Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma.

The sub-ventricular zone (SVZ) is the most well-characterized neurogenic area in the mammalian brain. We previously showed that in 65% of patients with glioblastoma (GBM), the SVZ is a reservoir of cancer stem-like cells that contribute to treatment resistance and emergence of recurrence. Here, we built a single-nucleus RNA-sequencing-based microenvironment landscape of the tumor mass (T_Mass) and the SVZ (T_SVZ) of 15 GBM patients and 2 histologically normal SVZ (N_SVZ) samples as controls. We identified a mesenchymal signature in the T_SVZ of GBM patients: tumor cells from the T_SVZ relied on the ZEB1 regulatory network, whereas tumor cells in the T_Mass relied on the TEAD1 regulatory network. Moreover, the T_SVZ microenvironment was predominantly characterized by tumor-supportive microglia, which spatially co-exist and establish heterotypic interactions with tumor cells. Lastly, differential gene expression analyses, predictions of ligand-receptor and incoming/outgoing interactions, and functional assays revealed that the IL-1ß/IL-1RAcP and Wnt-5a/Frizzled-3 pathways are therapeutic targets in the T_SVZ microenvironment. Our data provide insights into the biology of the SVZ in GBM patients and identify specific targets of this microenvironment.

Género, infodemia y desinformación en salud. Revisión de alcance global, vacíos de conocimiento y recomendaciones.

OBJETIVO: explorar el estado de la literatura científica sobre los aspectos de infodemia y desinformación en salud vinculados al género y a la interseccionalidad, detectar vacíos de conocimiento y brindar recomendaciones. MÉTODOS: revisión de alcance global, con la detección de vacíos de conocimiento y recomendaciones. Se buscó en ocho bases de datos: MEDLINE (Pubmed), Anthropological Index Online, Studies on Women & Gender Abstracts, LILACS, Scielo, Global Index Medicus, Web of Science, Google académico y se hizo una búsqueda manual en Google de documentos de los últimos 10 años, sin restricciones de idioma y geográficas. Se realizó un análisis de contenido de los estudios incluidos. RESULTADOS: 855 registros fueron identificados y 21 cumplieron con los criterios de inclusión. Predominan los estudios que tuvieron como primer autor/a una mujer (13/21), aunque en la autoría global se destacaron los hombres (10/21). El modelo binario fue el enfoque principal (16/21). La mayoría (18/21) se publicaron a partir del 2020. Se abordaron principalmente temas relacionados con la COVID-19 y la salud sexual y reproductiva (antes de la pandemia), y en menor medida la salud mental. Se identificaron interacciones entre diferencias de sexo/género en la desinformación/infodemia en salud especialmente en mujeres, colectivos de género diverso, personas mayores y población de bajo nivel socioeducativo. CONCLUSIONES: existen brechas de conocimiento en el tema explorado, con escaso número de estudios, y limitaciones de alcances y del enfoque de género y/o feminista (más allá del binario). No obstante, los resultados tentativos constatan la presencia de inequidades de género e interseccionalidad en la desinformación en salud. PALABRAS CLAVE: infodemia, desinformación, género, COVID-19, revisión sistemática.

Serotype b of Aggregatibacter actinomycetemcomitans triggers pro-inflammatory responses and amyloid beta secretion in hippocampal cells: a novel link between periodontitis and Alzheimer´s disease?

Introduction: Previous reports have proposed that Periodontal disease (PDis) predisposes to Alzheimer's disease (AD), both highly prevalent pathologies among the elderly. The bacteria Aggregatibacter actinomycetemcomitans (Aa), associated with the most aggressive forms of PDis, are classified in different serotypes with distinct virulence according to the antigenicity of their lipopolysaccharide (LPS). Methods: Here, we determined the effects of purified LPS, from serotypes a, b or c of Aa, on primary cultures of microglia or mixed hippocampal cells. Results: We found that both culture types exhibited higher levels of inflammatory cytokines (IL-1ß, IL-6 and TNFα) when treated with serotype b-LPS, compared with controls, as quantified by qPCR and/or ELISA. Also, cultures treated with serotype a-LPS displayed increased mRNA levels of the modulatory cytokines IL-4 and IL-10. Mixed hippocampal cultures treated with serotype b-LPS exhibited severe neuronal morphological changes and displayed increased levels of secreted Aß1-42 peptide. These results indicate that LPS from different Aa serotypes triggers discriminatory immune responses, which differentially affect primary hippocampal cells. Conclusion: Altogether, our results show that treatment with serotype b-LPS triggers the secretion of proinflammatory cytokines by microglia, induces neurite shrinking, and increases the extracellular Aß1-42 levels, all features strongly associated with the etiology of AD.

Composition dependent transport diffusion in non-ideal mixtures from spatially resolved nuclear magnetic resonance spectroscopy.

Nuclear magnetic resonance (NMR) spectroscopy is a well-established technique for the measurement of intra-diffusion coefficients. Recently, such information has been used as a basis of predictive models to extrapolate to the Fick diffusion coefficient of liquid mixtures. The present work presents a new approach to directly access the Fick diffusion coefficient by spatially resolved NMR experiments. The Fick diffusion coefficient of the binary mixture TEA/H2O was determined at two temperatures, 283.2 K and 275.2 K. The results are consistent with values previously reported either from optical experiments or predictive Darken-type models developed for this system. The proposed methodology adds high-resolution NMR to the toolbox for the study of the transport diffusion of multicomponent mixtures. It is, however, still limited to mixtures with liquid-liquid equilibrium phase separation.

Molecular Insight into the Liquid Propan-2-ol + Water Mixture.

The hydrogen bonding structure of the mixture propan-2-ol + water is analyzed at ambient conditions of temperature and pressure with molecular modeling and simulation techniques. A new force field for propan-2-ol is developed for this purpose on the basis of quantum chemical calculations and validated for a wide range of macroscopic properties. The basic mixing properties, excess volume and excess enthalpy, as well as the most important transport properties, that is, diffusion coefficients and shear viscosity, are considered to verify the suitability of the employed force fields for studying the complex behavior of this aqueous alcoholic mixture. Radial distribution functions and hydrogen bonding statistics are employed to characterize the hydrogen bond network and molecular clustering. Inhomogeneous mixing on the microscopic level, given by the presence of segregation pockets, is identified. The interrelation between the intriguing macroscopic behavior of this binary mixture and its microscopic structure is revealed.

Needs of relatives of critically ill patients in an academic hospital in Chile. / Necesidades de los familiares de pacientes críticos en un hospital académico de Chile.

OBJECTIVE: To identify the importance of the needs of family members of patients in an intensive care unit (ICU). METHOD: Descriptive, comparative and cross-sectional study based on a secondary data analysis of 251 relatives of ICU patients at a university hospital in Santiago, Chile. Using non-random sampling, the 'Critical Care Family Needs Inventory' was used to establish the family needs, as well as a sociodemographic questionnaire that included: age, gender, educational level, patient relationship and previous ICU experience. A descriptive statistical analysis, Student's T test and ANOVA were performed. RESULTS: The most important family needs related to the dimensions of 'security' (mean=3.90) and 'information' (mean=3.76), while those of minor importance with 'support' (mean=3.09). In the latter, differences were observed at an older age (P<.05), an educational level (P<.001) and relationship with the patient (P<.05). CONCLUSIONS: The most relevant needs for family members in the ICU are related to safety and information. Less important needs are influenced by certain sociodemographic variables. Identifying the degree of importance of family needs will allow the health team to improve its relationship with families in ICUs.

Generation of six multiple sclerosis patient-derived induced pluripotent stem cell lines.

Multiple sclerosis (MS) is considered a chronic autoimmune disease of the central nervous system that leads to gliosis, demyelination, axonal damage and neuronal death. The MS disease aetiology is unknown, though a polymorphism of the TNFRSF1A gene, rs1800693, is known to confer an increased risk for MS. Using retroviral delivery of reprogramming transgenes, we generated six MS patient-specific iPSC lines with two distinct genotypes, CC or TT, of the polymorphism rs1800693. iPSC lines had normal karyotype, expressed pluripotency genes and differentiated into the three germ layers. These lines offer a good tool to study MS pathomechanisms and for drug testing.

Understanding the Differing Fluid Phase Behavior of Cyclohexane + Benzene and Their Hydroxylated or Aminated Forms.

The three binary mixtures cyclohexane + benzene, cyclohexanol + phenol, and cyclohexylamine + aniline exhibit qualitatively different vapor-liquid phase behavior, that is, azeotropic with a pressure maximum, azeotropic with a pressure minimum, and zeotropic, respectively. Employing molecular modeling and simulation, the COSMO-SAC model, and a cubic equation of state, the root of these effects is studied on the basis of phase equilibria, excess properties for volume, enthalpy, and Gibbs energy as well as microscopic structure. It is found that cyclohexane + benzene is characterized by more pronounced repulsive interactions, leading to pressure maximum azeotropy and a positive excess Gibbs energy. Functionalizing the aliphatic and aromatic rings with one amine group each introduces attractive hydrogen bonding interactions of moderate strength that counterbalance such that the mixture becomes zeotropic. The hydroxyl groups introduce strong hydrogen bonding interactions, leading to pressure minimum azeotropy and a negative excess Gibbs energy.

Mutual diffusion of binary liquid mixtures containing methanol, ethanol, acetone, benzene, cyclohexane, toluene, and carbon tetrachloride.

Mutual diffusion coefficients of all 20 binary liquid mixtures that can be formed out of methanol, ethanol, acetone, benzene, cyclohexane, toluene, and carbon tetrachloride without a miscibility gap are studied at ambient conditions of temperature and pressure in the entire composition range. The considered mixtures show a varying mixing behavior from almost ideal to strongly non-ideal. Predictive molecular dynamics simulations employing the Green-Kubo formalism are carried out. Radial distribution functions are analyzed to gain an understanding of the liquid structure influencing the diffusion processes. It is shown that cluster formation in mixtures containing one alcoholic component has a significant impact on the diffusion process. The estimation of the thermodynamic factor from experimental vapor-liquid equilibrium data is investigated, considering three excess Gibbs energy models, i.e., Wilson, NRTL, and UNIQUAC. It is found that the Wilson model yields the thermodynamic factor that best suits the simulation results for the prediction of the Fick diffusion coefficient. Four semi-empirical methods for the prediction of the self-diffusion coefficients and nine predictive equations for the Fick diffusion coefficient are assessed and it is found that methods based on local composition models are more reliable. Finally, the shear viscosity and thermal conductivity are predicted and in most cases favorably compared with experimental literature values.

Polymorphisms in histone deacetylases improve the predictive value of IL-28B for chronic hepatitis C therapy.

Histone deacetylases (HDACs) influence many cellular processes, including the modulation of signal transducer and activator of transcription activity (STAT) in response to interferon (IFN). To identify genetic markers that help optimize the IL-28B prediction of chronic hepatitis C (CHC) sustained virological response (SVR), we evaluated 27 single-nucleotide polymorphisms (SNPs) in HDAC1-11. Three SNPs, rs3778216, rs976552 and rs368328 in HDAC2, HDAC3 and HDAC5, respectively, were independently associated with SVR (P<0.05). The addition of these three HDAC's SNPs to the IL-28B predictive model (area under the curve (AUC)=0.630) rendered an important improvement of AUC-receiver operating characteristic value (AUC=0.747, P=0.021). Chi-squared Automatic Interaction Detector (CHAID) analysis denoted the significance of the rs3778216 C/C genotype in identifying a group of good responders despite carrying IL-28B T allele (79.2% of SVR), whereas HDAC5 G allele characterized a subgroup with poor response rate (25.5%). However, HDAC3 rs976552 did not display a relevant role for the hierarchical classification of patients. Variables related to SVR in hepatitis C virus genotype 1 (HCV-1) cohort were the same of those obtained for the overall population. Interestingly, in non-HCV-1 patients (n=56) the HDAC2 C/C genotype was the unique predictive variable related to SVR (AUC=0.733, P<0.007). Thus, these preliminary results suggest the potential usefulness of combined IL-28B and HDAC genotyping for the CHC patients' classification by likelihood of an SVR.

Metabolism of dehydroepiandrosterone sulfate and estrone-sulfate by human platelets.

The aim of the present research was to study the uptake of DHEAS, and to establish the intracrine capacity of human platelets to produce sex steroid hormones. The DHEAS transport was evaluated through the uptake of [(3)H]-DHEAS in the presence or absence of different substrates through the organic anion transporting polypeptide (OATP) family. The activity of sulfatase enzyme was evaluated, and the metabolism of DHEAS was measured by the conversion of [(3)H]-DHEAS to [(3)H]-androstenedione, [(3)H]-testosterone, [(3)H]-estrone and [(3)H]-17beta-estradiol. Results indicated the existence in the plasma membrane of an OATP with high affinity for DHEAS and estrone sulphate (E(1)S). The platelets showed the capacity to convert DHEAS to active DHEA by the steroid-sulfatase activity. The cells resulted to be a potential site for androgens production, since they have the capacity to produce androstenedione and testosterone; in addition, they reduced [(3)H]-estrone to [(3)H]-17beta-estradiol. This is the first demonstration that human platelets are able to import DHEAS and E(1)S using the OATP family and to convert DHEAS to active DHEA, and to transform E(1)S to 17beta-estradiol.

Dehydroepiandrosterone prevents the aggregation of platelets obtained from postmenopausal women with type 2 diabetes mellitus through the activation of the PKC/eNOS/NO pathway.

The steroid hormone dehydroepiandrosterone (DHEA), suggested to be a cardioprotector, prevents platelet aggregation in healthy humans. This hormone is reduced in postmenopausal women by 60% of its normal value. Platelets in patients with type 2 diabetes (T2D) are more sensitive to aggregation, which has been attributed to a reduced ability to produce nitric oxide (NO). In light of these precedents and considering that DHEA is able to increase the production of NO in cultured endothelial cells, we suggest that DHEA prevents the aggregation of platelet from postmenopausal women with T2D through the activation of PKC/eNOS/NO/cGMP pathway. To determine the effect of DHEA in platelet aggregation, platelet-rich plasma (PRP) obtained from postmenopausal women with T2D was preincubated with DHEA, and aggregation induced by ADP was determined in the presence or absence of L-NNA (LNG-nitroarginine), Rottlerin, NOS, or PKC delta inhibitors, respectively. Platelet NO production was measured with the fluorescent probe DAF2DA and eNOS activation was determined by Western blot, using an anti-p-eNOS (ser 1177) antibody. DHEA 1) prevented platelet aggregation by 40% compared to control, 2) increased NO production by 63%, 3) increased p-eNOS (phosphorylated endothelial nitric oxide synthase) levels, and 4) increased cGMP production. These effects were reduced in the presence of L-NNA or Rottlerin. DHEA prevents platelet aggregation induced by ADP. This effect is mediated by the activation of the PKCδ/eNOS/NO/cGMP pathway. Our results suggest that DHEA could be considered to be a potential therapeutic tool in the prevention of atherothrombotic processes in postmenopausal women with T2D.

Genetic variants of interferon-stimulated genes and IL-28B as host prognostic factors of response to combination treatment for chronic hepatitis C.

Chronic hepatitis C (CHC) is a worldwide health problem that is highly related to liver fibrosis, cirrhosis, and hepatocellular carcinoma. The achievement of response to the current standard of care-pegylated interferon plus ribavirin-has recently been described to be associated with single-nucleotide polymorphisms (SNPs) near the IL-28B gene. Additionally, baseline expression levels of genes involved in interferon (IFN)-stimulated genes (ISGs) have been found to be related to treatment outcome. In the present study, 285 patients were genotyped for 63 SNPs within genes of the IFN signaling pathway (IPGs) and ISGs. Two ISG polymorphisms-OASL rs12819210 (odds ratio (OR)=2.1, P=0.03) and IFIT1 rs304478 (OR=2.5, P=0.01)-were found to be independent predictive factors of sustained virological response (SVR) after adjusting for other clinical covariates. Furthermore, the predictive value of IL-28B SNP was notably improved by simultaneous genotyping of rs12819210 and rs304478, particularly in patients with the worst prognosis (viral genotype 1, area under the curve (AUC)=0.74). In conclusion, ISG SNPs could constitute a valuable tool for individualizing CHC therapy.

Peripheral blood monocyte subsets predict antiviral response in chronic hepatitis C.

BACKGROUND: Hepatitis C virus infection evolves into chronic progressive liver disease in a significant percentage of patients. Monocytes constitute a diverse group of myeloid cells that mediate innate and adaptive immune response. In addition to proinflammatory CD16+ monocytes, a Tie-2+ subgroup - Tie-2 expressing monocytes (TEMs) - that has robust proangiogenic potential has been recently defined. AIM: To study the heterogeneity of peripheral blood monocytes in chronic hepatitis C (CHC) patients and to examine their proposed pathophysiological roles on disease progression and response to antiviral therapy. METHODS: We studied CD16+ and Tie-2+ peripheral monocyte subpopulations in 21 healthy subjects and 39 CHC patients in various stages of disease and responses to antiviral treatment using flow cytometry. Expression profiles of proangiogenic and tissue remodelling factors in monocyte supernatants were measured using ELISA and protein arrays. Intrahepatic expression of CD14, CD31 and Tie-2 was analysed using immunofluorescence. RESULTS: Increases of certain peripheral monocyte subsets were observed in the blood of CHC patients, wherein those cells with proinflammatory (CD16+) or proangiogenic (TEMs) potential expanded (P < 0.005, both). Notably, TEMs were significantly increased in nonresponders, particularly those with lower CD16 expression. In addition, many angiogenic factors were differentially expressed by peripheral monocytes from control or CHC patients, such as angiopoietin-1 and angiogenin (P < 0.05). Interestingly, intrahepatic TEMs were distinguished within portal infiltrates of CHC patients. CONCLUSIONS: These findings suggest for the first time the relevance of peripheral monocytes phenotypes for the achievement of response to treatment. Hence, the study of monocyte subset regulation might effect improved CHC prognoses and adjuvant therapies.

AM3, a natural glycoconjugate, induces the functional maturation of human dendritic cells.

BACKGROUND AND PURPOSE: Dendritic cells (DCs) are dedicated antigen-presenting cells able to initiate specific immune responses and their maturation is critical for the induction of antigen-specific T-lymphocyte responses. Here, we have investigated the effects of Inmunoferon-active principle (AM3), the active agent of a commercial immunomodulatory drug, on human monocyte-derived DCs (MDDCs). EXPERIMENTAL APPROACH: MDDCs derived from healthy and hepatitis C virus (HCV)-infected patients were stimulated with AM3. We analysed the expression of cell surface proteins by flow cytometry, that of cytokine production by ELISA, and the expression of chemokines and chemokine receptors by RNase protection assays. T-lymphocyte proliferation was assessed in mixed lymphocyte reactions, protein expression by western blot and luciferase-based reporter methods, and Toll-like receptor (TLR)-blocking antibodies were employed to analyse TLR activity. KEY RESULTS: In MDDCs, AM3 induced or enhanced expression of CD54, CD83, CD86, HLA-DR, chemokines and chemokine receptors, interleukin (IL)-12p70 and IL-10. Furthermore, AM3 stimulated MDDCs to increase proliferation of allogenic T cells. AM3 triggered nuclear translocation of NF-kappaB and phosphorylation of p38 mitogen-activated protein kinase. AM3 promoted NF-kappaB activation in a TLR-4-dependent manner, and blocking TLR-4 activity attenuated the enhanced expression of CD80, CD83 and CD86 induced by AM3. AM3 enhanced the expression of maturation-associated markers in MDDCs from HCV-infected patients and increased the proliferation of T lymphocytes induced by these MDDCs. CONCLUSIONS AND IMPLICATIONS: These results underline the effects of AM3 in promoting maturation of MDDCs and suggest that AM3 might be useful in regulating immune responses in pathophysiological situations requiring DC maturation.

Oral-health workshop targeted at 0-5-yr. old deprived children's parents and caregivers: effect on knowledge and practices.

One-session oral-health workshop was targeted at 770 parents and 60 caregivers of 0-5-year-old low-income children. Lower plaque scores (Silness & Löe-modified index) were observed in test-group-(TG) children after 1 and 6-months (Median=0) than control-group-(CG) (Median=1)(p<0.05), with a significant improvement from baseline among the TG (p<0.05). The questionnaire showed improvement in the TG parents/caregivers' knowledge after 1- 6-months regarding white-spot lesion visual recognition; with respect to the practices, these improved after 1-6 but decreased after 6-months.

[Job stress perceived by hospital medical staff]. / Exigencias laborales psicológicas percibidas por médicos especialistas hospitalarios.

OBJECTIVE: To identify the psychosocial risk factors related to psychological demands perceived by specialist physicians from six public hospitals in the province of Valencia in Spain. METHODS: A qualitative study was carried out. The population studied comprised the hospitals' specialist medical staff (Oncology, Internal Medicine, Traumatology, Radiology and Intensive Care). A trained interviewer performed 47 individual, face-to-face, semi-structured interviews. To select the participants, the following structural variables were taken into account: gender, age, family responsibilities, medical specialty, professional standing, length of service, and type of contract. Interviews were tape recorded and subsequently transcribed. Finally, the content of the interviews was analyzed. RESULTS: The main psychosocial risk factors mentioned by the participants were workload and lack of staff, mainly due to the characteristics of work organization in the hospital. Another job stressor was daily contact with suffering and death, and feeling responsible for human life. Other significant job stressors were interpersonal relations in the work environment, in the case of patients' relatives, uncertainty about diagnosis and treatment, the possibility of being sued for malpractice, and communicating bad news. CONCLUSIONS: Hospital physicians report a large number of psychosocial risk factors. Some involve the characteristics of the medical profession (contact with suffering and death, responsibility for human life, uncertainty about diagnosis and treatment) and others concern work organization (workload and staffing shortages).

[Chemical, sensory and clinical characterization of lupin marmalades]. / Caracterización química, sensorial y clínica de mermelada de lupino.

Legumes are characterized as showing interesting hypoglicemic properties. Their presence in the diet is very useful in controlling the level of blood glucose in diabetic people. Taking in mind this property different formulations of prune marmalades were developed using 5, -7.5, 10 and 15% of full fat sweet lupin flour (FFLF). These samples were submitted to chemical, physical, sensory and clinical analysis. The protein content increased from 0.6 to 5.2% in direct proportion to lupin flour concentration. Energy content remained relatively constant in all formulations. The incorporation of FFLF did not affect the natural dark red prune color and pH, acidity and soluble solids values remained under the limits of Chilean food regulation laws. The samples were analyzed by a Rank preference test. Reported data showed a significative preference for the prune marmalade with 10% HEL (p < 0.05). A facial Hedonic test was used to compare the degree of acceptability between this formula and a control marmalade with fructose as edulcorant. Statistical analysis using the student test did not show significant difference (p < 0.05) between them. The hypoglycemic effect of the lupin flour was tested in seven adult non insulin dependent diabetic patients using the glucose tolerance test. Postprandial blood glucose concentration data was lower in individuals after a test meal of lupin marmalade compared to fructose marmalade. This result would allow diabetic people to eat foods such as marmalades which are known to contain a large amount of carbohydrates.