Microglia-glioblastoma interactions: New role for Wnt signaling.

Glioblastoma, the most aggressive and fatal type of brain tumor, is capable of interacting with brain immune cells such as microglia, which contributes to the growth of these tumors. Various molecules, including growth factors and cytokines, have been identified as regulators of microglia-glioblastoma interaction. Recent studies suggest that the Wnt family of lipoglycoproteins plays an important role, not only in biological events during development, but also in cancer progression, and can be part of microglia recruitment to glioblastoma as well as of tumor growth and invasion. Here, we discuss recent interesting findings that support a role for Wnt signaling pathways in the microglia-glioblastoma crosstalk.

Defining sepsis on the wards: results of a multi-centre point-prevalence study comparing two sepsis definitions.

Our aim was to prospectively determine the predictive capabilities of SEPSIS-1 and SEPSIS-3 definitions in the emergency departments and general wards. Patients with National Early Warning Score (NEWS) of 3 or above and suspected or proven infection were enrolled over a 24-h period in 13 Welsh hospitals. The primary outcome measure was mortality within 30 days. Out of the 5422 patients screened, 431 fulfilled inclusion criteria and 380 (88%) were recruited. Using the SEPSIS-1 definition, 212 patients had sepsis. When using the SEPSIS-3 definitions with Sequential Organ Failure Assessment (SOFA) score ≥ 2, there were 272 septic patients, whereas with quickSOFA score ≥ 2, 50 patients were identified. For the prediction of primary outcome, SEPSIS-1 criteria had a sensitivity (95%CI) of 65% (54-75%) and specificity of 47% (41-53%); SEPSIS-3 criteria had a sensitivity of 86% (76-92%) and specificity of 32% (27-38%). SEPSIS-3 and SEPSIS-1 definitions were associated with a hazard ratio (95%CI) 2.7 (1.5-5.6) and 1.6 (1.3-2.5), respectively. Scoring system discrimination evaluated by receiver operating characteristic curves was highest for Sequential Organ Failure Assessment score (0.69 (95%CI 0.63-0.76)), followed by NEWS (0.58 (0.51-0.66)) (p < 0.001). Systemic inflammatory response syndrome criteria (0.55 (0.49-0.61)) and quickSOFA score (0.56 (0.49-0.64)) could not predict outcome. The SEPSIS-3 definition identified patients with the highest risk. Sequential Organ Failure Assessment score and NEWS were better predictors of poor outcome. The Sequential Organ Failure Assessment score appeared to be the best tool for identifying patients with high risk of death and sepsis-induced organ dysfunction.

Polymorphisms of genes encoding P2X7R, IL-1B, OPG and RANK in orthodontic-induced apical root resorption.

OBJECTIVE: Orthodontic-induced external apical root resorption (EARR) is a complex phenotype determined by poorly defined mechanical and patient intrinsic factors. The aim of this work was to construct a multifactorial integrative model, including clinical and genetic susceptibility factors, to analyze the risk of developing this common orthodontic complication. MATERIALS AND METHODS: This retrospective study included 195 orthodontic patients. Using a multiple-linear regression model, where the dependent variable was the maximum% of root resorption (%EARRmax) for each patient, we assessed the contribution of nine clinical variables and four polymorphisms of genes involved in bone and tooth root remodeling (rs1718119 from P2RX7, rs1143634 from IL1B, rs3102735 from TNFRSF11B, encoding OPG, and rs1805034 from TNFRSF11A, encoding RANK). RESULTS: Clinical and genetic variables explained 30% of%EARRmax variability. The variables with the most significant unique contribution to the model were: gender (P < 0.05), treatment duration (P < 0.001), premolar extractions (P < 0.01), Hyrax appliance (P < 0.001) and GG genotype of rs1718119 from P2RX7 gene (P < 0.01). Age, overjet, tongue thrust, skeletal class II and the other polymorphisms made minor contributions. CONCLUSION: This study highlights the P2RX7 gene as a possible factor of susceptibility to EARR. A more extensive genetic profile may improve this model.

Immune monitoring of islet and pancreas transplant recipients.

Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing beta-cells are destroyed. Islet or pancreas transplantation can restore insulin secretion and are established therapies for subgroups of T1D patients. Long-term insulin-independence is, however, hampered by recurrent autoimmunity and rejection. Accurate monitoring of these immune events is therefore of critical relevance for the timely detection of deleterious immune responses. The identification of relevant immune biomarkers of allo- and autoreactivity has allowed a more accurate monitoring of disease progression and responses to therapy at early stages, allowing proper therapeutic intervention, and possibly improvements in the success rate of islet and pancreas transplantation. This review describes the tools established and validated to monitor immune correlates of auto- and alloreactivity that associate with clinical outcome and identifies challenges that current immunosuppression strategies trying to preserve islet graft function face.

Treatment of exudative age-related macular degeneration with intravitreal ranibizumab in clinical practice: a 3-year follow-up.

PURPOSE: To evaluate the 36-month efficacy of intravitreal ranibizumab injections for choroidal neovascularization secondary to age-related macular degeneration (AMD) in real world clinical practice. METHODS: Retrospective study involving 84 eyes of 77 patients; 52 eyes completed 3 years of follow-up. Subjects were observed initially on a monthly basis and with extended follow-up intervals if signs of quiescence were detected, according to an established protocol. A comprehensive ophthalmologic examination was performed, including best-corrected visual acuity (BCVA) determined with Early Treatment Diabetic Retinopathy Study charts, stereoscopic macular biomicroscopy and optical coherence tomography (OCT) with fluorescein angiography and indocyanine green angiography if considered necessary. Treatment was given if signs of active lesions were present. RESULTS: The mean baseline BCVA was 49.33 and 49.52 letters at the 36-month visit. The average of treatments was 8.6 at 3 years. At this time point, 77% of treated eyes stabilized or improved their vision (VA loss ≤ 5 letters). A predictive value for better VA was found for younger age, better baseline VA, good response on OCT and more frequent treatments. CONCLUSION: At 3 years, intravitreal ranibizumab is able to maintain baseline VA in exudative AMD patients, with a reduced number of injections, but not to show VA improvement, in clinical practice.

CD8 T cell autoreactivity to preproinsulin epitopes with very low human leucocyte antigen class I binding affinity.

Beta cells presenting islet epitopes are recognized and destroyed by autoreactive CD8 T cells in type 1 diabetes. These islet-specific T cells are believed to react with epitopes binding with high affinity to human leucocyte antigen (HLA) expressed on beta cells. However, this assumption might be flawed in case of islet autoimmunity. We evaluated T cell recognition of the complete array of preproinsulin (PPI) peptides with regard to HLA binding affinity and T cell recognition. In a comprehensive approach, 203 overlapping 9-10mer PPI peptides were tested for HLA-A2 binding and subjected to binding algorithms. Subsequently, a high-throughput assay was employed to detect PPI-specific T cells in patient blood, in which conditional HLA ligands were destabilized by ultraviolet irradiation and HLA molecules refolded with arrays of PPI peptides, followed by quantum-dot labelling and T cell staining. Analysis of patient blood revealed high frequencies of CD8 T cells recognizing very low HLA binding peptides. Of 28 peptides binding to HLA-A2, a majority was predicted not to bind. Unpredicted peptides bound mainly with low affinities. HLA binding affinity and immunogenicity may not correlate in autoimmunity. Algorithms used to predict high-affinity HLA peptide binders discount the majority of low-affinity HLA binding epitopes. Appreciation that peptides binding HLA with very low affinity can act as targets of autoreactive T cells may help to understand loss of tolerance and disease pathogenesis and possibly point to tissue-specific immune intervention targets.

Stress responses of the endemic freshwater cururu stingray (Potamotrygon cf. histrix) during transportation in the Amazon region of the Rio Negro.

Potamotrygon cf. histrix (cururu stingray) are endemic freshwater stingrays from the middle region of the Rio Negro in the Brazilian Amazon basin and are exported worldwide as ornamentals caught by artisanal fishermen. The transport process from capture to final destination is long and stressful. This study quantified stress related changes in corticosterone, blood and water samples (baseline, pre-transport, 3h, 12h and 24h) analyzed during a transport experiment which tested two water additives (tetracycline and the probiotic Efinol). There was a significant stepwise increase in corticosterone levels in stingrays over transport time in combination with osmoregulatory disturbances suggesting a stress related role of this corticosteroid. There were significant increases in water conductivity, Na(+) and K(+) losses and ammonia excretion. Blood parameters such as glucose, hematocrit, red blood count and urea did not change significantly during the experiment. Glucose levels did not increase significantly during transport and this may be due to the fact that other elasmobranchs have been shown to rely more on ketone bodies for energy rather than glucose and produce ammonia as their main nitrogenous waste. The mineralocorticoid action of this hormone has been shown in elasmobranchs and most likely plays a role in osmotic homeostasis. The use of probiotic and especially antibiotic should be avoided since no beneficial effects were observed.

Complementary hydropathy identifies a cellular prion protein receptor.

Prions, the etiological agents for infectious degenerative encephalopathies, act by entering the cell and inducing conformational changes in PrPC (a normal cell membrane sialoglycoprotein), which result in cell death. A specific cell-surface receptor to mediate PrPC and prion endocytosis has been predicted. Complementary hydropathy let us generate a hypothetical peptide mimicking the receptor binding site. Antibodies raised against this peptide stain the surface of mouse neurons and recognize a 66-kDa membrane protein that binds PrPC both in vitro and in vivo. Furthermore, both the complementary prion peptide and antiserum against it inhibit the toxicity of a prion-derived peptide toward neuronal cells in culture. Such reagents might therefore have therapeutic applications.

Age-related macular degeneration and risk factors for the development of choroidal neovascularisation in the fellow eye: a 3-year follow-up study.

INTRODUCTION: The presence of large-sized drusen (≥125 µm), soft indistinct drusen, pigmentary changes, a large area of drusen and a choroidal neovascular membrane in one eye have been found to be predictive risk factors of late exudative age-related macular degeneration (AMD). Multimodal imaging potentially increases the possibility of indentifying further potential risk factors of developing wet AMD. PURPOSE: To identify morphological and/or functional baseline risk factors for the development of choroidal neovascularization (CNV) in a multimodal set of images from fellow eyes of patients with exudative AMD. METHODS: Single-center, prospective, observational, longitudinal 2-year plus 1-year extension study of 62 patients with neovascular AMD in one eye (the nonstudy eye) and early age-related maculopathy (ARM) in the fellow eye (study eye). Best-corrected ETDRS visual acuity, fluorescein angiography (FA) and indocyanine green angiography (ICG), fundus photography, retinal leakage analysis, fundus autofluorescence imaging and optical coherence tomography (OCT Stratus 4.0.2, Carl Zeiss Meditech Inc.) were performed at baseline and every 6 months in order to identify both conversion to CNV as well as possible predictive features present before conversion. A semiautomated computer-assisted grading system was used for classifying fundus color images. Only eyes with 3 years of follow-up were considered for statistical analysis. RESULTS: Fifty-two patients completed the 3-year study follow-up: 26 men and 26 women aged from 56 to 92 years (mean ± SD: 76 ± 6 years). CNV confirmed with FA developed in 46% of the 52 study eyes during the 3-year follow-up (24 converted eyes: 7 in the first year, 11 in the second and 6 in the third). A significantly higher risk for conversion to wet AMD was found only for leakage on a retinal leakage analyzer (odds ratio, OR = 5.0; 95% confidence interval, CI = 1.5-16.4; p = 0.006) detected at least in one visit before the onset of exudative lesions, for baseline ICG hot spots (OR = 7.2; 95% CI = 2.0-25.7; p = 0.002), baseline late ICG hot spots (OR = 4.7; 95% CI = 1.4-15.4; p = 0.009) and baseline early ICG hypofluorescent spots (OR = 3.7; 95% CI = 1.2-12.1; p = 0.025). The total area of drusen, the area of drusen in subfield 1, inner circle or outer circle, the total number of drusen and the number of drusen ≥125 µm, fundus autofluorescence patterns, OCT findings and the severity of ARM at baseline did not show any correlation with an increased risk of conversion to wet AMD. CONCLUSION: At 3 years, progression from early to late exudative AMD was superior to the expected rate (44%). ICG early and late hyperfluorescent spots or areas, ICG early hypofluorescent spots or areas and early leakage detected with the retinal leakage analyzer, but not pigmentary changes, large drusen, number and area of drusen at any location or a greater severity of ARM at baseline, showed to be a predictive parameter of conversion to wet AMD.

Nanoscale physico-mechanical properties of an aging resistant ZTA composite.

OBJECTIVE: To characterize the effects of aging on the nanomechanical properties and 3D surface topographical parameters of an experimental Zirconia Toughened Alumina (ZTA) composite compared to its respective individual counterpart materials. METHODS: Disk-shaped specimens comprised of three material groups were processed: 1) ZTA 70/30 (70% alumina reinforced with 30% second-generation 3Y-TZP); 2) Zpex (Second-generation 3Y-TZP), and; 3) Al2O3 (High purity Alumina) (n = 10/material, 12 × 1 mm). After synthesis, ceramic powders were pressed, the green-body samples were sintered and polished. Nanoindentation testing was performed to record elastic modulus (E) and hardness (H). Interferometry was utilized to assess 3D surface roughness parameters (Sa, Sq), while X-ray diffraction (XRD) and scanning electron microscope (SEM) assessed the crystalline content and microstructure. All tests were performed before and after simulated aging (134°C, 2.2 bar, 20 h). Statistical analyses were performed using linear mixed-model and least square difference pos-hoc tests (α = 5%). RESULTS: XRD spectra indicated increase of monoclinic peaks for Zpex (~18%) relative to ZTA 70/30 (~2.5%) after aging. Additionally, aging did not affect the surface roughness parameters of ZTA 70/30 and Al2O3, although a significant increase in Sa was recorded for Zpex following aging (~90 nm) (p < 0.001). Al2O3 yielded the highest H and E values (H:21 GPa, E: 254 GPa), followed by ZTA 70/30 (H: 13 GPa, E: 214 GPa) and Zpex (H:11 GPa, E: 167 GPa), all significantly different (p < 0.03). CONCLUSION: ZTA 70/30 and Al2O3 presented high hydrothermal stability with respect to all evaluated variables, where artificial aging significantly increased the monoclinic content and surface roughness of Zpex.

[Endoscopic techniques in bronchogenic carcinoma. Changes in recent decades]. / Técnicas endoscópicas en carcinoma broncogénico. Cambios en las últimas décadas.

A 57-year old woman with arterial hypertension under treatment. She has smoked since she was 18 years old with an accumulated index of 70 years/pack. She was studied in our Respiratory Department due to constitutional syndrome, the X-ray showing an image of focal pulmonary lesion in the right upper lobe of more than 3cm of peripheral location. The computed tomography (CT) scan confirmed the existence of a 3.3cm mass in the upper right lobe and detected paratracheal and subcarinal mediastinal abnormal lymph nodes. A subsequent Positron Emission Tomography (PET) confirmed pathological uptake of the mass and both lymph node locations. Which additional studies do you consider to be indicated for a correct diagnosis and mediastinal staging? Do bronchoscopy techniques alone establish the final diagnosis and staging of this patient?

SAFIIRA: A heavy-ion multi-purpose irradiation facility in Brazil.

This work describes the new facility for applied nuclear physics at the University of Sao Paulo, mainly for irradiation of electronic devices. It is a setup composed of a quadrupole doublet for beam focusing/defocusing plus multiple scattering through gold foils to produce low intensity, large-area, and high-uniformity heavy-ion beams from 1H to 107Ag. Beam intensities can be easily adjusted from 102 particles cm2/s to hundreds of nA for an area as large as 2.0 cm2 and uniformity better than 90%. Its irradiation chamber has a high-precision motorized stage, and the system is controlled by a LabViewTM environment, allowing measurement automation. Design considerations and examples of use are presented.

A case of aspartate aminotransferase macroenzyme.

Aspartate aminotransferase (AST) macroenzyme can result in elevated AST activity in patients with no disease. This case report describes a six-year-old boy who presented to his family doctor with a history of chronic constipation and lower back pain. Routine blood tests showed normal creatine kinase activity (CK), normal alanine aminotransferase activity (ALT) but raised AST. The patient was referred to a hospital paediatrician for further investigation of the abnormal AST and back pain. The raised AST was confirmed as the only biochemical abnormality. Further investigation with polyethylene glycol, followed by measurement of AST in the supernatant, showed undetectable enzyme activity. The sample was sent to a specialist laboratory where it was analysed by Sephacryl S300 gel filtration. This procedure confirmed the presence of a high molecular mass form of AST. AST macroenzyme should be considered as a cause of isolated AST increase, which may avoid further costly investigations.

Short-term efficacy and safety of intravitreal ranibizumab for myopic choroidal neovascularization.

PURPOSE: To evaluate the safety and efficacy of intravitreal ranibizumab in the treatment of choroidal neovascularization (CNV) secondary to pathologic myopia (PM). METHODS: Retrospective, multicenter, consecutive, nonrandomized, interventional case series. PARTICIPANTS: Twenty-six eyes of 26 patients with CNV secondary to pathologic myopia; 11 eyes with previous photodynamic therapy; and 15 eyes with no previous treatment. FOLLOW-UP: 3 or more months. Best-corrected visual acuity (BCVA), ocular coherence tomography, and the presence of metamorphopsia were assessed monthly. RESULTS: At 1 month, 31% of the eyes had an improvement in visual acuity of 3 or more lines. Twenty-six eyes completed 3 months of follow-up, and nine eyes completed 6 months of follow-up. Visual acuity improved significantly from 20/100 at baseline to 20/80 at 1 month (P = 0.003) to 20/63 at 3 months (P < 0.001), and 20/50 at 6 months (P = 0.01). A significant reduction in ocular coherence tomography central thickness was observed at 1, 3, and 6 months. No cases of severe visual acuity loss occurred, and no systemic or ocular side effects were registered during the follow-up. CONCLUSION: Short-term results of intravitreal ranibizumab for myopic CNV are encouraging. Further prospective long-term studies are necessary to evaluate safety and efficacy of intravitreal ranibizumab in the treatment of myopic CNV.

Correction to: Abstracts : 29th European Congress of Pathology.

In Poster Sessions, the first-author name was missing from the authorship group originally listed for Abstract PS-01-004 (page S52), entitled "Clinicopathological features of microinvasive breast cancer". The correct authorship group is shown above.

OliveCan: A Process-Based Model of Development, Growth and Yield of Olive Orchards.

Several simulation models of the olive crop have been formulated so far, but none of them is capable of analyzing the impact of environmental conditions and management practices on water relations, growth and productivity under both well-irrigated and water-limiting irrigation strategies. This paper presents and tests OliveCan, a process-oriented model conceived for those purposes. In short, OliveCan is composed of three main model components simulating the principal elements of the water and carbon balances of olive orchards and the impacts of some management operations. To assess its predictive power, OliveCan was tested against independent data collected in two 3-year field experiments conducted in Córdoba, Spain, each of them applying different irrigation treatments. An acceptable level of agreement was found between measured and simulated values of seasonal evapotranspiration (ET, range 393 to 1016 mm year-1; RMSE of 89 mm year-1), daily transpiration (Ep, range 0.14-3.63 mm d-1; RMSE of 0.32 mm d-1) and oil yield (Yoil, range 13-357 g m-2; RMSE of 63 g m-2). Finally, knowledge gaps identified during the formulation of the model and further testing needs are discussed, highlighting that there is additional room for improving its robustness. It is concluded that OliveCan has a strong potential as a simulation platform for a variety of research applications.

[Effects of nasal positive airway pressure treatment on oxidative stress in patients with sleep apnea-hypopnea syndrome]. / Efectos del tratamiento con CPAP nasal en el estrés oxidativo en pacientes con síndrome de apnea del sueño.

OBJECTIVE: To analyze whether nasal continuous positive airway pressure (CPAP) reduces oxidative stress in patients with sleep apnea-hypopnea syndrome (SAHS). PATIENTS AND METHODS: Thirty-six patients with SAHS requiring nasal CPAP treatment and 10 controls in whom SAHS was ruled out were enrolled. Oxidative stress was evaluated by measuring plasma malondialdehyde (MDA) concentrations to assess lipid peroxidation at the beginning of the study and then again after a mean (SD) of 2.9 (0.6) months of nasal CPAP. Plasma MDA concentrations were determined by measuring thiobarbituric acid reactive substances. We controlled for the following factors known to influence oxidative stress: age, sex, use of vitamin supplements, smoking habit, body mass index (kg/m2), ischemic cardiopathy, hypertension, diabetes, and hypercholesterolemia. RESULTS: The mean age of patients with SAHS was 51.4 (9.9) years and the mean body mass index was 32.9 (5.3) kg/m2. Nasal CPAP was titrated to a mean pressure of 8.9 (3.4) cm H2O. The mean score on the Epworth sleepiness scale was 10.2 (4.3) before treatment and 4.2 (2.8) after treatment (P<.001). The apnea-hypopnea index decreased from 43.7 (22.6) before treatment to 4 (3.5) after treatment (P<.001). Mean MDA concentrations in patients with SAHS were 2.0 (1.1) micromol/mL before treatment and decreased significantly to 1.6 (.07) micromol/mL after treatment, whereas MDA concentrations remained unchanged in control subjects. CONCLUSIONS: Nasal CPAP treatment significantly reduced oxidative stress in patients with SAHS in our study.