ctDNA quantification improves estimation of outcomes in patients with high-grade osteosarcoma: a translational study from the OS2006 trial.

BACKGROUND: Osteosarcoma stratification relies on clinical parameters and histological response. We developed a new personalized stratification using less invasive circulating tumor DNA (ctDNA) quantification. PATIENTS AND METHODS: Plasma from patients homogeneously treated in the prospective protocol OS2006, at diagnosis, before surgery and end of treatment, were sequenced using low-passage whole-genome sequencing (lpWGS) for copy number alteration detection. We developed a prediction tool including ctDNA quantification and known clinical parameters to estimate patients' individual risk of event. RESULTS: ctDNA quantification at diagnosis (diagCPA) was evaluated for 183 patients of the protocol OS2006. diagCPA as a continuous variable was a major prognostic factor, independent of other clinical parameters, including metastatic status [diagCPA hazard ratio (HR) = 3.5, P = 0.002 and 3.51, P = 0.012, for progression-free survival (PFS) and overall survival (OS)]. At the time of surgery and until the end of treatment, diagCPA was also a major prognostic factor independent of histological response (diagCPA HR = 9.2, P < 0.001 and 11.6, P < 0.001, for PFS and OS). Therefore, the addition of diagCPA to metastatic status at diagnosis or poor histological response after surgery improved the prognostic stratification of patients with osteosarcoma. We developed the prediction tool PRONOS to generate individual risk estimations, showing great performance ctDNA quantification at the time of surgery and the end of treatment still required improvement to overcome the low sensitivity of lpWGS and to enable the follow-up of disease progression. CONCLUSIONS: The addition of ctDNA quantification to known risk factors improves the estimation of prognosis calculated by our prediction tool PRONOS. To confirm its value, an external validation in the Sarcoma 13 trial is underway.

Chromatographic Fingerprinting Strategy to Delineate Chemical Patterns Correlated to Coffee Odor and Taste Attributes.

Coffee cupping includes both aroma and taste, and its evaluation considers several different attributes simultaneously to define flavor quality and therefore requires complementary data from aroma and taste. This study investigates the potential and limits of a data-driven approach to describe the sensory quality of coffee using complementary analytical techniques usually available in routine quality control laboratories. Coffee flavor chemical data from 155 samples were obtained by analyzing volatile (headspace-solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS)) and nonvolatile (liquid chromatography-ultraviolet/diode array detector (LC-UV/DAD)) fractions, as well as from sensory data. Chemometric tools were used to explore the data sets, select relevant features, predict sensory scores, and investigate the networks between features. A comparison of the Q model parameter and root-mean-squared error prediction (RMSEP) highlights the variable influence that the nonvolatile fraction has on prediction, showing that it has a higher impact on describing acid, bitter, and woody notes than on flowery and fruity. The data fusion emphasized the aroma contribution to driving sensory perceptions, although the correlative networks highlighted from the volatile and nonvolatile data deserve a thorough investigation to verify the potential of odor-taste integration.

Identifying cloud forest conservation areas in Mexico from the potential distribution of 19 representative species.

Cloud forest is a sensitive and vulnerable ecosystem that is threatened by human activities as well as climate change. Previous studies have shown how transitional ecosystems such as cloud forests will be the most negatively impacted by the global increase in temperature. Therefore, the niche modeling framework was used in this study to geographically identify the areas with the climatic potential to host the largest number of key tree species in this ecosystem and to propose them as priority conservation areas. A total of 19 species were modeled using the MaxEnt algorithm; binary maps were generated for each species and combined to produce one potential suitability map and identify climatic priority areas. Thus, 7% of the national area of Mexico shows suitability for the cloud forest ecosystem, although it is currently distributed in less than 1% of the country. Finally, potential suitability areas were compared with natural protected areas, current land use and priority conservation areas. We found that of the current suitable area, only 5% coincides with some federal or state protection regime. Natural protected areas have proven to be a mechanism for forest conservation, so we must consider increasing the number and area of those protected areas that favor the conservation of these key cloud forest species.

Unexpected acute renal injury after high-dose etoposide phosphate and total body irradiation in children undergoing hematopoietic stem cell transplantation.

High-dose etoposide phosphate, a water-soluble prodrug of etoposide, may be used after total body irradiation (TBI) in pediatric allogeneic bone marrow transplantation for lymphoblastic leukemia. In a retrospective study of 21 children treated at the Nancy University Hospital (2000-2014), we identified unprecedentedly an unexpectedly high incidence (57%) of acute renal injury following etoposide phosphate infusion. Patients who developed renal function impairment experienced more severe mucositis but had outcomes similar to those who did not. No risk factors were identified. We speculate that the etoposide phosphate diluent, dextran 40, may have been the causative agent in these post-TBI renal toxicity cases.

Long term variations measurement of electromagnetic field exposures in Alcalá de Henares (Spain).

Electromagnetic radiowave exposure is a major concern in most countries due to possible adverse health effects. Over the last 10years, many technological changes (digital television, mobile technologies, wireless networks…) have led to variations in the electromagnetic field (EMF) levels. A large number of studies devoted to the analysis of EMF levels with personal dosimeters or computer models of the exposure of mobile stations have been conducted. However, the study of the exposure values, taking into account all the existing sources, and their evolution in a wide area, using measurements, has rarely been performed. In this paper, we provide a comparison of the EMF exposure levels for the city of Alcalá de Henares (Spain) over a ten-year period using a broadband isotropic probe in the range from 100kHz to 3GHz. A statistical and spatial analysis of the measurements and their variations are also presented for the study of the global and local variations. The measured values in the period from 2006 to 2015 were ranging from 0.02 to 2.05V/m. Our global results show a moderate increase from 2006 to 2010 and they are almost invariant from 2010 to 2015. Although the whole dataset does not have relevant statistical difference, we have found marked local differences. In the city areas where the population density has remained unaltered, we have measured lower exposure levels. Conversely, new urban and industrial developments have demanded new resources, which have potentially contributed to the observed increase in the measured electric field levels within these areas.

Cytotoxic activity of hirsutanone, a diarylheptanoid isolated from Alnus glutinosa leaves.

BACKGROUND: The low efficacy of cancer therapy for the treatment of patients with advanced disease makes the development of new anticancer agents necessary. Because natural products are a significant source of anticancer drugs, it is important to explore cytotoxic activity of novel compounds from natural origin. PURPOSE: The aim of this work is to evaluate the cytotoxic capacity of hirsutanone, a diarylheptanoid isolated from Alnus glutinosa leaves. Hirsutanone cytotoxic way of action was also studied. MATERIAL AND METHODS: The cytotoxic ability of Alnus glutinosa leaves ethyl acetate extract was studied over HeLa and PC-3 cell lines, with the MTT colorimetric assay. Hirsutanone was isolated from this extract using chromatographic methods, and its structure elucidated by spectroscopic analysis. HT-29 cell viability after hirsutanone treatment was determined using SRB assay. In order to understand hirsutanone way of action, cytotoxicity was evaluated adding the diarylheptanoid and antioxidants. DNA topoisomerase II (topo II) poison activity, was also evaluated using purified topo II and a supercoiled form of DNA that bears specific topo II recognition and binding region; topo II poisons stabilize normally transient DNA-topo II cleavage complexes, and lead an increased yield of linear form as a consequence of a lack of double-strand breaks rejoining. RESULTS: The diarylheptanoid hirsutanone was isolated from Alnus glutinosa (L.) Gaertn. (Betulaceae) leaves extract that showed cytotoxic activity against PC-3 and HeLa cell lines. Hirsutanone showed cytotoxic activity against HT-29 human colon carcinoma cells. Pre-treatment with the antioxidants NAC (N-acetylcysteine) and MnTMPyP (Mn(III)tetrakis-(1-methyl-4-pyridyl)porthyrin) reduced this activity, suggesting that reactive oxygen species (ROS) participate in hirsutanone-induced cancer cell death. Using human topo II and a DNA supercoiled form, hirsutanone was found to stabilize topo II-DNA cleavage complexes, acting as a topo II poison. CONCLUSION: Our data suggest that, like curcumin, an induction of oxidative stress and topo II-mediated DNA damage may play a role in hirsutanone-induced cancer cell death. Since both compounds share similar structure and cytotoxic profile, and curcumin is in clinical trials for the treatment of cancer, our results warrant further studies to evaluate the anticancer potential of hirsutanone.

[Results of treatment of scaphoid nonunion with microvascularized bone grafts of the 1, 2 intercompartmental supraretinacular artery and osteosynthesis]. / Resultados del tratamiento de seudoartrosis de escafoides con injerto microvascularizado de arteria 1,2 intercompartimental suprarretinacular y osteosíntesis.

OBJECTIVE: To analyze the results of treatment of scaphoid nonunion with questionable viability of the proximal fragment, but without significant deformity or collapse, using a vascularized bone graft of 1,2 intercompartmental supraretinacular artery (1.2 ICSRA) and subsequent osteosynthesis. MATERIAL AND METHOD: A retrospective study was performed on 10 male patients with a radiographic diagnosis of nonunion. Functionality, pain using Visual Analog Score (VAS), grip strength, patient satisfaction and reintroduction to working life, using QuickDASH and May specific wrist scales were assessed after the treatment. The integration of the graft was checked by radiography. RESULTS: The mean follow-up was 31.4 months, and 90% of the questionnaires were satisfactory. The VAS decreased by 4.6 points and the flexor-extensor mobility gain was 5°. The total graft consolidation rate reached 40% in 5.5 months on average. DISCUSSION: Several studies have demonstrated better results using vascularized bone graft versus non-vascularized. From the description by Zaidemberg in 1991, the vascularized graft with 1.2 ICSRA artery, distal radius, has been the most widely used for the treatment of scaphoid nonunion. CONCLUSIONS: Our results are comparable with the literature reviewed, thus using vascular graft of the 1.2 ICSRA and osteosynthesis with Herbert-type screw, may be an alternative treatment for proximal scaphoid nonunion, without collapse or significant deformity.

Assessing the measurement error properties of interviewer observations of neighbourhood characteristics.

Interviewer observations made during the process of data collection are currently used to inform responsive design decisions, to expand the set of covariates for nonresponse adjustments, to explain participation in surveys, and to assess nonresponse bias. However, little effort has been made to assess the quality of such interviewer observations. Using data from the Los Angeles Family and Neighbourhood Survey (L.A.FANS), this paper examines measurement error properties of interviewer observations of neighbourhood characteristics. Block level and interviewer covariates are used in multilevel models to explain interviewer variation in the observations of neighbourhood features.

Casein induces the proliferation of bone marrow mononuclear cells, apoptosis of WEHI-3 leukaemic cells and increased survival in a leukaemia mouse model.

Acute myeloid leukaemia results from the neoplastic transformation of haematopoietic stem cells. Although advances have been made in its treatment, the mortality rate remains high. As a result, therapeutic alternatives continue to be explored. In this study, we present evidence that suggests that casein, the principal protein in milk, possesses significant antileukaemic properties. We investigated whether casein inhibited the in vitro proliferation and induced the apoptosis of the mouse myelomonocytic leukaemia cell line WEHI-3. By contrast, under identical conditions, casein markedly promotes the proliferation of mouse normal mononuclear bone marrow cells. Since the selective elimination of leukaemia cells is an ideal therapeutic strategy, we also evaluated the antileukaemic potential of casein in vivo. The results showed that casein increases the survival of mice bearing WEHI-3-induced tumours, suggesting that this molecule is also capable of inhibiting the proliferation of these cells in vivo. The evidence that casein inhibited cell proliferation and induced apoptosis in leukaemia cells in vitro, but increased survival in vivo in a leukaemia mouse model, indicates that casein may be useful in leukaemia therapy.

mfERG_LAB: Software for processing multifocal electroretinography signals.

The multifocal electroretinography technique consists of performing sectorized light excitation of the retina and capturing the resulting evoked potential. This provides functional localized information about the state of the retinal neurons. Analysis of multifocal electroretinography signals can be used for diagnosing different types of optic neuropathies (glaucomatous, demyelinating and ischemic ethiology). In order to obtain a reliable diagnosis, it is necessary to apply advanced processing algorithms (morphological, frequency and time-frequency analysis, etc.) to the multifocal electroretinography signal. This paper presents a software application developed in MATLAB(®) (MathWorks Inc., MA) designed to perform advanced multifocal electroretinography signal analysis and classification. This intuitive application, mfERG_LAB, is used to plot the signals, apply various algorithms to them and present the data in an appropriate format. The application's computational power and modular structure make it suitable for use in clinical settings as a powerful and innovative diagnostic tool, as well as in research and teaching settings as a means of assessing new algorithms.

[Pancreatitis in cystic fibrosis: association with genotype and pancreatic status]. / Pancreatitis en la fibrosis quística: correlación con el genotipo y estado pancreático.

INTRODUCTION: Pancreatitis is an uncommon complication of cystic fibrosis (CF). Either single or recurrent acute episodes can occur and it occasionally may follow a protracted course with relentless destruction of the pancreas. Moreover mild mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been found in many cases of idiopathic chronic pancreatitis. We describe a group of patients with CF who had one or more episodes of pancreatitis. We have estimated its prevalence in a large population of patients with CF across Spain. METHODS: A retrospective descriptive study was conducted by collecting the demographic, clinical and laboratory data, pancreatic status and genotype of CF patients who attended the CF Units in 5 Spanish hospitals. RESULTS: The overall number of CF patients under follow-up in the five centres was 520, of which 17 cases with pancreatitis were identified. The prevalence of pancreatitis in this population was 3.3%, higher than previously reported. Noticeably eight of the 17 patients (47.06%) had pancreatic insufficiency. This appears to be, partly, in contrast with that classically found, as this complication is usually associated with patients with a certain level of pancreatic reserve. No associations with genotype, age, gender or other factors were found. CONCLUSIONS: The prevalence of pancreatitis in our CF patients was higher than that found in other CF populations, and was not limited to patients with pancreatic sufficiency. It occurred mostly in teenagers and young adults often with mild pulmonary disease. The CF genotype was variable. The course of the patients should be carefully monitored, and further information on the long-term outcome of larger cohorts of patients is needed.

Quantitative determination of some volatile suspected allergens in cosmetic creams spread on skin by direct contact sorptive tape extraction-gas chromatography-mass spectrometry.

This study describes a method based on direct contact sorptive tape extraction followed by on-line thermal desorption gas chromatography-mass spectrometry (DC-STE-GC-MS) to detect and quantify a group of suspected volatile allergens on the European Union (E.U.) list and a related compound on the skin (the stratum corneum) of volunteers treated with a cream of known composition fortified with the reference allergens. The following compounds were tested: citronellol, Z-citral (neral), geraniol, cinnamaldehyde, anisyl alcohol, cinnamyl alcohol, eugenol, methyleugenol, coumarin, isoeugenol, alpha-isomethylionone, 2-(4-tert-butylbenzyl)propionaldehyde (lilial), alpha-amylcinnamaldehyde, alpha-hexylcinnamaldehyde. Sorptive tape extraction (STE) is a sorption-based sampling technique in which a flexible polydimethylsiloxane (PDMS) tape is used to recover analytes by direct contact with the surface of a solid matrix or from the headspace in equilibrium with it. The reliability of the method was confirmed by: (i) allergen recoveries varying from 52.3% for lilial to 95.7% for neral, (ii) linearity in the range 10-150ppm, with regression coefficient R(2) always above 0.97, (iii) repeatability of each analyte, RSD% never exceeding 10%, (iv) intermediate precision, always below 15%, and (v) LOD and LOQ in the ppb range, therefore fully compatible with E.U. prescriptions (ppm). Other parameters such as substantivity analyte, approximate permeation through skin and influence of different nature of stratum corneum on recovery were also investigated. The method was also successfully applied to five commercially available creams declared to contain some of the allergens in question spread on the skin of the same volunteers.

Analysis of environmental endocrine disrupting chemicals using the E-screen method and stir bar sorptive extraction in wastewater treatment plant effluents.

Endocrine disrupting chemicals (EDCs) have become a major issue in the field of environmental science due to their ability to interfere with the endocrine system. Recent studies show that surface water is contaminated with EDCs, many released from wastewater treatment plants (WWTP). This pilot study used biological (E-screen assay) and chemical (stir bar sorptive extraction-GC-MS) analyses to quantify estrogenic activity in effluent water samples from a municipal WWTP and in water samples of the recipient river, upstream and downstream of the plant. The E-screen assay was performed on samples after solid phase extraction (SPE) to determine total estrogenic activity; the presence of estrogenic substances can be evaluated by measuring the 17-beta-estradiol equivalency quantity (EEQ). Untreated samples were also assayed with an acute toxicity test (Vibrio fischeri) to study the correlation between toxicity and estrogenic disruption activity. Mean EEQs were 4.7 ng/L (+/-2.7 ng/L) upstream and 4.4 ng/L (+/-3.7 ng/L) downstream of the plant, and 11.1 ng/L (+/-11.7 ng/L) in the effluent. In general the WWTP effluent had little impact on estrogenicity nor on the concentration of EDCs in the river water. The samples upstream and downstream of the plant were non-toxic or weakly toxic (0

[Therapeutic education in asthma management]. / La educación terapéutica en el asma.

All guidelines, protocols and recommendations underline the importance of therapeutic education as a key element in asthma management and control. Considerable evidence supports the efficacy and effectiveness of this measure. Health personnel, as well as patients and their parents, can and should be educated with two main objectives: to achieve the best possible quality of life and to allow self control of the disease. These goals can be attained through an educational process that should be individually tailored, continuous, progressive, dynamic, and sequential. The process poses more than a few difficulties involving patients, health professionals, and the health systems. Knowledge of the various psychological factors that can be present in asthmatic patients, as well as the factors related to the highly prevalent phenomenon of non-adherence, is essential. Awareness of the factors influencing physician-patient-family communication is also highly important to achieve the objectives set in therapeutic education. The educational process helps knowledge and abilities to be acquired and allows attitudes and beliefs to be modified. Patients and caregivers should be provided with an individual written action plan based on symptoms and/or forced expiratory volume in 1 second. Periodic follow-up visits are also required.

Sorptive tape extraction in the analysis of the volatile fraction emitted from biological solid matrices.

Sorptive tape extraction (STE) is a recent sorption-based sampling technique in which a flexible polydimethylsiloxane (PDMS) tape is used to recover analytes at the surface of a solid matrix by direct contact as well as from the headspace in equilibrium with it. Solutes thus enriched on the inert PDMS material can be recovered either by solvent desorption or by thermo-desorption. The concentration capability of both direct contact and headspace STE was evaluated by sampling (a) aromatic plants to study the reaction of a vegetable matrix submitted to stress, and (b) fruits at the surface of the pulp or inside the pulp; the composition of the volatile fraction released from the skin when a perfume is sprayed on the back of the hand was also studied. The concentration capability of direct contact and headspace STE was compared to that of HSSE with a 20 microL PDMS twister and HS-SPME with a PDMS 100 microm fibre, by determining the relative abundances (RA) of the characterizing components of the aromatic plants under investigation. Repeatability and influence of tape surface on STE recovery were also evaluated.

[Nephrolitiasis in a patient with cystic fibrosis]. / Nefrolitiasis en un paciente con fibrosis quística.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Defects in the CFTR gene cause abnormal chloride conductance across the apical membrane of epithelial cells, which results in progressive lung disease and also affects other organs. Because life expectancy has increased, other complications of CF have become more apparent. We present a patient with CF and symptomatic nephrolithiasis. Several stones were evident in both kidneys. A 24-hour urine sample showed hyperoxaluria (141 mg/24 h/ 1.73 m(2)) and hypocitraturia and (206 mg/24 h/1.73 m(2), 177 mg citrate/g creatinine). Nephrolithiasis should be included in the differential diagnosis of patients with CF and abdominal pain; urinary excretion of oxalate and citrate should be investigated.

High-speed gas chromatography with direct resistively-heated column (ultra fast module-GC)-separation measure (S) and other chromatographic parameters under different analysis conditions for samples of different complexities and volatilities.

The influence of GC speed on the separation capability of a chromatographic system is reported measuring a series of parameters including separation measure (S), peak capacity (n), peak width (w), analysis time, t(b) (determined on the last eluting compound) and separation measure/analysis time ratio (S/t(b)) determined by analyzing a bergamot essential oil sample and a standard mixture of pesticides. Conventional GC, fast GC (with 10 m (FGC10) and 5 m (FGC5) narrow-bore columns), and direct resistively-heated ultra fast module-GC (UFM-GC) were the GC speed approaches used. The influence of different heating rates with a constant flow for FGC5, FGC 10, and UFM-GC and with variable flows for UFM-GC on S, n, w, S/t(b), and t(b) was also studied. The results of this study show that: (a) separation capability of the chromatographic system (i.e. S and n) and analysis time depend on the GC approaches. Within each GC approach, S and n and analysis time depend on the heating rates, although to a different extent, and S and n decrease much less than the gain in analysis time, in particular when fast heating rates are applied; (b) in UFM-GC, the loss of separation capability with heating rate can also be partially compensated by the choice of an appropriate flow rate that, within each heating rate, may contribute to increase S while reducing t(b); (c) within a specific GC approach, the chromatographic system (column and stationary phase) and conditions (heating and flow rates) must be such to achieve a suitable S-value when two analytes must be separated with a given resolution in a minimum analysis time.

Cytotoxic activity of five compounds isolated from Colombian plants.

Cytotoxic effect of five known compounds, khellin, berberine, lupeol, scopolin, rapanone, obtained from Colombian plants, were determined against human tumor cell lines as an indicator of the potential anticancer activity of these compounds. Berberine and rapanone presented interesting cytotoxicity.

Female choice of sexually antagonistic male adaptations: a critical review of some current research.

We contrast some recent uses of the concept of male-female conflict, with the type of conflict that is inherent in traditional Darwinian female choice. Females in apparent conflict situations with males may suffer reduced lifetime reproduction, but nevertheless benefit because they obtain sons with superior manipulative abilities. Female defences against male manipulations may not be 'imperfect' because of inability to keep pace with male evolution, but in order to screen males and favour those that are especially good manipulators. We examine the consequences of these ideas, and of the difficulties of obtaining biologically realistic measures of female costs, for some recent theoretical and empirical presentations of male-female conflict ideas, and find that male-female conflict in the new sense is less certain than has been commonly supposed. Disentangling previous sexual selection ideas and the new conflict of interest models will probably often be difficult, because the two types of payoffs are not mutually exclusive.