Low rCBV values in glioblastoma tumor progression under chemoradiotherapy.

PURPOSE: After standard treatment for glioblastoma, perfusion MRI remains challenging for differentiating tumor progression from post-treatment changes. Our objectives were (1) to correlate rCBV values at diagnosis and at first tumor progression and (2) to analyze the relationship of rCBV values at tumor recurrence with enhancing volume, localization of tumor progression, and time elapsed since the end of radiotherapy in tumor recurrence. METHODS: Inclusion criteria were (1) age > 18 years, (2) histologically confirmed glioblastoma treated with STUPP regimen, and (3) tumor progression according to RANO criteria > 12 weeks after radiotherapy. Co-registration of segmented enhancing tumor VOIs with dynamic susceptibility contrast perfusion MRI was performed using Olea Sphere software. For tumor recurrence, we correlated rCBV values with enhancing tumor volume, with recurrence localization, and with time elapsed from the end of radiotherapy to progression. Analyses were performed with SPSS software. RESULTS: Sixty-four patients with glioblastoma were included in the study. Changes in rCBV values between diagnosis and first tumor progression were significant (p < 0.001), with a mean and median decreases of 32% and 46%, respectively. Mean rCBV values were also different (p < 0.01) when tumors progressed distally (radiation field rCBV values of 1.679 versus 3.409 distally). However, changes and, therefore, low rCBV values after radiotherapy in tumor recurrence were independent of time. CONCLUSION: Chemoradiation alters tumor perfusion and rCBV values may be decreased in the setting of tumor progression. Changes in rCBV values with respect to diagnosis, with low rCBV in tumor progression, are independent of time but related to the site of recurrence.

Apathetic symptoms and white matter integrity after traumatic brain injury.

PRIMARY OBJECTIVE: The aim of the study was twofold. First, to study the relationship among apathy in the long term, initial clinical measures, and standard outcome scores after traumatic brain injury (TBI). Second, to describe white matter integrity correlates of apathy symptoms. RESEARCH DESIGN: Correlational study. Methods and Procedures: Correlation and Bayesian networks analyses were performed in a sample of 40 patients with moderate to severe TBI in order to identify the relationship among clinical variables, functionality, and apathy. A diffusion tensor imaging study was developed in 25 participants to describe correlations between fractional anisotropy (FA) measures and apathetic symptoms. MAIN OUTCOMES AND RESULTS: Correlation analysis revealed associations between pairs of variables as apathy in the long term and functional score at discharge from hospital. Bayesian network illustrated the relevant role of axonal injury mediating the relationship between apathy and initial clinical variables. FA in the superior longitudinal fasciculus, the inferior longitudinal fasciculus, and the internal capsule were negatively correlated with apathy measures. Widespread brain areas showed positive correlations between FA and apathy. CONCLUSIONS: These results highlight the relevance of white matter integrity measures in initial assessment after TBI and its relationship with apathetic manifestations in the chronic phase.

Altered pathways in methylome and transcriptome longitudinal analysis of normal weight and bariatric surgery women.

DNA methylation could provide a link between environmental, genetic factors and weight control and can modify gene expression pattern. This study aimed to identify genes, which are differentially expressed and methylated depending on adiposity state by evaluating normal weight women and obese women before and after bariatric surgery (BS). We enrolled 24 normal weight (BMI: 22.5 ± 1.6 kg/m2) and 24 obese women (BMI: 43.3 ± 5.7 kg/m2) submitted to BS. Genome-wide methylation analysis was conducted using Infinium Human Methylation 450 BeadChip (threshold for significant CpG sites based on delta methylation level with a minimum value of 5%, a false discovery rate correction (FDR) of q < 0.05 was applied). Expression levels were measured using HumanHT-12v4 Expression BeadChip (cutoff of p ≤ 0.05 and fold change ≥2.0 was used to detect differentially expressed probes). The integrative analysis of both array data identified four genes (i.e. TPP2, PSMG6, ARL6IP1 and FAM49B) with higher methylation and lower expression level in pre-surgery women compared to normal weight women: and two genes (i.e. ZFP36L1 and USP32) that were differentially methylated after BS. These methylation changes were in promoter region and gene body. All genes are related to MAPK cascade, NIK/NF-kappaB signaling, cellular response to insulin stimulus, proteolysis and others. Integrating analysis of DNA methylation and gene expression evidenced that there is a set of genes relevant to obesity that changed after BS. A gene ontology analysis showed that these genes were enriched in biological functions related to adipogenesis, orexigenic, oxidative stress and insulin metabolism pathways. Also, our results suggest that although methylation plays a role in gene silencing, the majority of effects were not correlated.

Evolution of cognitive impairment after a traumatic brain injury: is there any improvement after controlling the practice effect? / Evolución de las alteraciones cognitivas tras un traumatismo craneoencefálico: ¿hay mejoría tras controlar el efecto de la práctica?

INTRODUCTION: The importance of knowing the pattern of evolution of cognitive deficits in the first months after a traumatic brain injury (TBI) has encouraged the development of numerous longitudinal studies. However, the results of most of them should be taken with caution due to the lack of adequate control of practice effects that can lead to overestimating the genuine recovery of cognitive processes. AIM: To describe the cognitive changes between the acute and subacute phases of the TBI controlling the effect of the practice. PATIENTS AND METHODS: Twenty-two patients were assessed in two different time points after TBI (immediately and after six months) using the following tests: Trail Making Test (A, B, B/A, B-A), Stroop Test (W, C, CW, interference), Digit Symbol-Coding, Symbol Search, Digits Forward and Backward, Verbal Fluency and Short-term Memory. To control for the practice effects, a transformation of the scores was performed applying the procedure proposed by Calamia et al. RESULTS. Before controlling the practice effects, the scores of all tests improved (p > 0.001). However, afterward, the improvement remained only in the Trail Making Test-B, B/A and B-A, Digit Symbol-Coding, Symbol Search, Stroop CW and Digits Backward. CONCLUSIONS: The lack of control of practice effects in longitudinal studies can generate misleading interpretations about the evolution of cognitive deficits. The pattern of recovery after a TBI varies depending on the cognitive process.

TITLE: Evolución de las alteraciones cognitivas tras un traumatismo craneoencefálico: ¿hay mejoría tras controlar el efecto de la práctica?Introducción. La importancia de conocer el patrón de evolución de los déficits cognitivos en los primeros meses tras un traumatismo craneoencefálico (TCE) ha fomentado el desarrollo de numerosos estudios longitudinales. Sin embargo, los resultados de la mayoría de ellos deberían tomarse con cautela debido a la falta de un control adecuado del efecto de la práctica, que puede llevar a sobreestimar la recuperación genuina de los procesos cognitivos. Objetivo. Describir los cambios cognitivos entre las fases aguda y subaguda del TCE controlando el efecto de la práctica. Pacientes y métodos. Veintidós pacientes realizaron dos evaluaciones neuropsicológicas tras el TCE (inmediata y tras seis meses) mediante los siguientes tests: Trail Making Test (A, B, B/A y B-A), test de Stroop (P, C, PC e interferencia), clave de números, búsqueda de símbolos, dígitos directos e inversos, fluidez verbal y memoria inmediata. Para controlar el efecto de la práctica se realizó una transformación de las puntuaciones aplicando el procedimiento propuesto por Calamia et al. Resultados. Antes de controlar el efecto de la práctica, se evidenció una mejoría en las puntuaciones de todos los tests (p > 0,001). Sin embargo, tras él, la mejoría permaneció sólo en el Trail Making Test-B, B/A y B-A, la clave de números, la búsqueda de símbolos, el test de Stroop PC y los dígitos inversos. Conclusiones. La falta de control del efecto de la práctica en estudios longitudinales puede generar interpretaciones erróneas sobre el perfil de evolución de los déficits cognitivos. El patrón de recuperación tras un TCE varía en función del proceso cognitivo.

Uncommon case of Mycobacterium bovis brain abscess complicated by suppurative fistula, and review of the literature. / Caso insólito de absceso cerebral por Mycobacterium bovis complicado con fístula supurativa y revisión de la bibliografía.

INTRODUCTION: Mycobacterium bovis is an infrequent cause of central nervous system tuberculosis in Spain, with few cases described in the literature. Since compulsory pasteurization of milk and implementation of eradication programs on infected cattle, human sporadic illness with this organism has dramatically declined in developed countries. CASE REPORT: A 71-year-old immunocompromised male, who presented a calvarial lytic lesion. A craniotomy for the total resection of the lesion was performed and the microbiology results were positive for M. bovis, therefore antituberculous therapy was initiated. Despite of the correct treatment, the patient developed a tuberculous abscess that required an aggressive surgical management followed by a suppurative fistula. Based on the treatment of tuberculous lymphadenitis, we decided to perform a conservative management with antituberculous therapy (isoniazid + rifampicin + ethambutol + moxifloxacin + steroids during 12 months) and avoided new surgical cleanings of the surgical bed obtaining a good response and a good clinical evolution. CONCLUSIONS: As far as we know, this is the first case reported of a suppurative fistula after the resection of a cerebral abscess caused by M. bovis, therefore, there is no report in the literature about the treatment of this complication.

TITLE: Caso insólito de absceso cerebral por Mycobacterium bovis complicado con fístula supurativa y revisión de la bibliografía.Introducción. Mycobacterium bovis es una causa infrecuente de tuberculosis del sistema nervioso central en España, del cual existen pocos casos descritos en la bibliografía. Desde la pasteurización obligatoria de la leche y la implementación de programas de erradicación del ganado infectado, la enfermedad esporádica humana con este organismo ha disminuido drásticamente en los países desarrollados. Caso clínico. Varón inmunoafectado de 71 años, que presentaba una lesión lítica esporádica en la calota. Se realizó una craneotomía de la lesión y los resultados de microbiología fueron positivos para M. bovis, por lo que se inició tratamiento con terapia antituberculosa. A pesar del tratamiento correcto, el paciente desarrolló un absceso tuberculoso, que requirió un tratamiento quirúrgico agresivo, seguido de una complicación con una fístula supurativa. Sobre la base del tratamiento descrito para la linfadenitis tuberculosa, se decidió realizar un tratamiento conservador de la fístula supurativa, sin realizar nuevas limpiezas del lecho quirúrgico, y mantener de manera prolongada la terapia antituberculosa (isoniacida + rifampicina + etambutol + moxifloxacino + esteroides durante 12 meses), con lo que presentó una buena evolución clínica. Conclusiones. Hasta la fecha, éste es el primer caso descrito de una fístula supurativa después de la resección de un absceso cerebral causado por M. bovis, por lo que no existe en la bibliografía artículo alguno que describa el tratamiento adecuado de esta complicación.

Codon Usage Heterogeneity in the Multipartite Prokaryote Genome: Selection-Based Coding Bias Associated with Gene Location, Expression Level, and Ancestry.

Prokaryotes represent an ancestral lineage in the tree of life and constitute optimal resources for investigating the evolution of genomes in unicellular organisms. Many bacterial species possess multipartite genomes offering opportunities to study functional variations among replicons, how and where new genes integrate into a genome, and how genetic information within a lineage becomes encoded and evolves. To analyze these issues, we focused on the model soil bacterium Sinorhizobium meliloti, which harbors a chromosome, a chromid (pSymB), a megaplasmid (pSymA), and, in many strains, one or more accessory plasmids. The analysis of several genomes, together with 1.4 Mb of accessory plasmid DNA that we purified and sequenced, revealed clearly different functional profiles associated with each genomic entity. pSymA, in particular, exhibited remarkable interstrain variation and a high density of singletons (unique, exclusive genes) featuring functionalities and modal codon usages that were very similar to those of the plasmidome. All this evidence reinforces the idea of a close relationship between pSymA and the plasmidome. Correspondence analyses revealed that adaptation of codon usages to the translational machinery increased from plasmidome to pSymA to pSymB to chromosome, corresponding as such to the ancestry of each replicon in the lineage. We demonstrated that chromosomal core genes gradually adapted to the translational machinery, reminiscent of observations in several bacterial taxa for genes with high expression levels. Such findings indicate a previously undiscovered codon usage adaptation associated with the chromosomal core information that likely operates to improve bacterial fitness. We present a comprehensive model illustrating the central findings described here, discussed in the context of the changes occurring during the evolution of a multipartite prokaryote genome.IMPORTANCE Bacterial genomes usually include many thousands of genes which are expressed with diverse spatial-temporal patterns and intensities. A well-known evidence is that highly expressed genes, such as the ribosomal and other translation-related proteins (RTRPs), have accommodated their codon usage to optimize translation efficiency and accuracy. Using a bioinformatic approach, we identify core-genes sets with different ancestries, and demonstrate that selection processes that optimize codon usage are not restricted to RTRPs but extended at a genome-wide scale. Such findings highlight, for the first time, a previously undiscovered adaptation strategy associated with the chromosomal-core information. Contrasted with the translationally more adapted genes, singletons (i.e., exclusive genes, including those of the plasmidome) appear as the gene pool with the less-ameliorated codon usage in the lineage. A comprehensive summary describing the inter- and intra-replicon heterogeneity of codon usages in a complex prokaryote genome is presented.

DNA methylation screening after roux-en Y gastric bypass reveals the epigenetic signature stems from genes related to the surgery per se.

BACKGROUND/OBJECTIVES: Obesity has been associated with gene methylation regulation. Recent studies have shown that epigenetic signature plays a role in metabolic homeostasis after Roux-en Y gastric bypass (RYGB). To conduct a genome-wide epigenetic analysis in peripheral blood to investigate whether epigenetic changes following RYGB stem from weight loss or the surgical procedure per se. SUBJECTS/METHODS: By means of the Infinium Human Methylation 450 BeadChip array, global methylation was analyzed in blood of 24 severely obese women before and 6 months after RYGB and in 24 normal-weight women (controls). RESULTS: In blood cells, nine DMCpG sites showed low methylation levels before surgery, methylation levels increased after RYGB and neared the levels measured in the controls. Additionally, 44 CpG sites associated with the Wnt and p53 signaling pathways were always differently methylated in the severely obese patients as compared to the controls and were not influenced by RYGB. Finally, 1638 CpG sites related to inflammation, angiogenesis, and apoptosis presented distinct methylation in the post-surgery patients as compared to the controls. CONCLUSION: Bariatric surgery per se acts on CpGs related to inflammation, angiogenesis, and endothelin-signaling. However, the gene cluster associated with obesity remains unchanged, suggesting that weight loss 6 months after RYGB surgery cannot promote this effect.

DNA methylation map in circulating leukocytes mirrors subcutaneous adipose tissue methylation pattern: a genome-wide analysis from non-obese and obese patients.

The characterization of the epigenetic changes within the obesity-related adipose tissue will provide new insights to understand this metabolic disorder, but adipose tissue is not easy to sample in population-based studies. We aimed to evaluate the capacity of circulating leukocytes to reflect the adipose tissue-specific DNA methylation status of obesity susceptibility. DNA samples isolated from subcutaneous adipose tissue and circulating leukocytes were hybridized in the Infinium HumanMethylation 450 BeadChip. Data were compared between samples from obese (n = 45) and non-obese (n = 8-10) patients by Wilcoxon-rank test, unadjusted for cell type distributions. A global hypomethylation of the differentially methylated CpG sites (DMCpGs) was observed in the obese subcutaneous adipose tissue and leukocytes. The overlap analysis yielded a number of genes mapped by the common DMCpGs that were identified to reflect the obesity state in the leukocytes. Specifically, the methylation levels of FGFRL1, NCAPH2, PNKD and SMAD3 exhibited excellent and statistically significant efficiencies in the discrimination of obesity from non-obesity status (AUC > 0.80; p < 0.05) and a great correlation between both tissues. Therefore, the current study provided new and valuable DNA methylation biomarkers of obesity-related adipose tissue pathogenesis through peripheral blood analysis, an easily accessible and minimally invasive biological material instead of adipose tissue.

Leakage decrease detected by dynamic susceptibility-weighted contrast-enhanced perfusion MRI predicts survival in recurrent glioblastoma treated with bevacizumab

Background and purpose. In glioblastoma, tumor progression appears to be triggered by expression of VEGF, a regulator of blood vessel permeability. Bevacizumab is a monoclonal antibody that inhibits angiogenesis by clearing circulating VEGF, resulting in a decline in the contrast-enhancing tumor, which does not always correlate with treatment response. Our objectives were: (1) to evaluate whether changes in DSC perfusion MRI-derived leakage could predict survival in recurrent glioblastoma, and (2) to estimate whether leakage at baseline was related to treatment outcome. Materials and methods. We retrospectively analyzed DSC perfusion MRI in 24 recurrent glioblastomas treated with bevacizumab as second line chemotherapy. Leakage at baseline and changes in maximum leakage between baseline and the first follow-up after treatment were selected for quantitative analysis. Survival univariate analysis was made constructing survival curves using Kaplan-Meier method and comparing subgroups by log rank probability test. Results. Leakage reduction at 8 weeks after initiation of bevacizumab treatment had a significant influence on overall survival (OS) and progression-free survival (PFS). Median OS and PFS were 2.4 and 2.8 months longer for patients with leakage reduction at the first follow-up. Higher leakage at baseline was associated with leakage reduction after treatment. Odds ratio of treatment response was 9 for patients with maximum leakage at baseline >5. Conclusions. Leakage decrease may predict OS and PFS in recurrent glioblastomas treated with bevacizumab. Leakage reduction postulates as a potential biomarker for treatment response evaluation. Leakage at baseline seems to predict response to treatment, but was not independently associated with survival (AU)

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Leakage decrease detected by dynamic susceptibility-weighted contrast-enhanced perfusion MRI predicts survival in recurrent glioblastoma treated with bevacizumab.

BACKGROUND AND PURPOSE: In glioblastoma, tumor progression appears to be triggered by expression of VEGF, a regulator of blood vessel permeability. Bevacizumab is a monoclonal antibody that inhibits angiogenesis by clearing circulating VEGF, resulting in a decline in the contrast-enhancing tumor, which does not always correlate with treatment response. Our objectives were: (1) to evaluate whether changes in DSC perfusion MRI-derived leakage could predict survival in recurrent glioblastoma, and (2) to estimate whether leakage at baseline was related to treatment outcome. MATERIALS AND METHODS: We retrospectively analyzed DSC perfusion MRI in 24 recurrent glioblastomas treated with bevacizumab as second line chemotherapy. Leakage at baseline and changes in maximum leakage between baseline and the first follow-up after treatment were selected for quantitative analysis. Survival univariate analysis was made constructing survival curves using Kaplan-Meier method and comparing subgroups by log rank probability test. RESULTS: Leakage reduction at 8 weeks after initiation of bevacizumab treatment had a significant influence on overall survival (OS) and progression-free survival (PFS). Median OS and PFS were 2.4 and 2.8 months longer for patients with leakage reduction at the first follow-up. Higher leakage at baseline was associated with leakage reduction after treatment. Odds ratio of treatment response was 9 for patients with maximum leakage at baseline >5. CONCLUSIONS: Leakage decrease may predict OS and PFS in recurrent glioblastomas treated with bevacizumab. Leakage reduction postulates as a potential biomarker for treatment response evaluation. Leakage at baseline seems to predict response to treatment, but was not independently associated with survival.

Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects.

Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity-associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples. The identified sites represented 538 unique genes, 10% of which were diabetes-associated genes. The current work identified novel IR-related genes epigenetically regulated in VAT, such as COL9A1, COL11A2, CD44, MUC4, ADAM2, IGF2BP1, GATA4, TET1, ZNF714, ADCY9, TBX5, and HDACM. The gene with the largest methylation fold-change and mapped by 5 differentially methylated CpG sites located in island/shore and promoter region was ZNF714. This gene presented lower methylation levels in IR than in IS patients in association with increased transcription levels, as further reflected in a validation cohort (n = 24; 11 IR and 13 IS). This study reveals, for the first time, a potential epigenetic regulation involved in the dysregulation of VAT that could predispose patients to insulin resistance and future type 2 diabetes in morbid obesity, providing a potential therapeutic target and biomarkers for counteracting this process.

A consolidated analysis of the physiologic and molecular responses induced under acid stress in the legume-symbiont model-soil bacterium Sinorhizobium meliloti.

Abiotic stresses in general and extracellular acidity in particular disturb and limit nitrogen-fixing symbioses between rhizobia and their host legumes. Except for valuable molecular-biological studies on different rhizobia, no consolidated models have been formulated to describe the central physiologic changes that occur in acid-stressed bacteria. We present here an integrated analysis entailing the main cultural, metabolic, and molecular responses of the model bacterium Sinorhizobium meliloti growing under controlled acid stress in a chemostat. A stepwise extracellular acidification of the culture medium had indicated that S. meliloti stopped growing at ca. pH 6.0-6.1. Under such stress the rhizobia increased the O2 consumption per cell by more than 5-fold. This phenotype, together with an increase in the transcripts for several membrane cytochromes, entails a higher aerobic-respiration rate in the acid-stressed rhizobia. Multivariate analysis of global metabolome data served to unequivocally correlate specific-metabolite profiles with the extracellular pH, showing that at low pH the pentose-phosphate pathway exhibited increases in several transcripts, enzymes, and metabolites. Further analyses should be focused on the time course of the observed changes, its associated intracellular signaling, and on the comparison with the changes that operate during the sub lethal acid-adaptive response (ATR) in rhizobia.

Genome-Wide DNA Methylation Analysis Identifies Novel Hypomethylated Non-Pericentromeric Genes with Potential Clinical Implications in ICF Syndrome.

INTRODUCTION AND RESULTS: Immunodeficiency, centromeric instability and facial anomalies syndrome (ICF) is a rare autosomal recessive disease, characterized by severe hypomethylation in pericentromeric regions of chromosomes (1, 16 and 9), marked immunodeficiency and facial anomalies. The majority of ICF patients present mutations in the DNMT3B gene, affecting the DNA methyltransferase activity of the protein. In the present study, we have used the Infinium 450K DNA methylation array to evaluate the methylation level of 450,000 CpGs in lymphoblastoid cell lines and untrasformed fibroblasts derived from ICF patients and healthy donors. Our results demonstrate that ICF-specific DNMT3B variants A603T/STP807ins and V699G/R54X cause global DNA hypomethylation compared to wild-type protein. We identified 181 novel differentially methylated positions (DMPs) including subtelomeric and intrachromosomic regions, outside the classical ICF-related pericentromeric hypomethylated positions. Interestingly, these sites were mainly located in intergenic regions and inside the CpG islands. Among the identified hypomethylated CpG-island associated genes, we confirmed the overexpression of three selected genes, BOLL, SYCP2 and NCRNA00221, in ICF compared to healthy controls, which are supposed to be expressed in germ line and silenced in somatic tissues. CONCLUSIONS: In conclusion, this study contributes in clarifying the direct relationship between DNA methylation defect and gene expression impairment in ICF syndrome, identifying novel direct target genes of DNMT3B. A high percentage of the DMPs are located in the subtelomeric regions, indicating a specific role of DNMT3B in methylating these chromosomal sites. Therefore, we provide further evidence that hypomethylation in specific non-pericentromeric regions of chromosomes might be involved in the molecular pathogenesis of ICF syndrome. The detection of DNA hypomethylation at BOLL, SYCP2 and NCRNA00221 may pave the way for the development of specific clinical biomarkers with the aim to facilitate the identification of ICF patients.

Optimización de la metodología de cultivo de condrocitos de discos procedentes de hernias discales y comprobación de la presencia del Toll-like receptor 4 (TLR 4) / Optimization of methods of chondrocyte cell culture from human disc hernia subjects and testing the presence of Toll-like receptor 4 (TLR 4)

Objetivo: Optimizar la técnica de cultivo de células del disco intervertebral en humanos y confirmar la expresión del Toll-like receptor 4 (TLR4 ). Material y método: Se cultivaron muestras de núcleo pulposo obtenidas durante la cirugía de hernia discal. Las células cultivadas de los nueve pacientes (todos con degeneración del disco moderada-grave en la escala de Pfirrmann) fueron observadas para determinar su capacidad de crecimiento. Las células cultivadas obtenidas se estudiaron con el fin de determinar su fenotipo mediante inmunotinción y rtPCR. La presencia de TLR4 fue comprobada por los mismos métodos. Resultados: Las células aisladas se sembraron a diferentes concentraciones. La concentración ideal se obtuvo para las condiciones óptimas del cultivo. Se confirmó que el fenotipo de las células fue condrocitario y se confirmó la presencia del receptor TLR4 en las células cultivadas. Conclusión: Se confirma la presencia tanto de ARNm como de la proteína del receptor TLR4 en los condrocitos del disco intervertebral. Este hallazgo allana el camino para la caracterización de las funciones de este receptor en los procesos inflamatorios de la hernia de disco (AU)

Objective: To optimize the technique of culturing human intervertebral disc cells, and to confirm the expression of toll-like receptor 4 (TLR4) in these cells. Material and method: Samples of nucleus pulposus obtained during disc hernia surgery were cultured. Cells from nine patients (all with moderate-severe disc degeneration scores, based on the Pfirmann scale) were followed up to determine their growing capacity. The obtained cultured cells were tested for the chondrocyte phenotype by immunostaining and rt-PCR and the presence of TLR4 was tested by the same methods. Results: The cells were isolated and seeded at different concentrations. The ideal concentration was obtained for optimal culture conditions. The cells were confirmed to have the chondrocyte phenotype and TLR4 was confirmed to be present in the cultured cells. Conclusion: This study confirms the presence of both mRNA and TLR4 protein in intervertebral disc chondrocytes. This paves the way for elucidating of the roles of this receptor in the inflammatory processes of disc hernia (AU)

¿Existe correlación clínica o radiológica a la existencia de inflamación detectable histológicamente en el disco lumbar herniado? Resultados de una serie consecutiva de pacientes operados de hernia discal lumbar / Is there a clinical or radiological correlate to the histological evidence of an inflammatory infiltrate in the herniated disc? Results of a consecutive series of patients surgically treated of herniated lumbar disc

Objetivo: Establecer la relevancia clínica de la presencia de infiltrados de células inflamatorias evidenciables histológicamente en muestras de hernias de disco lumbares operadas. Material y método: Se obtuvieron muestras de discos lumbares de 50 pacientes operados de forma consecutiva durante el año 2012. Se recogieron los datos clínicos y epidemiológicos de los pacientes antes de la cirugía, el tiempo de evolución de los síntomas, así como la presencia de radiculopatía, déficits neurológicos y la exploración. Se estableció el carácter extruido o contenido de la hernia en RM. Se estableció la presencia y cuantía de celularidad condrocitaria como signo de degeneración discal. Resultados: Aunque casi todos las muestras reflejaban proliferación condrocitaria, la presencia de infiltrados inflamatorios o neovascularización fue escasa. La presencia de inflamación se relacionó invariablemente con la formación de nuevos vasos en el disco, no relacionándose con ninguna variable clínica o radiológica. Conclusión: No hay relación entre la presencia de infiltrados inflamatorios y los datos clínicos registrados. La presencia de infiltrados inflamatorios en el interior del disco herniado no tiene relación ni con la degeneración discal ni con la producción de clínica dolorosa (AU)

Objective: To establish the clinical relevance of the histological evidence of inflammatory cell infiltrates in surgical samples of operated lumbar disc hernia. Material and method: Surgical samples, clinical, and epidemiological data were obtained from 50 patients consecutively operated on of lumbar disc herniation during 2012 were obtained. Also the MR appearance as extruded or contained hernia was recorded. All samples were processed using hematoxilin-eosin staining and different histological parameters were determined such as the presence and quantity of chondrocytes present in the disc as a sign of disc degeneration. Results: Even though the majority of samples examined showed signs of disc degeneration, such as the presence of chondrocyte proliferation, the evidence of neovascularisation or inflammatory infiltrates was scarce. The presence of inflammatory infiltrates was invariably related to the presence of neovascularisation. However, the presence of inflammatory infiltrates was not related to any radiological or clinical variable. Conclusion: There is no relation between the presence of inflammatory infiltrates and the clinical data registered. The presence of histological evidence of inflammation in herniated lumbar disc tissue is not related to disc degeneration or the presence of pain (AU)

Pre-treatment circulating leptin/ghrelin ratio as a non-invasive marker to identify patients likely to regain the lost weight after an energy restriction treatment.

BACKGROUND: Leptin and ghrelin appear to play a role in weight regain after a successful weight loss. The pre-treatment plasma levels of leptin/ghrelin ratio (L/G) could have power to predict this clinically relevant issue in the obesity treatment. OBJECTIVE: To evaluate the ability of the L/G as a non-invasive tool for the early discrimination of obese patients who are more likely to regain weight after an energy restriction program (regainers) from those who maintain the lost weight (non-regainers). SUBJECTS AND METHODS: Fasting leptin and ghrelin levels were evaluated in 88 overweight/obese patients who followed an 8-week hypocaloric diet program and were categorized as regainers (≥10 % weight-lost regain) and non-regainers (<10 % weight-lost regain) 6 months (32 weeks) after finishing the dietary treatment. A receiver operating characteristic (ROC) curve analysis was employed to evaluate the diagnostic value of the L/G ratio and to establish a cut-off point to differentiate regainers from non-regainers. RESULTS: Regainers showed a statistically higher baseline (week 0) and after treatment (week 8) L/G ratio than non-regainers. The baseline L/G ratio was associated with an increased risk for weight regain (odds ratio 1.051; p = 0.008). Using the area under the ROC curve (AUC), the L/G ratio significantly identified female (AUC = 0.69; p = 0.040) and male regainers (AUC = 0.68; p = 0.030). The maximum combination of sensitivity and specificity was shown at the cut-off point of 26.0 for women and 9.5 for men. CONCLUSIONS: The pre-intervention fasting leptin/ghrelin ratio could be a useful non-invasive approach to personalize obesity therapy and avoid unsuccessful treatment outcomes.

A prognostic model based on preoperative MRI predicts overall survival in patients with diffuse gliomas.

BACKGROUND AND PURPOSE: Diffuse gliomas are classified as grades II-IV on the basis of histologic features, with prognosis determined mainly by clinical factors and histologic grade supported by molecular markers. Our aim was to evaluate, in patients with diffuse gliomas, the relationship of relative CBV and ADC values to overall survival. In addition, we also propose a prognostic model based on preoperative MR imaging findings that predicts survival independent of histopathology. MATERIALS AND METHODS: We conducted a retrospective analysis of the preoperative diffusion and perfusion MR imaging in 126 histologically confirmed diffuse gliomas. Median relative CBV and ADC values were selected for quantitative analysis. Survival univariate analysis was made by constructing survival curves by using the Kaplan-Meier method and comparing subgroups by log-rank probability tests. A Cox regression model was made for multivariate analysis. RESULTS: The study included 126 diffuse gliomas (median follow-up of 14.5 months). ADC and relative CBV values had a significant influence on overall survival. Median overall survival for patients with ADC < 0.799 × 10(-3) mm(2)/s was <1 year. Multivariate analysis revealed that patient age, relative CBV, and ADC values were associated with survival independent of pathology. The preoperative model provides greater ability to predict survival than that obtained by histologic grade alone. CONCLUSIONS: ADC values had a better correlation with overall survival than relative CBV values. A preoperative prognostic model based on patient age, relative CBV, and ADC values predicted overall survival of patients with diffuse gliomas independent of pathology. This preoperative model provides a more accurate predictor of survival than histologic grade alone.

Spinal cord injury after blunt cervical spine trauma: correlation of soft-tissue damage and extension of lesion.

BACKGROUND AND PURPOSE: In patients with spinal cord injury after blunt trauma, several studies have observed a correlation between neurologic impairment and radiologic findings. Few studies have been performed to correlate spinal cord injury with ligamentous injury. The purpose of this study was to retrospectively evaluate whether ligamentous injury or disk disruption after spinal cord injury correlates with lesion length. MATERIALS AND METHODS: We retrospectively reviewed 108 patients diagnosed with traumatic spinal cord injury after cervical trauma between 1990-2011. Plain films, CT, and MR imaging were performed on patients and then reviewed for this study. MR imaging was performed within 96 hours after cervical trauma for all patients. Data regarding ligamentous injury, disk injury, and the extent of the spinal cord injury were collected from an adequate number of MR images. We evaluated anterior longitudinal ligaments, posterior longitudinal ligaments, and the ligamentum flavum. Length of lesion, disk disruption, and ligamentous injury association, as well as the extent of the spinal cord injury were statistically assessed by means of univariate analysis, with the use of nonparametric tests and multivariate analysis along with linear regression. RESULTS: There were significant differences in lesion length on T2-weighted images for anterior longitudinal ligaments, posterior longitudinal ligaments, and ligamentum flavum in the univariate analysis; however, when this was adjusted by age, level of injury, sex, and disruption of the soft tissue evaluated (disk, anterior longitudinal ligaments, posterior longitudinal ligaments, and ligamentum flavum) in a multivariable analysis, only ligamentum flavum showed a statistically significant association with lesion length. Furthermore, the number of ligaments affected had a positive correlation with the extension of the lesion. CONCLUSIONS: In cervical spine trauma, a specific pattern of ligamentous injury correlates with the length of the spinal cord lesion in MR imaging studies. Ligamentous injury detected by MR imaging is not a dynamic finding; thus it proved to be useful in predicting neurologic outcome in patients for whom the MR imaging examination was delayed.

Oxidative stress associated to dysfunctional adipose tissue: a potential link between obesity, type 2 diabetes mellitus and breast cancer.

Diabetes mellitus and breast cancer are two important health problems. Type 2 diabetes (T2DM) and obesity are closely linked with both being associated with breast cancer. Despite abundant epidemiological data, there is no definitive evidence regarding the mechanisms responsible for this association. The proposed mechanisms by which diabetes affects breast cancer risk and prognosis are the same as the mechanisms hypothesised for the contribution of obesity to breast cancer risk. The obesity-induced inflammation promoted by adipose tissue dysfunction is a key feature, which is thought to be an important link between obesity and cancer. Inflammation induces an increase in free radicals and subsequently promotes oxidative stress, which may create a microenvironment favourable to the tumor development in obese persons. Oxidative stress is also proposed as the link between obesity and diabetes mellitus. Therefore, obesity-related oxidative stress could be a direct cause of neoplastic transformation associated with obesity and T2DM in breast cancer cells. This review is focused on the role of obesity-related oxidative stress in the context of chronic inflammation, on the time of breast cancer onset and progression, which provide targets for preventive and therapeutic strategies in the fields of diabetes and obesity-related breast cancer.