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The application of metal-based nanoparticles (mNPs) in cancer therapy and diagnostics (theranostics) has been a hot research topic since the early days of nanotechnology, becoming even more relevant in recent years. However, the clinical translation of this technology has been notably poor, with one of the main reasons being a lack of understanding of the disease and conceptual errors in the design of mNPs. Strikingly, throughout the reported studies to date on in vivo experiments, the concepts of "tumor targeting" and "tumor cell targeting" are often intertwined, particularly in the context of active targeting. These misconceptions may lead to design flaws, resulting in failed theranostic strategies. In the context of mNPs, tumor targeting can be described as the process by which mNPs reach the tumor mass (as a tissue), while tumor cell targeting refers to the specific interaction of mNPs with tumor cells once they have reached the tumor tissue. In this review, we conduct a critical analysis of key challenges that must be addressed for the successful targeting of either tumor tissue or cancer cells within the tumor tissue. Additionally, we explore essential features necessary for the smart design of theranostic mNPs, where 'smart design' refers to the process involving advanced consideration of the physicochemical features of the mNPs, targeting motifs, and physiological barriers that must be overcome for successful tumor targeting and/or tumor cell targeting.

Background: Glioblastoma is one of the most devastating and incurable cancers due to its aggressive behaviour and lack of available therapies, being its overall-survival from diagnosis ∼14-months. Thus, identification of new therapeutic tools is urgently needed. Interestingly, metabolism-related drugs (e.g., metformin/statins) are emerging as efficient antitumour agents for several cancers. Herein, we evaluated the in vitro/in vivo effects of metformin and/or statins on key clinical/functional/molecular/signalling parameters in glioblastoma patients/cells., Methods: An exploratory-observational-randomized retrospective glioblastoma patient cohort (n = 85), human glioblastoma/non-tumour brain human cells (cell lines/patient-derived cell cultures), mouse astrocytes progenitor cell cultures, and a preclinical xenograft glioblastoma mouse model were used to measure key functional parameters, signalling-pathways and/or antitumour progression in response to metformin and/or simvastatin., Findings: Metformin and simvastatin exerted strong antitumour actions in glioblastoma cell cultures (i.e., proliferation/migration/tumoursphere/colony-formation/VEGF-secretion inhibition and apoptosis/senescence induction). Notably, their combination additively altered these functional parameters vs. individual treatments. These actions were mediated by the modulation of key oncogenic signalling-pathways (i.e., AKT/JAK-STAT/NF-κB/TGFβ-pathways). Interestingly, an enrichment analysis uncovered a TGFβ-pathway activation, together with AKT inactivation, in response to metformin + simvastatin combination, which might be linked to an induction of the senescence-state, the associated secretory-phenotype, and to the dysregulation of spliceosome components. Remarkably, the antitumour actions of metformin + simvastatin combination were also observed in vivo [i.e., association with longer overall-survival in human, and reduction in tumour-progression in a mouse model (reduced tumour-size/weight/mitosis-number, and increased apoptosis)]., Interpretation: Altogether, metformin and simvastatin reduce aggressiveness features in glioblastomas, being this effect significantly more effective (in vitro/in vivo) when both drugs are combined, offering a clinically relevant opportunity that should be tested for their use in humans., Funding: Spanish Ministry of Science, Innovation and Universities; Junta de Andalucía; CIBERobn (CIBER is an initiative of Instituto de Salud Carlos III, Spanish Ministry of Health, Social Services and Equality)., Competing Interests: Declaration of interests The authors declare that no-competing financial and/or non-financial interests concerning the work exist., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Computer-assisted navigated piezoelectric surgery (CANPS) is a surgical technique that combines the surgical navigation with a piezoelectric device. This association multiplies the advantages of both technologies, taking the best of each one providing a synergistic association., Objective: To describe and assess the indications, advantages, disadvantages, and complications of this association of surgical techniques., Methods: CANPS was used in 32 patients. The clinical diagnosis was facial trauma, tumors, orthognathic surgeries, temporomandibular joint ankylosis, pathology of the frontal sinus, and alveolar distraction. Nineteen patients were men and 13 were women. Planning software iPlan 3.05 of Brainlab, and Elements of Brainlab were used for planning and the Kolibri and Kurve of Brainlab for surgical navigation. The piezoelectric device used was a "Vercelotti" type in all patients., Results: CAPNS could be performed successfully in all cases without complications and reduced the surgeon's uncertainty during the osteotomies. There is continuous control of the position of the surgical instrument. The use of the navigated piezoelectric device allowed the surgeon's uncertainty to be reduced during the performance of the osteotomies in depth, in poorly visible areas, with little access or reduced visibility. It also increases the safety of bone resections near important anatomical structures., Conclusions: CANPS combines the advantages of piezoelectric surgery and navigation. CANPS affords real-time control of the position of the cutting tip and allows semiburied approaches. CANPS allows surgery to be precise, safer, and minimally invasive., Competing Interests: The first author has received speakers’ fees from the BrainLab Company., (© 2022 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Background: Glioblastoma is one of the most devastating cancer worldwide based on its locally aggressive behavior and because it cannot be cured by current therapies. Defects in alternative splicing process are frequent in cancer. Recently, we demonstrated that dysregulation of the spliceosome is directly associated with glioma development, progression, and aggressiveness., Methods: Different human cohorts and a dataset from different glioma mouse models were analyzed to determine the mutation frequency as well as the gene and protein expression levels between tumor and control samples of the splicing-factor-3B-subunit-1 (SF3B1), an essential and druggable spliceosome component. SF3B1 expression was also explored at the single-cell level across all cell subpopulations and transcriptomic programs. The association of SF3B1 expression with relevant clinical data (e.g., overall survival) in different human cohorts was also analyzed. Different functional (proliferation/migration/tumorspheres and colonies formation/VEGF secretion/apoptosis) and mechanistic (gene expression/signaling pathways) assays were performed in three different glioblastomas cell models (human primary cultures and cell lines) in response to SF3B1 blockade (using pladienolide B treatment). Moreover, tumor progression and formation were monitored in response to SF3B1 blockade in two preclinical xenograft glioblastoma mouse models., Results: Our data provide novel evidence demonstrating that the splicing-factor-3B-subunit-1 (SF3B1, an essential and druggable spliceosome component) is low-frequency mutated in human gliomas (~ 1 %) but widely overexpressed in glioblastoma compared with control samples from the different human cohorts and mouse models included in the present study, wherein SF3B1 levels are associated with key molecular and clinical features (e.g., overall survival, poor prognosis and/or drug resistance). Remarkably, in vitro and in vivo blockade of SF3B1 activity with pladienolide B drastically altered multiple glioblastoma pathophysiological processes (i.e., reduction in proliferation, migration, tumorspheres formation, VEGF secretion, tumor initiation and increased apoptosis) likely by suppressing AKT/mTOR/ß-catenin pathways, and an imbalance of BCL2L1 splicing., Conclusions: Together, we highlight SF3B1 as a potential diagnostic and prognostic biomarker and an efficient pharmacological target in glioblastoma, offering a clinically relevant opportunity worth to be explored in humans., (© 2022. The Author(s).)

Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12-15 months. Thus, the identification of novel therapeutic targets to treat this devastating pathology is urgently needed. In this context, the truncated splicing variant of the somatostatin receptor subtype 5 (sst5TMD4), which is produced by aberrant alternative splicing, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several tumors. However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in GBM have not been yet explored. Therefore, we performed a comprehensive analysis to characterize the expression and pathophysiological role of sst5TMD4 in human GBM. sst5TMD4 was significantly overexpressed (at mRNA and protein levels) in human GBM tissue compared to non-tumor (control) brain tissue. Remarkably, sst5TMD4 expression was significantly associated with poor overall survival and recurrent tumors in GBM patients. Moreover, in vitro sst5TMD4 overexpression (by specific plasmid) increased, whereas sst5TMD4 silencing (by specific siRNA) decreased, key malignant features (i.e., proliferation and migration capacity) of GBM cells (U-87 MG/U-118 MG models). Furthermore, sst5TMD4 overexpression in GBM cells altered the activity of multiple key signaling pathways associated with tumor aggressiveness/progression (AKT/JAK-STAT/NF-κB/TGF-β), and its silencing sensitized GBM cells to the antitumor effect of pasireotide (a somatostatin analog). Altogether, these results demonstrate that sst5TMD4 is overexpressed and associated with enhanced malignancy features in human GBMs and reveal its potential utility as a novel diagnostic/prognostic biomarker and putative therapeutic target in GBMs.

Background: The possibility of harvesting the profunda artery perforator (PAP) flap in a chimeric configuration together with the innervated gracilis muscle may be a good option for dynamic reconstruction following total glossectomies. In this paper, we present a retrospective radiological study, which evaluates the presence and characteristics of the anatomical variation of the chimeric PAP - gracilis flap., Methods: The study sample comprised 66 patients (132 legs), 38 men, and 28 women with an average age of 56 ± 2 years old, who underwent head and neck reconstruction with a free flap. Preoperative computed tomographic angiography (CTA) was used for morphologic analysis. We present a case report of a patient with a total glossectomy reconstructed with this flap., Results: A perforator in the PAP area joining with the main pedicle of the gracilis muscle was found in 38 legs (28.8%). Mean length of the pedicle from the profunda femoral artery to the point where the perforator in the PAP area and the pedicle of the gracilis joined was 3.0 ± 0.3 cm. Differences in the existence of this vascular configuration were not significant comparing groups by sex, BMI, height, side or source vessel. Motion of the new tongue was documented clinically and with electromyography. The patient achieved an intelligible speech and normal diet., Conclusions: Preoperative evaluation is necessary to assess the existence of a perforator in the PAP area joining with the main pedicle of the gracilis muscle. This chimeric flap has been demonstrated useful for dynamic reconstruction of a patient with a total glossectomy., (© 2021 Wiley Periodicals LLC.)

Glioblastomas remain the deadliest brain tumour, with a dismal ∼12-16-month survival from diagnosis. Therefore, identification of new diagnostic, prognostic and therapeutic tools to tackle glioblastomas is urgently needed. Emerging evidence indicates that the cellular machinery controlling the splicing process (spliceosome) is altered in tumours, leading to oncogenic splicing events associated with tumour progression and aggressiveness. Here, we identify for the first time a profound dysregulation in the expression of relevant spliceosome components and splicing factors (at mRNA and protein levels) in well characterized cohorts of human high-grade astrocytomas, mostly glioblastomas, compared to healthy brain control samples, being SRSF3, RBM22, PTBP1 and RBM3 able to perfectly discriminate between tumours and control samples, and between proneural-like or mesenchymal-like tumours versus control samples from different mouse models with gliomas. Results were confirmed in four additional and independent human cohorts. Silencing of SRSF3, RBM22, PTBP1 and RBM3 decreased aggressiveness parameters in vitro (e.g. proliferation, migration, tumorsphere-formation, etc.) and induced apoptosis, especially SRSF3. Remarkably, SRSF3 was correlated with patient survival and relevant tumour markers, and its silencing in vivo drastically decreased tumour development and progression, likely through a molecular/cellular mechanism involving PDGFRB and associated oncogenic signalling pathways (PI3K-AKT/ERK), which may also involve the distinct alteration of alternative splicing events of specific transcription factors controlling PDGFRB (i.e. TP73). Altogether, our results demonstrate a drastic splicing machinery-associated molecular dysregulation in glioblastomas, which could potentially be considered as a source of novel diagnostic and prognostic biomarkers as well as therapeutic targets for glioblastomas. Remarkably, SRSF3 is directly associated with glioblastoma development, progression, aggressiveness and patient survival and represents a novel potential therapeutic target to tackle this devastating pathology., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST 2 and SST 5 . Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST 2 . However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST 3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST 3 -agonists and characterize their effects on experimental NFPT models., Experimental Design: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST 3 -agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST 3 -agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST 3 -agonist., Results: We successfully identified the first SST 3 -agonist peptides. SST 3 -agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro , and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST 3 -agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST 3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST 3 -agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs., Conclusions: This study demonstrates that SST 3 -agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST 3 , suggesting that targeting this receptor could be an efficacious treatment for NFPTs., (©2019 American Association for Cancer Research.)

Several surgical procedures have been described to correct the deformities associated with craniosynostosis. To simplify the prediction of results, virtual planning techniques and image-guided surgery have been used. Digital planning can be transferred to the operating room using osteotomy and cutting guides or surgical navigation. We describe a novel bone fixation method that allows for anchoring of a cranial dynamic reference frame (DRF) in a steady manner. DRF can be used for registration and as a reference for surgical navigation in an infant's skull. We describe this novel technique to overcome the problems of DRF fixation on an infant's thin and weak calvarium. We fixed the DRF to the cranium using this new system. A 6-hole X-shaped miniplate was placed using 5 screws, leaving 1 of the central holes free. The self-drilling screw that anchors the DRF in position was placed in the free central hole, avoiding calvarial bone breakage and allowing for surgical navigation. To the best of our knowledge, the present study is the first report of this DRF anchorage modification for surgical navigation during surgery of craniosynostosis in an infant., (Copyright © 2019 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Pituitary neuroendocrine tumors (PitNETs), the most abundant of all intracranial tumors, entail severe comorbidities. First-line therapy is transsphenoidal surgery, but subsequent pharmacological therapy is often required. Unfortunately, many patients are/become unresponsive to available drugs (somatostatin analogues [SSAs]/dopamine agonists), underscoring the need for new therapies. Statins are well-known drugs commonly prescribed to treat hyperlipidemia/cardiovascular diseases, but can convey additional beneficial effects, including antitumor actions. The direct effects of statins on normal human pituitary or PitNETs are poorly known. Thus, we aimed to explore the direct effects of statins, especially simvastatin, on key functional parameters in normal and tumoral pituitary cells, and to evaluate the combined effects of simvastatin with metformin (MF) or SSAs., Methods: Effects of statins in cell proliferation/viability, hormone secretion, and signaling pathways were evaluated in normal pituitary cells from a primate model (Papio anubis), tumor cells from corticotropinomas, somatotropinomas, nonfunctioning pituitary tumors, and PitNET cell-lines (AtT20/GH3-cells)., Results: All statins decreased AtT20-cell proliferation, simvastatin showing stronger effects. Indeed, simvastatin reduced cell viability and/or hormone secretion in all PitNETs subtypes and cell-lines, and ACTH/GH/PRL/FSH/LH secretion (but not expression), in primate cell cultures, by modulating MAPK/PI3K/mTOR pathways and expression of key receptors (GH-releasing hormone-receptor/ghrelin-R/Kiss1-R) regulating pituitary function. Addition of MF or SSAs did not enhance simvastatin antitumor effects., Conclusion: Our data reveal direct antitumor effects of simvastatin on PitNET-cells, paving the way to explore these compounds as a possible tool to treat PitNETs., (© 2020 S. Karger AG, Basel.)

Background: Pituitary neuroendocrine tumors (PitNETs) represent approximately 15% of all intracranial tumors and usually are associated with severe comorbidities. Unfortunately, a relevant number of patients do not respond to currently available pharmacological treatments, that is, somatostatin analogs (SSAs) or dopamine-agonists (DA). Thus, novel, chimeric somatostatin/dopamine compounds (dopastatins) that could improve medical treatment of PitNETs have been designed., Objective: This study aims to determine the direct therapeutic effects of a new-generation dopastatin, BIM-065, on primary cell cultures from different PitNETs subtypes., Methods: Thirty-one PitNET-derived cell cultures (9 corticotropinomas, 9 somatotropinomas, 11 nonfunctioning pituitary adenomas [NFPAs], and 2 prolactinomas), were treated with BIM-065, and key functional endpoints were assessed (cell viability, apoptosis, hormone secretion, expression levels of key genes, free cytosolic [Ca2+]i dynamics, etc.). AtT-20 cell line was used to evaluate signaling pathways in response to BIM-065., Results: This chimeric compound decreased cell viability in all corticotropinomas and somatotropinomas tested, but not in NFPAs. BIM-065 reduced ACTH, GH, chromogranin-A and PRL secretion, and increased apoptosis in corticotropinomas, somatotropinomas, and NFPAs. These effects were possibly mediated through modulation of pivotal signaling cascades like [Ca2+]i kinetic and Akt- or ERK1/2-phosphorylation., Conclusions: Our results unveil a robust antitumoral effect in vitro of the novel chimeric compound BIM-065 on the main PitNET subtypes, inform on the mechanisms involved, and suggest that BIM-065 could be an efficacious therapeutic option to be considered in the treatment of PitNETs., (© 2019 S. Karger AG, Basel.)

Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered an attractive therapeutic target in tumor pathologies, and the inhibition of SF3B1 (e.g., using pladienolide-B) has been shown to exert antitumor effects. Therefore, we aimed to analyze the expression levels of selected splicing-machinery components in 261 PitNETs (somatotropinomas/non-functioning PitNETS/corticotropinomas/prolactinomas) and evaluated the direct effects of pladienolide-B in cell proliferation/viability/hormone secretion in human PitNETs cell cultures and pituitary cell lines (AtT-20/GH3). Results revealed a severe dysregulation of splicing-machinery components in all the PitNET subtypes compared to normal pituitaries and a unique fingerprint of splicing-machinery components that accurately discriminate between normal and tumor tissue in each PitNET subtype. Moreover, expression of specific components was associated with key clinical parameters. Interestingly, certain components were commonly dysregulated throughout all PitNET subtypes. Finally, pladienolide-B reduced cell proliferation/viability/hormone secretion in PitNET cell cultures and cell lines. Altogether, our data demonstrate a drastic dysregulation of the splicing-machinery in PitNETs that might be associated to their tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in PitNETs., Competing Interests: The authors declare no conflict of interest.

Context: Pituitary neuroendocrine tumors (PitNETs) are a commonly underestimated pathology in terms of incidence and associated morbimortality. Currently, an appreciable subset of patients are resistant or poorly responsive to the main current medical treatments [i.e., synthetic somatostatin analogs (SSAs) and dopamine agonists]. Thus, development and optimization of novel and available medical therapies is necessary. Biguanides (metformin, buformin, and phenformin) are antidiabetic drugs that exert antitumoral actions in several tumor types, but their pharmacological effects on PitNETs are poorly known., Objective: We aimed to explore the direct effects of biguanides on key functions (cell viability, hormone release, apoptosis, and signaling pathways) in primary cell cultures from human PitNETs and cell lines. Additionally, we evaluated the effect of combined metformin with SSAs on cell viability and hormone secretion., Design: A total of 13 corticotropinomas, 13 somatotropinomas, 13 nonfunctioning PitNETs, 3 prolactinomas, and 2 tumoral pituitary cell lines (AtT-20 and GH3) were used to evaluate the direct effects of biguanides on cell viability, hormone release, apoptosis, and signaling pathways., Results: Biguanides reduced cell viability in all PitNETs and cell lines (with phenformin being the most effective biguanide) and increased apoptosis in somatotropinomas. Moreover, buformin and phenformin, but not metformin, reduced hormone secretion in a cell type-specific manner. Combination metformin/SSA therapy did not increase SSA monotherapy effectiveness. Effects of biguanides on PitNETs could involve the modulation of AMP-activated protein kinase-dependent ([Ca2+]i, PI3K/Akt) and independent (MAPK) mechanisms., Conclusion: Altogether, our data unveil clear antitumoral effects of biguanides on PitNET cells, opening avenues to explore their potential as drugs to treat these pathologies., (Copyright © 2019 Endocrine Society.)

Objective: We assess the efficacy of the metabolomic profile from glioma biopsies in providing estimates of postsurgical Overall Survival in glioma patients. Methods: Tumor biopsies from 46 patients bearing gliomas, obtained neurosurgically in the period 1992-1998, were analyzed by high resolution 1 H magnetic resonance spectroscopy (HR- 1 H MRS), following retrospectively individual postsurgical Overall Survival up to 720 weeks. Results: The Overall Survival profile could be resolved in three groups; Short (shorter than 52 weeks, n = 19), Intermediate (between 53 and 364 weeks, n = 19) or Long (longer than 365 weeks, n = 8), respectively. Classical histopathological analysis assigned WHO grades II-IV to every biopsy but notably, some patients with low grade glioma depicted unexpectedly Short Overall Survival, while some patients with high grade glioma, presented unpredictably Long Overall Survival. To explore the reasons underlying these different responses, we analyzed HR- 1 H MRS spectra from acid extracts of the same biopsies, to characterize the metabolite patterns associated to OS predictions. Poor prognosis was found in biopsies with higher contents of alanine, acetate, glutamate, total choline, phosphorylcholine, and glycine, while more favorable prognosis was achieved in biopsies with larger contents of total creatine, glycerol-phosphorylcholine, and myo-inositol. We then implemented a multivariate analysis to identify hierarchically the influence of metabolomic biomarkers on OS predictions, using a Classification Regression Tree (CRT) approach. The CRT based in metabolomic biomarkers grew up to three branches and split into eight nodes, predicting correctly the outcome of 94.7% of the patients in the Short Overall Survival group, 78.9% of the patients in the Intermediate Overall Survival group, and 75% of the patients in the Long Overall Survival group, respectively. Conclusion: Present results indicate that metabolic profiling by HR- 1 H MRS improves the Overall Survival predictions derived exclusively from classical histopathological gradings, thus favoring more precise therapeutic decisions.

Rationale: Metabolic syndrome (MetS) is a high-prevalence condition characterized by altered energy metabolism, insulin resistance, and elevated cardiovascular risk., Objectives: Although many individual single nucleotide polymorphisms (SNPs) have been linked to certain MetS features, there are few studies analyzing the influence of SNPs on carbohydrate metabolism in MetS., Methods: A total of 904 SNPs (tag SNPs and functional SNPs) were tested for influence on 8 fasting and dynamic markers of carbohydrate metabolism, by performance of an intravenous glucose tolerance test in 450 participants in the LIPGENE study., Findings: From 382 initial gene-phenotype associations between SNPs and any phenotypic variables, 61 (16% of the preselected variables) remained significant after bootstrapping. Top SNPs affecting glucose metabolism variables were as follows: fasting glucose, rs26125 (PPARGC1B); fasting insulin, rs4759277 (LRP1); C-peptide, rs4759277 (LRP1); homeostasis assessment of insulin resistance, rs4759277 (LRP1); quantitative insulin sensitivity check index, rs184003 (AGER); sensitivity index, rs7301876 (ABCC9), acute insulin response to glucose, rs290481 (TCF7L2); and disposition index, rs12691 (CEBPA)., Conclusions: We describe here the top SNPs linked to phenotypic features in carbohydrate metabolism among approximately 1000 candidate gene variations in fasting and postprandial samples of 450 patients with MetS from the LIPGENE study.

We present a patient with an otogenic cerebellar abscess caused by Enterococcus avium, a microorganism that is a rare cause of infection in humans. The patient experienced full recovery after early needle aspiration of the abscess and surgical treatment of the primary focus. Linezolid was selected as a first-line antimicrobial drug., (Georg Thieme Verlag KG Stuttgart · New York.)

Context: IL1b (IL1B or IL1β), a key modulator of the immune response, exerts its functions mainly via IL6 regulation. Fatty meals cause transient hypertriglyceridemia and are considered to be proinflammatory, but the extent of these responses shows high interindividual susceptibility., Objective: We evaluated the influence of a genetic variant located in the promoter region of IL1B (-1473G/C) on fasting and postprandial lipids and IL6., Design, Setting, and Participants: A total of 477 people over age 65 yr were genotyped for IL1B -1473G/C, and we evaluated fasting lipids depending on genotype. Then, 88 healthy young men were also genotyped and were fed a saturated fatty acid-rich meal. Serial blood samples were drawn for 11 h after the meal, and lipid fractions and IL6 were assayed. MAIN OUTCOME AND INTERVENTIONS: Fasting lipids were studied in the aged persons. Fasting and postprandial measurements of lipids and IL6 were performed in the healthy young men., Results: In the aged persons, CC subjects (minor allele homozygotes) showed higher triglyceride (P = 0.002) and cholesterol (P = 0.011) levels. Healthy young male carriers of the minor C allele showed higher postprandial triglycerides (P = 0.037), and those carried into large triglyceride-rich lipoproteins (P = 0.004). In addition, they showed higher postprandial IL6 concentrations (P = 0.008)., Conclusions: Our work shows that inflammatory genes may regulate fasting and postprandial lipids because the carriers of the minor allele of an IL gene variant have altered lipid metabolism. To reinforce these gene-phenotype findings, IL6 (the natural effector of IL1B) was increased in these persons.

We describe a novel protocol for the non-histological diagnosis of human brain tumors in vitro combining high-resolution (31)P magnetic resonance spectroscopy ((31)P-MRS) of their phospholipid profile and statistical multivariate analysis. Chloroform/methanol extracts from 40 biopsies of human intracranial tumors obtained during neurosurgical procedures were prepared and analyzed by high-resolution (31)P-MRS. The samples were grouped in the following seven major classes: normal brain (n = 3), low-grade astrocytomas (n = 4), high-grade astrocytomas (n = 7), meningiomas (n = 9), schwannomas (n = 3), pituitary adenomas (n = 4), and metastatic tumors (n = 4). The phospholipid profile of every biopsy was determined by (31)P-NMR analysis of its chloroform/methanol extract and characterized by 19 variables including 10 individual phospholipid contributions and 9 phospholipid ratios. Most tumors depicted a decrease in phosphatidylethanolamine (PtdEtn) and phosphatidylserine (PtdSer), the former mainly in neuroepithelial neoplasms and the latter in metastases. An increase in phosphatidylcholine (PtdCho) and phosphatidylinositol (PtdIns) appeared predominantly in primary non-neuroepithelial tumors. Linear discriminant analysis (LDA) revealed the optimal combination of variables that could classify each biopsy between every pair of classes. The resultant discriminant functions were used to calculate the probability of correct classifications for each individual biopsy within the seven classes considered. Multilateral analysis classified correctly 100% of the normal brain samples, 89% of the meningiomas, 75% of the metastases, and 57% of the high-grade astrocytomas. The use of phospholipid profiles may complement appropriately previously proposed methods of intelligent diagnosis of human cerebral tumors., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

Objective: To establish some therapeutic criteria about the treatment of AVMs of III, IV and V grade of Spetzler and Martin and to analyse the results in the subgroup of preoperative embolization plus surgery., Methods: We perform a retrospective analysis of a group of 31 patients with arteriovenous malformations (AVMs) treated in our center between 1999 and 2004. There were 19 women and 12 men, with a mean age of 31.6 years old (range, 1-62a). Their symptoms upon admission were intracranial hemorrhage in 77.4%, seizures in 12.9%, headache, ischemic event and incidental finding in 3.2% each group. Diagnostic angiography was performed in 29 cases and anatomopathologic diagnostic in 2 cases. The malformations were classified with Spetzler and Martin Grading Scale, in 10.3% grade I, 24.1% grade II, 37.9% grade III, 24.1% grade IV and 3.4% grade V. Patients were classified in 6 subgroups of treatment (surgery, embolization, radiosurgery, embolization plus surgery, embolization plus radiosurgery and conservative treatment)., Results: AVMs grade III, IV and V (19 patients) were treated with surgery (6 cases), embolization plus surgery (5 cases), but also other kind of treatments (embolization alone, radiosurgery and conservative) were used. Functional results in these groups of patients were 36.8% (7 cases) with no symptoms or slights symptoms (modified Rankin 0-1), 52.6% (10 cases) minor disability (mRankin 2), 5.3% (1 case) moderate disability and 5.3% (1 case) mortality. We observe a high rate of postembolization hemorrhage in the group of patients in which the combination of preoperative embolization plus surgery was used. In these cases, early surgery was performed with a good functional recovery. There was one case of postoperative mortality., Conclusion: We should consider some factors like the natural history, clinical presentation (hemorrhage), angiographic features (deep arterial supply, aneurisms), Spetzler and Martin Grading and the clinical condition of the patient before treating a cerebral AVM. In the subgroup of treatment with embolization plus surgery, we recommend to achieve a subtotal preoperative embolization > 50%, not to obliterate more than 50% in one session, to perform staged embolization waiting from 4 to 6 weeks between procedures, and from 1 to 3 weeks between the last embolization and surgery.

Experimental models of traumatic brain injury (TBI) provide a useful tool for understanding the cerebral metabolic changes induced by this pathological condition. Here, we report on the time course of changes in cerebral metabolites after TBI and its correlation with early brain morphological changes using a combination of high-resolution proton magnetic resonance spectroscopy ((1)H MRS) and magnetic resonance imaging (MRI). Adult male Sprague-Dawley rats were subjected to closed head impact and examined by MRI at 1, 9, 24, 48, and and 72 h after the injury. Extracts from funnel frozen rat brains were then obtained and analyzed quantitatively by high-resolution (1)H MRS. Finally, statistical multivariate analysis was carried out to identify the combination of cerebral metabolites that best described the time evolution of diffuse TBI. The temporal changes observed in the concentration of cerebral metabolites followed three different patterns. The first pattern included taurine, threonine, and glycine, with concentrations peaking 24 h after the injury. The second pattern included glutamate, GABA, and alanine, with concentrations remaining elevated between 24 and 48 h post-injury. The third one involved creatine-phosphocreatine, N-acetylaspartate, and myo-inositol, with concentrations peaking 48 h after the injury. A multivariate stepwise discriminant analysis revealed that the combination of the organic osmolytes taurine and myo-inositol allowed optimal discrimination among the different time groups. Our findings suggest that the profile of some specific brain molecules that play a role as organic osmolytes can be used to follow-up the progression of the early diffuse brain edema response induced by TBI.

Introduction: Orbital emphysema can be associated with optic nerve and vascular compromise, with subsequent potentially irreversible visual loss., Materials and Methods: We report a 4-year-old girl who presented right orbital emphysema after posterior fossa surgery for pilocytic astrocytoma resection in the sitting position. Endoscopic third ventriculostomy (ETV) had been previously carried out for the treatment of symptomatic obstructive hydrocephalus. Our hypothesis is that periorbital emphysema developed due to air passing from the intracranial to the extracranial compartment through the ETV burr hole., Result and Discussion: The emphysema resolved spontaneously without any sequelae. To our knowledge, this is the first description of orbital emphysema after posterior fossa surgery in the sitting position.

Neurophysiological monitoring during surgery to avoid damaging of eloquent brain areas is a useful tool. We are performing intraoperative neurophysiological test to locate motor, sensitive and speech areas with cortical stimulation and cranial nerves during cerebellopontine cranial base surgery. Neurophysiological monitoring during brain stem surgery has been less described. Brain stem surgery implies a careful selection of patients for surgery given the high risk of morbidity and mortality. For this reason, conservative treatment is usually indicated when an asymptomatic cavernoma is incidentally found. Instead, when bleeding or neurological deficit appear, operative treatment may be indicated and then the goal of surgery is to avoid the disability linked to the natural history. We present the case of a 29 year old woman with diagnosis of multiple cavernomas. She was admitted at our hospital because she presented weakness and sensitive disturbance of left limbs and dizziness. The CT scan and MRI showed a pontine haemorrhage caused by a cavernous hemangioma. We operated her on using neurophysiological monitoring of VII, VIII, X and XII cranial nerves with electromyographic recordings. Postoperative disability could be reduced with a better knowledge of entry zone into the brain stem and early physiotherapy.

We describe a multivariate analysis procedure to classify human cerebral tumors nonhistologically in vitro, combining the use of 1H magnetic resonance spectroscopy (MRS) with automatic amino acid analysis of biopsy extracts. Eighty-one biopsies were obtained surgically and classified histologically in eight classes: high-grade astrocytomas (class 1, n = 19), low-grade astrocytomas (class 2, n = 10), normal brain (class 3, n = 9), medulloblastomas (class 4, n = 4), meningiomas (class 5, n = 18), metastases (class 6, n = 8), neurinomas (class 7, n = 9), and oligodendrogliomas (class 8, n = 4). Perchloric acid extracts were prepared from every biopsy and analyzed by high resolution 1H MRS and automatic amino acid analysis by ionic exchange chromatography. Intensities of 27 resonances and ratios of resonances were measured in the 1H MRS spectra, and 17 amino acid concentrations were determined in the chromatograms. Linear discriminant analysis provided the most adequate combination of these variables for binary classifications of a biopsy between any two possible classes and in multiple choice comparisons, involving the eight possible classes considered. Correct diagnosis was obtained when the class selected by the computer matched the histological diagnosis. In binary comparisons, consideration of the amino acid profile increased the percentage of correct classifications, being always higher than 75% and reaching 100% in many cases. In multilateral comparisons, scores were: high-grade astrocytomas, 80%; low-grade astrocytomas, 74%; normal brain, 100%; medulloblastomas, 100%; meningiomas, 94.5%; metastases, 86%; neurinomas, 100%; and oligodendrogliomas, 75%. These results indicate that statistical multivariate procedures, combining 1H MRS and amino acid analysis of tissue extracts, provide a valuable classifier for the nonhistological diagnosis of biopsies from brain tumors in vitro.