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Background We aimed to develop a convolutional neural network (CNN) model for detecting neoplastic lesions during real-time digital single-operator cholangioscopy (DSOC) and to clinically validate the model through comparisons with DSOC expert and nonexpert endoscopists. Methods In this two-stage study, we first developed and validated CNN1. Then, we performed a multicenter diagnostic trial to compare four DSOC experts and nonexperts against an improved model (CNN2). Lesions were classified into neoplastic and non-neoplastic in accordance with Carlos Robles-Medranda (CRM) and Mendoza disaggregated criteria. The final diagnosis of neoplasia was based on histopathology and 12-month follow-up outcomes. Results In stage I, CNN2 achieved a mean average precision of 0.88, an intersection over the union value of 83.24 %, and a total loss of 0.0975. For clinical validation, a total of 170 videos from newly included patients were analyzed with the CNN2. Half of cases (50 %) had neoplastic lesions. This model achieved significant accuracy values for neoplastic diagnosis, with a 90.5 % sensitivity, 68.2 % specificity, and 74.0 % and 87.8 % positive and negative predictive values, respectively. The CNN2 model outperformed nonexpert #2 (area under the receiver operating characteristic curve [AUC]-CRM 0.657 vs. AUC-CNN2 0.794, P Conclusions The proposed CNN model distinguished neoplastic bile duct lesions with good accuracy and outperformed two nonexpert and one expert endoscopist.

Background and Purpose: Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage. Neutrophil β1 adrenoceptors (β1AR) have been linked to neutrophil migration during exacerbated inflammation. Given the central role of neutrophils in cerebral damage during stroke, we hypothesize that β1AR blockade will improve stroke outcomes. Experimental Approach: Rats were subjected to middle cerebral artery occlusion–reperfusion to evaluate the effect on stroke of the selective β1AR blocker metoprolol (12.5 mg·kg−1) when injected i.v. 10 min before reperfusion. Key Results: Magnetic resonance imaging and histopathology analysis showed that pre-reperfusion i.v. metoprolol reduced infarct size. This effect was accompanied by reduced cytotoxic oedema at 24 h and vasogenic oedema at 7 days. Metoprolol-treated rats showed reduced brain neutrophil infiltration and those which infiltrated displayed a high proportion of anti-inflammatory phenotype (N2, YM1+). Additional inflammatory models demonstrated that metoprolol specifically blocked neutrophil migration via β1AR and excluded a significant effect on the glia compartment. Consistently, metoprolol did not protect the brain in neutrophil-depleted rats upon stroke. In patients suffering an ischaemic stroke, β1AR blockade by metoprolol reduced circulating neutrophil–platelet co-aggregates. Conclusions and Implications: Our findings describe that β1AR blockade ameliorates cerebral damage by targeting neutrophils, identifying a novel therapeutic target to improve outcomes in patients with stroke. This therapeutic strategy is in the earliest stages of the translational pathway and should be further explored. This study received funding from the Instituto de Salud Carlos III (ISCIII; PI16/02110 to B.I. and PT20/00044 to M.D.), the European Regional Development Fund (ERDF) "A way of making Europe" the Comunidad de Madrid (S2017/BMD-3867 RENIM-CM to M.D. and B.I.), cofunding from European structural, and investment funds, and by Agencia Estatal de Investigación (PID2019-110369RB-I00 to B.I.). B.I. is a recipient of funding from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Programme (ERC-Consolidator Grant agreement No. 819775). E.O. is a recipient of funds from the Comunidad de Madrid Programa de Atracción de Talento (2017-T1/BMD-5185) and from a Ramón y Cajal grant (RYC2020-028884-I) funded by MCIN/AEI/10.13039/501100011033 and by "ESF Investing in your future." A.C.M. is the beneficiary of an FPU fellowship from the Ministerio de Ciencia e Innovación (FPU2017/01932). M.C.C. is the beneficiary of a Miguel Servet contract (MS16/00174). The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020-001041-S).

Introducción: Los tumores de la glándula suprarrenal son inusuales y por lo general son hallados de forma incidental por estudios de imágenes. Dentro de este grupo los mielolipomas son uno de los tumores más raros, considerados el 2% de los tumores suprarrenales.Caso clínico: Presentamos una paciente femenina de 60 años de edad con antecedentes de dolor a tipo cólico de forma esporádica a nivel del hipocondrio derecho. La ecografía abdominal detectó colelitiasis y una masa sugerente de adenoma suprarrenal izquierdo. La tomografía abdominal corroboró el tumor suprarrenal gigante y la litiasis vesicular. Se realizó suprarrenalectomía y colecistectomía convencional sin complicaciones. El diagnóstico histopatológico mostró un mielolipoma suprarrenal y una colecistitis crónica.Discusión: El mielolipoma suprarrenal es infrecuente, la etiología se desconoce, por lo general es asintomático y su hallazgo es incidental, habitualmente son unilaterales, menores a 4cm y la incidencia aumenta con la edad.Conclusiones: Cuando los mielolipomas alcanzan dimensiones mayores de 10cm se recomienda realizar una suprarrenalectomía convencional.

Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage. Neutrophil βRats were subjected to middle cerebral artery occlusion-reperfusion to evaluate the effect on stroke of the selective β1AR blocker metoprolol (12.5 mg·kgMagnetic resonance imaging and histopathology analysis showed that pre-reperfusion i.v. metoprolol reduced infarct size. This effect was accompanied by reduced cytotoxic oedema at 24 h and vasogenic oedema at 7 days. Metoprolol-treated rats showed reduced brain neutrophil infiltration and those which infiltrated displayed a high proportion of anti-inflammatory phenotype (N2, YM1Our findings describe that β1AR blockade ameliorates cerebral damage by targeting neutrophils, identifying a novel therapeutic target to improve outcomes in patients with stroke. This therapeutic strategy is in the earliest stages of the translational pathway and should be further explored.

Stimuli-responsive nanomaterials are very attractive for biomedical applications. They can be activated through external stimuli or by the physico-chemical conditions present in cells or tissues. Here, we describe the preparation of hybrid iron oxide-manganese oxide core-satellite shell nanostructures that change their contrast mode in magnetic resonance imaging (MRI) from T2 to T1, after being internalized by cells. This occurs by the dissolution of the MnO2 of the shell, preserving intact the iron oxide at the core. First, we study the seeded-growth synthesis of iron oxide-manganese oxide nanoparticles studying the effect of varying the core size of the magnetic seeds and the concentration of the surfactant. This allows tuning the size and shape of the final hybrid nanostructure. Then, we show that the shell can be removed by a redox reaction with glutathione, which is naturally present inside the cells at much higher concentrations than outside the cells. Finally, the dissolution of the MnO2 shell and the change in the contrast mode is confirmed in cell cultures. After this process, the iron oxide nanoparticles at the core remain intact and are still active as heating mediators when an alternating magnetic field is applied., This work was supported by the Ministerio de Ciencia e Innovación (PID2019-106301RB-I00 to GS and PGC2018-096016-B-I00 to L.G.), Instituto de Salud Carlos III (PT20/00044; co‐funded by European Union, European Regional Development Fund, ERDF, “A way of making Europe”), Ministerio de Economía y Competitividad (SAF2017-87305-R), Comunidad de Madrid (fellowships PEJD-2016/IND-2293 and IND2017/IND-7809; projects B2017/BMD-3867; P2018/NMT-4321), European Commission H2020 programme (project NOCANTHER, grant agreement no. 685795), and Asociación Española Contra el Cáncer. IMDEA Nanociencia acknowledges support from the 'Severo Ochoa' Programme for Centres of Excellence in R&D (MINECO, Grant SEV-2016-0686). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation. L.G. acknowledges financial support from the Ramón y Cajal program (RYC-2014-15512). N. L-G also thanks the Spanish Education Ministry for the funding (FPU18/02323). P. M-R- acknowledges the support from the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (MINECO, Grant SEV-2016-0686).

[Background]: Colorectal cancer (CRC) is the second most common cause of cancer death worldwide. It is broadly described that cyclooxygenase-2 (COX-2) is mainly overexpressed in CRC but less is known regarding post-translational modifications of this enzyme that may regulate its activity, intracellular localization and stability. Since metabolic and proteomic profile analysis is essential for cancer prognosis and diagnosis, our hypothesis is that the analysis of correlations between these specific parameters and COX-2 state in tumors of a high number of CRC patients could be useful for the understanding of the basis of this cancer in humans., [Aim]: To analyze COX-2 regulation in colorectal cancer and to perform a detailed analysis of their metabolic and proteomic profile., [Methods]: Biopsies from both healthy and pathological colorectal tissues were taken under informed consent from patients during standard colonoscopy procedure in the University Hospital of Bellvitge (Barcelona, Spain) and Germans Trias i Pujol University Hospital (Campus Can Ruti) (Barcelona, Spain). Western blot analysis was used to determine COX-2 levels. Deglycosylation assays were performed in both cells and tumor samples incubating each sample with peptide N-glycosidase F (PNGase F). Prostaglandin E2 (PGE2) levels were determined using a specific ELISA. 1H high resolution magic angle spinning (HRMAS) analysis was performed using a Bruker AVIII 500 MHz spectrometer and proteomic analysis was performed in a nano-liquid chromatography-tandem mass spectrometer (nano LC-MS/MS) using a QExactive HF orbitrap MS., [Results]: Our data show that COX-2 has a differential expression profile in tumor tissue of CRC patients vs the adjacent non-tumor area, which correspond to a glycosylated and less active state of the protein. This fact was associated to a lesser PGE2 production in tumors. These results were corroborated in vitro performing deglycosylation assays in HT29 cell line where COX-2 protein profile was modified after PNGase F incubation, showing higher PGE2 levels. Moreover, HRMAS analysis indicated that tumor tissue has altered metabolic features vs non-tumor counterparts, presenting increased levels of certain metabolites such as taurine and phosphocholine and lower levels of lactate. In proteomic experiments, we detected an enlarged number of proteins in tumors that are mainly implicated in basic biological functions like mitochondrial activity, DNA/RNA processing, vesicular trafficking, metabolism, cytoskeleton and splicing., [Conclusion]: In our colorectal cancer cohort, tumor tissue presents a differential COX-2 expression pattern with lower enzymatic activity that can be related to an altered metabolic and proteomic profile., MINECO, No. SAF2017-82436R, SAF2016-75004R, RTC-2017-6283-1, PRB3 (IPT17/0019-ISCIII-SGEFI/ERDF) and BIO2015-67580P; Comunidad de Madrid, No. S2017/BMD-3686; Fundación Ramón Areces, No. 2016/CIVP18A3864; Instituto de Salud Carlos III, Spain, CIBERCV, No. CB/11/00222 and CB16/11/00277; FEDER, CIBEREHD; the Ministerio de Ciencia, Innovación y Universidades (MCNU); the Pro CNIC Foundation; and Severo Ochoa Center of Excellence, No. SEV-2015-0505.

Human influenza A virus (hIAV) infection is associated with important cardiovascular complications, although cardiac infection pathophysiology is poorly understood. We aimed to study the ability of hIAV of different pathogenicity to infect the mouse heart, and establish the relationship between the infective capacity and the associated in vivo, cellular and molecular alterations. We evaluated lung and heart viral titres in mice infected with either one of several hIAV strains inoculated intranasally. 3D reconstructions of infected cardiac tissue were used to identify viral proteins inside mouse cardiomyocytes, Purkinje cells, and cardiac vessels. Viral replication was measured in mouse cultured cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to confirm infection and study underlying molecular alterations associated with the in vivo electrophysiological phenotype. Pathogenic and attenuated hIAV strains infected and replicated in cardiomyocytes, Purkinje cells, and hiPSC-CMs. The infection was also present in cardiac endothelial cells. Remarkably, lung viral titres did not statistically correlate with viral titres in the mouse heart. The highly pathogenic human recombinant virus PAmut showed faster replication, higher level of inflammatory cytokines in cardiac tissue and higher viral titres in cardiac HL-1 mouse cells and hiPSC-CMs compared with PB2mut-attenuated virus. Correspondingly, cardiac conduction alterations were especially pronounced in PAmut-infected mice, associated with high mortality rates, compared with PB2mut-infected animals. Consistently, connexin43 and NaV1.5 expression decreased acutely in hiPSC-CMs infected with PAmut virus. YEM1L protease also decreased more rapidly and to lower levels in PAmut-infected hiPSC-CMs compared with PB2mut-infected cells, consistent with mitochondrial dysfunction. Human IAV infection did not increase myocardial fibrosis at 4-day post-infection, although PAmut-infected mice showed an early increase in mRNAs expression of lysyl oxidase. Human IAV can infect the heart and cardiac-specific conduction system, which may contribute to cardiac complications and premature death. JV is a PhD fellow of the La Caixa Foundation International Fellowship Programme (La Caixa/CNB). This work was supported by the European Molecular Biology Organizat ion (STF-7649 to AF), the Spanish Ministry of Science, Innovation and Universities (MCIU), (BFU2011-26175 and BFU2014-57797-R to AN), and the network Ciber de Enfermedades Respiratorias (CIBERES) including the Improvement and Mobilit y Programme. The CNIC is a Severo Ochoa Center of Excellence (SEV-2015-0505). CNIC is supported by MCIU and the Pro CNIC Foundation. This study was supported by grants from Fondo Europeo de Desarrollo Regional (CB16/11/00458), grants SAF2015-65607-R and SAF2016-80324-R from MCIU (A.H. and D.F-R.) and fellowship SVP-2014-068595 to J.A.N-A. This study was supported by Frankel Cardiovascular Centre, Michigan Medicine (Grant 332475). JJ is supported in part by the National Heart, Lung, and Blood Institute (R01 Grant HL122352). S.F.N is supported in part by the National Heart, Lung, and Blood Institute grants R21HL138064 and R01HL129136. Sí

In both clinical and preclinical scenarios, 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) is the radiotracer most widely used to study brain glucose metabolism with positron emission tomography (PET). In clinical practice, there is a worldwide standardized protocol for preparing patients for [18F]FDG-PET studies, which specifies the room lighting. However, this standard is typically not observed in the preclinical field, although it is well known that animal handling affects the biodistribution of [18F]FDG. The present study aimed to evaluate the effect of ambient lighting on brain [18F]FDG uptake in mice. Two [18F]FDG-PET studies were performed on each animal, one in light and one in dark conditions. Thermal video recordings were acquired to analyse animal motor activity in both conditions. [18F]FDGPET images were analysed with the Statistical Parametric Mapping method. The results showed that [18F]FDG uptake is higher in darkness than in light condition in mouse nucleus accumbens, hippocampus, midbrain, hindbrain, and cerebellum. The SPM analysis also showed an interaction between the illumination condition and the sex of the animal. Mouse activity was significantly different (p = 0.01) between light conditions (632 ± 215 s of movement) and dark conditions (989 ± 200 s), without significant effect of sex (p = 0.416). We concluded that room illumination conditions during [18F]FDG uptake in mice affected the brain [18F]FDG biodistribution. Therefore, we highlight the importance to control this factor to ensure more reliable and reproducible mouse brain [18F]FDG-PET results. This work was partially supported by the Comunidad de Madrid (S2017/BMD-3867 RENIMCM), and it was co-financed by the European Structural and Investment Fund. And by Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (PT20/00044), cofunded by European Union, European Regional Development Fund (ERDF),"A way of making Europe". The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación.

We report on the magnetic properties of stable suspensions from oxidized Multiwalled Carbon Nanotubes (MWCNT) functionalized with aminopyrene (AP). MWCNT form π−π stacking adducts with AP (AP-MWCNT), originating homogenous, stable, suspensions in N,N-dimethylformamide (DMF) or melted agarose. First, we investigated the magneto-optical properties of these adducts. When applying series of pulsed magnetic fields to nanotube suspensions in DMF, the pattern of light dispersed increased during the magnetic pulse and decreased in the intervals, a behavior consistent with magnetic field induced orientation of the adducts. When adducts were suspended in a melted agarose gel under an external magnetic field, the extinction coefficient of polarized light through the gel, was larger when the polarization plane was parallel to the magnetic field direction. Based on the magneto-optical responses observed, we further investigated the magnetic properties of AP-MWCNT implementing measurements with Superconducting Quantum Interference Device, Zero Field Cooling and Field Cooling, Thermogravimetric and Differential Scanning Calorimetry. Pre-oriented AP-MWCNT suspensions depicted a clear superparamagnetic character with hysteresis loops revealing larger magnetic susceptibility values along their longitudinal axis. In summary, magneto-optical and SQUID measurements revealed that nanotube adducts in suspension, behave as nanoscale compass needles aligning their long axis parallel to externally applied magnetic fields., This work was supported in part by grants SAF2014-53739-R/IPT-2012-06000/SAF2017-08343-R (to SC), CTQ-2013-47669-R (to PB), MAT2013-43301-R and MAT2016-76106-R (to M O Ramírez) from the Spanish Ministry of Economy and Competitiveness and grants S2010/BMD-2349 and B2017/BMD-3688 (to PB and SC) and S2013/MIT-2740 (to M O Ramírez) from the Community of Madrid. DC and VN held postdoctoral contracts from CSIC. CM acknowledges the financial support by the “Ramón y Cajal” Program of MINECO RYC-2014-16626.

In recent years, while the research budget and development times increased for different phases of drug development, the number of clinically approved new medicines declined. In fact, many promising drug candidates failed to demonstrate their full therapeutic potential in vivo. Reasons for unfavorable outcome include some intrinsic properties of drugs, like biodegradation, solubility, and systemic toxicity, as well as the ways in which they are administered or the time elapsed until therapeutic efficiency is demonstrated. Therefore, to develop the full therapeutic potential of drug candidates in vivo, there is a need for advanced drug delivery systems that would carry the drug specifically to the target and release it there at desired concentrations. In addition, there is a requirement for non-invasive biomedical imaging technologies allowing for rapid and sensitive evaluations of drug performance in vivo. This review will present recent developments in bioengineered drug delivery systems, highlighting the biomedical imaging tools needed to evaluate the success of drug delivery strategies.

Commonly, the most of organizations tend to manage the timetables of their employees according to traditional guidelines (imposing an 8-hour work day). The primary objective of this approach is controlling some variables such as the attendance and absenteeism of the employees, and even, in some cases considering this situation as work efficiency. However, the new organizational tendencies have broken specific paradigms based on mechanistic orientation, trying to create a new horizon towards the construction of organic and dynamic organizations. For these reasons, in this paper, we present an expert system based on integer linear programming and data mining with the aim of addressing the problem of assigning courses to teachers and timetabling (considered an NP-complete problem). The preliminary results are encouraging, given that the system was able to assign courses on a database consisting off 133.000 registers of teachers, and at the same time, generate timetables with minimal computational costs., En general, varias de las organizaciones tienden a manejar la asignación de cargas horarias de sus empleados de manera tradicional (imposición de una jornada de trabajo de 8). Todo esto a fin de mantener cierto control sobre variables como asistencia y ausentismo del personal e incluso en algunos casos considerando aquello como sinónimo de eficacia laboral. Sin embargo, la nueva tendencia organizacional ha roto ciertos paradigmas con orientación mecanicista, pretendiendo crear un nuevo horizonte hacia la construcción de organizaciones orgánicas y dinámicas. Por lo expuesto, en este artículo se describe una propuesta de sistema experto basado en programación entera lineal y minería de datos para abordar el problema de asignación de materias y el diseño de horarios (considerado un problema NP-completo). Los resultados preliminares son alentadores, ya que han permitido realizar la asignación de materias en una base de 133.000 registros de docentes y generar horarios con un mínimo de coste computacional.

Magnetic resonance images are obtained by a combination of different radiofrequency pulses and gradient waveforms applied to the subject inside a magnetic field. There are multiple pulse sequences used in clinical and preclinical studies adjusted to whatever physician or researches want to analyze, from basic anatomic images to accurate diagnostic techniques as diffusion, perfusion, or functional imaging. In this chapter, we present the most used radiofrequency pulse combinations of the two groups of sequences available in magnetic resonance imaging: spin-echo and gradient-echo sequences.

Magnetic resonance imaging (MRI) is a technique based on the contents and relaxation features of water in tissues. In basic MRI sequences, diffusion phenomenon of water molecules is not taken into account although it has a notable influence in the relaxation times, and therefore in the signal intensity of images. In fact, MRI techniques that take advantage of water diffusion have experienced a huge development in last years. Diffusion-weighted imaging (DWI) has spectacularly evolved reaching nowadays a great impact both in clinical and preclinical imaging-especially in the neuroimaging field-and in basic research. We present here a protocol to perform DWI studies in a high-field preclinical setup.

Clinical imaging modalities have reached a prominent role in medical diagnosis and patient management in the last decades. Different image methodologies as Positron Emission Tomography, Single Photon Emission Tomography, X-Rays, or Magnetic Resonance Imaging are in continuous evolution to satisfy the increasing demands of current medical diagnosis. Progress in these methodologies has been favored by the parallel development of increasingly more powerful contrast agents. These are molecules that enhance the intrinsic contrast of the images in the tissues where they accumulate, revealing noninvasively the presence of characteristic molecular targets or differential physiopathological microenvironments. The contrast agent field is currently moving to improve the performance of these molecules by incorporating the advantages that modern nanotechnology offers. These include, mainly, the possibilities to combine imaging and therapeutic capabilities over the same theranostic platform or improve the targeting efficiency in vivo by molecular engineering of the nanostructures. In this review, we provide an introduction to multimodal imaging methods in biomedicine, the sub-nanometric imaging agents previously used and the development of advanced multimodal and theranostic imaging agents based in nanotechnology. We conclude providing some illustrative examples from our own laboratories, including recent progress in theranostic formulations of magnetoliposomes containing ω-3 poly-unsaturated fatty acids to treat inflammatory diseases, or the use of stealth liposomes engineered with a pH-sensitive nanovalve to release their cargo specifically in the acidic extracellular pH microenvironment of tumors.

Magnetic resonance imaging (MRI) is a technique based on the contents and relaxation features of water in tissues. In basic MRI sequences, diffusion phenomenon of water molecules is not taken into account although it has a notable influence in the relaxation times, and therefore in the signal intensity of images. In fact, MRI techniques that take advantage of water diffusion have experienced a huge development in last years. Diffusion-weighted imaging (DWI) has spectacularly evolved reaching nowadays a great impact both in clinical and preclinical imaging—especially in the neuroimaging field—and in basic research. We present here a protocol to perform DWI studies in a high-field preclinical setup., This work was supported by grant SAF2014-53739-R. IG held a predoctoral contract from Ministerio de Economía, Indrustria y Competitividad (MINECO) of Spain. DC held a postdoctoral contract from Consejo Superior de Investigaciones Científicas (CSIC).

Magnetic resonance images are obtained by a combination of different radiofrequency pulses and gradient waveforms applied to the subject inside a magnetic field. There are multiple pulse sequences used in clinical and preclinical studies adjusted to whatever physician or researches want to analyze, from basic anatomic images to accurate diagnostic techniques as diffusion, perfusion, or functional imaging. In this chapter, we present the most used radiofrequency pulse combinations of the two groups of sequences available in magnetic resonance imaging: spin-echo and gradient-echo sequences.

Clinical imaging modalities have reached a prominent role in medical diagnosis and patient management in the last decades. Different image methodologies as Positron Emission Tomography, Single Photon Emission Tomography, X-Rays, or Magnetic Resonance Imaging are in continuous evolution to satisfy the increasing demands of current medical diagnosis. Progress in these methodologies has been favored by the parallel development of increasingly more powerful contrast agents. These are molecules that enhance the intrinsic contrast of the images in the tissues where they accumulate, revealing noninvasively the presence of characteristic molecular targets or differential physiopathological microenvironments. The contrast agent field is currently moving to improve the performance of these molecules by incorporating the advantages that modern nanotechnology offers. These include, mainly, the possibilities to combine imaging and therapeutic capabilities over the same theranostic platform or improve the targeting efficiency in vivo by molecular engineering of the nanostructures. In this review, we provide an introduction to multimodal imaging methods in biomedicine, the sub-nanometric imaging agents previously used and the development of advanced multimodal and theranostic imaging agents based in nanotechnology. We conclude providing some illustrative examples from our own laboratories, including recent progress in theranostic formulations of magnetoliposomes containing ω-3 poly-unsaturated fatty acids to treat inflammatory diseases, or the use of stealth liposomes engineered with a pH-sensitive nanovalve to release their cargo specifically in the acidic extracellular pH microenvironment of tumors.

This work are distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License., We describe the preparation, physico-chemical characterization and anti-inflammatory properties of liposomes containing the superparamagnetic nanoparticle Nanotex, the fluorescent dye Rhodamine-100 and omega-3 polyunsaturated fatty acid ethyl ester (ω-3 PUFA-EE), as theranostic anti-inflammatory agents. Liposomes were prepared after drying chloroform suspensions of egg phosphatidylcholine, hydration of the lipid film with aqueous phases containing or not Nanotex, Rhodamine-100 dye or ω-3 PUFA-EE, and eleven extrusion steps through nanometric membrane filters. This resulted in uniform preparations of liposomes of approximately 200 nm diameter. Extraliposomal contents were removed from the preparation by gel filtration chromatography. High Resolution Magic Angle Spinning 1H NMR Spectroscopy of the liposomal preparations containing ω-3 PUFA-EE revealed well resolved 1H resonances from highly mobile ω-3 PUFA-EE, suggesting the formation of very small (ca. 10 nm) ω-3 PUFA-EE nanogoticules, tumbling fast in the NMR timescale. Chloroform extraction of the liposomal preparations revealed additionally the incorporation of ω-3 PUFA-EE within the membrane domain. Water diffusion weighted spectra, indicated that the goticules of ω-3 PUFA-EE or its insertion in the membrane did not affect the average translational diffusion coefficient of water, suggesting an intraliposomal localization, that was confirmed by ultrafiltration. The therapeutic efficacy of these preparations was tested in two different models of inflammatory disease as inflammatory colitis or the inflammatory component associated to glioma development. Results indicate that the magnetoliposomes loaded with ω-3 PUFA-EE allowed MRI visualization in vivo and improved the outcome of inflammatory disease in both animal models, decreasing significantly colonic inflammation and delaying, or even reversing, glioma development. Together, our results indicate that magnetoliposomes loaded with ω-3 PUFA-EE may become useful anti-inflammatory agents for image guided drug delivery., This work was supported in part by grants from SOLUTEX SL to SC, grants from the Spanish Ministry of Economy and Competitivity SAF2011-23622, IPT-2012-1331-006000 to SC, grant CTQ2013-47669-R to PB, and grant S2010/BMD-2349 from the Community of Madrid to S.C. and P.B. D.C. and V.N. held predoctoral contracts from Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC).

Even though alterations in the microenvironmental properties of tissues underlie the development of the most prevalent and morbid pathologies, they are not directly observable in vivo by Magnetic Resonance Imaging (MRI) or Spectroscopy (MRS) methods. This circumstance has lead to the development of a wide variety of exogenous paramagnetic and diamagnetic MRI and MRS probes able to inform non invasively on microenvironmental variables such as pH, pO(2), ion concentration o even temperature. This review covers the fundamentals of environmental contrast and the current arsenal of endogenous and exogenous MRI and MRS contrast enhancing agents available to visualize it. We begin describing the physicochemical background necessary to understand paramagnetic and diamagnetic contrast enhancement with a special reference to novel magnetization transfer and C-13 hiperpolarization strategies. We describe then the main macrocyclic structures used to support the environmentally sensitive paramagnetic sensors, including CEST and PARACEST pH sensitive probes, temperature probes and enzyme activity or gene expression activatable probes. Finally we address the most commonly used diamagnetic contrast agents including imidazolic derivatives to reveal extracellular pH and tissue pO(2) values by MRS. The potential applications of these agents in mutimodal and molecular imaging approaches are discussed., This work was supported in part by grants: CTQ2006-06505/BQU, CTQ2009-14146-C01/C02, to P.B. and P.L.L., S-BIO/0179/2006 and SAF2008/01381 to SC and EU MEDITRANS Integrated Project NMP4-CT- 2006-02668 to S.C., P.L.L. and P.B. J. P- T, D. C., B.L. and V.N. are predoctoral fellows from the Community of Madrid and CSIC and V.N. and C.U hold contracts from UNED

et al., The relaxivity displayed by Gd3+ chelates immobilized onto gold nanoparticles is the result of the complex interplay between the nanoparticle size, the water exchange rate and the chelate structure. In this work we study the effect of the length of ω-thioalkyl linkers, anchoring fast water exchanging Gd3+ chelates onto gold nanoparticles, on the relaxivity of the immobilized chelates. Gold nanoparticles functionalized with Gd3+ chelates of mercaptoundecanoyl and lipoyl amide conjugates of the DO3A-N-(α-amino)propionate chelator were prepared and studied as potential CA for MRI. High relaxivities per chelate, of the order of magnitude 28-38 mM-1 s-1 (30 MHz, 25 °C), were attained thanks to simultaneous optimization of the rotational correlation time and of the water exchange rate. Fast local rotational motions of the immobilized chelates around connecting linkers (internal flexibility) still limit the attainable relaxivity. The degree of internal flexibility of the immobilized chelates seems not to be correlated with the length of the connecting linkers. Biodistribution and MRI studies in mice suggest that the in vivo behavior of the gold nanoparticles was determined mainly by size. Small nanoparticles (HD = 3.9 nm) undergo fast renal clearance and avoidance of the RES organs while larger nanoparticles (HD = 4.8 nm) undergo predominantly hepatobiliary excretion. High relaxivities, allied to chelate and nanoparticle stability and fast renal clearance in vivo suggest that functionalized gold nanoparticles hold great potential for further investigation as MRI contrast agents. This study contributes to a better understanding of the effect of linker length on the relaxivity of gold nanoparticles functionalized with Gd3+ complexes. It is a relevant contribution towards >design rules> for nanostructures functionalized with Gd3+ chelates as Contrast Agents for MRI and multimodal imaging., This work was financially supported by Fundação para a Ciência e a Tecnologia, Portugal: PhD grant SFRH/BD/63994/2009 to Miguel Ferreira and Sabbatical Grant SFRH/BSAB/1328/2013 to José Martins at Bath University, UK; and Rede Nacional de NMR (REDE/1517/RMN/2005) for the acquisition of the Varian VNMRS 600 NMR spectrometer in Coimbra. T.B.R. was supported by a Marie Curie Fellowship (FP/- PEOPLE-2009-IEF 254380) and an EMBO Fellowship (ALTF1145-2009). Financial support from Ministerio de Ciencia e Innovación, Spain, projects SAF2011-23622 (S.C.) and CTQ2010-20960-C02-02 (P.L.-L.), and Comunidad de Madrid, Spain, project S2010/BMD-2349 (S.C. and P.L.-L), is also acknowledged. B. Mousavi and L. Helm acknowledge financial support by the Swiss National Science Foundation.

We analyze 3."5 resolution, high sensitivity radio continuum images of the nearby spiral galaxy NGC 4258 at 6 and 20 cm derived from multiple observations used to monitor the radio supernova SN 1981K (Van Dyk et al. 1992, [ApJ, 396, 1995]). Seven bright H II region and five supernova remnant candidates are identified. Extinctions to the H II regions are estimated for the first time from a comparison of radio flux densities to new optical fluxes derived from H-alpha observations by Dutil & Roy (1999, [ApJ, 516, 62]). The bright end of the H II region luminosity function is established at each wavelength. The luminosity functions are best fit by power laws consistent with the shape of previously published radio and optical luminosity functions for a number of galaxies. The supernova remnants are all about 2--3 times the radio luminosity of Cas A. In addition, the galaxy's nucleus is shown to have been variable over the SN 1981K monitoring period. The spectral index (alpha) distribution of the anomalous radio arms is investigated and found to be relatively uniform at alpha = -0.65 +/- 0.10., 14 pages, 10 figures, to appear in the ApJ

The Trousseau syndrome, first described in 1865, is the relationship of venous thromboembolisms and cancer. We present a case with rectal cancer and Trousseau syndrome.Female 40 years old, went to the Coloproctology Service for painless bleeding. A computed tomography report showed a tumor of 5 by 6 cm up 5 cm from the anal margin. Ultra-low anterior resection with colonic reservoir and loop ileostomy surgery was performed. The pathology report showed a semidiferenciate adenocarcinoma of the rectum and we established the stage as T3N0M0. Within 72 hours of her operation, she experienced sudden hypotension and painful abdominal distention. A second surgery was done finding necrosis of the colon from the splenic angle until the colonic reservoir with thrombi in the left colic artery, ischemic signs of bilateral fallopian tubes, ovaries, uterus, pelvic floor and the small intestine, 40 cm before ileostomy and ileon. Left hemicolectomy and colostomy was done. She was taken to intensive care where continuous administration of heparin was given; she died within 5 days because of multiorgan failure.The mechanism for this syndrome was unknown but there are several hypotheses, suggesting that hematological cancer patients are at an increased risk of deep vein thrombosis. Pancreatic cancer is the most common presentation with this syndrome (in 50% of cases). We suggested continuing with the standards of prevention of thromboembolism.antecedentes: el síndrome de Trousseau se describió por primera vez en 1865; es la relación entre tromboembolismo venoso y cáncer. Objetivo: informar el caso de una paciente con cáncer de recto y síndrome de Trousseau. Caso clínico: paciente femenina de 40 años de edad que acudió al servicio de Coloproctología por rectorragia indolora. La TAC reportó un tumor de 5 por 6cm y del margen anal a 5cm. Se efectuó resección anterior ultrabaja, con reservorio colónico e ileostomía de protección. El reporte de patología fue de: adenocarcinoma semidiferenciado del recto, con clasificación T3N0M0. A las 72 horas del postoperatorio tuvo hipotensión arterial súbita y distensión abdominal dolorosa. En la reintervención quirúrgica se encontró: necrosis del colon desde el ángulo esplénico hasta el reservorio colónico, con trombos en meso, signos de isquemia en el útero, trompa de Falopio y ovarios, piso pélvico y 40 cm de intestino delgado, antes de la ileostomía e íleon. Se realizó hemicolectomía izquierda y colostomía. Se trasladó a la unidad de terapia intensiva donde continuó con la administración de heparina; falleció a los cinco días por insuficiencia multiorgánica. Conclusiones: el mecanismo de este síndrome se desconoce pero existen varias hipótesis: se ha sugerido que los cánceres hematológicos son los que tienen mayor riesgo de trombosis venosa profunda. El cáncer de páncreas se relaciona con este síndrome en 50% de los casos. Se sugiere continuar con las normas de prevención del tromboembolismo.

A novel synthetic methodology for preparing amide conjugates of the DO3A-N-(α-amino)propionate chelator is described, using the synthesis of the DO3A-N-(α-benzoylamido)propionate chelator as an illustrative example. The model Gd[DO3A-N-(α-benzoylamido)propionate] chelate displays accelerated water exchange, stability in a wide pH range and inertness towards transmetallation by Zn(2+). The Gd[DO3A-N-(α-benzoylamido)propionate] complex is mainly excreted via the kidneys, producing a significant increase in the kidney medulla/cortex enhancement ratio in MR images of Wistar rats, reflecting probably its higher lipophilicity compared with Gd(DTPA). The results presented suggest that Gd[DO3A-N-(α-amido)propionate] chelates can be valuable leads for preparing potentially safe high relaxivity MRI contrast agents.

Information security guards perform an important function in multilevel security (MLS) environments. To perform their functions correctly, guards must contain data release and sanitization rules that accurately reflect the reclassification or declassification requirements to move data across information security boundaries. The current guards, however, require considerable technical skill to express release and sanitization rules, which data producers typically do not possess. Another limitation of the current guards is that once the data passes through a guard, all access control requirements to that data is lost. In this paper, we propose a high-level language to express release and sanitization rules, as well as post-release access control rules. We also describe a prototype that demonstrates the applicability of our approach.

Paracoccidioidomycosis (PCM) is a primary pulmonary infection that often disseminates to other organs and systems. Involvement of the central nervous system (CNS) is rare and due to the fact that both clinical alertness and establishment of the diagnosis are delayed, the disease progresses causing serious problems. We report here a case of neuroparacoccidioidomycosis (NPCM), observed in a 55 year-old male, who consulted due to neurological symptoms (left hemiparesis, paresthesias, right palpebral ptosis, headache, vomiting and tonic clonic seizures) of a month duration. Upon physical examination, an ulcerated granulomatous lesion was observed in the abdomen. To confirm the diagnosis a stereotactic biopsy was taken; additionally, mycological tests from the ulcerated lesion and a bronchoalveolar lavage were performed. In the latter specimens, P. brasiliensis yeast cells were visualized and later on, the brain biopsy revealed the presence of the fungus. Treatment with itraconazole (ITZ) was initiated but clinical improvement was unremarkable; due to the fact that the patient was taking sodium valproate for seizure control, drug interactions were suspected and confirmed by absence of ITZ plasma levels. The latter medication was changed to clonazepam and after several weeks, clinical improvement began to be noticed and was accompanied by diminishing P. brasiliensis antigen and antibody titers. In the PCM endemic areas, CNS involvement should be considered more often and the efficacy of itraconazole therapy should also be taken into consideration. RESUMO: A paracoccidioidomicose (PCM) é infecção pulmonar primária que algumas vezes pode se disseminar a outros órgãos e sistemas. O envolvimento do sistema nervoso central (SNC) é raro e devido ao fato que a alerta clínica e o estabelecimento do diagnóstico são tardios, a doença progride e o paciente piora. Aquí apresentamos caso de neuroparacoccidioidomicose (NPCM) observada em homem de 55 anos de idade que referia sintomas neurológicos (hemiparalisia esquerda, parestesias, ptose pálpebral direita, dor de cabeça, vômito e convulsões) de um mes de duração. Ao exame físico, foi achada lesão ulcerada e granulomatosa no abdômen. Como o diagnóstico era duvidoso, foi indicada biopsia estereotáxica; além disso provas micológicas a partir da lesão ulcerada e um lavado broncoalveolar foram realizados. Nas últimas amostras P. brasiliensis foi observado e depois a biopsia do cérebro revelou a presença do fungo. O tratamento com itraconazol foi iniciado mas a melhoria clínica não foi detectável; devido ao fato que o paciente estava tomando valproato de sódio para o controle das convulsôes, foi suspeita interação entre os dois medicamentos, que foi confirmada pela ausência do nível plasmático do antimicótico. Este último medicamento foi trocado por clonazepam e depois de algumas semanas a melhoria clínica foi percebida e acompanhada pela diminuição dos títulos de antígenos e anticorpos do P. brasiliensis. Em áreas endêmicas, o envolvimento do SNC deve ser considerado em doentes com PCM e a eficácia do itraconazole deve ser considerada. COL0013709