. Procedures: We have applied a registration algorithm based on information theory, using different approaches to mask the reference image. The registration consistency allows for the detection of incorrect registrations. This methodology has been evaluated on a test dataset(FDG-PET rat brain images). Results: The results show that a multiresolution two-step registration approach based on the use of the whole image at the low resolution step, while masking the brain at the high resolution step, provides the best robustness (87.5% registration success) and highest accuracy (0.67-mm average). Conclusions: The major advantages of our approach are minimal user interaction and automatic assessment of the registration error, avoiding visual inspection of the results, thus facilitating the accurate, objective, and rapid analysis of large groups of rodent PET images This work was supported by projects CIBER CB06/01/0079 (Ministerio de Sanidad y Consumo) and CDTEAM (CENIT program, Ministerio de Industria). Further support came from NIAAA Intramural Research Program (AA 11034 and AA07574, AA07611) and the US Department of Energy (DE-AC02-98CH10886) Publicado

Transnasal administration is one of the most common routes for allergen challenge in mouse models of airway diseases. Although this technique is widely used, neither the amount of allergen that reaches the lung nor its airway distribution has been well established. We used positron emission tomography (PET) and computed tomography (CT) to examine the anatomical distribution of a solution containing a tracer immediately after transnasal delivery and to determine the possible influence of age and administered volume. Procedures: Forty-six female BALB/c mice were divided into three groups according to instillation volume and age: (A) 15 μl, 8–10 weeks old (N=10), (B) 30 μl, 8–10 weeks old (N=20), and (C) 30 μl, 32 weeks old (N=16). Anesthetized animals underwent a dynamic scan in a dedicated small-animal PET scanner immediately after transnasal administration of a solution containing 18FDG. Regions of interest were used to obtain quantitative data. Animals were also imaged with a small-animal CT scanner to obtain complementary anatomical information. Results: Mean±SD (5.69±4.51%) of the solution administered reached the lungs in group A,41.84±8.03% in group B, and 36.65±16.15% in group C. A comparable percentage was delivered to the left and right lungs in all the groups. Analysis of variance revealed a significant difference between the groups in the proportion of the solution that reached the lungs depending on the injection volume (PG0.001), but not depending on animal age. Conclusions: In this first report on quantitative imaging by PET and CT in small animals, we confirmed the suitability of the transnasal route with an instilled volume of 30 μl delivering fluids into the lower airways, although only about 40% of the dose reaches the lungs This work was supported by grants from Ministerio de Ciencia y Tecnología (TEC2004-07052-C02-01), Ministerio de Sanidad y Consumo (CIBER CB06/01/0079 CIBER CB07/09/0031 and FIS 2001/0598), Ministerio de Industria (CDTEAM Project) and Fundación de Investigación Médica Mutua Madrileña Publicado

Melanoma is the most aggressive skin cancer once metastasis begins; therefore, it is important to characterize the molecular players involved in melanoma dissemination. The chemokine receptor CXCR4 and the membrane-bound metalloproteinase MT1-MMP are expressed on melanoma cells and represent candidate molecules for the control of metastasis. Using human melanoma transfectants that either overexpress or silence CXCR4 or MT1-MMP, or that have a combination of overexpression and interference of these proteins, we show that CXCR4 and MT1-MMP coordinate their activities at different steps along melanoma cell metastasis into the lungs. Results from in vivo xenograft mouse models of melanoma lung colonization and mice survival and short-term, homing nested polymerase chain reaction experiments from lung samples indicated that CXCR4 is required at early phases of melanoma cell arrival in the lungs. In contrast, MT1-MMP is not needed for these initial steps but promotes subsequent invasion and dissemination of the tumor with CXCR4. Investigation of potential cross talk between CXCR4 and MT1-MMP revealed that MT1-MMP accumulates intracellularly after melanoma cell stimulation with the CXCR4 ligand CXCL12, and that this process involves the activation of the Rac-Erk1/2 pathway. Subsequent to cell contact with specific basement membrane proteins, MT1-MMP redistributes to the cell membrane in a phosphatidylinositol 3-kinase-dependent manner. These results suggest that combination therapies that target CXCR4 and MT1-MMP should improve the limitations of the current therapies for metastatic melanoma. Copyright © American Society for Investigative Pathology.

To investigate changes in glucose brain metabolism after deep brain stimulation (DBS) in the lateral hypothalamic area (LHA) in a rat model of obesity. Ten obese male Zucker rats were divided into two groups: LHA-control and LHA-DBS. Concentric bipolar platinum-iridium electrodes were implanted bilaterally. After 7 days, DBS was applied for 15 days. Weight and food and water intake were monitored. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET-CT imaging studies were performed the day after the end of DBS. Differences in glucose uptake between the groups were assessed with statistical parametric mapping. A difference in weight gain of 3.19 percentage points was found between groups. Average food consumption during the first 15 days was lower in DBS-treated animals than in non-stimulated animals. DBS increased metabolism in the mammillary body, subiculum-hippocampal area, and amygdala, while a decrease in metabolism was recorded in the thalamus, caudate, temporal cortex, and cerebellum. DBS produced significant changes in brain regions associated with the control of food intake and the brain reward system. DBS seems to normalize the impaired hippocampal functioning that has been described in obese rats. The smaller weight gain in the DBS group suggests that this technique could be considered an option for the treatment of obesity.

Proceeding of: 2007 IEEE Nuclear Science Symposium Conference Record (NSS'07), Honolulu, Hawaii, USA, Oct. 27 - Nov. 3, 2007 The potential of PET imaging for pre-clinical studies will be fully realized only if repeatable, reliable and accurate quantitative analysis can be performed. The characteristic blurring of PET images due to positron range and non co-linearity, as well as random, pile-up and scatter contributions, that may be significant for fully 3D PET acquisitions of small animal, make it difficult their quantitative analysis. In this work specific activity versus specific counts in the image calibration curves for 3D-OSEM reconstructions from a commercially available small animal PET scanner are determined. Both linear and non-linear calibration curves are compared and the effect of corrections for random and scatter contributions are studied. To assess the improvement in the calibration procedure when scatter and random corrections are considered, actual data from a rat tumor pre- and postcancer therapy are analyzed. The results show that correcting for random and scatter corrections can increase the sensitivity of PET images to changes in the biological response of tumors by more than 15%, compared to uncorrected reconstructions. This work has been partially funded by projects TEC2004-07052-C02 of Ministerio de Educación y Ciencia and CD-TEAM, program CENIT, Ministerio de Industria, Spain. Part of the computations of this work were done at the '`High capacity cluster for physical techniques'' of the Faculty for Physical Sciences of the UCM, funded in part by the UE under the FEDER program and in part by the UCM.

Purpose This study was designed to assess changes in glucose metabolism in rats administered single or repeated doses of MDMA. Methods Two different experiments were performed: (1) A single-dose study with four groups receiving 20 mg/kg, 40 mg/kg, saline or heat, and (2) a repeated-dose study with two groups receiving three doses, at intervals of 2 h, of 5 mg/kg or saline. Rats were imaged using a dedicated small-animal PET scanner 1 h after single-dose administration or 7 days after repeated doses. Glucose metabolism was measured in 12 cerebral regions of interest. Rectal temperature and blood glucose were monitored. Results Peak body temperature was reached 1 h after MDMA administration. Blood glucose levels decreased significantly after MDMA administration. In the single-dose experiment, brain glucose metabolism showed hyperactivation in cerebellum and hypo-activation in the hippocampus, amygdala and auditory cortex. In the repeated-dose experiment, brain glucose metabolism did not show any significant change at day 7. Conclusion These results are the first to indicate that MDMA has the potential to produce significant hypoglycaemia. In addition, they show that MDMA alters glucose metabolism in components of the motor, limbic and somatosensory systems acutely but not on a long-term basis Publicado

Introduction: Hydroxyurea (HU) induction of fetal hemoglobin (HbF) is a major therapeutic effect for sickle cell disease (SCD) HbSS or HbSB0thalassemia. Non-adherence to a HU daily regimen is a barrier to its full effect. As no uniform level of HbF induction exists, we hypothesized that a child’s historical “personal best” (PB) HbF level at maximum clinical dose can be used as a marker for HU adherence. The NIH-funded “HABIT” study is a two-site randomized trial to improve patient-centered HU adherence in adolescents age 10-18 years. Eligibility is determined by fall-off from PB HbF over the previous year. Adherence measures include tracking HbF, pharmacy refill data and self-report. Methods: In a cross-sectional analysis of the entire 2-site clinic-based sample of 95 youth with SCD on HU, ages 10-18 years, and from the subset enrolled in HABIT to date, we assessed demographics, HU use and HbF at pre-treatment, PB and a recent time point. Here, HU non-adherence was defined as ≥20% deviation from PB HbF. Data were analyzed using descriptive statistics and Pearson correlation; groups were stratified by site and participation in HABIT, and were compared using chi-square and student’s t-tests. Results: Only ethnicity and mean HU dosing significantly differed by site (more Latinos/other and lower HU dosing at Columbia vs. Einstein). Only 39 (41%) youth remained within 20% of their PB HbF, with no significant differences in deviation from PB HbF by: site, gender; ethnicity; age (< or ≥14 years); higher induced PB (HbF of ≥20%); or time to PB (≤ or >1 year). For the 39 adherent to HU, mean deviation from PB HbF was 7.3±8.4% (median 7.2); for the 56 non-adherent, mean deviation was 40.5±16.4% (median 36.8; p Conclusion: Our definition of HU non-adherence as ≥20% deviation from Personal Best HbF identified two non-overlapping patient groups ages 10-18 years, with the majority found to be non-adherent. These findings also suggest that HU initiation at younger ages may increase risk of under-adherence during adolescence. PB HbF appears to be a useful marker for HU adherence, and may aid in clinical and patient-centered assessment and intervention. These results underscore the need to assess HU adherence in adolescent patients and for intervention trials such as HABIT. Abstract 1383. Table: Characteristics of the 2-site sample on hydroxyurea and subjects enrolled in the HABIT study Total(N =95) Columbia (N=39) Einstein (N=56) P value HABIT (N=13) P1 value N % N % N % N % Female gender 43 45.3 18 46.2 25 44.6 0.88 5 38.5 0.60 Ethnicity Hispanic/other2 African Amer 25 59 26.3 62.1 22 17 56.4 43.6 14 42 25.0 75.0 0.002 9 4 69.2 30.8 0.03 Age group 10-13 years 14-18 years 44 51 46.3 53.7 21 18 53.9 46.1 23 33 41.1 58.9 0.22 3 10 23.1 76.9 0.07 Mean SD Mean SD Mean SD Mean SD Current age (years) 14.3 2.6 14.1 2.7 14.4 2.5 0.63 15.7 2.3 0.03 Age at HU initiation (years) 9.2 3.7 8.8 4.3 9.5 3.7 0.44 9.1 4.8 0.91 Age at Personal Best (years) 11.9 3.3 11.2 3.7 12.3 3.0 0.14 13.2 3.7 0.12 HU duration (years) 4.6 3.2 4.9 3.5 4.3 2.9 0.36 6.0 4.2 0.10 Pre-HU HbF HU 7.7 4.8 7.2 4.6 8.1 4.9 0.41 6.6 2.0 0.42 Time to Personal Best (years) 2.5 2.3 2.5 2.7 2.4 2.1 0.96 4.0 3.3 0.09 Personal Best HbF 18.7 6.6 18.5 6.6 18.7 6.7 0.87 18.0 5.8 0.72 HU dose at Personal Best (mg/kg/day) 24.1 3.8 22.6 4.1 25.1 3.3 0.002 25.0 3.8 0.32 Recent HbF 13.6 6.3 13.2 6.4 13.8 6.3 0.62 12.1 5.9 0.36 HbF increase from pre-HU to PB 10.8 6.0 11.6 4.7 10.2 6.8 0.29 11.0 7.2 0.92 Recent HU dose (mg/kg/day) 23.9 4.0 21.9 4.5 25.4 2.7 20% deviation) 56 58.9 24 61.5 32 57.1 10 76.9 1Comparing HABIT subjects to the remaining 82 patients in the sample. 2Designation of “other” includes multi-racial HABIT: Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment Funding: 5R21NR013745 (PIs NSG and AMS) Disclosures Off Label Use: Hydroxyurea is not FDA approved for use in children..

The results showed that female rats that had received the CP treatment reached a significantly higher number of injections when compared to the other groups. In a parallel study, we analysed cerebral glucose metabolism in female CP- and vehicle-treated rats by using positron emission tomography. When [ 18 F]fluorodeoxyglucose (FDG) was injected, a PET scan was performed after 35 min of FDG uptake. Images were reconstructed using 3D-OSEM. Assessment of the quantification results is still in progress. Additionally, a food-reinforced task experiment was carried out in the same animals (implanted with an i.v. catheter) that subsequently self-administered cocaine. This study was performed for 6 days in daily 30 min sessions. CP-treated female rats consistently reached a significantly higher responding rate compared to the other groups. These behavioural results suggest that cannabinoid pre-exposure during adolescence might facilitate cocaine self-administration as a part of a more general reorganization of the reward circuitry in adulthood induced by the cannabinoid exposure.

The performance of natural extracts obtained from underutilized and residual vegetal and macroalgal biomass processed with food-grade green solvents was compared with that of commercial antioxidants. Selected extracts were obtained from two terrestrial sources: winery byproducts concentrate (WBC) and chestnut burs hydrothermally fractionated extract (CBAE), and from two underutilized seaweeds: Sargassum muticum extracts, either extracted with ethanol (SmEE) or after alginate extraction and hydrothermal fractionation (SmAE) and from Ulva lactuca processed by mild acid extraction and membrane concentration (UlAE). These extracts showed in vitro antioxidant properties comparable to commercial antioxidants and were safe for topical use based on the absence of skin-irritant effects at 0.1% on reconstructed human tissues. The stability of several cosmetic model emulsions was assessed during accelerated oxidation assays. The incorporation of natural extracts produced from renewable underutilized resources at 0.4–0.5% in an oil-in-water emulsions reduced lipid oxidation during storage.