Venous-plexus-associated lymphoid hubs support meningeal humoral immunity.

There is increasing interest in how immune cells in the meninges-the membranes that surround the brain and spinal cord-contribute to homeostasis and disease in the central nervous system1,2. The outer layer of the meninges, the dura mater, has recently been described to contain both innate and adaptive immune cells, and functions as a site for B cell development3-6. Here we identify organized lymphoid structures that protect fenestrated vasculature in the dura mater. The most elaborate of these dural-associated lymphoid tissues (DALT) surrounded the rostral-rhinal confluence of the sinuses and included lymphatic vessels. We termed this structure, which interfaces with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. Immune aggregates were present in DALT during homeostasis and expanded with age or after challenge with systemic or nasal antigens. DALT contain germinal centre B cells and support the generation of somatically mutated, antibody-producing cells in response to a nasal pathogen challenge. Inhibition of lymphocyte entry into the rostral-rhinal hub at the time of nasal viral challenge abrogated the generation of germinal centre B cells and class-switched plasma cells, as did perturbation of B-T cell interactions. These data demonstrate a lymphoid structure around vasculature in the dura mater that can sample antigens and rapidly support humoral immune responses after local pathogen challenge.

NeuroEPO plus (NeuralCIM®) in mild-to-moderate Alzheimer's clinical syndrome: the ATHENEA randomized clinical trial.

BACKGROUND: NeuroEPO plus is a recombinant human erythropoietin without erythropoietic activity and shorter plasma half-life due to its low sialic acid content. NeuroEPO plus prevents oxidative damage, neuroinflammation, apoptosis and cognitive deficit in an Alzheimer's disease (AD) models. The aim of this study was to assess efficacy and safety of neuroEPO plus. METHODS: This was a double-blind, randomized, placebo-controlled, phase 2-3 trial involving participants ≥ 50 years of age with mild-to-moderate AD clinical syndrome. Participants were randomized in a 1:1:1 ratio to receive 0.5 or 1.0 mg of neuroEPO plus or placebo intranasally 3 times/week for 48 weeks. The primary outcome was change in the 11-item cognitive subscale of the AD Assessment Scale (ADAS-Cog11) score from baseline to 48 weeks (range, 0 to 70; higher scores indicate greater impairment). Secondary outcomes included CIBIC+, GDS, MoCA, NPI, Activities of Daily Living Scales, cerebral perfusion, and hippocampal volume. RESULTS: A total of 174 participants were enrolled and 170 were treated (57 in neuroEPO plus 0.5 mg, 56 in neuroEPO plus 1.0 mg and 57 in placebo group). Mean age, 74.0 years; 121 (71.2%) women and 85% completed the trial. The median change in ADAS-Cog11 score at 48 weeks was -3.0 (95% CI, -4.3 to -1.7) in the 0.5 mg neuroEPO plus group, -4.0 (95% CI, -5.9 to -2.1) in the 1.0 mg neuroEPO plus group and 4.0 (95% CI, 1.9 to 6.1) in the placebo group. The difference of neuroEPO plus 0.5 mg vs. placebo was 7.0 points (95% CI, 4.5-9.5) P = 0.000 and between the neuroEPO plus 1.0 mg vs. placebo was 8.0 points (95% CI, 5.2-10.8) P = 0.000. NeuroEPO plus treatment induced a statistically significant improvement in some of clinical secondary outcomes vs. placebo including CIBIC+, GDS, MoCA, NPI, and the brain perfusion. CONCLUSIONS: Among participants with mild-moderate Alzheimer's disease clinical syndrome, neuroEPO plus improved the cognitive evaluation at 48 weeks, with a very good safety profile. Larger trials are warranted to determine the efficacy and safety of neuroEPO plus in Alzheimer's disease. TRIAL REGISTRATION: https://rpcec.sld.cu Identifier: RPCEC00000232.

Atypical B cells and impaired SARS-CoV-2 neutralization following heterologous vaccination in the elderly.

Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here, we show that individuals 70 years or older (median age 73, range 70-75) who received a primary two-dose schedule with AZD1222 and booster third dose with mRNA vaccine achieve significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared with those younger than 70 (median age 66, range 54-69) at 1 month post booster. Impaired neutralization potency and breadth post third dose in the elderly is associated with circulating "atypical" spike-specific B cells expressing CD11c and FCRL5. However, when considering individuals who received three doses of mRNA vaccine, we did not observe differences in neutralization or enrichment in atypical B cells. This work highlights the finding that AdV and mRNA COVID-19 vaccine formats differentially instruct the memory B cell response.

In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue.

Improving the efficacy of immune checkpoint therapies will require a better understanding of how immune cells are recruited and sustained in tumors. Here, we used the photoconversion of the tumor immune cell compartment to identify newly entering lymphocytes, determine how they change over time, and investigate their egress from the tumor. Combining single-cell transcriptomics and flow cytometry, we found that while a diverse mix of CD8 T cell subsets enter the tumor, all CD8 T cells retained within this environment for more than 72 h developed an exhausted phenotype, revealing the rapid establishment of this program. Rather than forming tumor-resident populations, non-effector subsets, which express TCF-1 and include memory and stem-like cells, were continuously recruited into the tumor, but this recruitment was balanced by concurrent egress to the tumor-draining lymph node. Thus, the TCF-1+ CD8 T cell niche in tumors is highly dynamic, with the circulation of cells between the tumor and peripheral lymphoid tissue to bridge systemic and intratumoral responses.

The impact of hypoxia on B cells in COVID-19.

BACKGROUND: Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This presentation resembles the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. METHODS: Detailed B cell phenotyping was undertaken by flow-cytometry on longitudinal samples from patients with COVID-19 across a range of severities (NIHR Cambridge BioResource). The impact of hypoxia on the transcriptome was assessed by single-cell and whole blood RNA sequencing analysis. The direct effect of hypoxia on B cells was determined through immunisation studies in genetically modified and hypoxia-exposed mice. FINDINGS: We demonstrate the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes also observed in B cell VHL-deficient mice. These findings were associated with hypoxia-related transcriptional changes in COVID-19 patient B cells, and similar B cell abnormalities were seen in mice kept in hypoxic conditions. INTERPRETATION: Hypoxia may contribute to the pronounced and persistent B cell pathology observed in acute COVID-19 pneumonia. Assessment of the impact of early oxygen therapy on these immune defects should be considered, as their correction could contribute to improved outcomes. FUNDING: Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR, Wellcome Trust.

Anogenital distance and anti-Müllerian hormone combined improves the diagnosis of polycystic ovary syndrome.

The objective of this study was to assess the accuracy of the combination of anogenital distance (AGD) and anti-Müllerian hormone (AMH) in the diagnosis of polycystic ovary syndrome (PCOS). The study included women diagnosed with PCOS and a control group who attended the Clinical University Hospital 'Virgen de la Arrixaca' in Murcia (Spain). Serum concentrations of AMH were measured and two AGD measurements were obtained: (i) from the anterior clitoral surface to the upper verge of the anus (AGDAC); and (ii) from the posterior fourchette to the upper verge of the anus (AGDAF). Data were assessed by receiver operator characteristic (ROC) curves. Women with PCOS (n = 126) had significantly larger AGDAC (80.5 ± 11.3 versus 76.0 ± 10.4 mm; p < 0.001) and higher AMH (7.2 ± 4.7 versus 3.1 ± 2.2; p < 0.001) compared to control women (n = 159). Women with serum AMH above 3.8 ng/mL (clinical cut-off used in PCOS) were 9.1 times more likely to have PCOS (95% CI: 5.1-16.2). The area under the ROC curve of combined model of AMH and AGDAC was 0.87 (95% CI: 0.83-0.91). The combined model for predicting PCOS based on AMH and AGDAC has better diagnostic accuracy than that of AMH or AGDAC alone. This model could be useful for clinicians and improve diagnosis and clinical management of these women.

Race, Genetic Admixture, and Cognitive Performance in the Cuban Population.

BACKGROUND: Population aging will lead to a dramatic increase in dementia prevalence, which will disproportionally affect racial minorities. The presence of racial differences in dementia prevalence has been widely reported in United States, but there are no relevant studies on this topic in low- and middle-income countries. METHODS: In a cross-sectional survey, 2944 older Cubans were recruited at a community-based level aimed to identify the effects of self-identified race and genetic admixture on cognitive performance. Dementia diagnosis was established using 10/66 Dementia and DSM-IV criteria. APOE-ε4 genotype was determined in 2511 (85%) and genetic admixture was completed for all dementia cases and in a randomly selected sample of cognitive healthy participants (218 dementia cases and 367 participants without dementia). RESULTS: The overall prevalence of dementia was 8.7%, without large or statistically significant differences on dementia prevalence (p = .12) by self-identified race. Mean cognitive scores were similar across racial groups (p = .46). After controlling for age, sex, and education, greater proportion of African ancestry was not associated with cognitive performance (p = .17). CONCLUSIONS: We found no evidence of an independent effect of self-identified race and/or population ancestry on dementia prevalence or cognitive performance. This suggests that observed differences in dementia prevalence among diverse populations may be driven primarily by social determinants of health.

The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes.

Hypoxia-inducible transcription factors (HIFs) are fundamental to cellular adaptation to low oxygen levels, but it is unclear how they interact with chromatin and activate their target genes. Here, we use genome-wide mutagenesis to identify genes involved in HIF transcriptional activity, and define a requirement for the histone H3 lysine 4 (H3K4) methyltransferase SET1B. SET1B loss leads to a selective reduction in transcriptional activation of HIF target genes, resulting in impaired cell growth, angiogenesis and tumor establishment in SET1B-deficient xenografts. Mechanistically, we show that SET1B accumulates on chromatin in hypoxia, and is recruited to HIF target genes by the HIF complex. The selective induction of H3K4 trimethylation at HIF target loci is both HIF- and SET1B-dependent and, when impaired, correlates with decreased promoter acetylation and gene expression. Together, these findings show SET1B as a determinant of site-specific histone methylation and provide insight into how HIF target genes are differentially regulated.

Assessment of Optimism in Women with Polycystic Ovary Syndrome: A Case Control-Study.

Polycystic ovary syndrome (PCOS) is a chronic endocrinopathy characterized by hyperandrogenism and anovulation that may pervade psychological dimensions such as dispositional optimism. Considering how PCOS influences mental health and the lack of studies on this matter, this research was aimed at assessing optimism and associated factors in PCOS. A case-control study of 156 patients with PCOS and 117 controls was conducted. All woman filled out the Life Orientation Test-Revised (LOT-R), a self-report questionnaire for measuring dispositional optimism. Medication, pain severity, gynecological, and sociodemographic information was also collected. Lower optimism was found in patients with PCOS compared to controls, even after covariate adjustment (LOT-R global scores: 14.1 vs. 15.9, p = 0.020). Our study provides evidence that a personality characteristic with important implications in illness prognosis may be affected in PCOS. We propose to assess dispositional optimism with the LOT-R scale in the gynecological appointment and tailor medical attention accordingly as a way to improve the comprehensive care of these patients within a multidisciplinary team.

Glutaminase isoforms expression switches microRNA levels and oxidative status in glioblastoma cells.

BACKGROUND: Glutaminase isoenzymes GLS and GLS2 play apparently opposing roles in cancer: GLS acts as an oncoprotein, while GLS2 (GAB isoform) has context specific tumour suppressive activity. Some microRNAs (miRNAs) have been implicated in progression of tumours, including gliomas. The aim was to investigate the effect of GLS and GAB expression on both miRNAs and oxidative status in glioblastoma cells. METHODS: Microarray profiling of miRNA was performed in GLS-silenced LN229 and GAB-transfected T98G human glioblastoma cells and their wild-type counterparts. Results were validated by real-time quantitative RT-PCR. Oxidative status and antioxidant enzymes were determined by spectrophotometric or fluorescence assays in GLS-silenced LN229 and T98G, and GAB-transfected LN229 and T98G. RESULTS: MiRNA-146a-5p, miRNA-140-3p, miRNA-21-5p, miRNA-1260a, and miRNA-92a-3p were downregulated, and miRNA-1246 was upregulated when GLS was knocked down. MiRNA-140-3p, miRNA-1246, miRNA-1260a, miRNA-21-5p, and miRNA-146a-5p were upregulated when GAB was overexpressed. Oxidative status (lipid peroxidation, protein carbonylation, total antioxidant capacity, and glutathione levels), as well as antioxidant enzymes (catalase, superoxide dismutase, and glutathione reductase) of silenced GLS glioblastoma cells and overexpressed GAB glioblastoma cells significantly changed versus their respective control glioblastoma cells. MiRNA-1246, miRNA-1260a, miRNA-146a-5p, and miRNA-21-5p have been characterized as strong biomarkers of glioblastoma proliferation linked to both GLS silencing and GAB overexpression. Total glutathione is a reliable biomarker of glioblastoma oxidative status steadily associated to both GLS silencing and GAB overexpression. CONCLUSIONS: Glutaminase isoenzymes are related to the expression of some miRNAs and may contribute to either tumour progression or suppression through certain miRNA-mediated pathways, proving to be a key tool to switch cancer proliferation and redox status leading to a less malignant phenotype. Accordingly, GLS and GAB expression are especially involved in glutathione-dependent antioxidant defence.

Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development.

B lymphocyte development and selection are central to adaptive immunity and self-tolerance. These processes require B cell receptor (BCR) signaling and occur in bone marrow, an environment with variable hypoxia, but whether hypoxia-inducible factor (HIF) is involved is unknown. We show that HIF activity is high in human and murine bone marrow pro-B and pre-B cells and decreases at the immature B cell stage. This stage-specific HIF suppression is required for normal B cell development because genetic activation of HIF-1α in murine B cells led to reduced repertoire diversity, decreased BCR editing and developmental arrest of immature B cells, resulting in reduced peripheral B cell numbers. HIF-1α activation lowered surface BCR, CD19 and B cell-activating factor receptor and increased expression of proapoptotic BIM. BIM deletion rescued the developmental block. Administration of a HIF activator in clinical use markedly reduced bone marrow and transitional B cells, which has therapeutic implications. Together, our work demonstrates that dynamic regulation of HIF-1α is essential for normal B cell development.

Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation.

Glutaminase (GA) catalyzes the first step in mitochondrial glutaminolysis playing a key role in cancer metabolic reprogramming. Humans express two types of GA isoforms: GLS and GLS2. GLS isozymes have been consistently related to cell proliferation, but the role of GLS2 in cancer remains poorly understood. GLS2 is repressed in many tumor cells and a better understanding of its function in tumorigenesis may further the development of new therapeutic approaches. We analyzed GLS2 expression in HCC, GBM and neuroblastoma cells, as well as in monkey COS-7 cells. We studied GLS2 expression after induction of differentiation with phorbol ester (PMA) and transduction with the full-length cDNA of GLS2. In parallel, we investigated cell cycle progression and levels of p53, p21 and c-Myc proteins. Using the baculovirus system, human GLS2 protein was overexpressed, purified and analyzed for posttranslational modifications employing a proteomics LC-MS/MS platform. We have demonstrated a dual targeting of GLS2 in human cancer cells. Immunocytochemistry and subcellular fractionation gave consistent results demonstrating nuclear and mitochondrial locations, with the latter being predominant. Nuclear targeting was confirmed in cancer cells overexpressing c-Myc- and GFP-tagged GLS2 proteins. We assessed the subnuclear location finding a widespread distribution of GLS2 in the nucleoplasm without clear overlapping with specific nuclear substructures. GLS2 expression and nuclear accrual notably increased by treatment of SH-SY5Y cells with PMA and it correlated with cell cycle arrest at G2/M, upregulation of tumor suppressor p53 and p21 protein. A similar response was obtained by overexpression of GLS2 in T98G glioma cells, including downregulation of oncogene c-Myc. Furthermore, human GLS2 was identified as being hypusinated by MS analysis, a posttranslational modification which may be relevant for its nuclear targeting and/or function. Our studies provide evidence for a tumor suppressor role of GLS2 in certain types of cancer. The data imply that GLS2 can be regarded as a highly mobile and multilocalizing protein translocated to both mitochondria and nuclei. Upregulation of GLS2 in cancer cells induced an antiproliferative response with cell cycle arrest at the G2/M phase.

[Quality of Clinical Practice Guidelines for COPD.] / Calidad de las guías de práctica clínica para la EPOC.

OBJECTIVE: World Health Organization deem Chronic Obstructive Pulmonary Disease as the fourth leading cause of death in the world. Because of its impact on Public Health, it represents a great burden from an international economic point of view, despite it is an avoidable and treatable disease. Hence it is suitable to use Clinical Practice Guidelines which are recommendations systematically developed to aid decision making about health care to improve quality, and they must be subject to a review and update of an enriching methodological rigor. There is currently many Clinical Practice Guidelines for Chronic Obstructive Pulmonary Disease but there is insufficient evidence to determine if they have the degree of methological quality for been used in clinical practice. For which, we have evaluated the quality of these Clinical Practice Guidelines in Spanish using the AGREE II instrument. METHODS: We carried out a systematic search to find the Clinical Practice Guidelines for Chronic Obstructive Pulmonary Disease published in Spanish between 2010-2017 and put a quality evaluation into effect by means of AGREE II instrument. RESULTS: We got six guidelines wich achieved inclusion criteria of the study and we draw the compliance of the domains in these guidelines by means of AGREE II instrument: Scope and purpose (55.56-92.59%), Stakeholder involvement (37.04-79.63%), Rigour of development (29.86-84.72%), Clarity of presentation (90.74-100%), Applicability (5.56-63.89%) and Editorial independence (5.56-94.44%). CONCLUSIONS: Only one guideline got the score to classify as Very Good Fulfilling/Very Hight Score; another four got Good Fulfilling/Hight Score; and last one got Low Fulfilling/Low Score.

OBJETIVO: La Enfermedad Pulmonar Obstructiva Crónica es considerada por la Organización Mundial de la Salud como la cuarta causa de muerte en el mundo. Dado su impacto en la Salud Pública supone una gran carga desde un punto de vista económico a nivel internacional, pese a ser una enfermedad evitable y tratable. De ahí que resulte conveniente el empleo de Guías de Práctica Clínica, las cuales son recomendaciones elaboradas sistemáticamente para ayudar a la toma de decisiones respecto a los cuidados de salud para la mejora de la calidad asistencial, debiendo estar sujetas a revisión y actualización, a fin de enriquecer su rigor metodológico. Actualmente existen numerosas Guías de Práctica Clínica para la Enfermedad Pulmonar Obstructiva Crónica, pero no tenemos evidencia suficiente para determinar su grado de calidad metodológica para ser utilizadas en la práctica clínica. Por tanto, nuestro objetivo fue evaluar la calidad de las Guías de Práctica Clínica en español para la Enfermedad Pulmonar Obstructiva Crónica mediante el instrumento AGREE II. METODOS: Realizamos una búsqueda sistemática para localizar las Guías de Práctica Clínica para la Enfermedad Pulmonar Obstructiva Crónica publicadas en español entre 2010-2017 y ejecutamos una evaluación de la calidad mediante el instrumento AGREE II. RESULTADOS: Obtuvimos seis guías que cumplían los criterios de inclusión en el estudio y de la aplicación del instrumento AGREE II extrajimos el cumplimiento de los dominios en las distintas guías: Alcance y Objetivo (55,56-92,59%), Participación de los implicados (37,04-79,63%), Rigor en la elaboración (29,86-84,72%), Claridad en la presentación (90,74-100%), Aplicabilidad (5,56-63,89%) y Independencia editorial (5,56-94,44%). CONCLUSIONES: Podemos decir que solo una de las guías obtuvo puntuación para clasificarla como Muy Buen Cumplimiento/Muy Alta puntuación; otras cuatro obtuvieron Buen Cumplimiento/Alta Puntuación; y, finalmente, la última Bajo Cumplimiento/Baja Puntuación.

Lysophosphatidic Acid and Glutamatergic Transmission.

Signaling through bioactive lipids regulates nervous system development and functions. Lysophosphatidic acid (LPA), a membrane-derived lipid mediator particularly enriched in brain, is able to induce many responses in neurons and glial cells by affecting key processes like synaptic plasticity, neurogenesis, differentiation and proliferation. Early studies noted sustained elevations of neuronal intracellular calcium, a primary response to LPA exposure, suggesting functional modifications of NMDA and AMPA glutamate receptors. However, the crosstalk between LPA signaling and glutamatergic transmission has only recently been shown. For example, stimulation of presynaptic LPA receptors in hippocampal neurons regulates glutamate release from the presynaptic terminal, and excess of LPA induce seizures. Further evidence indicating a role of LPA in the modulation of neuronal transmission has been inferred from animal models with deficits on LPA receptors, mainly LPA1 which is the most prevalent receptor in human and mouse brain tissue. LPA1 null-mice exhibit cognitive and attention deficits characteristic of schizophrenia which are related with altered glutamatergic transmission and reduced neuropathic pain. Furthermore, silencing of LPA1 receptor in mice induced a severe down-regulation of the main glutaminase isoform (GLS) in cerebral cortex and hippocampus, along with a parallel sharp decrease on active matrix-metalloproteinase 9. The downregulation of both enzymes correlated with an altered morphology of glutamatergic pyramidal cells dendritic spines towards a less mature phenotype, indicating important implications of LPA in synaptic excitatory plasticity which may contribute to the cognitive and memory deficits shown by LPA1-deficient mice. In this review, we present an updated account of current evidence pointing to important implications of LPA in the modulation of synaptic excitatory transmission.

Are there differences in basal thrombophilias and C-reactive protein between women with or without PCOS?

RESEARCH QUESTION: Polycystic ovary syndrome (PCOS) women have increased cardiovascular risks, although it is unclear whether the haemostatic system and coagulation contribute to that increased risk. DESIGN: Women attending the Gynecology Unit of the 'Virgen de la Arrixaca' University Hospital (Murcia, Spain) for routine gynaecological examinations between September 2014 and May 2016 were assessed for PCOS using the Rotterdam criteria (hyperandrogenism [H], oligo/amenorrhoea [O] and polycystic ovarian morphology [POM]) and were classified into four phenotypic. In total, 126 cases were identified and 159 control women were selected. All women underwent physical and gynaecological examinations, and blood tests between the second and fifth day of the menstrual cycle. Differences in hormonal, basal thrombophilia and metabolic parameters, and C-reactive protein (CRP) between PCOS and controls were analysed. RESULTS: After adjusting by BMI and age, PCOS women had higher LH (P < 0.001), testosterone (P < 0.001), free testosterone (P = 0.01) and anti-Müllerian hormone (P < 0.001) and lower FSH (P = 0.03) compared with controls, whereas sex hormone-binding globulin was no different. Cases showed significantly higher protein S, glucose, insulin and insulin resistance (HOMA-IR) compared with controls (P < 0.05). There were no differences in protein C levels, antithrombin III, prothrombin time, homocysteine, D-dimer, factor V Leyden, prothrombin G20210A polymorphism or CRP. The H+O phenotype showed the poorest results for insulin and HOMA-IR (P = 0.04 and 0.05). CONCLUSIONS: The results suggest that there are no differences in the basal thrombophilias between women with and without PCOS. However, PCOS with H+O shows the poorest metabolic profile.

Accuracy of anogenital distance and anti-Müllerian hormone in the diagnosis of endometriosis without surgery.

OBJECTIVE: To assess the predictive ability of a combination of anogenital distance (AGD) and anti-Müllerian hormone (AMH) to diagnosis the presence of endometriosis without surgery. METHODS: The present study included women diagnosed with endometriosis and a control group who attended the "Virgen de la Arrixaca" University Hospital, Murcia, Spain, between September 1, 2014, and May 31, 2015. Serum concentrations of AMH were measured, and two AGD measurements were obtained: from the anterior clitoral surface to the upper verge of the anus (AGDAC ), and from the posterior fourchette to the upper verge of the anus (AGDAF ). Data were assessed by receiver operator characteristic (ROC) curves. RESULTS: Women in the endometriosis group (n=57) had significantly shorter AGDAF (22.8 ± 4.6 vs 27.2 ± 5.7 mm; P<0.001) and lower AMH (2.2 ± 2.5 vs 3.3 ± 1.9 ng/mL; P<0.003) compared with the control group (n=93). Women with serum AMH below the clinical cut-off (1 ng/mL) were 17.40-times more likely to have endometriosis (95% confidence interval [CI] 5.64-53.82). The area under the ROC curve of combined AMH and AGDAF was 0.77 (95% CI 0.70-0.85). CONCLUSION: The model for predicting endometriosis on the basis of AMH and AGD could be useful for clinicians and epidemiologists to improve diagnosis and prognosis of this condition.

Calidad de las guías de práctica clínica para la EPOC / Quality of clinical practice guidelines for COPD

OBJETIVO: La Enfermedad Pulmonar Obstructiva Crónica es considerada por la Organización Mundial de la Salud como la cuarta causa de muerte en el mundo. Dado su impacto en la Salud Pública supone una gran carga desde un punto de vista económico a nivel internacional, pese a ser una enfermedad evitable y tratable. De ahí que resulte conveniente el empleo de Guías de Práctica Clínica, las cuales son recomendaciones elaboradas sistemáticamente para ayudar a la toma de decisiones respecto a los cuidados de salud para la mejora de la calidad asistencial, debiendo estar sujetas a revisión y actualización, a fin de enriquecer su rigor metodológico. Actualmente existen numerosas Guías de Práctica Clínica para la Enfermedad Pulmonar Obstructiva Crónica, pero no tenemos evidencia suficiente para determinar su grado de calidad metodológica para ser utilizadas en la práctica clínica. Por tanto, nuestro objetivo fue evaluar la calidad de las Guías de Práctica Clínica en español para la Enfermedad Pulmonar Obstructiva Crónica mediante el instrumento AGREE II. MÉTODOS: Realizamos una búsqueda sistemática para localizar las Guías de Práctica Clínica para la Enfermedad Pulmonar Obstructiva Crónica publicadas en español entre 2010-2017 y ejecutamos una evaluación de la calidad mediante el instrumento AGREE II. RESULTADOS: Obtuvimos seis guías que cumplían los criterios de inclusión en el estudio y de la aplicación del instrumento AGREE II extrajimos el cumplimiento de los dominios en las distintas guías: Alcance y Objetivo (55,56-92,59%), Participación de los implicados (37,04-79,63%), Rigor en la elaboración (29,86-84,72%), Claridad en la presentación (90,74-100%), Aplicabilidad (5,56-63,89%) y Independencia editorial (5,56-94,44%). CONCLUSIONES: Podemos decir que solo una de las guías obtuvo puntuación para clasificarla como Muy Buen Cumplimiento/Muy Alta puntuación; otras cuatro obtuvieron Buen Cumplimiento/Alta Puntuación; y, finalmente, la última Bajo Cumplimiento/Baja Puntuación

OBJECTIVE: World Health Organization deem Chronic Obstructive Pulmonary Disease as the fourth leading cause of death in the world. Because of its impact on Public Health, it represents a great burden from an international economic point of view, despite it is an avoidable and treatable disease. Hence it is suitable to use Clinical Practice Guidelines which are recommendations systematically developed to aid decision making about health care to improve quality, and they must be subject to a review and update of an enriching methodological rigor. There is currently many Clinical Practice Guidelines for Chronic Obstructive Pulmonary Disease but there is insufficient evidence to determine if they have the degree of methological quality for been used in clinical practice. For which, we have evaluated the quality of these Clinical Practice Guidelines in Spanish using the AGREE II instrument. METHODS: We carried out a systematic search to find the Clinical Practice Guidelines for Chronic Obstructive Pulmonary Disease published in Spanish between 2010-2017 and put a quality evaluation into effect by means of AGREE II instrument. RESULTS: We got six guidelines wich achieved inclusion criteria of the study and we draw the compliance of the domains in these guidelines by means of AGREE II instrument: Scope and purpose (55.56-92.59%), Stakeholder involvement (37.04-79.63%), Rigour of development (29.86-84.72%), Clarity of presentation (90.74-100%), Applicability (5.56-63.89%) and Editorial independence (5.56-94.44%). CONCLUSIONS: Only one guideline got the score to classify as Very Good Fulfilling/Very Hight Score; another four got Good Fulfilling/Hight Score; and last one got Low Fulfilling/Low Score

A Distinct Metabolite Profile Correlates with Neurodegenerative Conditions and the Severity of Congenital Hydrocephalus.

In congenital hydrocephalus, cerebrospinal fluid accumulation is associated with increased intracranial pressure (ICP), ischemia/hypoxia, metabolic impairment, neuronal damage, and astrocytic reaction. The aim of this study was to identify whether a metabolite profile revealing tissue responses according to the severity of hydrocephalus can be detected. The hyh mutant mouse used for this study exhibits 2 different forms of hydrocephalus, severe and moderate. In a comprehensive investigation into the 2 progressions of hydrocephalus, mice with severe hydrocephalus were found to have higher ICP and astrocytic reaction. Several metabolites from the mouse brain cortex were analyzed with 1H high-resolution magic angle spinning nuclear magnetic resonance (1H HR-MAS NMR) spectroscopy. A differential profile for metabolites including glutamate and glutamine was found to correlate with the severity of hydrocephalus and can be explained due to differential astrocytic reactions, neurodegenerative conditions, and the presence of ischemia. The glutamate transporter EAAT2 and the metabolite taurine were found to be key histopathological markers of affected parenchymata. In conclusion, a differential metabolite profile can be detected according to the severity of hydrocephalus and associated ICP and therefore can be used to monitor the efficacy of experimental therapies.