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Antecedentes: los hemangiomas infantiles son los tumores vasculares benignos más frecuentes en la infancia, siendo su localización más habitual la cabeza y el cuello, representando el 50 % de las masas que afectan a la glándula parótida. Debido al rápido crecimiento expansivo de estas lesiones, pueden aparecer complicaciones significativas, como pérdida de la función del órgano o desfiguración permanente, por lo que la intervención terapéutica precoz es de gran importancia para minimizar estos efectos indeseables. Reporte de caso: presentamos dos casos de pacientes con hemangioma parotídeo tratados con propranolol, con resultados muy favorables, y con escasas o nulas reacciones adversas. Conclusiones: actualmente, el propranolol oral está considerado como el fármaco de primera elección en el tratamiento de los hemangiomas parotídeos, mostrando un adecuado perfil de seguridad y una excelente eficacia.

Synaptic tract-tracing studies in macaques have provided a wealth of data about cortico-cortical connections that have been used to identify regularities and propose models and theories to explain cortical connectivity. The two most relevant of these models are the distance rule model (DRM) and the structural model (SM). They relate the strength and laminar pattern of cortico-cortical connections to two different factors: Euclidean distance (according to the DRM) and cortical type distance (according to the SM). If both predictive factors were correlated, the DRM and the SM would be compatible, but quite often, two cortical areas of similar cortical type are far apart from each other. In the present article, we have performed a conceptual analysis of the DRM and the SM to obtain predictions from each of the two models about strength and laminar pattern of cortico-cortical connections. We then tested the predictive power of each model with analyses of several cortico-cortical connectivity databases to check which of them provide the most accurate predictions. We conclude that the DRM and the SM capture the decrease in connection strength with increasing Euclidean and cortical type distances, respectively; but, for laminar pattern, type distance is a better predictor than Euclidean distance.

Supplementary Figures S1-S4; Supplementary Tables S1-S3.

Purpose: Preoperative chemoradiotherapy (CRT) is the treatment of choice for rectal cancer (RC), but half of the patients do not respond, suffer unnecessary toxicities, and surgery delays. We aimed to develop a model that could predict a clinically meaningful response to CRT by using formalin-fixed paraffin-embedded (FFPE) biopsies.Experimental Design: We first carried out an exploratory screening of candidate genes by using SAGE technology to evaluate dynamic changes in the RC transcriptome in selected refractory patients before and after CRT. Next, 53 genes (24 from SAGE and 29 from the literature) were analyzed by qPCR arrays in FFPE initial biopsies from 94 stage II/III RC patients who were preoperatively treated with CRT. Tumor response was defined by using Dworak's tumor regression grade (2–3–4 vs. 0–1). Multivariate Cox methods and stepwise algorithms were applied to generate an optimized predictor of response and outcome.Results: In the training cohort (57 patients), a 13-gene signature predicted tumor response with 86% accuracy, 87% sensitivity, and 82% specificity. In a testing cohort (37 patients), the model correctly classified 6 of 7 nonresponders, with an overall accuracy of 76%. A signature-based score identified patients with a higher risk of relapse in univariate (3-year disease-free survival 64% vs. 90%, P = 0.001) and multivariate analysis (HR = 4.35 95% CI: 1.2–15.75, P = 0.02), in which it remained the only statistically significant prognostic factor.Conclusions: A basal 13-gene signature efficiently predicted CRT response and outcome. Multicentric validation by the GEMCAD collaborative group is currently ongoing. If confirmed, the predictor could be used to improve patient selection in RC studies. Clin Cancer Res; 17(12); 4145–54. ©2011 AACR.

Neuromodulatory afferents to thalamic nuclei are key for information transmission and thus play critical roles in sensory, motor, and limbic processes. Over the course of the last decades, diverse attempts have been made to map and describe subcortical neuromodulatory afferents to the primate thalamus, including axons using acetylcholine, serotonin, dopamine, noradrenaline, adrenaline, and histamine. Our group has been actively involved in this endeavor. The published descriptions on neuromodulatory afferents to the primate thalamus have been made in different laboratories and are not fully comparable due to methodological divergences (for example, fixation procedures, planes of cutting, techniques used to detect the afferents, different criteria for identification of thalamic nuclei…). Such variation affects the results obtained. Therefore, systematic methodological and analytical approaches are much needed. The present article proposes reproducible methodological and terminological frameworks for primate thalamic mapping. We suggest the use of standard stereotaxic planes to produce and present maps of the primate thalamus, as well as the use of the Anglo-American school terminology (vs. the German school terminology) for identification of thalamic nuclei. Finally, a public repository of the data collected under agreed-on frameworks would be a useful tool for looking up and comparing data on the structure and connections of primate thalamic nuclei. Important and agreed-on efforts are required to create, manage, and fund a unified and homogeneous resource of data on the primate thalamus. Likewise, a firm commitment of the institutions to preserve experimental brain material is much needed because neuroscience work with non-human primates is becoming increasingly rare, making earlier material still more valuable, Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. CC and IP-S were the recipients of grants from Chair in Neuroscience UAM-Fundación Tatiana Pérez de Guzmán el Bueno, Spain. MAG-C was the recipient of a Beatriz Galindo senior research position in the School of Medicine, Universidad Autónoma de Madrid (BEAGAL18/00098) and of a Grant for I+D Projects to the Beatriz Galindo Program Researchers at Universidad Autónoma de Madrid (SI2/PBG/2020–00014) from the Madrid Government (Comunidad de Madrid-Spain) under the Multiannual Agreement with Universidad Autónoma de Madrid in the line of action encouraging young research doctors, in the context of the V PRICIT (Regional Programme of Research and Technological Innovation)

The primate thalamus has been subdivided into multiple nuclei and nuclear groups based on cytoarchitectonic, myeloarchitectonic, connectional, histochemical, and genoarchitectonic differences. Regarding parcellation and terminology, two main schools prevailed in the twentieth century: the German and the Anglo-American Schools, which proposed rather different schemes. The German parcellation and terminology has been mostly used for the human thalamus in neurosurgery atlases; the Anglo-American parcellation and terminology is the most used in experimental research on the primate thalamus. In this article, we review the historical development of terminological and parcellation schemes for the primate thalamus over the last 200 years. We trace the technological innovations and conceptual advances in thalamic research that underlie each parcellation, from the use of magnifying lenses to contemporary genoarchitectonic stains during ontogeny. We also discuss the advantages, disadvantages, and practical use of each parcellation.

Sixty years ago, Friedrich Sanides traced the origin of the tangential expansion of the primate neocortex to two ancestral anlagen in the allocortex of reptiles and mammals, and proposed the Hypothesis on the Dual Origin of the Neocortex. According to Sanides, paraolfactory and parahippocampal gradients of laminar elaboration expanded in evolution by addition of successive concentric rings of gradually different cortical types inside the allocortical ring. Rodents had fewer rings and primates had more rings in the inner part of the cortex. In the present article, we perform cortical type analysis of the neocortex of adult rats, Rhesus macaques, and humans to propose hypotheses on homology of cortical areas applying the principles of the Hypothesis on the Dual Origin of the Neocortex. We show that areas in the outer rings of the neocortex have comparable laminar elaboration in rats and primates, while most 6-layer eulaminate areas in the innermost rings of primate neocortex lack homologous counterparts in rats. We also represent the topological distribution of cortical types in simplified flat maps of the cerebral cortex of monotremes, rats, and primates. Finally, we propose an elaboration of the Hypothesis on the Dual Origin of the Neocortex in the context of modern studies of pallial patterning that integrates the specification of pallial sectors in development of vertebrate embryos. The updated version of the hypothesis of Sanides provides explanation for the emergence of cortical hierarchies in mammals and will guide future research in the phylogenetic origin of neocortical areas, This work was supported by grants from the National Institute of Mental Health to BZ (Grant Nos. R01 MH101209 and R01 MH118500). MAG-C was the recipient of a Beatriz Galindo senior research position in the Faculty of Medicine at Universidad Autónoma de Madrid (BEAGAL18/00098) and of a Grant for I+D Projects by the Madrid Government (Comunidad de Madrid-Spain) under the Multiannual Agreement with Universidad Autónoma de Madrid in the line of action encouraging youth research doctors, in the context of the V PRICIT (Regional Program of Research and Technological Innovation), reference: SI2/PBG/2020-00014

The delicate balance among primate prefrontal networks is necessary for homeostasis and behavioral flexibility. Dorsolateral prefrontal cortex (dlPFC) is associated with cognition, while the most ventromedial subgenual cingulate area 25 (A25) is associated with emotion and emotional expression. Yet A25 is weakly connected with dlPFC, and it is unknown how the two regions communicate. In rhesus monkeys of both sexes, we investigated how these functionally distinct areas may interact through pregenual anterior cingulate area 32 (A32), which is strongly connected with both. We found that dlPFC innervated the deep layers of A32, while A32 innervated all layers of A25, mostly targeting spines of excitatory neurons. Approximately 20% of A32 terminations formed synapses on inhibitory neurons in A25, notably the powerful parvalbumin inhibitory neurons in the deep layers, and the disinhibitory calretinin neurons in the superficial layers. By innervating distinct inhibitory microenvironments in laminar compartments, A32 is positioned to tune activity in columns of A25. The circuitry of the sequential pathway indicates that when dlPFC is engaged, A32 can dampen A25 output through the parvalbumin inhibitory microsystem in the deep layers of A25. A32 thus may flexibly recruit or reduce activity in A25 to maintain emotional equilibrium, a process that is disrupted in depression. Moreover, pyramidal neurons in A25 had a heightened density of NMDARs, which are the targets of novel rapid-acting antidepressants. Pharmacologic antagonism of NMDARs in patients with depression may reduce excitability in A25, mimicking the effects of the neurotypical serial pathway identified here.SIGNIFICANCE STATEMENTThe anterior cingulate is a critical hub in prefrontal networks through connections with functionally distinct areas. Dorsolateral and polar prefrontal areas that are associated with complex cognition are connected with the anterior cingulate in a pattern that allows them to indirectly control downstream activity from the anterior cingulate to the subgenual cingulate, which is associated with heightened activity and negative affect in depression. This set of pathways provides a circuit mechanism for emotional regulation, with the anterior cingulate playing a balancing role for integration of cognitive and emotional processes. Disruption of these pathways may perturb network function and the ability to regulate cognitive and affective processes based on context.

The prosomeric model explains the embryological development of the central nervous system (CNS) shared by all vertebrates as a Bauplan. As a primary event, the early neural plate is patterned by intersecting longitudinal plates and transverse segments, forming a mosaic of progenitor units. The hypothalamus is specified by three prosomeres (hp1, hp2, and the acroterminal domain) of the secondary prosencephalon with corresponding alar and basal plate parts, which develop apart from the diencephalon. Mounting evidence suggests that progenitor units within alar and basal plate parts of hp1 and hp2 give rise to distinct hypothalamic nuclei, which preserve their relative invariant positioning (topology) in the adult brain. Nonetheless, the principles of the prosomeric model have not been applied so far to the hypothalamus of adult primates. We parcellated hypothalamic nuclei in adult rhesus monkeys (Macaca mulatta) using various stains to view architectonic boundaries. We then analyzed the topological relations of hypothalamic nuclei and adjacent hypothalamic landmarks with homology across rodent and primate species to trace the origin of adult hypothalamic nuclei to the alar or basal plate components of hp1 and hp2. We generated a novel atlas of the hypothalamus of the adult rhesus monkey with developmental ontologies for each hypothalamic nucleus. The result is a systematic reinterpretation of the adult hypothalamus whose prosomeric ontology can be used to study relationships between the hypothalamus and other regions of the CNS. Further, our atlas may serve as a tool to predict causal patterns in physiological and pathological pathways involving the hypothalamus.

Understanding the origin of Greek and Latin words used as metaphors to label brain structures gives a unique window into how scientific and medical knowledge was produced, preserved, and transmitted through generations. The history of the term thalamus exemplifies the complex historical process that led to the current anatomical terminology. From its first mention by Galen of Pergamon in the 2nd century A.D. to its definitive and current use by Thomas Willis in 1664, the thalamus had an epical journey through 1500 years across Europe, the Middle East, and the North of Africa. The thalamus was confusingly described by Galen, in the Greek language, as a chamber to the brain ventricles. The term thalamus was transferred from Greek to Syriac through the translations of Galen’s books done in Baghdad and also from Syriac to Arabic. Then, it was translated in Europe during the Middle Ages from the Arabic versions of Galen’s books to Latin. Later, during the Early Renaissance, it was translated again to Latin directly from the Greek versions of Galen’s books. Along this epical journey through languages, the term thalamus switched from referring to a hollow structure connected to brain ventricles to naming a solid structure at the rostral end of the brainstem. Finally, the thalamus was translated from Latin to modern languages, where it is used, until today, to name a nuclear complex of subcortical gray matter in the lateral walls of the third ventricle.

High-level characterizations of the primate cerebral cortex sit between two extremes: on one end the cortical mantle is seen as a mosaic of structurally and functionally unique areas, and on the other it is seen as a uniform six-layered structure in which functional differences are defined solely by extrinsic connections. Neither of these extremes captures the crucial neuroanatomical finding: that the cortex exhibits systematic gradations in architectonic structure. These gradations have been shown to predict cortico-cortical connectivity, which in turn suggests powerful ways to ground connectomics in anatomical structure, and by extension cortical function. A challenge to more widespread use of this concept is the labor-intensive and invasive nature of histological staining, which is the primary means of recognizing anatomical gradations. Here we show that a novel computational analysis technique can be used to derive a coarse-grained picture of cortical variation. For each of 78 cortical areas spanning the entire cortical mantle of the rhesus macaque, we created a high dimensional set of anatomical features derived from captured images of cortical tissue stained for myelin and SMI-32. The method involved semi-automated de-noising of images, and enabled comparison of brain areas without hand-labeling of features such as layer boundaries. We applied nonmetric multidimensional scaling (NMDS) to the dataset to visualize similarity among cortical areas. This analysis shows a systematic variation between weakly laminated (limbic) cortices and sharply laminated (eulaminate) cortices. We call this smooth continuum the ‘cortical spectrum’. We also show that this spectrum is visible within subsystems of the cortex: the occipital, parietal, temporal, motor, prefrontal, and insular cortices. We compared the NMDS-derived spectrum with a spectrum produced using T1- and T2-weighted magnetic resonance imaging (MRI) data derived from macaque, and found close agreement of the two coarse-graining methods. This evidence suggests that T1/T2 data, routinely obtained in human MRI studies, can be used as an effective proxy for data derived from high-resolution histological methods. More generally, this approach shows that the cortical spectrum is robust to the specific method used to compare cortical areas, and is therefore a powerful tool to understand the principles of organization of the primate cortex.

Background: Bloodstream infections (BSIs) are the most frequent nosocomial infections in neonatal intensive care units (NICUs), especially in very low birth weight (VLBW) infants (birth weight ≤ 1500 g). An epidemiologic surveillance system may contribute to the prevention of infection by continuous monitoring of its frequency and associated risk factors. The aim of this article was to describe the implementation of the NeoKissEs surveillance system for BSIs in VLBW newborns in a group of Spanish NICUs. Methods: We assessed the clinical cohort consisting of all VLBW newborns aged less than 28 days admitted to the participating units. In the pilot phase, 2 NICUs translated and adapted materials from the original German NEO-KISS system. During implementation, 210 health care professionals attended one of 8 educational workshops. A web-based system was created that allows entering data regarding patients and BSI episodes, data monitoring, benchmarking and providing feedback to the units. At each NICU, one neonatologist was responsible for the implementation of the system and reporting the difficulties perceived throughout the process. Results: Out of the 50 units that agreed to participate, 45 successfully started using the surveillance platform during the implementation phase, recording 1108 episodes of catheter-associated BSI (CABSI) in 3638 newborns, and finding an overall rate of CABSI of 18.4 (95% CI, 17.8-19.1) per 1000 catheter days. Conclusions: The NeoKissEs surveillance system constitutes a helpful source of information for the purpose of benchmarking the performance of neonatal units, assessing factors associated with BSI in VLBW infants and measuring the impact of future preventive interventions in NICUs. Resumen: Antecedentes: Las sepsis son las infecciones nosocomiales más frecuentes en las Unidades de Cuidados Intensivos Neonatales (UCIN), afectando especialmente a los recién nacidos de muy bajo peso al nacer (RNMBP, ≤ 1.500 g). Un sistema de vigilancia epidemiológica puede contribuir a su prevención mediante una evaluación continua de su frecuencia y factores de riesgo asociados. El objetivo de este artículo es describir la implementación del sistema de vigilancia de las sepsis nosocomiales en RNMBP (NeoKissEs) en un grupo de UCIN españolas. Métodos: Estudio de cohorte de RNMBP con < 28 días de edad ingresados en las UCIN participantes. Dos UCIN tradujeron y adaptaron materiales a partir del sistema original alemán NEO-KISS. Durante la implementación, se desarrollaron 8 talleres formativos, con participación de 210 profesionales. Se creó un sistema web para la introducción de datos de pacientes y episodios de sepsis, su monitorización, análisis comparativo y retroalimentación a las unidades. En cada UCIN, un neonatólogo fue responsable de la implementación, recogiendo información sobre las dificultades percibidas durante el proceso. Resultados: De 50 unidades que aceptaron participar, 45 utilizaron NeoKissEs durante la fase de implementación, registrando 1.108 episodios de sepsis asociados a catéter vascular en 3.638 neonatos, con una tasa de 18,4 episodios por 1.000 pacientes-día con catéter (IC del 95%: 17,8-19,1). Conclusiones: El sistema de vigilancia epidemiológica NeoKissEs representa una fuente útil de información para la comparación estandarizada de la incidencia de sepsis de las UCIN, evaluar factores de riesgo y facilitar la evaluación del efecto de futuras intervenciones preventivas.

Autism is a neurodevelopmental connectivity disorder characterized by cortical network disorganization and imbalance in excitation/inhibition. However, little is known about the development of autism pathology and the disruption of laminar-specific excitatory and inhibitory cortical circuits. To begin to address these issues, we examined layer 1 of the lateral prefrontal cortex (LPFC), an area with prolonged development and maturation that is affected in autism. We focused on layer 1 because it contains a distinctive, diverse population of interneurons and glia, receives input from feedback and neuromodulatory pathways, and plays a critical role in the development, maturation, and function of the cortex. We used unbiased quantitative methods at high resolution to study the morphology, neurochemistry, distribution, and density of neurons and myelinated axons in post-mortem brain tissue from children and adults with and without autism. We cross-validated our findings through comparisons with neighboring anterior cingulate cortices and optimally-fixed non-human primate tissue. In neurotypical controls we found an increase in the density of myelinated axons from childhood to adulthood. Neuron density overall declined with age, paralleled by decreased density of inhibitory interneurons labeled by calretinin (CR), calbindin (CB), and parvalbumin (PV). Importantly, we found PV neurons in layer 1 of typically developing children, previously detected only perinatally. In autism there was disorganization of cortical networks within layer 1: children with autism had increased variability in the trajectories and thickness of myelinated axons in layer 1, while adults with autism had a reduction in the relative proportion of thin axons. Neurotypical postnatal changes in layer 1 of LPFC likely underlie refinement of cortical activity during maturation of cortical networks involved in cognition. Our findings suggest that disruption of the maturation of feedback pathways, rather than interneurons in layer 1, has a key role in the development of imbalance between excitation and inhibition in autism.

The classical theory of cortical systematic variation has been independently described in reptiles, monotremes, marsupials and placental mammals, including primates, suggesting a common bauplan in the evolution of the cortex. The Structural Model is based on the systematic variation of the cortex and is a platform for advancing testable hypotheses about cortical organization and function across species, including humans. The Structural Model captures the overall laminar structure of areas by dividing the cortical architectonic continuum into discrete categories (cortical types), which can be used to test hypotheses about cortical organization. By type, the phylogenetically ancient limbic cortices ─ which form a ring at the base of the cerebral hemisphere ─ are agranular if they lack layer IV, or dysgranular if they have an incipient granular layer IV. Beyond the dysgranular areas, eulaminate type cortices have six layers. The number and laminar elaboration of eulaminate areas differs depending on species or cortical system within a species. The construct of cortical type retains the topology of the systematic variation of the cortex and forms the basis for a predictive Structural Model, which has successfully linked cortical variation to the laminar pattern and strength of cortical connections, the continuum of plasticity and stability of areas, the regularities in the distribution of classical and novel markers, and the preferential vulnerability of limbic areas to neurodegenerative and psychiatric diseases. The origin of cortical types has been recently traced to cortical development, and helps explain the variability of diseases with an onset in ontogeny.

Studies on the thalamus have mostly focused on sensory relay nuclei, but the organization of pathways associated with emotions is not well understood. We addressed this issue by testing the hypothesis that the primate amygdala acts, in part, like a sensory structure for the affective import of stimuli and conveys this information to the mediodorsal thalamic nucleus, magnocellular part (MDmc). We found that primate sensory cortices innervate amygdalar sites that project to the MDmc, which projects to the orbitofrontal cortex. As in sensory thalamic systems, large amygdalar terminals innervated excitatory relay and inhibitory neurons in the MDmc that facilitate faithful transmission to the cortex. The amygdala, however, uniquely innervated a few MDmc neurons by surrounding and isolating large segments of their proximal dendrites, as revealed by three-dimensional high-resolution reconstruction. Physiologic studies have shown that large axon terminals are found in pathways issued from motor systems that innervate other brain centers to help distinguish self-initiated from other movements. By analogy, the amygdalar pathway to the MDmc may convey signals forwarded to the orbitofrontal cortex to monitor and update the status of the environment in processes deranged in schizophrenia, resulting in attribution of thoughts and actions to external sources., Pathways from the amygdala target specific neurons in the thalamic magnocellular mediodorsal nucleus to enable speedy and faithful transmission of emotional information to prefrontal cortex.

Research on plasticity markers in the cerebral cortex has largely focused on their timing of expression and role in shaping circuits during critical and normal periods. By contrast, little attention has been focused on the spatial dimension of plasticity-stability across cortical areas. The rationale for this analysis is based on the systematic variation in cortical structure that parallels functional specialization and raises the possibility of varying levels of plasticity. Here, we investigated in adult rhesus monkeys the expression of markers related to synaptic plasticity or stability in prefrontal limbic and eulaminate areas that vary in laminar structure. Our findings revealed that limbic areas are impoverished in three markers of stability: intracortical myelin, the lectin Wisteria floribunda agglutinin, which labels perineuronal nets, and parvalbumin, which is expressed in a class of strong inhibitory neurons. By contrast, prefrontal limbic areas were enriched in the enzyme calcium/calmodulin-dependent protein kinase II (CaMKII), known to enhance plasticity. Eulaminate areas have more elaborate laminar architecture than limbic areas and showed the opposite trend: they were enriched in markers of stability and had lower expression of the plasticity-related marker CaMKII. The expression of glial fibrillary acidic protein (GFAP), a marker of activated astrocytes, was also higher in limbic areas, suggesting that cellular stress correlates with the rate of circuit reshaping. Elevated markers of plasticity may endow limbic areas with flexibility necessary for learning and memory within an affective context, but may also render them vulnerable to abnormal structural changes, as seen in neurologic and psychiatric diseases.

Background: Dopamine loss beyond the mesostriatal system might be relevant in pathogenic mechanisms and some clinical manifestations in PD. The primate thalamus is densely and heterogeneously innervated with dopaminergic axons, most of which express the dopamine transporter, as does the nigrostriatal system. We hypothesized that dopamine depletion may be present in the thalamus of the parkinsonian brain and set out to ascertain possible regional differences. Methods: The toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was administered to adult macaque monkeys using a slow intoxication protocol. The treated macaques were classified into 2 groups according to their motor status: nonsymptomatic and parkinsonian. Dopamine innervation was studied with immunohistochemistry for the dopamine transporter. Topographic maps of the dopamine transporter-immunoreactive axon distribution were generated and the total length and length density of these axons stereologically estimated using a 3-dimensional fractionator. Results: Parkinsonian macaques exhibited lower dopamine transporter-immunoreactive axon length density than controls in mediodorsal and centromedianparafascicular nuclei. Dopamine denervation in the mediodorsal nucleus was already noticeable in nonsymptomatic macaques and was even greater in parkinsonian macaques. Reticular nucleus dopamine transporter-immunoreactive axon length density presented an inverse pattern, increasing progressively to the maximum density seen in parkinsonian macaques. No changes were observed in ventral thalamic nuclei. Dopamine transporter-immunoreactive axon maps supported the quantitative findings. Conclusions: Changes in the dopamine innervation of various thalamic nuclei are heterogeneous and start in the premotor parkinsonian stage. These changes may be involved in some poorly understood nonmotor manifestations of PD., Chair in Neuroscience UAM-Fundación Tatiana Pérez de Guzmán el Bueno directed by C.C. J.A.O. and J.B. are currently funded by MINECO/AEI/FEDER-UE (SAF2015-67239-P), grant S2017/BMD-3700 (NEUROMETAB-CM) from Comunidad de Madrid cofinanced with Structural Funds from the European Union, La Caixa Foundation, Fundación BBVA, and Fundación Tatiana Pérez de Guzmán el Bueno.

Transporte neonatal; Transporte intraútero; Recién nacido de alto riesgo In utero transport; Neonatal transport; High risk newborn Transport neonatal; Transport intraúter; Nounat de risc alt The first hours of life of a sick or premature newborn are crucial for its prognosis and therefore delivery should take place in a center prepared for that degree of complexity. When this condition is not met, the newborn must be transferred in an optimal and safe way to the center that can offer the necessary care. The training, staffing, organization and coordination of the neonatal transport team are essential to guarantee a safe transfer. Being aware of the interest and the advances that are currently taking place in this area of ​​pediatrics, the Standards Commission and the Neonatal Transport Commission of the Spanish Society of Neonatology have prepared this document. In it, both the provision of human and material resources necessary as well as the bases of clinical stabilization in transport to carry out the neonatal transfer in a safe way and proportionate to the needs of the critical newborn have been exhaustively reviewed and detailed. Las primeras horas de vida de un recién nacido enfermo o prematuro son cruciales para su pronóstico y por lo tanto el parto debería acontecer en un centro preparado para ese grado de complejidad. Cuando no se cumple esta condición, el recién nacido debe ser trasladado de un modo óptimo y seguro al centro que pueda ofrecerle los cuidados necesarios. La formación, dotación, organización y coordinación del equipo de transporte neonatal son indispensables para garantizar un traslado en condiciones. Siendo conscientes del interés y los avances que en la actualidad se están produciendo en esta área de la pediatría, la Comisión de Estándares y la Comisión de Transporte Neonatal de la Sociedad Española de Neonatología han elaborado el presente documento. En él, se ha revisado y detallado de forma exhaustiva tanto la dotación de recursos humanos y materiales necesarios como las bases de la estabilización clínica en transporte para llevar a cabo el traslado neonatal de forma segura y proporcionada a las necesidades del recién nacido crítico.

Pathways from cortical and subcortical structures give the prefrontal cortex a panoramic view of the sensory environment and the internal milieu of motives and drives. The prefrontal cortex also receives privileged information from the output of the basal ganglia and cerebellum and innervates widely the inhibitory thalamic reticular nucleus that gates thalamo-cortical communication. Connections, in general, are strongly related to the systematic structural variation of the cortex that can be traced to development. Insights from development have profound implications for the special connections of the prefrontal cortex for executive control, learning and memory, and vulnerability in psychiatric and neurologic diseases.

The organization of the inhibitory intercalated cell masses (IM) of the primate amygdala is largely unknown despite their key role in emotional processes. We studied the structural, topographic, neurochemical and intrinsic connectional features of IM neurons in the rhesus monkey brain. We found that the intercalated neurons are not confined to discrete cell clusters, but form a neuronal net that is interposed between the basal nuclei and extends to the dorsally located anterior, central, and medial nuclei of the amygdala. Unlike the IM in rodents, which are prominent in the anterior half of the amygdala, the primate inhibitory net stretched throughout the antero-posterior axis of the amygdala, and was most prominent in the central and posterior extent of the amygdala. There were two morphologic types of intercalated neurons: spiny and aspiny. Spiny neurons were the most abundant; their somata were small or medium size, round or elongated, and their dendritic trees were round or bipolar, depending on location. The aspiny neurons were on average slightly larger and had varicose dendrites with no spines. There were three non-overlapping neurochemical populations of IM neurons, in descending order of abundance: (1) Spiny neurons that were positive for the striatal associated dopamine- and cAMP-regulated phosphoprotein (DARPP-32+); (2) Aspiny neurons that expressed the calcium-binding protein calbindin (CB+); and (3) Aspiny neurons that expressed nitric oxide synthase (NOS+). The unique combinations of structural and neurochemical features of the three classes of IM neurons suggest different physiological properties and function. The three types of IM neurons were intermingled and likely interconnected in distinct ways, and were innervated by intrinsic neurons within the amygdala, or by external sources, in pathways that underlie fear conditioning and anxiety.

Humans engage in many daily activities that rely on working memory, the ability to hold and sequence information temporarily to accomplish a task. We focus on the process of working memory, based on circuit mechanisms for attending to relevant signals and suppressing irrelevant stimuli. We discuss that connections critically depend on the systematic variation in laminar structure across all cortical systems. Laminar structure is used to group areas into types regardless of their placement in the cortex, ranging from low-type agranular areas that lack layer IV to high-type areas that have six well-delineated layers. Connections vary in laminar distribution and strength based on the difference in type between linked areas, according to the “structural model” (Barbas H, Rempel-Clower N. Cereb Cortex 7: 635–646, 1997). The many possible pathways thus vary systematically by laminar distribution and strength, and they interface with excitatory neurons to select relevant stimuli and with functionally distinct inhibitory neurons that suppress activity at the site of termination. Using prefrontal pathways, we discuss how systematic architectonic variation gives rise to diverse pathways that can be recruited, along with amygdalar and hippocampal pathways that provide sensory, affective, and contextual information. The prefrontal cortex is also connected with thalamic nuclei that receive the output of the basal ganglia and cerebellum, which may facilitate fast sequencing of information. The complement of connections and their interface with distinct inhibitory neurons allows dynamic recruitment of areas and shifts in cortical rhythms to meet rapidly changing demands of sequential components of working memory tasks.

Noninvasive imaging and tractography methods have yielded information on broad communication networks but lack resolution to delineate intralaminar cortical and subcortical pathways in humans. An important unanswered question is whether we can use the wealth of precise information on pathways from monkeys to understand connections in humans. We addressed this question within a theoretical framework of systematic cortical variation and used identical high-resolution methods to compare the architecture of cortical gray matter and the white matter beneath, which gives rise to short- and long-distance pathways in humans and rhesus monkeys. We used the prefrontal cortex as a model system because of its key role in attention, emotions, and executive function, which are processes often affected in brain diseases. We found striking parallels and consistent trends in the gray and white matter architecture in humans and monkeys and between the architecture and actual connections mapped with neural tracers in rhesus monkeys and, by extension, in humans. Using the novel architectonic portrait as a base, we found significant changes in pathways between nearby prefrontal and distant areas in autism. Our findings reveal that a theoretical framework allows study of normal neural communication in humans at high resolution and specific disruptions in diverse psychiatric and neurodegenerative diseases., Author summary Can the wealth of information from animal studies on the structure and connections of the cerebral cortex—the brain’s outer rim—be translated to understand neural communication in humans and disruption in brain diseases? To address this question, we examined the prefrontal cortex, which is associated with attention, emotions, and executive control—functions that are disrupted in psychiatric and neurologic diseases. We compared the architecture of the human and rhesus monkey cortex, using identical methods in both species to maximize the accuracy of comparisons. High-resolution microscopy revealed features of gray matter regions, made up of many cells, as well as of the white matter beneath, which contains axons that form connections between brain regions. We found that the architecture of the gray and white matter in humans and monkeys varies systematically (and in parallel) and reflects connections assessed by tracers. Using the template established with control human brains, we found significant differences in short- and long-distance pathways in the brains of individuals with autism. The framework established here helps predict patterns in the architecture and connections of areas across mammalian species and sets the stage to integrate functional imaging data from control subjects to compare with pathological states in humans.

Ideas from classical philosophy and psychology that emotion and cognition are distinct and separate have been challenged by evidence of their intricate interaction in the brain. Accumulated evidence shows that areas associated with emotions and cognition are strongly linked and influence each other according to principles based on the structural organization of the cortex. Subcortical structures that process information about needs and drives are old in phylogeny and innervate the prefrontal cortex, targeting strongly the posterior orbitofrontal cortex (pOFC) and the anterior cingulate cortex (ACC). These two prefrontal regions are part of the cortical component of the limbic system but are functionally distinct. Through widespread connections, the pOFC acts as an integrator of the internal and external environments for the perception of affective events. In contrast, the ACC specializes in the expression of emotions through robust pathways to central autonomic structures. Both prefrontal limbic regions are connected with lateral prefrontal areas associated with cognitive functions, effectively linking areas associated with emotion and cognition. Functional and circuit studies in animals and humans indicate that even simple tasks necessitate interaction between areas associated with cognition and emotions and suggest that their linkage is disrupted in several psychiatric and neurologic diseases.

CDC42 is an oncogenic Rho GTPase overexpressed in colorectal cancer (CRC). Although CDC42 has been shown to regulate gene transcription, the specific molecular mechanisms regulating the oncogenic ability of CDC42 remain unknown. Here, we have characterized the transcriptional networks governed by CDC42 in the CRC SW620 cell line using gene expression analysis. Our results establish that several cancer-related signaling pathways, including cell migration and cell proliferation, are regulated by CDC42. This transcriptional signature was validated in two large cohorts of CRC patients and its clinical relevance was also studied. We demonstrate that three CDC42-regulated genes offered a better prognostic value when combined with CDC42 compared to CDC42 alone. In particular, the concordant overexpression of CDC42 and silencing of the putative tumor suppressor gene CACNA2D2 dramatically improved the prognostic value. The CACNA2D2/CDC42 prognostic classifier was further validated in a third CRC cohort as well as in vitro and in vivo CRC models. Altogether, we show that CDC42 has an active oncogenic role in CRC via the transcriptional regulation of multiple cancer-related pathways and that CDC42-mediated silencing of CACNA2D2 is clinically relevant. Our results further support the use of CDC42 specific inhibitors for the treatment of the most aggressive types of CRC, This work has been supported by grants to JCL from Ministerio de Ciencia e Innovación (SAF2008- 03750, RD06-0020-0016 and RD12/0036/0019) and to DGO Cancer Institute New South Wales (2017/CDF625). FVM is a National Breast Cancer Foundation/Cure Cancer Australia Foundation Postdoctoral Training Fellow.

Resumen Objetivo Determinar las anomalias vesicales precoces en un modelo animal de mielomeningocele (MMC) con y sin correccion quirurgica intrautero. Metodo Creamos una lesion similar al MMC en 18 fetos de cordero entre los dias 60 y 80 de gestacion. Ocho de ellos no se repararon prenatalmente (grupo A), 3 se intervinieron mediante cierre abierto en 2 planos (grupo B), 3 se cerraron con pegamento biologico (grupo C ) y 4 por fetoscopia (grupo D). Al final de la gestacion las vejigas se estudiaron macroscopica e histologicamente usando tincion de hematoxilina-eosina y tricromico de Masson. Resultados Cinco animales del grupo A (5/8, 62%), 2 en el grupo B (2/3, 66%), uno en el grupo C (1/3, 33%) y uno en el grupo D (1/4, 25%) sobrevivieron. Macroscopicamente las vejigas del grupo A estaban muy dilatadas y sus paredes eran muy finas. Microscopicamente mostraban una delgada capa de colageno (capa azul [CA]) inmediatamente por debajo del urotelio; las capas musculares estaban muy adelgazadas. En el grupo no corregido tambien encontramos vejigas de baja acomodacion, con paredes engrosadas y capacidad disminuida. El grupo B y el control mostraban preservacion de las capas musculares y ausencia de CA. Los grupos C y D presentaban CA y preservacion de las capas musculares. Conclusion Los cambios vesicales en el modelo quirurgico de MMC en corderos pueden describirse mediante datos histopatologicos. Ambos extremos del espectro pueden darse en dicho modelo. Estos cambios pueden prevenirse por completo mediante cirugia fetal abierta y parcialmente a traves de otras formas de cobertura.

Objective To assess the presence of early bladder abnormalities in a prenatally corrected and uncorrected animal model of Myelomeningocele (MMC). Method A MMC-like lesion was surgically created in 18 fetal lambs between the 60th and the 80th day of gestation. Eight of them did not undergo fetal repair (group A), three were repaired with an open two-layer closure (group B), three using BioGlue ® (group C) and four fetoscopically (group D). At term, bladders were examined macroscopically and histopathological changes were assessed using H–E and Masson Trichrome. Results Five animals in group A (5/8, 62%), two in group B (2/3, 66%), one in group C (1/3, 33%) and one in group D (1/4, 25%) survived. Macroscopically bladders in group A were severely dilated and showed thinner walls. Microscopically they showed a thin layer of colagenous tissue (Blue layer. BL) lying immediately subjacent to the urothelium. The muscular layers were thinner. Non compliant pattern with thick wall and low capacity was also found in the non corrected model. Group B and the control showed preservation of muscular layers and absence of BL. Groups C and D presented BL but also preservation of muscular layers. Conclusion Bladder changes in a surgically induced model of MMC can be described using histopathological data. Both extremes of bladder changes can be observed in the model. These changes were completely prevented with open fetal surgery and partially with other coverage modalities.

The stratified motor cortex is variously thought to either lack or contain layer 4. Yamawaki et al. described a functional layer 4 in mouse motor cortex with properties and connections similar to layer 4 in sensory areas. Their results bolster a theoretical framework suggesting all primary cortical areas are equivalent.

Behavioral and functional studies in humans suggest that attention plays a key role in activating the primary olfactory cortex through an unknown circuit mechanism. We report that a novel pathway from the anterior cingulate cortex, an area which has a key role in attention, projects directly to the primary olfactory cortex in rhesus monkeys, innervating mostly the anterior olfactory nucleus. Axons from the anterior cingulate cortex formed synapses mostly with spines of putative excitatory pyramidal neurons and with a small proportion of a neurochemical class of inhibitory neurons that are thought to have disinhibitory effect on excitatory neurons. This novel pathway from the anterior cingulate is poised to exert a powerful excitatory effect on the anterior olfactory nucleus, which is a critical hub for odorant processing via extensive bilateral connections with primary olfactory cortices and the olfactory bulb. Acting on the anterior olfactory nucleus, the anterior cingulate may activate the entire primary olfactory cortex to mediate the process of rapid attention to olfactory stimuli.

Resumen El neuroblastoma de bulbo olfatorio es un tumor de celulas pequenas y origen neuroectodermico que aparece en el area superior de la cavidad nasal en la region de la lamina cribosa y puede mostrar un patron de agresividad y afectar a estructuras intracraneales. Presentamos el caso de un paciente de 25 anos de edad con una masa a nivel de fosas nasales que invade la orbita y muestra afectacion intracraneal extracerebral. Fue intervenido mediante un abordaje combinado por neurocirugia y cirugia maxilofacial, siendo el diagnostico de neuroblastoma. Al mes de realizarse esta cirugia radical se produjo una recidiva muy agresiva fundamentalmente a nivel intracerebral, que es nuevamente intervenida, mostrando en el estudio histopatologico areas de diferenciacion rabdomioblastica dentro del neuroblastoma. A pesar de lo infrecuente de la aparicion de areas rabdomioblasticas en el seno de un neuroblastoma, la existencia de este dato anatomopatologico confiere al neuroblastoma un grado de agresividad y capacidad de recidiva extremadamente elevado. La cirugia debe ser lo mas radical posible, lo cual no garantiza una supervivencia prolongada.

The anterior cingulate cortex (ACC) and posterior orbitofrontal cortex (pOFC) are associated with emotional regulation. These regions are old in phylogeny and have widespread connections with eulaminate neocortices, intricately linking areas associated with emotion and cognition. The ACC and pOFC have distinct cortical and subcortical connections and are also interlinked, but the pattern of their connections-which may be used to infer the flow of information between them-is not well understood. Here we found that pathways from ACC area 32 innervated all pOFC areas with a significant proportion of large and efficient terminals, seen at the level of the system and the synapse. The pathway from area 32 targeted overwhelmingly elements of excitatory neurons in pOFC, with few postsynaptic sites found on presumed inhibitory neurons. Moreover, pathways from area 32 originated mostly in the upper layers and innervated preferentially the middle-deep layers of the least differentiated pOFC areas, in a pattern reminiscent of feedforward communication. Pathway terminations from area 32 overlapped in the deep layers of pOFC with output pathways that project to the thalamus and the amygdala, and may have cascading downstream effects on emotional and cognitive processes and their disruption in psychiatric disorders.

[Purpose]: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance. [Methods]: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival. [Results]: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis. [Conclusion]: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target. © 2012 Elsevier Inc. All rights reserved., Funded by Fondo de Investigaciones SanitariasPI021094 and Fundación Mutua Madrileña. P. Cejas is supported by Asociación Española Contra el Cáncer programa PAO 2010, and V. M. García is supported by Fundación Para la Investigación Biomédica del Hospital La Paz grant REX 09.

Malignant peripheral nerve sheath tumor (MPNST) is an uncommon type of sarcoma that arises from peripheral nerve sheaths and rarely involves the spinal roots. The origin of this tumor is thought to be Schwann cells or pluripotent cells of the neural crest. The subgroup of tumors in which malignant Schwann cells coexist with malignant rhabdomyoblasts is termed malignant triton tumor (MTT). MPNSTs can show different degrees of malignancy, but overall spinal MTTs are high-grade lesions. We report the exceptional instance of a spinal low-grade MTT in a 39-year-old man treated with total surgical removal followed by local radiation therapy. Histological low grade was based on the lack of necrosis, a low grade of atypia, a low mitotic rate and a Ki-67 labelling index