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In the field of orthopedic surgery, there is an increasing need for the development of bone replacement materials for the treatment of bone defects. One of the main focuses of biomaterials engineering are advanced bioceramics like mesoporous bioactive glasses (MBG´s). The present study compared the new bone formation after 12 weeks of implantation of MBG scaffolds with composition 82,5SiO 2 -10CaO-5P 2 O 5 -x 2.5SrO alone (MBGA), enriched with osteostatin, an osteoinductive peptide, (MBGO) or enriched with bone marrow aspirate (MBGB) in a long bone critical defect in radius bone of adult New Zealand rabbits. New bone formation from the MBG scaffold groups was compared to the gold standard defect filled with iliac crest autograft and to the unfilled defect. Radiographic follow-up was performed at 2, 6, and 12 weeks, and microCT and histologic examination were performed at 12 weeks. X-Ray study showed the highest bone formation scores in the group with the defect filled with autograft, followed by the MBGB group, in addition, the microCT study showed that bone within defect scores (BV/TV) were higher in the MBGO group. This difference could be explained by the higher density of newly formed bone in the osteostatin enriched MBG scaffold group. Therefore, MBG scaffold alone and enriched with osteostatin or bone marrow aspirate increase bone formation compared to defect unfilled, being higher in the osteostatin group. The present results showed the potential to treat critical bone defects by combining MBGs with osteogenic peptides such as osteostatin, with good prospects for translation into clinical practice. STATEMENT OF SIGNIFICANCE: Treatment of bone defects without the capacity for self-repair is a global problem in the field of Orthopedic Surgery, as evidenced by the fact that in the U.S alone it affects approximately 100,000 patients per year. The gold standard of treatment in these cases is the autograft, but its use has limitations both in the amount of graft to be obtained and in the morbidity produced in the donor site. In the field of materials engineering, there is a growing interest in the development of a bone substitute equivalent. Mesoporous bioactive glass (MBG´s) scaffolds with three-dimensional architecture have shown great potential for use as a bone substitutes. The osteostatin-enriched Sr-MBG used in this long bone defect in rabbit radius bone in vivo study showed an increase in bone formation close to autograft, which makes us think that it may be an option to consider as bone substitute., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Several studies performed on human subjects have examined the effects of adolescent cannabis consumption on brain structure or function using brain imaging techniques. However, the evidence from these studies is usually heterogenous and affected by several confounding variables. Animal models of adolescent cannabinoid exposure may help to overcome these difficulties. In this exploratory study, we aim to increase our understanding of the protracted effects of adolescent Δ 9 -tetrahydrocannabinol (THC) in rats of both sexes using magnetic resonance (MR) to obtain volumetric data, assess grey and white matter microstructure with diffusion tensor imaging (DTI) and measure brain metabolites with 1 H-MR spectroscopy (MRS); in addition, we studied brain function using positron emission tomography (PET) with 2-deoxy-2-[ 18 F]fluoro-d-glucose as the tracer. THC-exposed rats exhibited volumetric and microstructural alterations in the striatum, globus pallidus, lateral ventricles, thalamus, and septal nuclei in a sex-specific manner. THC administration also reduced fractional anisotropy in several white matter tracts, prominently in rostral sections, while in vivo MRS identified lower levels of cortical choline compounds. THC-treated males had increased metabolism in the cerebellum and olfactory bulb and decreased metabolism in the cingulate cortex. By contrast, THC-treated females showed hypermetabolism in a cluster of voxels comprising the entorhinal piriform cortices and in the cingulate cortex. These results indicate that mild THC exposure during adolescence leaves a lingering mark on brain structure and function in a sex-dependant manner. Some of the changes found here resemble those observed in human studies and highlight the importance of studying sex-specific effects in cannabinoid research., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

This study evaluates the long-term effects of a six and 14-week morphine withdrawal in rats pretreated with a cannabinoid agonist (CP-55,940, CP) during periadolescence. Wistar rats (33 males; 32 females) were treated with CP or its vehicle (VH) from postnatal day (PND) 28-38. At PND100, rats performed morphine self-administration (MSA, 15d/12 h/session). Eight groups were defined according to pretreatment (CP), treatment (morphine), and sex. Three [ 18 F]FDG-PET brain images were acquired: after MSA, and after six and 14 weeks of withdrawal. PET data were analyzed with SPM12. Endocannabinoid (EC) markers were evaluated in frozen brain tissue at endpoint. Females showed a higher mean number of self-injections than males. A main Sex effect on global brain metabolism was found. FDG uptake in males was discrete, whereas females showed greater brain metabolism changes mainly in areas of the limbic system after morphine treatment. Moreover, the morphine-induced metabolic pattern in females was exacerbated when CP was previously present. In addition, the CP-Saline male group showed reduced CB1R, MAGL expression, and NAPE/FAAH ratio compared to the control group, and morphine was able to reverse CB1R and MAGL expression almost to control levels. In conclusion, females showed greater and longer-lasting metabolic changes after morphine withdrawal than males, indicating a higher vulnerability and a different sensitivity to morphine in subjects pre-exposed to CP. In contrast, males primarily showed changes in EC markers. Together, our results suggest that CP pre-exposure contributes to the modulation of brain metabolism and EC systems in a sex-dependent manner., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Escitalopram is a selective serotonin reuptake inhibitor (SSRIs) antidepressant, drug that is currently used as first-line agents for the treatment of depression and it is also used in the treatment of other psychiatric disorders. The main goal of this study was to identify which brain areas are affected by escitalopram administration. This study was carried out on male Wistar rats that received escitalopram daily over 14 days and that were studied by 2-deoxy-2[ 18 F]fluoro-D-glucose ([ 18 F]FDG)-PET on the last day of treatment. Computed tomography (CT) images were acquired immediately before each PET scan and the main effects of drug administration were elucidated by Statistical Parametric Mapping. The results obtained indicated that repeated exposure to escitalopram increased metabolic activity in the retrosplenial and posterior cingulate cortices, while it decreased such activity in the ventral hippocampus, cerebellum, brainstem and midbrain regions, including the raphe nuclei and ventral tegmental area. Therefore, repeated exposure to escitalopram alters the activity of several brain areas closely related to the serotonergic system, and previously identified as key regions in the antidepressant effect induced by SSRIs. Furthermore, some of the changes found, such as the dampened metabolism in the ventral tegmental area, are similar to changes that have been described after treating with other fast-acting antidepressant approaches., Competing Interests: Conflict of interest All the authors declare that they have no conflicts of interest., (Copyright © 2021 Elsevier B.V. and ECNP. All rights reserved.)

Objectives: This study sought to clinically validate a novel 3-dimensional (3D) ultrafast cardiac magnetic resonance (CMR) protocol including cine (anatomy and function) and late gadolinium enhancement (LGE), each in a single breath-hold., Background: CMR is the reference tool for cardiac imaging but is time-consuming., Methods: A protocol comprising isotropic 3D cine (Enhanced sensitivity encoding [SENSE] by Static Outer volume Subtraction [ESSOS]) and isotropic 3D LGE sequences was compared with a standard cine+LGE protocol in a prospective study of 107 patients (age 58 ± 11 years; 24% female). Left ventricular (LV) mass, volumes, and LV and right ventricular (RV) ejection fraction (LVEF, RVEF) were assessed by 3D ESSOS and 2D cine CMR. LGE (% LV) was assessed using 3D and 2D sequences., Results: Three-dimensional and LGE acquisitions lasted 24 and 22 s, respectively. Three-dimensional and LGE images were of good quality and allowed quantification in all cases. Mean LVEF by 3D and 2D CMR were 51 ± 12% and 52 ± 12%, respectively, with excellent intermethod agreement (intraclass correlation coefficient [ICC]: 0.96; 95% confidence interval [CI]: 0.94 to 0.97) and insignificant bias. Mean RVEF 3D and 2D CMR were 60.4 ± 5.4% and 59.7 ± 5.2%, respectively, with acceptable intermethod agreement (ICC: 0.73; 95% CI: 0.63 to 0.81) and insignificant bias. Both 2D and 3D LGE showed excellent agreement, and intraobserver and interobserver agreement were excellent for 3D LGE., Conclusions: ESSOS single breath-hold 3D CMR allows accurate assessment of heart anatomy and function. Combining ESSOS with 3D LGE allows complete cardiac examination in <1 min of acquisition time. This protocol expands the indication for CMR, reduces costs, and increases patient comfort., Competing Interests: Funding Support and Author Disclosures Funding included Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund (ERDF) Grants DTS17/00136 to Dr. Ibáñez and PI19/01704 to Dr. Fernandez-Jimenez; Spanish Society of Cardiology Translational Research Grant 2016 to Dr. Ibáñez; European Research Council ERC-CoG 819775-MATRIX to Dr. Ibáñez; Comunidad de Madrid S2017/BMD-3867-RENIM-CM to Drs. Desco and Ibáñez; and Ministerio de Ciencia e Innovación (MICINN) RETOS2019-107332RB-I00 to Dr. Ibáñez. Dr. Fernandez-Jimenez received funding from the European Union Horizon 2020 research and innovation programme under Marie Skłodowska-Curie Hrant Agreement No. 707642. The CNIC is supported by the ISCIII, the MICINN, and the Pro CNIC Foundation. Drs. Fernandez-Jimenez, Nothnagel, Fuster, Ibáñez, and Javier Sánchez-González are inventors of a joint patent (Philips/CNIC) for the new cine imaging method here described and validated/protected under the IP #2014P00960EP. Drs. Nothnagel, Kouwenhoven, Clemence, and Javier Sánchez-González are Philips employees. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Conflict of interest CA has been a consultant to or received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen-Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering-Plough, Sumitomo Dainippon Pharma, Sunovion, and Takeda. JCL received honoraria from Esteve, Janssen, Lundbeck and Fundación Alicia Koplowitz. EB has been a consultant for or has received grants from nLife Therapeutics, Esteve, Grünenthal, Servier and Merck. All other authors declare that they have no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Impaired multisensory integration in autism spectrum disorder (ASD) may arise from functional dysconnectivity among brain systems. Our study examines the functional connectivity integration between primary modal sensory regions and heteromodal processing cortex in ASD, and whether abnormalities in network integration relate to clinical severity., Method: We studied a sample of 55 high-functioning ASD and 64 healthy control (HC) male children and adolescents (total n = 119, age range 7-18 years). Stepwise functional connectivity analysis (SFC) was applied to resting state functional magnetic resonance images (rsfMRI) to characterize the connectivity paths that link primary sensory cortices to higher-order brain cognitive functional circuits and to relate alterations in functional connectivity integration with three clinical scales: Social Communication Questionnaire, Social Responsiveness Scale, and Vineland Adaptive Behavior Scales., Results: HC displayed typical functional connectivity transitions from primary sensory systems to association areas, but the ASD group showed altered patterns of multimodal sensory integration to heteromodal systems. Specifically, compared to the HC group, the ASD group showed the following: (1) hyperconnectivity in the visual cortex at initial link step distances; (2) hyperconnectivity between sensory unimodal regions and regions of the default mode network; and (3) hypoconnectivity between sensory unimodal regions and areas of the fronto-parietal and attentional networks. These patterns of hyper- and hypoconnectivity were associated with increased clinical severity in ASD., Conclusion: Networkwise reorganization in high-functioning ASD individuals affects strategic regions of unimodal-to-heteromodal cortical integration predicting clinical severity. In addition, SFC analysis appears to be a promising approach for studying the neural pathophysiology of multisensory integration deficits in ASD., (Copyright © 2019 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

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. [ 18 F]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., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

Trehalose analogues bearing fluorescent and click chemistry tags have been developed as probes of bacterial trehalose metabolism, but these tools have limitations with respect to in vivo imaging applications. Here, we report the radiosynthesis of the 18 F-modified trehalose analogue 2-deoxy-2-[ 18 F]fluoro-d-trehalose ([ 18 F]-2-FDTre), which in principle can be used in conjunction with positron emission tomography (PET) imaging to allow in vivo imaging of trehalose metabolism in various contexts. A chemoenzymatic method employing the thermophilic TreT enzyme from Thermoproteus tenax was used to rapidly (15-20 min), efficiently (70% radiochemical yield; ≥ 95% radiochemical purity), and reproducibly convert the commercially available radiotracer 2-deoxy-2-[ 18 F]fluoro-d-glucose ([ 18 F]-2-FDG) into the target radioprobe [ 18 F]-2-FDTre in a single step; both manual and automated syntheses were performed with similar results. Cellular uptake experiments showed that radiosynthetic [ 18 F]-2-FDTre was metabolized by Mycobacterium smegmatis but not by various mammalian cell lines, pointing to the potential future use of this radioprobe for selective PET imaging of infections caused by trehalose-metabolizing bacterial pathogens such as M. tuberculosis., (Copyright © 2018. Published by Elsevier Ltd.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Unlabelled: We present a novel segmentation algorithm for dynamic PET studies that groups pixels according to the similarity of their time-activity curves., Methods: Sixteen mice bearing a human tumor cell line xenograft (CH-157MN) were imaged with three different (68)Ga-DOTA-peptides (DOTANOC, DOTATATE, DOTATOC) using a small animal PET-CT scanner. Regional activities (input function and tumor) were obtained after manual delineation of regions of interest over the image. The algorithm was implemented under the jClustering framework and used to extract the same regional activities as in the manual approach. The volume of distribution in the tumor was computed using the Logan linear method. A Kruskal-Wallis test was used to investigate significant differences between the manually and automatically obtained volumes of distribution., Results: The algorithm successfully segmented all the studies. No significant differences were found for the same tracer across different segmentation methods. Manual delineation revealed significant differences between DOTANOC and the other two tracers (DOTANOC - DOTATATE, p=0.020; DOTANOC - DOTATOC, p=0.033). Similar differences were found using the leader-follower algorithm., Conclusion: An open implementation of a novel segmentation method for dynamic PET studies is presented and validated in rodent studies. It successfully replicated the manual results obtained in small-animal studies, thus making it a reliable substitute for this task and, potentially, for other dynamic segmentation procedures., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Autism spectrum disorders (ASD) have been associated with atypical cortical gray and subcortical white matter development. Neurodevelopmental theories postulate that a relation between cortical maturation and structural brain connectivity may exist. We therefore investigated the development of gyrification and white matter connectivity and their relationship in individuals with ASD and their typically developing peers., Method: T1- and diffusion-weighted images were acquired from a representative sample of 30 children and adolescents with ASD (aged 8-18 years), and 29 typically developing children matched for age, sex, hand preference, and socioeconomic status. The FreeSurfer suite was used to calculate cortical volume, surface area, and gyrification index. Measures of structural connectivity were estimated using probabilistic tractography and tract-based spatial statistics (TBSS)., Results: Left prefrontal and parietal cortex showed a relative, age-dependent decrease in gyrification index in children and adolescents with ASD compared to typically developing controls. This result was replicated in an age-and IQ-matched sample provided by the Autism Brain Imaging Data Exchange (ABIDE) initiative. Furthermore, tractography and TBSS showed a complementary pattern in which left prefrontal gyrification was negatively related to radial diffusivity in the forceps minor in participants with ASD., Conclusion: The present study builds on earlier findings of abnormal gyrification and structural connectivity in the prefrontal cortex in ASD. It provides a more comprehensive neurodevelopmental characterization of ASD, involving interdependent changes in microstructural white and cortical gray matter. The findings of related abnormal patterns of gyrification and white matter connectivity support the notion of the intertwined development of 2 major morphometric domains in ASD., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Motivation: This work presents the development of an open source tool for the quantification of dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion studies. The development of this tool is motivated by the lack of open source tools implemented on open platforms to allow external developers to implement their own quantification methods easily and without the need of paying for a development license., Materials and Methods: This quantification tool was developed as a plugin for the ImageJ image analysis platform using the Java programming language. A modular approach was used in the implementation of the components, in such a way that the addition of new methods can be done without breaking any of the existing functionalities. For the validation process, images from seven patients with brain tumors were acquired and quantified with the presented tool and with a widely used clinical software package. The resulting perfusion parameters were then compared., Results: Perfusion parameters and the corresponding parametric images were obtained. When no gamma-fitting is used, an excellent agreement with the tool used as a gold-standard was obtained (R(2)>0.8 and values are within 95% CI limits in Bland-Altman plots)., Conclusion: An open source tool that performs quantification of perfusion studies using magnetic resonance imaging has been developed and validated using a clinical software package. It works as an ImageJ plugin and the source code has been published with an open source license., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Neuroblasts represent the predominant migrating cell type in the adult mouse brain. There are, however, increasing evidences of migration of other neural precursors. This work aims at identifying in vivo endogenous early neural precursors, different from neuroblasts, able to migrate in response to brain injuries. The monoclonal antibody Nilo1, which unequivocally identifies type B astrocytes and embryonic radial glia, was coupled to magnetic glyconanoparticles (mGNPs). Here we show that Nilo1-mGNPs in combination with magnetic resonance imaging in living mice allowed the in vivo identification of endogenous type B astrocytes at their niche, as well as their migration to the lesion site in response to glioblastoma, demyelination, cryolesion or mechanical injuries. In addition, Nilo1(+) adult radial glia-like structures were identified at the lesion site a few hours after damage. For all damage models used, type B astrocyte migration was fast and orderly. Identification of Nilo1(+) cells surrounding an induced glioblastoma was also possible after intraperitoneal injection of the antibody. This opens up the possibility of an early identification of the initial damage site(s) after brain insults, by the migration of type B astrocytes., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Accurate detection of liver lesions is of great importance in hepatic surgery planning. Recent studies have shown that the detection rate of liver lesions is significantly higher in gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) than in contrast-enhanced portal-phase computed tomography (CT); however, the latter remains essential because of its high specificity, good performance in estimating liver volumes and better vessel visibility. To characterize liver lesions using both the above image modalities, we propose a multimodal nonrigid registration framework using organ-focused mutual information (OF-MI). This proposal tries to improve mutual information (MI) based registration by adding spatial information, benefiting from the availability of expert liver segmentation in clinical protocols. The incorporation of an additional information channel containing liver segmentation information was studied. A dataset of real clinical images and simulated images was used in the validation process. A Gd-EOB-DTPA-enhanced MRI simulation framework is presented. To evaluate results, warping index errors were calculated for the simulated data, and landmark-based and surface-based errors were calculated for the real data. An improvement of the registration accuracy for OF-MI as compared with MI was found for both simulated and real datasets. Statistical significance of the difference was tested and confirmed in the simulated dataset (p<0.01)., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background & Aims: Weight gain is an undesirable side effect of second-generation antipsychotics (SGAs). We performed this study to examine the influence of SGAs on resting energy expenditure (REE) and the relationship of REE to weight gain in adolescent patients., Methods: Antipsychotic-naïve or quasi-naïve (<72 h of exposure to antipsychotics) adolescent patients taking olanzapine, quetiapine, or risperidone in monotherapy were followed up for one year. We performed a prospective study (baseline, 1, 3, 6, and 12 months after treatment) based on anthropometric measurements, bioelectrical impedance analysis, and indirect calorimetry (Deltatrac™ II MBM-200) to measure REE. We also analyzed metabolic and hormonal data and adiponectin concentrations., Results: Forty-six out of the 54 patients that started treatment attended at least 2 visits, and 16 completed 1 year of follow-up. Patients gained 10.8 ± 6.2 kg (60% in the form of fat mass) and increased their waist circumference by 11.1 ± 5.0 cm after 1 year of treatment. The REE/kg body mass ratio decreased (p = 0.027), and the REE/percentage fat-free mass (FFM) ratio increased (p = 0.007) following the fall in the percentage of FFM during treatment. Weight increase was significantly correlated with the REE/percentage FFM ratio at all the visits (1-3-6-12 months) (r = 0.69, p = 0.004 at 12 months)., Conclusions: SGAs seem to induce a hypometabolic state (reflected as decreased REE/kg body mass and increased REE/percentage FFM). This could explain, at least in part, the changes in weight and body composition observed in these patients., (Copyright © 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Psychosis is associated with volumetric decreases of cortical structures. Whether these volumetric decreases imply abnormalities in cortical thickness, surface, or cortical folding is not clear. Due to differences in cytoarchitecture, cortical gyri and sulci might be differentially affected by psychosis. Therefore, we examined differences in gyral and sulcal cortical thickness, surface, folding, and volume between a minimally treated male adolescent population with early-onset first-episode psychosis (EOP) and a healthy control group, with surface-based morphometry., Methods: Magnetic resonance imaging brain scans were obtained from 49 adolescent EOP patients and 34 healthy control subjects. Subjects were younger than 18 years (age range 12 years-18 years), and EOP patients had a duration of positive symptoms of <6 months., Results: Early-onset first-episode psychosis was associated with local bilateral cortical thinning and volume deficits in both the gyri and sulci of the superior temporal cortex and the inferior, middle, medial, and superior prefrontal cortex. In the pars triangularis and opercularis cortex of patients, gyral cortical thickness was thinner, whereas sulcal thickness was not. Patients exhibited cortical thinning together with a decreased degree of cortical folding in the right superior frontal cortex., Conclusions: Cortical thinning of both gyri and sulci seem to underlie most cortical volume deficits in adolescent patients with EOP. Except for the right superior frontal region, the degree of cortical folding was normal in regions showing decreased cortical thickness, suggesting that the process of cortical thinning in adolescent patients with EOP primarily takes place after the formation of cortical folds.

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.

Objective: The current study combined baseline voxel-based morphometry and 1-year clinical follow-up assessments to examine whether and where regional gray matter (GM) volumes differed between a control group and diagnostic subgroups of early-onset first-episode psychosis (FEP)., Method: Magnetic resonance imaging brain scans were obtained from 70 patients with early-onset FEP, and 51 non-FEP controls. Early-onset FEP was defined as age younger than 18 years and a duration of positive symptoms of less than 6 months. The age range of the sample was 7 to 18 years. After a 1-year follow-up, patients were stratified into three subgroups: schizophrenia (n = 25), bipolar I disorder (n = 20), and other psychoses (n = 25). Regional GM volumes of each patient subgroup were compared with those of the control group., Results: A follow-up diagnosis of schizophrenia was associated with GM volume deficits in the left medial and left middle frontal gyrus; bipolar I disorder was related to a GM volume deficit in the left medial frontal gyrus; and not having a follow-up diagnosis of schizophrenia or bipolar disorder was associated with smaller bilateral GM volumes in the insula and right middle occipital gyrus., Conclusions: Left medial frontal GM volume deficits were common in the groups with schizophrenia and bipolar I disorder, which may point to shared underlying pathological findings.

Gene silencing by CpG island promoter hypermethylation has awakened the interest for DNA demethylating agents as chemotherapy drugs. Zebularine (1-[beta-D-ribofuranosil]-1,2-dihydropyrimidin-2-1) has been recently described as a new DNA methylation inhibitor. Here we have studied its effects in a mouse model of radiation-induced lymphomagenesis using nuclear magnetic resonance (NMR) and positron emission tomography (PET). All control animals presented large thymic T lymphomas and died between 4 and 5.5 months. In contrast, 40% (12 of 30) of zebularine-treated animals were still alive after 1 year (Kaplan-Meier P < .001). NMR and PET imaging showed that surviving animals presented a thymus structure/volume similar to normal mice of the same age. Most important, zebularine demonstrated a complete lack of toxicity in nonirradiated control mice. DNA hypomethylation induced by zebularine occurred in association with depletion in extractable DNA methyltransferase 1 protein. Thus, our data support the role of zebularine as a DNA demethylating agent with antitumor activity and little toxicity.

Objective: The objective of the present study is to replicate findings in first-episode psychosis reporting a smaller volume in brain structures in a population with adolescent onset., Method: Magnetic resonance imaging studies were performed on 23 psychotic adolescents (12-18 years old, 17 males, 6 females) consecutively admitted to an adolescent inpatient unit and on 37 normal controls (13-18 years, 23 males, 14 females) matched for age, sex, and years of education. Diagnosis was made at baseline on the basis of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version and confirmed after 12 months of follow-up. Total brain volume and gray matter, white matter, and cerebrospinal fluid (CSF) volumes of the frontal, parietal, temporal, and occipital lobes were measured bilaterally using a segmentation method based on the Talairach grid system., Results: Male patients showed significantly larger volumes than did male controls in overall CSF and left frontal and right parietal sulci CSF. Male patients also showed significantly lower volumes of gray matter in the right and left frontal lobes. No significant volumetric differences were found in females. There were no differences between individuals with a diagnosis of schizophrenia at follow-up and the rest of the patients., Conclusions: This study suggests that larger CSF and lower gray matter volumes in the frontal lobes may be a nonspecific vulnerability marker for psychosis in male adolescents.

This study analysed 89 episodes of catheter-related bloodstream infection (CR-BSI) occurring during one week in 107 hospitals from 21 European countries (1.02 episodes/1,000 admissions). Patients from European Union (EU) countries had a higher incidence of CR-BSI than patients from non-EU countries (1.55 vs. 0.33/1,000 admissions). Most (67%) catheters were non-tunneled central venous catheters, were in the jugular vein (44%), had been implanted for > 7 days (70%), were made of polyurethane (61%) and were multi-lumen (67%). In 36% of cases, catheters were implanted by physicians other than anaesthetists or surgeons, and 50% were inserted by junior staff.

The laboratory workload, microbiological techniques and aetiology of catheter-related infections in European hospitals are mostly unknown. The present study (ESGNI-005) comprised a 1-day (22 October 2001), laboratory-based, point-prevalence survey based on a questionnaire completed by microbiology laboratories in European (European Union (EU) and non-EU) hospitals. Also included were questions requesting retrospective information for the year 2000. In total, 151 hospitals from 26 European countries participated, of which 78.1% were teaching institutions. Overall, the estimated population served by these institutions was 121,363,800, and the estimated number of admissions during 2000 was 6,712,050. The total number of catheter tips processed during 2000 was 142,727, or 21/1,000 admissions, of which 23.7% were considered to be positive in the institutions using semiquantitative or quantitative techniques. Overall, EU centres received significantly more catheter tip samples/1,000 admissions and had a significantly higher rate of 'positivity' (p < 0.0001) than non-EU centres. Of the institutions surveyed, 11.4% (7.2% in EU countries and 23.7% in non-EU countries; p 0.04) used only qualitative techniques for catheter tip sample processing. On the day of the study, 167 microorganisms were recovered from significant catheter tip cultures (122 patients), of which Gram-positive bacteria represented 70.7%, Gram-negative bacteria 22.2%, and yeasts 7.2%. The five most common microorganisms were coagulase-negative staphylococci, Staphylococcus aureus, Candida spp., Enterococcus spp. and Pseudomonas spp. Overall, 19% of catheter tip cultures were polymicrobial. In the case of S. aureus, 40% of isolates were resistant to oxacillin, as were 63.4% of coagulase-negative staphylococcus isolates. Of 37 Gram-negative isolates, 35% were resistant to cefotaxime, 31% to ceftazidime, and 27% to ciprofloxacin. Imipenem and cefepime had the lowest reported rates of resistance (11%).

The study was designed to identify a subset of heart transplant (HT) recipients who could benefit from the administration of targeted antifungal prophylaxis and to evaluate the efficacy of oral itraconazole as the preventive drug. We have analyzed the risk factors for invasive aspergillosis (IA) in our entire population of HT recipients (1988-2002) and also the role of oral itraconazole prophylaxis that was provided to all patients since 1995 [400 mg q.d. of itraconazole oral (PO) for 3-6 months]. There were 24 cases of IA. Our main results indicate that the independent risk factors for IA after heart transplantation are: re-operation (RR 5.8; 95% CI 1.8-18, p=0.002), cytomegalovirus (CMV) disease (RR 5.2; 95% CI 2-13.9, p=0.001), post-transplant hemodialysis (RR 4.9; 95% CI 1.2-18, p=0.02), and the existence of an episode of IA in the HT program 2 months before or after the transplantation date (RR 4.6; 95% CI 1.5-14.4, p=0.007). Itraconazole prophylaxis showed an independent protective value against developing IA (RR 0.2; 95% CI 0.07-0.9, p=0.03) and also determined a significantly prolonged 1-year survival (RR 0.5; 95% CI 0.3-0.8, p=0.01). We believe that antifungal prophylaxis in heart transplant patients should be offered at least to patients with one or more of these predisposing conditions.

Turbo Spin Echo (TSE) is a sequence of choice for obtaining T(2)-weighted images. TSE reduces acquisition time by acquiring several echoes within each TR, at the cost of introducing an exponential weighting in the k-space that leads to a certain image blurring. This is particularly important for short-T(2) structures, which can even disappear if their size in the phase encoding direction is comparable to the degree of blurring. This article suggests the use of a combination of Half Fourier (HF) and segmented (multishot) TSE (sHF-TSE) to recover the original resolution of the SE images. The improved symmetry of the dataset achieved by HF reconstruction is used to increase the resolution of the TSE images. The proposed combination, available in most clinical scanners, reduces the blurring artifact inherent to the TSE sequence without increasing the scan time or the number of acquisitions, but at the cost of a slight reduction of the signal-to-noise ratios (SNR). Qualitative and quantitative results are presented using both numerical simulation and imaging. Significant edge enhancement has been achieved for structures with short T(2), (narrowing of the full width at half maximum [FWHM] up to 45%). The proposed sequence is more sensitive to movement artifacts but has proven to be superior to the conventional TSE for imaging static structures.

The objective of this work was to confirm the main role of elastic fibers in differing responses of certain vessels during cooling from 37 to 8 degrees C. Previous results have shown that the nature of the vessel (conduit vessel vs muscular vessel) determines the different behavior (dilatation vs contraction) of isolated vessel segments when temperature decreases from 37 to 8 degrees C. In this work, it has been demonstrated that vessels with a great amount of elastic fibers show a dilatation when cooling. On the other hand, muscular vessels with fewer elastic fibers, such as the renal artery, undergo a contraction. The output of calcium from intracellular stores causes contraction of the renal artery during cooling. In this vessel, vasodilatation occurs only when mechanisms of smooth muscle contraction are inactive, as is the case with vessels that have undergone a cold storage period of 48 h. The results presented in this work confirm that there are two main effects, which directly depend on the vessel origin. In conduit arteries, the decrease of temperature induces a vascular relaxation, dependent on the elastic component of the vessel wall. In muscular vessels, the predominant effect is cooling-induced contraction due to an increase of intracellular calcium. This cooling-induced contraction needs the vessel to be in optimal conditions with an active metabolism of the muscular cells. These results are a crucial issue in the sense of explaining several biomedical mechanisms where hypothermia is implicated. The type of vessel implicated in procedures, such as isolated organ perfusion, extracorporeal circulation, and bypass surgery, must be taken into account., ((c) 2002 Elsevier Science (USA).)

Temperature may have significant influence on vascular tone in such cases as organ preservation, coronary bypass surgery, and extracorporeal circulation. The aim of this research was to study the direct effect of temperature variation on vascular tone in an attempt to elucidate the mechanisms involved. In a first series of experiments, the isometric tension of two different vessels (rat thoracic aorta and pig renal branch artery) was studied at different temperatures. To study the role of calcium in this response, a second series of experiments was performed. In this the vessels were incubated with the intracellular chelator BAPTA/AM. Further experiments were performed to test the effect of cold storage. Our results show that changes in temperature lead to different results in pig renal artery and rat aorta. A decrease in temperature induced a highly reproducible relaxation in rat aorta, whereas pig renal artery presented cooling-induced contraction. Moreover, whereas calcium depletion failed to inhibit cooling-induced relaxation in rat aorta, it did not provoke cooling-induced contraction in pig renal artery. Similar responses were obtained with cold storage and calcium depletion. We intend to demonstrate that, just as the effect of temperature variation on pig renal artery is due to a metabolic mechanism, its effect on rat aorta may be due to structural factors. This hypothesis is supported by the result of histological studies which demonstrate a higher proportion of elastin fibres in rat aorta than in pig renal artery., (Copyright 2000 Academic Press.)