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Background: Robotic surgery has found increasing use in multiple subfields of neurosurgery. While the initial applications of stereotactic robotic surgery were for the placement of electrodes for extra-operative seizure monitoring, this technique has become increasingly relevant in other areas of neurosurgery. To the best of our knowledge, we report the first case of successful robotic surgery utilization to drain a cerebral abscess and place an external ventricular drain., Case Report: The authors demonstrate a novel use for stereotactic robotic assistance to drain a cerebral abscess and place ventriculostomy in a 74-year-old female patient who presented with a left basal ganglia Streptococcus intermedius abscess and concomitant ventriculitis. Drainage of a deep-seated abscess and placement of ventriculostomy was successfully performed in this patient without intraoperative difficulties or complications. The total operative time, including registration was 64 minutes and the estimated blood loss was 25 mL. The patient recovered well and was discharged to inpatient rehabilitation on postoperative day 19., Conclusions: The use of robotic surgery to drain cerebral abscesses and place ventriculostomies is technically feasible and may potentially decrease operative time and increase accuracy and safety.

Decision-making is a cognitive process involving working memory, executive function, and attention. However, the connectivity of large-scale brain networks during decision-making is not well understood. This is because gaining access to large-scale brain networks in humans is still a novel process. Here, we used SEEG (stereoelectroencephalography) to record neural activity from the default mode network (DMN), dorsal attention network (DAN), and frontoparietal network (FN) in ten humans while they performed a gambling task in the form of the card game, "War". By observing these networks during a decision-making period, we related the activity of and connectivity between these networks. In particular, we found that gamma band activity was directly related to a participant's ability to bet logically, deciding what betting amount would result in the highest monetary gain or lowest monetary loss throughout a session of the game. We also found connectivity between the DAN and the relation to a participant's performance. Specifically, participants with higher connectivity between and within these networks had higher earnings. Our preliminary findings suggest that connectivity and activity between these networks are essential during decision-making.

The use of transmedia storytelling (TST) experiences is increasingly common in today's media ecology. Mediated by participatory culture, the role of the prosumer, and competency processes that connect with the reality of learners, the incorporation of storytelling motivates and deploys diverse didactic strategies. Considering the engagement generated by these strategies, and the need to promote literacies to provide competences to a plural society, a systematic review of the literature on transmedia storytelling experiences from the perspective of universal design for learning (UD-L) using PRISMA is carried out: a priori , we start from the idea that, if UD-L is based on the principles of educational neuroscience and TST, in turn, concretizes some of the guidelines of UD-L, TST can naturally result in a didactic approach that capitalizes on educational neuroscientific knowledge in a harmonious way with the digital context in which we live. The review analyzes a total of 50 articles from four databases: ERIC, Scopus, Web of Science, and Dialnet. The results show a low development of the checkpoints of the UD-L guides, and it is concluded that the most worked checkpoints are those closest to the definition of transmedia storytelling, followed by the foundational aspects of UD-L and, finally, aspects of access. Engagement is reflected in the experiences, but scaffolding is required to consolidate learning. In addition to this is the need to guarantee a true participatory culture, which requires the integration of more elements that incorporate accessibility into didactic strategies, offering learning possibilities for different styles and forms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Meyerhofer-Parra and González-Martínez.)

Phase-amplitude modulation (the modulation of the amplitude of higher frequency oscillations by the phase of lower frequency oscillations) is a specific type of cross-frequency coupling that has been observed in neural recordings from multiple species in a range of behavioral contexts. Given its potential importance, care must be taken with how it is measured and quantified. Previous studies have quantified phase-amplitude modulation by measuring the distance of the amplitude distribution from a uniform distribution. While this method is of general applicability, it is not targeted to the specific modulation pattern frequently observed with low-frequency oscillations. Here we develop a new method that has increased specificity to detect modulation in the sinusoidal shape commonly observed in neural data.

The AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here, we show that MASTL/Greatwall, a cell cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K-AKT activity by sustaining mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10. Genetic depletion of MASTL results in an inefficient feedback loop and AKT hyperactivity. These defects are rescued by the expression of phosphomimetic ENSA/ARPP19 or inhibition of PP2A/B55 phosphatases. MASTL is directly phosphorylated by mTORC1, thereby limiting the PP2A/B55-dependent dephosphorylation of IRS1 and GRB10 downstream of mTORC1. Downregulation of MASTL results in increased glucose uptake in vitro and increased glucose tolerance in adult mice, suggesting the relevance of the MASTL-PP2A/B55 kinase-phosphatase module in controlling AKT and maintaining metabolic homeostasis., (© 2022 The Authors.)

Maintenance of stemness is tightly linked to cell cycle regulation through protein phosphorylation by cyclin-dependent kinases (CDKs). However, how this process is reversed during differentiation is unknown. We report here that exit from stemness and differentiation of pluripotent cells along the neural lineage are controlled by CDC14, a CDK-counteracting phosphatase whose function in mammals remains obscure. Lack of the two CDC14 family members, CDC14A and CDC14B, results in deficient development of the neural system in the mouse and impairs neural differentiation from embryonic stem cells (ESCs). Mechanistically, CDC14 directly dephosphorylates specific proline-directed Ser/Thr residues of undifferentiated embryonic transcription Factor 1 (UTF1) during the exit from stemness, triggering its proteasome-dependent degradation. Multiomic single-cell analysis of transcription and chromatin accessibility in differentiating ESCs suggests that increased UTF1 levels in the absence of CDC14 prevent the proper firing of bivalent promoters required for differentiation. CDC14 phosphatases are dispensable for mitotic exit, suggesting that CDC14 phosphatases have evolved to control stemness rather than cell cycle exit and establish the CDK-CDC14 axis as a critical molecular switch for linking cell cycle regulation and self-renewal., (© 2022 The Authors.)

Precise localization of the "epileptogenic zone(EZ)" is the goal of presurgical investigations in patients with drug-resistant focal epilepsy. Intracranial electroencephalography recordings are required when noninvasive evaluation results are not consistent. Although subdural grid electrodes(SDG)have been widely used in Japan, stereoelectroencephalography(SEEG)has been recently introduced. The principle of SEEG is based on anatomo-electro-clinical correlations to investigate surgical hypotheses that are primarily driven by the analysis of seizure semiology as well as other noninvasive investigations. The most important element of the SEEG methodology is to formulate preimplantation electrode trajectories considering the anatomo-electro-clinical correlations of epileptic seizures. If the preimplantation hypotheses are insufficient or incorrect, SEEG recordings will not identify the EZ. A detailed analysis of seizure semiology with respect to anatomo-electro-clinical correlates, particularly including various deep structures, such as the insular, operculum, and cingulate cortex, forms the basis of the implantation strategy for SEEG. The strategy of implantation is not to map the lobes/lobules but the epileptic networks, which usually involve multiple lobes, indicating that the theory of SEEG is completely different from that of SDG. Herein, we introduce the basics of SEEG, especially presurgical evaluations, with a representative case presentation.

Alteration of centrosome function and dynamics results in major defects during chromosome segregation and is associated with primary autosomal microcephaly (MCPH). Despite the knowledge accumulated in the last few years, why some centrosomal defects specifically affect neural progenitors is not clear. We describe here that the centrosomal kinase PLK1 controls centrosome asymmetry and cell fate in neural progenitors during development. Gain- or loss-of-function mutations in Plk1, as well as deficiencies in the MCPH genes Cdk5rap2 (MCPH3) and Cep135 (MCPH8), lead to abnormal asymmetry in the centrosomes carrying the mother and daughter centriole in neural progenitors. However, whereas loss of MCPH proteins leads to increased centrosome asymmetry and microcephaly, deficient PLK1 activity results in reduced asymmetry and increased expansion of neural progenitors and cortical growth during mid-gestation. The combination of PLK1 and MCPH mutations results in increased microcephaly accompanied by more aggressive centrosomal and mitotic abnormalities. In addition to highlighting the delicate balance in the level and activity of centrosomal regulators, these data suggest that human PLK1, which maps to 16p12.1, may contribute to the neurodevelopmental defects associated with 16p11.2-p12.2 microdeletions and microduplications in children with developmental delay and dysmorphic features., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Chromosome segregation requires that centromeres properly attach to spindle microtubules. This essential step regulates the accuracy of cell division and must therefore be precisely regulated. One of the main centromeric regulatory signaling pathways is the haspin-H3T3ph-chromosomal passenger complex (CPC) cascade, which is responsible for the recruitment of the CPC to the centromeres. During mitosis, the haspin kinase phosphorylates histone H3 at threonine 3 (H3T3ph), an essential epigenetic mark that recruits the CPC, in which the catalytic component is Aurora B kinase (AURKB). However, the centromeric haspin-H3T3ph-CPC pathway remains largely uncharacterized in mammalian male meiosis. We have analyzed haspin functions by either its chemical inhibition with LDN-192960 in cultured spermatocytes, or the ablation of the Haspin gene in Haspin-/- mice. Our studies suggest that haspin kinase activity is required for proper chromosome congression both during meiotic divisions and for the recruitment of Aurora B and kinesin MCAK (also known as KIF2C) to meiotic centromeres. However, the absence of H3T3ph histone mark does not alter borealin (or CDCA8) and SGO2 centromeric localization. These results add new and relevant information regarding the regulation of the haspin-H3T3ph-CPC pathway and centromere function during meiosis., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

The integration of new media literacies and, consequently, strategies such as transmedia learning in the teaching-learning processes has been a topic of interest among various types of national and international institutions and governments. In this sense, the current article deals with the abilities, thoughts and expectations that Italian students in classical high schools have in order to face these new formative changes. For this purpose, a mixed methods approach (qualitative and quantitative) was designed and applied in the context of a classical high school in Cagliari (Italy): a questionnaire on digital skills (N = 128), a set of semi-structured interviews (N = 17) and two focus groups (N = 14). The results obtained allow us to verify that, from the point of view of skills, adolescents are prepared to take on the challenges of transmedia learning (navigation, information management), although their collaboration skills need to be strengthened. On the other hand, from the cognitive and affective points of view, they are positive and enthusiastic about these new possibilities: greater interaction, flexibility, engagement and variety of resources and learning strategies.

Introduction: To determine whether clinicopathological characteristics can improve the prediction of metastasis to nonsentinel lymph nodes (NSLNs) over the use of only mRNA copy number in sentinel lymph node (SLN) biopsies., Methods: This was a retrospective, observational study that included a total of 824 patients with T1-3 breast cancer who had clinically negative, ultrasound-negative axilla without evidence of metastasis and who underwent one-step nucleic acid amplification in SLN biopsies., Results: 118 required a complete axillary lymph node dissection (ALNhD). About 35.6% (42/118) had metastases to a NSLN, and 64.4% (76/118) had no metastasis to a NSLN. The ROC curve of the total tumor load (TTL) presented an area under the curve (AUC) of 0.651 (95%; CI: 0.552-0.751). The 7294 copies of CK19 mRNA were established as the optimal cutoff point, with sensitivity: 93%, specificity: 63%, positive predictive value: 44%, and negative predictive value: 91%. By associating the clinicopathological parameters (multicentricity, pooled immunohistochemistry [IHC], and progesterone receptors), the AUC went up to 0.752 (95% CI: 0.663-0.841)., Conclusions: Clinicopathological factors should be considered together with the total CK19 mRNA copy number (the TTL) of the SLNs to improve the predictive capacity of metastatic involvement of the NSLNs., (Copyright: © 2022 Permanyer.)

Pluripotent stem cells (PSCs) have proven to be an essential tool in many research fields including basic cell biology, development, or human disease. In addition, we are only starting to see their potential in regenerative medicine. Manipulation and culture of PSCs, however, imposes limitations in the quality of these cells and their ability to differentiate into functional cells with physiological function. Here we propose a novel and simple technique based on the transient expression of a single microRNA molecule to expand the differentiation potency of a wide range of PSCs including induced PSCs (iPSCs) as well as embryonic stem cells (ESCs). This method requires no genetic modification of PSCs and achieves stable improvement of the differentiation potential of these cells through several cell passages both in vitro and in vivo., (© 2021. Springer Science+Business Media, LLC.)

Robotics applied to cranial surgery is a fast-moving and fascinating field, which is transforming the practice of neurosurgery. With exponential increases in computing power, improvements in connectivity, artificial intelligence, and enhanced precision of accessing target structures, robots are likely to be incorporated into more areas of neurosurgery in the future-making procedures safer and more efficient. Overall, improved efficiency can offset upfront costs and potentially prove cost-effective. In this narrative review, we aim to translate a broad clinical experience into practical information for the incorporation of robotics into neurosurgical practice. We begin with procedures where robotics take the role of a stereotactic frame and guide instruments along a linear trajectory. Next, we discuss robotics in endoscopic surgery, where the robot functions similar to a surgical assistant by holding the endoscope and providing retraction, supplemental lighting, and correlation of the surgical field with navigation. Then, we look at early experience with endovascular robots, where robots carry out tasks of the primary surgeon while the surgeon directs these movements remotely. We briefly discuss a novel microsurgical robot that can perform many of the critical operative steps (with potential for fine motor augmentation) remotely. Finally, we highlight 2 innovative technologies that allow instruments to take nonlinear, predetermined paths to an intracranial destination and allow magnetic control of instruments for real-time adjustment of trajectories. We believe that robots will play an increasingly important role in the future of neurosurgery and aim to cover some of the aspects that this field holds for neurosurgical innovation., (© Congress of Neurological Surgeons 2021.)

Congenital microcephaly (MCPH) is a neurodevelopmental disease associated with mutations in genes encoding proteins involved in centrosomal and chromosomal dynamics during mitosis. Detailed MCPH pathogenesis at the cellular level is still elusive, given the diversity of MCPH genes and lack of comparative in vivo studies. By generating a series of CRISPR/Cas9-mediated genetic KOs, we report here that - whereas defects in spindle pole proteins (ASPM, MCPH5) result in mild MCPH during development - lack of centrosome (CDK5RAP2, MCPH3) or centriole (CEP135, MCPH8) regulators induces delayed chromosome segregation and chromosomal instability in neural progenitors (NPs). Our mouse model of MCPH8 suggests that loss of CEP135 results in centriole duplication defects, TP53 activation, and cell death of NPs. Trp53 ablation in a Cep135-deficient background prevents cell death but not MCPH, and it leads to subcortical heterotopias, a malformation seen in MCPH8 patients. These results suggest that MCPH in some MCPH patients can arise from the lack of adaptation to centriole defects in NPs and may lead to architectural defects if chromosomally unstable cells are not eliminated during brain development.

Introduction: To describe the outbreak of Clostridioides difficile infection (CDI), and the impact of the prevention and control measures that were implemented in the "Hospital Juárez de México" (HJM) for its control., Methods: A cross-sectional, descriptive, observational, and retrospective study was designed. All information on the hospital outbreak and on health care-associated infections (HCAI) was obtained from the files of the Hospital Epidemiological Surveillance Unit (HESU) of the HJM., Results: A total of 15 cases of CDI were detected from February 20 th to May 22 nd , 2018, which represented 55.6% and 44.4% for the male and female gender, respectively, with an average age of 56 years and a range of 24 to 86 years old. It was possible to identify six failures and deficiencies that involved health personnel and hospital logistics through analyses based on the situational diagnosis in the services involved and through the construction of cause-effect diagrams. Additionally, through the detection of the outbreak by means of laboratory tests and timeline, the HESU team implemented measures and prospective surveillance to control and prevent the emergence of new cases., Conclusions: The implementation of basic quality tools, control measures, and the prospective epidemiological surveillance had a positive impact on the control against the outbreak of C. difficile producing toxin B., Competing Interests: Conflict of interest statement None, (©2021 Pacini Editore SRL, Pisa, Italy.)

Bacterial small RNAs (sRNAs) play a vital role in pathogenesis by enabling rapid, efficient networks of gene attenuation during infection. In recent decades, there has been a surge in the number of proposed and biochemically-confirmed sRNAs in both Gram-positive and Gram-negative pathogens. However, limited homology, network complexity, and condition specificity of sRNA has stunted complete characterization of the activity and regulation of these RNA regulators. To streamline the discovery of the expression of sRNAs, and their post-transcriptional activities, we propose an integrative in vivo data-mining approach that couples DNA protein occupancy, RNA-seq, and RNA accessibility data with motif identification and target prediction algorithms. We benchmark the approach against a subset of well-characterized E. coli sRNAs for which a degree of in vivo transcriptional regulation and post-transcriptional activity has been previously reported, finding support for known regulation in a large proportion of this sRNA set. We showcase the abilities of our method to expand understanding of sRNA RseX, a known envelope stress-linked sRNA for which a cellular role has been elusive due to a lack of native expression detection. Using the presented approach, we identify a small set of putative RseX regulators and targets for experimental investigation. These findings have allowed us to confirm native RseX expression under conditions that eliminate H-NS repression as well as uncover a post-transcriptional role of RseX in fimbrial regulation. Beyond RseX, we uncover 163 putative regulatory DNA-binding protein sites, corresponding to regulation of 62 sRNAs, that could lead to new understanding of sRNA transcription regulation. For 32 sRNAs, we also propose a subset of top targets filtered by engagement of regions that exhibit binding site accessibility behavior in vivo . We broadly anticipate that the proposed approach will be useful for sRNA-reliant network characterization in bacteria. Such investigations under pathogenesis-relevant environmental conditions will enable us to deduce complex rapid-regulation schemes that support infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mihailovic, Ekdahl, Chen, Leistra, Li, González Martínez, Law, Ejindu, Massé, Freddolino and Contreras.)

Cell division requires the regulation of karyokinesis and cytokinesis, which includes an essential role of the achromatic spindle. Although the functions of centrosomes are well characterised in somatic cells, their role during vertebrate spermatogenesis remains elusive. We have studied the dynamics of the meiotic centrosomes in male mouse during both meiotic divisions. Results show that meiotic centrosomes duplicate twice: first duplication occurs in the leptotene/zygotene transition, while the second occurs in interkinesis. The maturation of duplicated centrosomes during the early stages of prophase I and II are followed by their separation and migration to opposite poles to form bipolar spindles I and II. The study of the genetic mouse model Plk1(Δ/Δ) indicates a central role of Polo-like kinase 1 in pericentriolar matrix assembly, in centrosome maturation and migration, and in the formation of the bipolar spindles during spermatogenesis. In addition, in vitro inhibition of Polo-like kinase 1 and Aurora A in organotypic cultures of seminiferous tubules points out to a prominent role of both kinases in the regulation of the formation of meiotic bipolar spindles., (© 2021 The Authors.)

For epileptic patients requiring resective surgery, a modality called stereo-electroencephalography (SEEG) may be used to monitor the patient's brain signals to help identify epileptogenic regions that generate and propagate seizures. SEEG involves the insertion of multiple depth electrodes into the patient's brain, each with 10 or more recording contacts along its length. However, a significant fraction (≈ 30% or more) of the contacts typically reside in white matter or other areas of the brain which can not be epileptogenic themselves. Thus, an important step in the analysis of SEEG recordings is distinguishing between electrode contacts which reside in gray matter vs. those that do not. MRI images overlaid with CT scans are currently used for this task, but they take significant amounts of time to manually annotate, and even then it may be difficult to determine the status of some contacts. In this paper we present a fast, automated method for classifying contacts in gray vs. white matter based only on the recorded signal and relative contact depth. We observe that bipolar referenced contacts in white matter have less power in all frequencies below 150 Hz than contacts in gray matter, which we use in a Bayesian classifier to attain an average area under the receiver operating characteristic curve of 0.85 ± 0.079 (SD) across 29 patients. Because our method gives a probability for each contact rather than a hard labeling, and uses a feature of the recorded signal that has direct clinical relevance, it can be useful to supplement decision-making on difficult to classify contacts or as a rapid, first-pass filter when choosing subsets of contacts from which to save recordings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Greene, Li, González-Martínez and Sarma.)

Background: Preoperative planning of microsurgical perforator free flaps continues to be a discussion topic among microsurgeons. The purpose of this study was to compare the ability of three methods of preoperative vascular mapping-hand-held Doppler imaging, color Doppler ultrasonography, and computed tomographic angiography-to detect perforators and their concordance with surgical findings., Methods: A prospective study was performed to evaluate the sensitivity, specificity, and accuracy of hand-held Doppler imaging, color Doppler ultrasonography, and computed tomographic angiography to detect free flap perforators. Each patient undergoing a free flap reconstruction was studied preoperatively with the three methods, and the results were compared to the intraoperative findings., Results: Fifty-three patients undergoing autologous tissue reconstruction were included. Most reconstructions (71.7 percent) were performed with anterolateral thigh flaps. The positive predictive value (color Doppler ultrasonography, 100 percent; computed tomographic angiography, 100 percent; hand-held Doppler imaging, 88.6 percent) and negative predictive value (color Doppler ultrasonography, 100 percent; computed tomographic angiography, 94.3 percent; hand-held Doppler imaging, 90.5 percent) rates were significantly different between methods. The high resolution of the color Doppler ultrasonography probe provided a direct vision of the vasculature arborization and efficiently detected vessels with diameters of less than 0.5 mm. The sensitivity, specificity, and accuracy of color Doppler ultrasonography were greater than those of both computed tomographic angiography and hand-held Doppler imaging. There was 100 percent concordance between color Doppler ultrasonography perforators and the surgical findings., Conclusions: Color Doppler ultrasonography provides a reproducible, harmless, and accurate way to visualize vascular anatomy. It has a high correlation with the surgical findings, signifying advantages over hand-held Doppler and computed tomographic angiography in sensitivity, specificity, and accuracy., Clinical Question/level of Evidence: Diagnostic, II.

Introduction: In patients receiving anticoagulation for deep vein thrombosis (DVT), a variety of reasons (including active bleeding or high-risk for bleeding) may lead into premature discontinuation of therapy (prior to completing 90 days). The relative frequency and clinical consequences of premature discontinuation in contemporary patients remain unknown., Methods: We used the data from RIETE, an international registry of patients with venous thromboembolism (VTE), to identify patients with proximal (above knee) lower limb DVT who prematurely discontinued anticoagulation. We assessed the incidence of the composite outcome: pulmonary embolism (PE)-related death, sudden death, or recurrent VTE within the subsequent 30 days after discontinuation and compared the risk of these events vs. the risk in patients without premature discontinuation, once adjusted for demographics and clinical factors., Results: Of 26,335 patients with proximal DVT recruited from 2001 to 2018, 1322 (5.02%) prematurely discontinued anticoagulation. Thirty days after discontinuation, 12 (0.91%) patients suffered fatal PE (n = 8) or sudden death (n = 4) and 33 (2.50%) had non-fatal recurrent VTE (PE = 15; recurrent DVT = 18). In patients with premature discontinuation, the 30-day incidence of the composite outcome was 1.62 per 1000 patient-days (95%CI: 0.00-3.80). During the first week after discontinuation, the incidence rate was 4.09 per 1000 patient-days (95%CI: 0.65-7.52). The adjusted odds of the composite outcome was 7.88 times (95%CI: 6.39-9.72) higher in patients who discontinued prematurely than in those without premature discontinuation., Conclusion: Premature discontinuation of anticoagulation occurred in 5% of patients with proximal DVT, and was associated an 8-fold increased odds for the composite outcome., Competing Interests: Declaration of competing interest Authors do not have any conflict of interest regarding this study. The sponsors of RIETE had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Dr. Bikdeli was supported by the National Heart, Lung, and Boos Institute, National Institutes of Health (NIH), through grant number T32 HL007854. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Dr. Bikdeli reports that he has been a consulting expert (on behalf of the plaintiff) for litigation related to a specific type of IVC filters. The current study is the idea of the investigators and has not been performed at the request of a third party., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM) is one of the most aggressive forms of cancer. It has been proposed that the presence within these tumors of a population of cells with stem-like features termed Glioma Initiating Cells (GICs) is responsible for the relapses that take place in the patients with this disease. Targeting this cell population is therefore an issue of great therapeutic interest in neuro-oncology. We had previously found that the neurotrophic factor MIDKINE (MDK) promotes resistance to glioma cell death. The main objective of this work is therefore investigating the role of MDK in the regulation of GICs. Methods : Assays of gene and protein expression, self-renewal capacity, autophagy and apoptosis in cultures of GICs derived from GBM samples subjected to different treatments. Analysis of the growth of GICs-derived xenografts generated in mice upon blockade of the MDK and its receptor the ALK receptor tyrosine kinase (ALK) upon exposure to different treatments. Results : Genetic or pharmacological inhibition of MDK or ALK decreases the self-renewal and tumorigenic capacity of GICs via the autophagic degradation of the transcription factor SOX9. Blockade of the MDK/ALK axis in combination with temozolomide depletes the population of GICs in vitro and has a potent anticancer activity in xenografts derived from GICs. Conclusions : The MDK/ALK axis regulates the self-renewal capacity of GICs by controlling the autophagic degradation of the transcription factor SOX9. Inhibition of the MDK/ALK axis may be a therapeutic strategy to target GICs in GBM patients., Competing Interests: Competing Interests: Research in G Velasco's group was partially funded by LYRAMID. J Sepúlveda received a grant from Pfizer that provided pure substance for the study., (© The author(s).)

Aurora A is a serine/threonine kinase whose role in cell cycle progression and tumour generation has been widely studied. Recent work has revealed an unexpected function for Aurora A during CD4 + T cell activation and, also, in graft versus host disease development. However, it remains unknown whether Aurora A is involved in CD8 + T cell effector function and in cytotoxic T lymphocyte-mediated antiviral response. Here, we show that Aurora A chemical inhibition leads to an impairment of both the peptide-specific cytotoxicity and the degranulation activity of CD8 + T cells. This finding was similarly proven for both mice and human CD8 + CTL activity. As a result of Aurora A blockade, we detected a reduction in the expression induced by T cell activation of genes classically related to the effector function of cytotoxic T lymphocytes such as granzyme B or perforin1. Finally, we have found that Aurora A is necessary for CD8 + T cell-mediated antiviral response, in an in vivo model of vaccinia virus infection. Thus, we can conclude that Aurora A activity is, indeed, needed for the proper effector function of cytotoxic T lymphocytes and for their activity against viral threats.

Language is mediated by pathways connecting distant brain regions that have diverse functional roles. For word production, the network includes a ventral pathway, connecting temporal and inferior frontal regions, and a dorsal pathway, connecting parietal and frontal regions. Despite the importance of word production for scientific and clinical purposes, the functional connectivity underlying this task has received relatively limited attention, and mostly from techniques limited in either spatial or temporal resolution. Here, we exploited data obtained from depth intra-cerebral electrodes stereotactically implanted in eight epileptic patients. The signal was recorded directly from various structures of the neocortex with high spatial and temporal resolution. The neurophysiological activity elicited by a picture naming task was analyzed in the time-frequency domain (10-150 Hz), and functional connectivity between brain areas among ten regions of interest was examined. Task related-activities detected within a network of the regions of interest were consistent with findings in the literature, showing task-evoked desynchronization in the beta band and synchronization in the gamma band. Surprisingly, long-range functional connectivity was not particularly stronger in the beta than in the high-gamma band. The latter revealed meaningful sub-networks involving, notably, the temporal pole and the inferior frontal gyrus (ventral pathway), and parietal regions and inferior frontal gyrus (dorsal pathway). These findings are consistent with the hypothesized network, but were not detected in every patient. Further research will have to explore their robustness with larger samples.

High-resolution whole brain recordings have the potential to uncover unknown functionality but also present the challenge of how to find such associations between brain and behavior when presented with a large number of regions and spectral frequencies. In this paper, we propose an exploratory data analysis method that sorts through a massive quantity of multivariate neural recordings to quickly extract a subset of brain regions and frequencies that encode behavior. This approach combines existing tools and exploits low-rank approximation of matrices without a priori selection of regions and frequency bands for analysis. In detail, the spectral content of neural activity across all frequencies of each recording contact is computed and represented as a matrix. Then, the rank-1 approximation of the matrix is computed using singular value decomposition and the associated singular vectors are extracted. The temporal singular vector, which captures the salient features of the spectrogram, is then correlated to the trial-varying behavioral signal. The distribution of correlations for each brain region is efficiently computed and used to find a subset of regions and frequency bands of interest for further examination. As an illustration, we apply this approach to a data set of local field potentials collected using stereoelectroencephalography from a human subject performing a reaching task. Using the proposed procedure, we produced a comprehensive set of brain regions and frequencies related to our specific behavior. We demonstrate how this tool can produce preliminary results that capture neural patterns related to behavior and aid in formulating data-driven hypotheses, hence reducing the time it takes for any scientist to transition from the exploratory to the confirmatory phase.

In patients with venous thromboembolism (VTE), male sex has been associated with an increased risk of occult cancer. The influence of sex on clinical characteristics, treatment, cancer sites, and outcome has not been thoroughly investigated yet. We used the Registro Informatizado Enfermedad TromboEmbólica registry to compare the clinical characteristics, treatment strategies, cancer sites, and clinical outcomes in patients with VTE having occult cancer, according to sex. As of June 2014, 5864 patients were recruited, of whom 444 (7.6%; 95% confidence interval: 6.8-8.2) had occult cancer. Of these, 246 (55%) were men. Median time elapsed from VTE to occult cancer was 4 months (interquartile range: 2-8.4), with no sex differences. Women were older, weighed less, and were less likely to have chronic lung disease than men. The most common cancer sites were the lung (n = 63), prostate (n = 42), and colorectal (n = 29) in men and colorectal (n = 38), breast (n = 23), uterine (n = 18), hematologic (n = 17), or pancreas (n = 15) in women. Men were more likely to have lung cancer than women (2.18% vs 0.30%; P < .01) and less likely to have pancreatic cancer (0.17% vs 0.5%; P = .03). Interestingly, breast cancer was more likely found in women aged ≥50 years than in those aged <50 years (0.97% vs 0.14%; P = .03). This study highlights the existence of sex differences in patients with VTE having occult cancer. One in every 2 men had lung, prostate, or colorectal cancer. In women, there is a heterogeneity of cancer sites, increasing risk of breast cancer in those aged >50 years.

We assessed the real-life use of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and exclusion criteria for randomized trials. From 2013 to 2016, 3,578 of 18,853 patients (19%) had exclusion criteria. Irrespective of which anticoagulant was chosen, they had more VTE recurrences (hazard ratio (HR): 3.10; 95% confidence interval (CI): 2.47-3.88), major bleeds (HR: 4.10; 95% CI: 3.38-4.96), and deaths (HR: 9.47; 95% CI: 8.46-10.6) than those without exclusion criteria. During initial therapy, no patient with exclusion criteria on DOACs (n = 115) recurred, but those on rivaroxaban bled less often (adjusted HR: 0.18; 95% CI: 0.04-0.79) than those on unfractionated heparin (n = 224) and similar to those (n = 3,172) on low-molecular-weight (LMWH) heparin. For long-term therapy, patients on rivaroxaban (n = 151) had nonsignificantly fewer VTE recurrences (adjusted HR: 0.74; 95% CI: 0.08-1.32) and major bleeds (adjusted HR: 0.41; 95% CI: 0.15-1.15) than those on LMWH (n = 2,071). The efficacy and safety of DOACs were similar to standard therapy., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Although motor control has been extensively studied, most research involving neural recordings has focused on primary motor cortex, pre-motor cortex, supplementary motor area, and cerebellum. These regions are involved during normal movements, however, associative cortices and hippocampus are also likely involved during perturbed movements as one must detect the unexpected disturbance, inhibit the previous motor plan, and create a new plan to compensate. Minimal data is available on these brain regions during such "robust" movements. Here, epileptic patients implanted with intracerebral electrodes performed reaching movements while experiencing occasional unexpected force perturbations allowing study of the fronto-parietal, limbic and hippocampal network at unprecedented high spatial, and temporal scales. Areas including orbitofrontal cortex (OFC) and hippocampus showed increased activation during perturbed trials. These results, coupled with a visual novelty control task, suggest the hippocampal MTL-P300 novelty response is modality independent, and that the OFC is involved in modifying motor plans during robust movement.

Autophagy is considered primarily a cell survival process, although it can also lead to cell death. However, the factors that dictate the shift between these 2 opposite outcomes remain largely unknown. In this work, we used Δ 9 -tetrahydrocannabinol (THC, the main active component of marijuana, a compound that triggers autophagy-mediated cancer cell death) and nutrient deprivation (an autophagic stimulus that triggers cytoprotective autophagy) to investigate the precise molecular mechanisms responsible for the activation of cytotoxic autophagy in cancer cells. By using a wide array of experimental approaches we show that THC (but not nutrient deprivation) increases the dihydroceramide:ceramide ratio in the endoplasmic reticulum of glioma cells, and this alteration is directed to autophagosomes and autolysosomes to promote lysosomal membrane permeabilization, cathepsin release and the subsequent activation of apoptotic cell death. These findings pave the way to clarify the regulatory mechanisms that determine the selective activation of autophagy-mediated cancer cell death.

Background: Robot-assisted stereoelectroencephalography (SEEG) may represent a simplified, precise, and safe alternative to the more traditional SEEG techniques., Objective: To report our clinical experience with robotic SEEG implantation and to define its utility in the management of patients with medically refractory epilepsy., Methods: The prospective observational analyses included all patients with medically refractory focal epilepsy who underwent robot-assisted stereotactic placement of depth electrodes for extraoperative brain monitoring between November 2009 and May 2013. Technical nuances of the robotic implantation technique are presented, as well as an analysis of demographics, time of planning and procedure, seizure outcome, in vivo accuracy, and procedure-related complications., Results: One hundred patients underwent 101 robot-assisted SEEG procedures. Their mean age was 33.2 years. In total, 1245 depth electrodes were implanted. On average, 12.5 electrodes were implanted per patient. The time of implantation planning was 30 minutes on average (range, 15-60 minutes). The average operative time was 130 minutes (range, 45-160 minutes). In vivo accuracy (calculated in 500 trajectories) demonstrated a median entry point error of 1.2 mm (interquartile range, 0.78-1.83 mm) and a median target point error of 1.7 mm (interquartile range, 1.20-2.30 mm). Of the group of patients who underwent resective surgery (68 patients), 45 (66.2%) gained seizure freedom status. Mean follow-up was 18 months. The total complication rate was 4%., Conclusion: The robotic SEEG technique and method were demonstrated to be safe, accurate, and efficient in anatomically defining the epileptogenic zone and subsequently promoting sustained seizure freedom status in patients with difficult-to-localize seizures.

The circadian clock disorders in humans remain poorly understood. However, their impact on the development and progression of major human conditions, from cancer to insomnia, metabolic or mental illness becomes increasingly apparent. Addressing human circadian disorders in animal models is, in part, complicated by inverse temporal relationship between the core clock and specific physiological or behavioral processes in diurnal and nocturnal animals. Major advantages of a macaque model for translational circadian research, as a diurnal vertebrate phylogenetically close to humans, are further emphasized by the discovery of the first familial circadian disorder in non-human primates among the rhesus monkeys originating from Cayo Santiago. The remarkable similarity of their pathological phenotypes to human Delayed Sleep Phase Disorder (DSPD), high penetrance of the disorder within one branch of the colony and the large number of animals available provide outstanding opportunities for studying the mechanisms of circadian disorders, their impact on other pathological conditions, and for the development of novel and effective treatment strategies., (© 2016 The Authors. American Journal of Primatology published by Wiley Periodicals, Inc.)

Object: Stereoelectroencephalography (SEEG) is a methodology that permits accurate 3D in vivo electroclinical recordings of epileptiform activity. Among other general indications for invasive intracranial electroencephalography (EEG) monitoring, its advantages include access to deep cortical structures, its ability to localize the epileptogenic zone when subdural grids have failed to do so, and its utility in the context of possible multifocal seizure onsets with the need for bihemispheric explorations. In this context, the authors present a brief historical overview of the technique and report on their experience with 2 SEEG techniques (conventional Leksell frame-based stereotaxy and frameless stereotaxy under robotic guidance) for the purpose of invasively monitoring difficult-to-localize refractory focal epilepsy., Methods: Over a period of 4 years, the authors prospectively identified 200 patients with refractory epilepsy who collectively underwent 2663 tailored SEEG electrode implantations for invasive intracranial EEG monitoring and extraoperative mapping. The first 122 patients underwent conventional Leksell frame-based SEEG electrode placement; the remaining 78 patients underwent frameless stereotaxy under robotic guidance, following acquisition of a stereotactic ROSA robotic device at the authors' institution. Electrodes were placed according to a preimplantation hypothesis of the presumed epileptogenic zone, based on a standardized preoperative workup including video-EEG monitoring, MRI, PET, ictal SPECT, and neuropsychological assessment. Demographic features, seizure semiology, number and location of implanted SEEG electrodes, and location of the epileptogenic zone were recorded and analyzed for all patients. For patients undergoing subsequent craniotomy for resection, the type of resection and procedure-related complications were prospectively recorded. These results were analyzed and correlated with pathological diagnosis and postoperative seizure outcomes., Results: The epileptogenic zone was confirmed by SEEG in 154 patients (77%), of which 134 (87%) underwent subsequent craniotomy for epileptogenic zone resection. Within this cohort, 90 patients had a minimum follow-up of at least 12 months; therein, 61 patients (67.8%) remained seizure free, with an average follow-up period of 2.4 years. The most common pathological diagnosis was focal cortical dysplasia Type I (55 patients, 61.1%). Per electrode, the surgical complications included wound infection (0.08%), hemorrhagic complications (0.08%), and a transient neurological deficit (0.04%) in a total of 5 patients (2.5%). One patient (0.5%) ultimately died due to intracerebral hematoma directly ensuing from SEEG electrode placement., Conclusions: Based on these results, SEEG methodology is safe, reliable, and effective. It is associated with minimal morbidity and mortality, and serves as a practical, minimally invasive approach to extraoperative localization of the epileptogenic zone in patients with refractory epilepsy.

Objectives: To evaluate the agreement between magnetoencephalography (MEG) and intracranial electroencephalography (ICEEG) results, to determine the characteristics that lead to concordance, and to assess how these factors relate to favorable epilepsy surgery outcome., Materials: This retrospective study reviewed 50 patients who had positive MEG findings and ICEEG recordings between 2008 and 2010. The anatomical concordance between MEG and ICEEG recordings, the features of the MEG focus, and the relationship between the MEG focus and the surgically resected regions were correlated with the epilepsy surgery outcome., Results: Thirty-six of the 50 patients with positive MEG and ICEEG findings underwent epilepsy surgery, and 27 (75%) of the patients had an anatomical concordance of MEG/ICEEG. Among the patients with concordant MEG/ICEEG, the seizure free outcome rate was significantly higher compared to the discordant group [18/27 (66.7%) patients concordant vs. 1/9 (11.1%) patients discordant (p<0.006)]. Nineteen (53%) of the 36 patients had complete resection when the MEG focus overlapped with the resection area, and 15 (79%) of these 19 patients became seizure-free following surgery (p<0.001); 17 (47%) of the 36 patients had an MEG focus that was not completely resected (the MEG foci of 7 patients partially overlapped the resection areas, and 10 patients had MEG foci that were in a different area from the resection area), and 13/17 (76.5%) patients had seizure recurrences (p<0.001)., Conclusions: Both the anatomical concordance of MEG/ICEEG and the complete resection of the MEG foci significantly increased the chance of seizure-free outcomes following epilepsy surgery., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Surgery for frontal lobe epilepsy often has poor results, likely because of incomplete resection of the epileptogenic zone., Objective: To present our experience with a series of patients manifesting 2 different anatomo-electro-clinical patterns of refractory orbitofrontal epilepsy, necessitating different surgical approaches for resection in each group., Methods: Eleven patients with refractory epilepsy involving the orbitofrontal region were consecutively identified over 3 years in whom stereoelectroencephalography identified the epileptogenic zone. All patients underwent preoperative evaluation, stereoelectroencephalography, and postoperative magnetic resonance imaging. Demographic features, seizure semiology, imaging characteristics, location of the epileptogenic zone, surgical resection site, and pathological diagnosis were analyzed. Surgical outcome was correlated with type of resection., Results: Five patients exhibited orbitofrontal plus frontal epilepsy with the epileptogenic zone consistently residing in the frontal lobe; after surgery, 4 patients were free of disabling seizures (Engel I) and 1 patient improved (Engel II). The remaining 6 patients had multilobar epilepsy with the epileptogenic zone located in the orbitofrontal cortex associated with the temporal polar region (orbitofrontal plus temporal polar epilepsy). After surgery, all 6 patients were free of disabling seizures (Engel I). Pathology confirmed focal cortical dysplasia in all patients. We report no complications or mortalities in this series., Conclusion: Our findings highlight the importance of differentiating between orbitofrontal plus frontal and orbitofrontal plus temporal polar epilepsy in patients afflicted with seizures involving the orbitofrontal cortex. For identified cases of orbitofrontal plus temporal polar epilepsy, a multilobar resection including the temporal pole may lead to improved postoperative outcomes with minimal morbidity or mortality.

Introduction: Support systems in clinical decision-making use individual characteristics of the patient to generate recommendations to the clinician., Objective: To assess the impact of a tool for adjusting drug dosing in renal failure asa support system in clinical decision-making regarding the level of acceptance of the interventions as well as the time invested by the pharmacist., Method: Non-randomized, prospective and hospital interventional study comparing pre- and post-implementation phases of an automated renal function alert system, carried out at two county hospitals. Forty drugs were monitored before the intervention(2007). The blood work of the patients receiving any of these drugs was reviewed. In case of impaired renal function, an adjustment recommendation was inserted in the medical prescription. If the physician accepted it, it was rated as success. The average time was 1 minute per blood work reviewed and 3 minutes per recommendation. An automated adjustment recommendation system according to renal function with alert pop-ups was implemented in 2008 for 100 drugs. Later (2009), the number of interventions and the success rate for this tool were assessed and compared., Results: Pre-implementation phase. 28,234 electronic medical prescriptions corresponding to a mean number of 205 hospitalized patients/day were validated and 4,035 blood works were reviewed. One hundred and twenty-one pharmaceutical interventions(0.43% of the medical prescriptions) were inserted. A success rate of 33.06% of the interventions was obtained. The time invested by the pharmacist for consulting the bloodworks and making the recommendations was 73.3 hours (67.25 hours corresponding to patients without renal function impairment and in whom no intervention was made).Post-implementation phase. 26,584 electronic medical orders corresponding to 193 hospitalized patients/day were validated and 1,737 automated interventions were performed(6.53% of total medical orders), of which 65.69% were accepted (success)., Conclusions: The implementation of clinical decision-making support systems allows extending the number of patients and drugs monitored, optimizing the time invested by the pharmacist. Simultaneous occurrence of an alert during prescription may have contributed to the greater success rate observed., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Density-dependence is hypothesized as the major mechanism of population regulation. However, the lack of long-term demographic data has hampered the use of density-dependent models in nonhuman primates. In this study, we make use of the long-term demographic data from Cayo Santiago's rhesus macaques to parameterize and analyze both a density-independent and a density-dependent population matrix model, and compare their projections with the observed population changes. We also employ a retrospective analysis to determine how variance in vital rates, and covariance among them, contributed to the observed variation in long-term fitness across different levels of population density. The population exhibited negative density-dependence in fertility and the model incorporating this relationship accounted for 98% of the observed population dynamics. Variation in survival and fertility of sexually active individuals contributed the most to the variation in long-term fitness, while vital rates displaying high temporal variability exhibited lower sensitivities. Our findings are novel in describing density-dependent dynamics in a provisioned primate population, and in suggesting that selection is acting to lower the variance in the population growth rate by minimizing the variation in adult survival at high density. Because density-dependent mechanisms may become stronger in wild primate populations due to increasing habitat loss and food scarcity, our study demonstrates that it is important to incorporate variation in population size, as well as demographic variability into population viability analyses for a better understanding of the mechanisms regulating the growth of primate populations., (© 2013 Wiley Periodicals, Inc.)

Background and Objective: To describe the uveitis pattern in our geographic area. Recent demographic, environmental and scientific changes can determine uveitis pattern changes, which we aim to investigate., Patients and Methods: A cross-sectional study between 1(st) January 2009 and 30(th) June 2010 was done. All uveitis patients visited at our institution were included. Anatomical (IUSG & SUN) and aetiological patterns (by "tailored" tests), age, sex, origin and laterality were analyzed. Results from first visits and controls were compared statistically, by chi-square and ANOVA tests., Results: From 416 patients included, 150 (36%) were anterior uveitis, 128 (31%) posterior, 101 (24%) panuveitis and 37 (9%) intermediate uveitis (IU). Fifty-six percent (236) were bilateral, mean age was 46 years (6-87) and 58% were women. Fourteen percent (58) were from non-Spanish origin. By aetiology, 20% were unclassifiable, 31% infectious, 26% associated with systemic immune diseases and 23% were ocular specific syndromes. Among classified causes, herpes virus (11%), Toxoplasma (8%), Behçet (8%) and tuberculosis (6%) were the most common. IU were diagnosed more frequently at first time in foreign patients (P=.018); they affected younger patients (P=.008), were more chronic (P=.003) and unclassifiable (P=.024)., Conclusion: In our area, 80% of uveitis can be correctly classified. IU have an increased frequency among foreigners, and they use to be unclassifiable and chronic. Tuberculosis (6%) and Birdshot chorio-retinopathy (4%) must be kept in mind as uveitis causes., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

In view of the inverse temporal relationship of central clock activity to physiological or behavioral outputs in diurnal and nocturnal species, understanding the mechanisms and physiological consequences of circadian disorders in humans would benefit from studies in a diurnal animal model, phylogenetically close to humans. Here we report the discovery of the first intrinsic circadian disorder in a family of diurnal non-human primates, the rhesus monkey. The disorder is characterized by a combination of delayed sleep phase, relative to light-dark cycle, mutual desynchrony of intrinsic rhythms of activity, food intake and cognitive performance, enhanced nighttime feeding or, in the extreme case, intrinsic asynchrony. The phenotype is associated with normal length of intrinsic circadian period and requires an intact central clock, as demonstrated by an SCN lesion. Entrainment to different photoperiods or melatonin administration does not eliminate internal desynchrony, though melatonin can temporarily reinstate intrinsic activity rhythms in the animal with intrinsic asynchrony. Entrainment to restricted feeding is highly effective in animals with intrinsic or SCN lesion-induced asynchrony. The large isolated family of rhesus macaques harboring the disorder provides a powerful new tool for translational research of regulatory circuits underlying circadian disorders and their effective treatment.

Objectives: To report the experience in the management of penile necrosis at our hospital., Methods: We performed a review of the medical records with the diagnosis of penile necrosis at the Department of the Urology of the Hospital de Especialidades Centro Médico nacional Siglo XXI from January 1995 to March 2005., Results: 18 cases of penile necrosis were found, with ages from 28 to 78 years (mean age 58.1 yr.). Diabetes mellitus and end stage renal disease were the most frequent associated diseases, with 10 and 11 cases respectively. Reasons for consultation were penile scars in 5 cases, purulent exudation, inflammation of the glans penis and prepuce in 3, ischemic priapism in 2, Fournier's syndrome in 2, urethral bleeding in one, penile necrosis secondary to extrinsic compression in one, and periurethral abscess in another. Thirteen out of the 18 cases underwent partial or complete penectomy, and three of them died. Five patients were managed conservatively with antibiotics, one of them died. The pathology report showed ischemic necrosis in 3 cases, arterial and venous thrombosis, ischemic necrosis and dystrophic arterial and venous calcifications in 10 cases., Conclusions: Occlusive vascular changes are a conditioning factor in most patients with penile necrosis. This is more evident in patients with end stage renal disease, diabetes mellitus and hypertension. Clinical features of penile necrosis include scars, mummification, self-amputation, and superinfection, so that an early diagnosis and proper treatment are decisive for the evolution of this disease.

Cortical dysplasia (CD) is often associated with pharmacoresistant epilepsy. Previous studies showed increased expression of the NMDA receptor subunit NR2B in dysplastic and epileptic human neocortex. We tested the hypothesis that differential increase of NR2B constitutes an epileptogenic mechanism in humans. Dysplastic neocortex and lateral temporal lobe regions resected for treatment of pharmacoresistant seizures were processed for electrophysiological, histological, and immunocytochemical studies. Assignment to the "dysplastic" (n = 8) and "non-dysplastic" (n = 8) groups was based on histology. Neurons in "dysplastic" samples differentially stained for NR2B. Western blot (n = 6) showed an immunoreactive band for NR2B in three out of four "dysplastic" samples. Epileptiform field potentials (EFP) were elicited in vitro by omission of magnesium from the bath. EFP in "dysplastic" slices were characterized by multiple afterdischarges, occurring at a significantly higher repetition rate than EFP in non-dysplastic slices. The NR2B-specific NMDA receptor inhibitor ifenprodil (10muM) suppressed EFP in dysplastic slices. In non-dysplastic slices, burst repetition rate did not change with ifenprodil application. In both dysplastic and non-dysplastic slices, EFP were suppressed by a non-specific NMDAR antagonist (APV) or AMPA receptor antagonist (CNQX). These results provide additional evidence that the differential expression of NR2B in dysplastic human neocortex may play a role in the expression of in-situ epileptogenesis in human CD. NR2B may constitute a target for new diagnostic and pharmacotherapeutic approaches.

In Puerto Rico, risk for transmission of B-virus from free-ranging rhesus monkeys to humans has become a serious challenge. An incident with an injured rhesus monkey, seropositive for B-virus, resulted in inappropriate administration of antiviral postexposure prophylaxis. This incident underscores the importance of education about risks associated with interactions between humans and nonhuman primates.

Rhesus (Macaca mulatta) and patas (Erythrocebus patas) monkeys escaped to the mainland of southwestern Puerto Rico (SWPR) from research colonies on small offshore islands during the 1960s and through 1982. A three year study (1990-1993) combined radio-telemetry with visual observations to collect information on population sizes, the composition of social groups, their daily movements, and their home ranges. Two populations of rhesus monkeys were identified in SWPR: one within the study area in Sierra Bermeja and a second population located 10 km north of the study area. The size of the Sierra Bermeja rhesus population was derived from escapees from research colonies and at the time of the study was 65-85 individuals. Within their home range area (3.7 km2) the density of this population was >>18.9 individuals/km2. A second rhesus population was found in a mountainous region 10 km north of the study area. This population consisted of one (or two) heterosexual groups with a total of 40-45 individuals. Although a primary characteristic of this species in India is its ability to live as a commensal with humans, the rhesus monkey populations of SWPR are extremely shy and elusive, they avoid contact with humans. The patas monkey population consisted of >>120 individuals in four heterosexual groups and several all-male bands. There was no evidence of patas monkeys outside the study area. Within their home ranges (26.8 km2) the population density was 4.47 individuals/km2). Patas monkeys have not previously been considered a territorial species, their behavior in SWPR suggested territoriality. In contrast to studies in Africa, where the amount of home range overlap between patas monkey groups in high, in SWPR the amount of range overlap between groups is small and each group uses areas with clearly defined boundaries.

Reversible posterior leukoencephalopathy syndrome is a brain disorder characterized by headache, nausea, vomiting, visual disturbance, depressed level of consciousness, convulsions and occasionally focal neurologic deficits. It is commonly associated with malignant hypertension, toxemia of pregnancy or the use of immunosuppressive agents. Early diagnosis and specific treatment is essential. We report a case of reversible posterior leukoencephalopathy in the context of a hypertensive crisis in an habitual cocaine sniffer. Reversible posterior leukoencephalopathy must be suspected in every patient with hypertensive crisis and compatible clinic manifestation. Neuroimaging studies show characteristic features which confirm the diagnosis.

This paper presents the results of a study on the introduced, free-ranging patas monkey population of Southwestern Puerto Rico (SWPR). It describes information on the population size, social group composition, diet, daily ranging patterns, and patas home range during a 3 year period. The patas monkey population in the study area consisted of approximately 120 individuals in four heterosexual groups and several all-male bands. Within their home ranges (26.8 km2), the population density was 4.47 individuals/km2. Home range size among the population's four heterosexual groups varied from 3.72 km2 to 15.39 km2, and minimum daily distance traveled ranged from 0.8-2.0 km. In general, the social structure and mating system of this population parallels what has been described for African populations. However, habitat use, ranging behavior, and the quality of intergroup interactions suggests that patas of this population exhibit territorial behavior.

Pancreatic adenocarcinoma continues increasing in frequency, its diagnosis is usually realized very late and the results of the surgery, that is the only possibility of cure, gives often a feeling of frustration. During the period between 1973 and 1992, 1032 patients were diagnosed of pancreatic carcinoma at the different hospital institutions of our region. The incidence has increased from 1.28 to 6.42 cases/100,000. The proportion male/female was 1.5/1. Mean age of the patients was 67.5 +/- 11.35 and the median age was 65 years. In relation with the sex, the women age was higher: 70.2 +/- 11.81 (p < 0.01). The best diagnostic test was the CAT scan with 87.5 sensitivity. The overall resectability rate was low (11%), but there is a large difference between the beginning and the end of the period (6.8% and 14.1% respectively). Staging of the disease was stage IV in 36.4% of the cases. The 66.5% of the patients underwent palliative surgery. Cholecystojejunostomy was the most frequent operation. It wasn't possible any surgical management at the 3.5% of the cases cause of the disease was very extended; laparotomy was the only method used in 18.7%. The average survival rate with exeresis surgery was 18 months; with palliative surgery, it was only of eight months. The natural history of pancreatic carcinoma was situated at 5.57 +/- 2.63.