MICB Genomic Variant Is Associated with NKG2D-mediated Acute Lung Injury and Death.

Rationale: Acute lung injury (ALI) carries a high risk of mortality but has no established pharmacologic therapy. We previously found that experimental ALI occurs through natural killer (NK) cell NKG2D receptor activation and that the cognate human ligand, MICB, was associated with ALI after transplantation. Objectives: To investigate the association of a common missense variant, MICBG406A, with ALI. Methods: We assessed MICBG406A genotypes within two multicenter observational study cohorts at risk for ALI: primary graft dysfunction (N = 619) and acute respiratory distress syndrome (N = 1,376). Variant protein functional effects were determined in cultured and ex vivo human samples. Measurements and Main Results: Recipients of MICBG406A-homozygous allografts had an 11.1% absolute risk reduction (95% confidence interval [CI], 3.2-19.4%) for severe primary graft dysfunction after lung transplantation and reduced risk for allograft failure (hazard ratio, 0.36; 95% CI, 0.13-0.98). In participants with sepsis, we observed 39% reduced odds of moderately or severely impaired oxygenation among MICBG406A-homozygous individuals (95% CI, 0.43-0.86). BAL NK cells were less frequent and less mature in participants with MICBG406A. Expression of missense variant protein MICBD136N in cultured cells resulted in reduced surface MICB and reduced NKG2D ligation relative to wild-type MICB. Coculture of variant MICBD136N cells with NK cells resulted in less NKG2D activation and less susceptibility to NK cell killing relative to the wild-type cells. Conclusions: These data support a role for MICB signaling through the NKG2D receptor in mediating ALI, suggesting a novel therapeutic approach.

Assessment of the oxidative status in mother-child couples from Seville (Spain): A prospective cohort study.

Pregnancy requires a high demand of energy, which leads to an increase of oxidative stress. The aim of this study was to assess the oxidative status in 200 couples of pregnant women-newborns at the time of delivery, for the first time, who gave birth in two University Hospitals from the province of Seville. Recruited women filled an epidemiological questionnaire with their demographic characteristics and dietary habits during pregnancy. At the time of delivery, both maternal and cord blood samples were collected. Protein oxidation, superoxide dismutase, and catalase levels were measured to assess the oxidative status of these women, together with the levels of vitamins D, B12, Zn, Se, and Cu. Our results showed a tendency for all biomarkers measured to be higher in cord blood than in maternal blood. For the correlations established between the OS markers and sociodemographic characteristics, only significant differences for carbonyl groups values were found on both maternal and cord blood, relating these higher values to the use of insecticides in the women's homes. For newborns, only a significant correlation was detected between antioxidant enzymes and the newborn's weight, specifically for superoxide dismutase activity. Additionally, the higher values obtained in cord blood might suggest metabolization, while a higher production of ROS and antioxidant enzymes might be required to maintain the balance. Measured levels for Se were similar in both maternal and cord blood, unlike Cu and Zn, where higher levels were found for maternal blood than cord blood, indicating a correlation between maternal Se values and SOD as OS biomarker. Furthermore, vitamin D levels were around the optimum values established, finding a relationship between vitamin D and new-born's height, unlike for vitamin B12 values, where a correlation with maternal food consumption characteristics was established. Overall values were inside normal ranges and consistent for our population.

Cytotoxic Effects and Oxidative Stress Produced by a Cyanobacterial Cylindrospermopsin Producer Extract versus a Cylindrospermopsin Non-Producing Extract on the Neuroblastoma SH-SY5Y Cell Line.

The incidence and interest of cyanobacteria are increasing nowadays because they are able to produce some toxic secondary metabolites known as cyanotoxins. Among them, the presence of cylindrospermopsin (CYN) is especially relevant, as it seems to cause damage at different levels in the organisms: the nervous system being the one most recently reported. Usually, the effects of the cyanotoxins are studied, but not those exerted by cyanobacterial biomass. The aim of the present study was to assess the cytotoxicity and oxidative stress generation of one cyanobacterial extract of R. raciborskii non-containing CYN (CYN-), and compare its effects with those exerted by a cyanobacterial extract of C. ovalisporum containing CYN (CYN+) in the human neuroblastoma SH-SY5Y cell line. Moreover, the analytical characterization of potential cyanotoxins and their metabolites that are present in both extracts of these cultures was also carried out using Ultrahigh Performance Liquid Chromatography-Mass Spectrometry, in tandem (UHPLC-MS/MS). The results show a reduction of cell viability concentration- and time-dependently after 24 and 48 h of exposure with CYN+ being five times more toxic than CYN-. Furthermore, the reactive oxygen species (ROS) increased with time (0-24 h) and CYN concentration (0-1.11 µg/mL). However, this rise was only obtained after the highest concentrations and times of exposure to CYN-, while this extract also caused a decrease in reduced glutathione (GSH) levels, which might be an indication of the compensation of the oxidative stress response. This study is the first one performed in vitro comparing the effects of CYN+ and CYN-, which highlights the importance of studying toxic features in their natural scenario.

Toxic effects of the cylindrospermopsin and chlorpyrifos combination on the differentiated SH-SY5Y human neuroblastoma cell line.

Due to climate change and anthropogenic activities, the levels of pollution of aquatic and terrestrial environments have increased in the last decades. In this sense, the rise of cyanobacterial blooms, which release secondary metabolites with toxic properties, and the global use of pesticides for agricultural purposes have a negative impact on ecosystems. Thus, it would be interesting to study the concomitance of both types of toxicants in the same sample, since it is possible that they appear together. The aim of the present work was to state the effects of the interaction between the cyanotoxin cylindrospermopsin and the pesticide chlorpyrifos in differentiated SH-SY5Y neuronal cells to assess how they could affect the nervous system. To this end, cytotoxicity, morphological, and acetylcholinesterase activity studies were performed during 24 and 48 h. The results revealed a concentration-dependent decrease in viability and interaction between both toxicants, together with clear signs of apoptosis and necrosis induction. In this sense, different stages on the differentiation process would lead to differences in the toxicity exerted by the compounds both isolated as in combination, which it is not observed in non-differentiated cells. Additionally, the acetylcholinesterase activity appeared not to be affected, which is a clear difference compared to non-differentiated cells. These results show the importance of studying not only the toxicants themselves, but also in combination, to assess their possible effects in a more realistic scenario.

The CD16 and CD32b Fc-gamma receptors regulate antibody-mediated responses in mouse natural killer cells.

Natural killer (NK) cells are innate lymphocytes capable of mediating immune responses without prior sensitization. NK cells express Fc-gamma receptors (FcγRs) that engage the Fc region of IgG. Studies investigating the role of FcγRs on mouse NK cells have been limited due to lack specific reagents. In this study, we characterize the expression and biological consequences of activating mouse NK cells through their FcγRs. We demonstrate that most NK cells express the activating CD16 receptor, and a subset of NK cells also expresses the inhibitory CD32b receptor. Critically, these FcγRs are functional on mouse NK cells and can modulate antibody-mediated responses. We also characterized mice with conditional knockout alleles of Fcgr3 (CD16) or Fcgr2b (CD32b) in the NK and innate lymphoid cell (ILC) lineage. NK cells in these mice did not reveal any developmental defects and were responsive to cross-linking activating NK receptors, cytokine stimulation, and killing of YAC-1 targets. Importantly, CD16-deficient NK cells failed to induce antibody-directed cellular cytotoxicity of antibody-coated B-cell lymphomas in in vitro assays. In addition, we demonstrate the important role of CD16 on NK cells using an in vivo model of cancer immunotherapy using anti-CD20 antibody treatment of B-cell lymphomas.

Methylmercury-induced DNA methylation-From epidemiological observations to experimental evidence.

Methylmercury (MeHg) is a developmental neurotoxicant, and one potential mechanism of MeHg toxicity is epigenetic dysregulation. In a recent meta-analysis of epigenome-wide association studies (EWAS), associations between prenatal MeHg exposure and DNA methylation at several genomic sites were identified in blood from newborns and children. While EWASs reveal human-relevant associations, experimental studies are required to validate the relationship between exposure and DNA methylation changes, and to assess if such changes have implications for gene expression. Herein, we studied DNA methylation and gene expression of five of the top genes identified in the EWAS meta-analysis, MED31, MRPL19, GGH, GRK1, and LYSMD3, upon MeHg exposure in human SH-SY5Y cells exposed to 8 or 40 nM of MeHg during differentiation, using bisulfite-pyrosequencing and qPCR, respectively. The concentrations were selected to cover the range of MeHg concentrations in cord blood (2-8.5 µg/L) observed in the cohorts included in the EWAS. Exposure to MeHg increased DNA methylation at MED31, a transcriptional regulator essential for fetal development. The results were in concordance with the epidemiological findings where more MED31 methylation was associated with higher concentrations of MeHg. Additionally, we found a non-significant decrease in DNA methylation at GGH, which corresponds to the direction of change observed in the EWAS, and a significant correlation of GGH methylation with its expression. In conclusion, this study corroborates some of the EWAS findings and puts forward candidate genes involved in MeHg's effects on the developing brain, thus highlighting the value of experimental validation of epidemiological association studies.

Cytotoxicity and Effects on the Synapsis Induced by Pure Cylindrospermopsin in an E17 Embryonic Murine Primary Neuronal Culture in a Concentration- and Time-Dependent Manner.

Cylindrospermopsin (CYN) is a cyanotoxin whose incidence has been increasing in the last decades. Due to its capacity to exert damage at different levels of the organism, it is considered a cytotoxin. Although the main target organ is the liver, recent studies indicate that CYN has potential toxic effects on the nervous system, both in vitro and in vivo. Thus, the aim of the present work was to study the effects of this cyanotoxin on neuronal viability and synaptic integrity in murine primary cultures of neurons exposed to environmentally relevant concentrations (0-1 µg/mL CYN) for 12, 24, and 48 h. The results demonstrate a concentration- and time-dependent decrease in cell viability; no cytotoxicity was detected after exposure to the cyanotoxin for 12 h, while all of the concentrations assayed decreased this parameter after 48 h. Furthermore, CYN was also demonstrated to exert damage at the synaptic level in a murine primary neuronal culture in a concentration- and time-dependent manner. These data highlight the importance of studying the neurotoxic properties of this cyanotoxin in different experimental models.

Influence of Self-MHC Class I Recognition on the Dynamics of NK Cell Responses to Cytomegalovirus Infection.

Although interactions between inhibitory Ly49 receptors and their self-MHC class I ligands in C57BL/6 mice are known to limit NK cell proliferation during mouse CMV (MCMV) infection, we created a 36-marker mass cytometry (CyTOF) panel to investigate how these inhibitory receptors impact the NK cell response to MCMV in other phenotypically measurable ways. More than two thirds of licensed NK cells (i.e., those expressing Ly49C, Ly49I, or both) in uninfected mice had already differentiated into NK cells with phenotypes indicative of Ag encounter (KLRG1+Ly6C-) or memory-like status (KLRG1+Ly6C+). These pre-existing KLRG1+Ly6C+ NK cells resembled known Ag-specific memory NK cell populations in being less responsive to IL-18 and IFN-α stimulation in vitro and by selecting for NK cell clones with elevated expression of a Ly49 receptor. During MCMV infection, the significant differences between licensed and unlicensed (Ly49C-Ly49I-) NK cells disappeared within both CMV-specific (Ly49H+) and nonspecific (Ly49H-) responses. This lack of heterogeneity carried into the memory phase, with only a difference in CD16 expression manifesting between licensed and unlicensed MCMV-specific memory NK cell populations. Our results suggest that restricting proliferation is the predominant effect licensing has on the NK cell population during MCMV infection, but the inhibitory Ly49-MHC interactions that take place ahead of infection contribute to their limited expansion by shrinking the pool of licensed NK cells capable of robustly responding to new challenges.

Impact of endocrine disrupting chemicals on neurodevelopment: the need for better testing strategies for endocrine disruption-induced developmental neurotoxicity.

INTRODUCTION: Brain development is highly dependent on hormonal regulation. Exposure to chemicals disrupting endocrine signaling has been associated with neurodevelopmental impairment. This raises concern about exposure to the suspected thousands of endocrine disruptors, and has resulted in efforts to improve regulation of these chemicals. Yet, the causal links between endocrine disruption and developmental neurotoxicity, which would be required for regulatory action, are still largely missing. AREAS COVERED: In this review, we illustrate the importance of two endocrine systems, thyroid hormone and retinoic acid pathways, for neurodevelopment. We place special emphasis on TH and RA synthesis, metabolism, and how endocrine disrupting chemicals known or suspected to affect these systems are associated with developmental neurotoxicity. EXPERT OPINION: While it is clear that neurodevelopment is dependent on proper hormonal functioning, and evidence is increasing for developmental neurotoxicity induced by endocrine disrupting chemicals, this is not grasped by current chemical testing. Thus, there is an urgent need to develop test methods detecting endocrine disruption in the context of neurodevelopment. Key to this development is further mechanistic insights on the involvement of endocrine signaling in neurodevelopment as well as increased support to develop and validate new test methods for the regulatory context.

Embolia de líquido amniótico asociada a paro cardiorrespiratorio recuperado y síndrome de Sheehan / Amniotic fluid embolism associated with recovered cardiac arrest and postpartum Sheehan's syndrome

Resumen La embolia de líquido amniótico es una condición catastrófica propia del embarazo que ocurre típicamente durante el parto o justo posterior a este, cuyo sustrato fisiopatológico no ha sido aclarado por completo. Se ha estimado, según cifras de los Estados Unidos, que su incidencia rondaría 1 por cada 12.953 partos, y en el Reino Unido 1 por cada 50.000 partos; sin embargo, estas cifras pueden ser imprecisas debido a que no existen una referencia ni un consenso respecto a los criterios diagnósticos, además de que el cuadro clínico se puede confundir con otras emergencias obstétricas. Se presenta el caso de una paciente sin antecedentes mórbidos que presenta un cuadro de embolia de líquido amniótico no fatal, caracterizado por un estado fetal no tranquilizador durante la inducción del trabajo de parto, seguido de un paro cardiorrespiratorio durante la cesárea de urgencia y la rápida y catastrófica aparición de signos clínicos de una coagulopatía de consumo grave. Se describen además las complicaciones posoperatorias y su manejo, entre ellas un síndrome de Sheehan y la aparición de convulsiones tónico-clónicas generalizadas con alteración de neuroimágenes.

Abstract Amniotic fluid embolism is a catastrophic pregnancy condition that typically occurs during or inmediately after delivery, and whose pathophysiological background has not been fully clarified. According to US records the incidence of amniotic fluid embolism could been around 1 for every 12,953 births and in the United Kingdom 1 for every 50,000 births, however these numbers may be imprecise because there is no gold standard as well as no consensus regarding the diagnostic criteria, in addition that the clinical presentation can be misdiagnosis with other obstetric emergencies. We present the clinical case of a patient without a morbid history who presents with a non-fatal amniotic fluid embolism, characterized by an non-reassuring fetal status during labor induction, followed by cardiorespiratory arrest during emergency cesarean section and the rapid and catastrophic appearance of clinical signs of a severe consumptive coagulopathy. Postoperative complications and their management are also described, including Sheehans syndrome and the appearance of generalized tonic-clonic seizures with impaired neuroimaging.

Caracterización de la prevalencia de la hipertensión arterial en Cuba en 2019 / Characterization of Arterial Hypertension Prevalence in Cuba in 2019

Introducción: La hipertensión arterial pudiera ser un elemento clave para la prevención de las enfermedades cardiovasculares, pues constituye su principal denominador común. Es el principal factor de riesgo, para la carga mundial de morbilidad y mortalidad. Objetivo: Caracterizar la prevalencia de hipertensión arterial en Cuba en el año 2019. Métodos: Se realizó un estudio ecológico. Se compararon las prevalencias de hipertensión arterial en las encuestas nacionales de factores de riesgo en los años 1995, 2001 y 2010 respecto a las de la dispensarización de esos años. Se tuvieron en cuenta las prevalencias totales de hipertensión arterial por grupos de edad y sexo, las de cada provincia y del municipio especial Isla de la Juventud. Los datos se procesaron de forma automatizada. Los resultados se expresaron en una tabla y gráficos. Resultados: Las prevalencias de hipertensión arterial encontradas en las encuestas nacionales de factores de riesgo superaron a las de la dispensarización en esos años. La prevalencia de hipertensión arterial se incrementó en la medida que lo hizo la edad. En el grupo de edad de 60 a 64 años, más del 75 por ciento de las personas resultaron hipertensas. En los de 25 a 59, de 65 y más y en el total predominaron las mujeres hipertensas. Conclusiones: Es preciso reducir la brecha entre los pacientes conocidos como hipertensos, dentro del sistema de salud y los que realmente son portadores de la enfermedad, conseguir el manejo adecuado de esta y con eso influir favorablemente en la morbilidad y mortalidad por enfermedades vasculares(AU)

Introduction: Hypertension could be a key element for the prevention of cardiovascular diseases, since it constitutes its main common denominator. It is the main risk factor for the global burden of morbidity and mortality. Objective: To characterize the prevalence of arterial hypertension in Cuba in 2019. Methods: An ecological study was carried out. The prevalence rates of arterial hypertension in the national surveys of risk factors in the years 1995, 2001 and 2010 were compared to those of the dispensarization carried out in those years. The total prevalence rates of arterial hypertension were taken into account by age groups and sex, considering also those of each province and of the special municipality of Isla de la Juventud. The data was processed automatically. The results were expressed in a table and in graphs. Results: The prevalence rates of arterial hypertension found in the national surveys of risk factors exceeded those of dispensarization in those years. The prevalence of hypertension increased with age. In the age group 60-64 years, more than 75 percent of people were hypertensive. In those aged 25-59, 65 and over, as well as in the total, hypertensive women predominated. Conclusions: It is necessary to reduce, within the health system, the gap between patients known as hypertensive and those who really are carriers of the disease, to achieve proper management of this and, thus, to have a favorable influence on morbidity and mortality from vascular diseases(AU)

Nutritional Quality of the Most Consumed Varieties of Raw and Cooked Rice in Spain Submitted to an In Vitro Digestion Model.

Rice is one of the most consumed staple foods around the world and its trade is highly globalized. Increased environmental pollution generates a large amount of waste that, in many cases, is discarded close to culture fields. Some species are able to bioaccumulate toxic substances, such as metals, that could be transferred to the food chain. The main goal of this study was to evaluate the content of metallic (Al, Cd, Pb, and Cr) and metalloid elements (As) in 14 of the most consumed varieties of rice in Spain and their effects on human health. The samples were cooked, and human digestion was simulated by using a standard in vitro digestion method. Metallic and metalloid element levels were analysed by Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES), previous called microwave digestion. Both the human health risk index, Hazard Quotient, and Lifetime Cancer Risk did not show toxic values in any case. Rice with a higher non-digestible fraction showed a higher liberation of proteins and a lower glycemic index. There were no significant differences in the concentrations of metallic and metalloid elements in cooked rice or in the digestible fraction in all varieties analysed. However, Al concentrations were higher than other metals in all varieties studied due to its global distribution. No relationship has been observed between the digestibility of rice and the bioaccessibility of each metallic and metalloid element. All of the studied rice varieties are healthy food products and its daily consumption is safe. The regular monitoring of metals and As in rice consumed in Spain may contribute to improvements in the human health risk evaluation.

Acute effects of the imidacloprid metabolite desnitro-imidacloprid on human nACh receptors relevant for neuronal signaling.

Several neonicotinoids have recently been shown to activate the nicotinic acetylcholine receptor (nAChR) on human neurons. Moreover, imidacloprid (IMI) and other members of this pesticide family form a set of diverse metabolites within crops. Among these, desnitro-imidacloprid (DN-IMI) is of special toxicological interest, as there is evidence (i) for human dietary exposure to this metabolite, (ii) and that DN-IMI is a strong trigger of mammalian nicotinic responses. We set out here to quantify responses of human nAChRs to DN-IMI and an alternative metabolite, IMI-olefin. To evaluate toxicological hazards, these data were then compared to those of IMI and nicotine. Ca2+-imaging experiments on human neurons showed that DN-IMI exhibits an agonistic effect on nAChRs at sub-micromolar concentrations (equipotent with nicotine) while IMI-olefin activated the receptors less potently (in a similar range as IMI). Direct experimental data on the interaction with defined receptor subtypes were obtained by heterologous expression of various human nAChR subtypes in Xenopus laevis oocytes and measurement of the transmembrane currents evoked by exposure to putative ligands. DN-IMI acted on the physiologically important human nAChR subtypes α7, α3ß4, and α4ß2 (high-sensitivity variant) with similar potency as nicotine. IMI and IMI-olefin were confirmed as nAChR agonists, although with 2-3 orders of magnitude lower potency. Molecular docking studies, using receptor models for the α7 and α4ß2 nAChR subtypes supported an activity of DN-IMI similar to that of nicotine. In summary, these data suggest that DN-IMI functionally affects human neurons similar to the well-established neurotoxicant nicotine by triggering α7 and several non-α7 nAChRs.

Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons.

Neonicotinoid pesticides, originally developed to target the insect nervous system, have been reported to interact with human receptors and to activate rodent neurons. Therefore, we evaluated in how far these compounds may trigger signaling in human neurons, and thus, affect the human adult or developing nervous system. We used SH-SY5Y neuroblastoma cells as established model of nicotinic acetylcholine receptor (nAChR) signaling. In parallel, we profiled dopaminergic neurons, generated from LUHMES neuronal precursor cells, as novel system to study nAChR activation in human post-mitotic neurons. Changes of the free intracellular Ca2+ concentration ([Ca2+]i) were used as readout, and key findings were confirmed by patch clamp recordings. Nicotine triggered typical neuronal signaling responses that were blocked by antagonists, such as tubocurarine and mecamylamine. Pharmacological approaches suggested a functional expression of α7 and non-α7 nAChRs on LUHMES cells. In this novel test system, the neonicotinoids acetamiprid, imidacloprid, clothianidin and thiacloprid, but not thiamethoxam and dinotefuran, triggered [Ca2+]i signaling at 10-100 µM. Strong synergy of the active neonicotinoids (at low micromolar concentrations) with the α7 nAChR-positive allosteric modulator PNU-120596 was observed in LUHMES and SH-SY5Y cells, and specific antagonists fully inhibited such signaling. To provide a third line of evidence for neonicotinoid signaling via nAChR, we studied cross-desensitization: pretreatment of LUHMES and SH-SY5Y cells with active neonicotinoids (at 1-10 µM) blunted the signaling response of nicotine. The pesticides (at 3-30 µM) also blunted the response to the non-α7 agonist ABT 594 in LUHMES cells. These data show that human neuronal cells are functionally affected by low micromolar concentrations of several neonicotinoids. An effect of such signals on nervous system development is a toxicological concern.

Validation of a population pharmacokinetic model of adalimumab in a cohort of patients with inflammatory bowel disease

Background: therapeutic monitoring of anti-TNF drugs and anti-drug antibody levels are useful for clinical decision-making, via the rationalization and optimization of the use of anti-TNF treatments. The objective of the present study was to validate the model of Ternant et al., in a cohort of patients with inflammatory bowel diseases (IBD). This model was originally established for patients with rheumatoid arthritis and was used in this study to optimize the adalimumab (ADA) dose and predict ADA trough levels (ATL). Methods: this study used concentration data points from 30 IBD patients who received ADA treatment between 2014 and 2015. A goodness-of-fit of the model was determined by evaluating the relationship between the observed ATL values and population model-predicted values (PRED) or individual model-predicted values (IPRED). Results: a total of 51 ADA concentration points were analyzed. The bias of the model was 2.39 (95% CI, 1.63-3.15) for PRED and 0.63 (95% CI, 0.23-1.03) for IPRED. The precision was 3.57 (95% CI, 2.90-4.13) and 1.53 (95% CI, 1.22-1.80), respectively. Conclusions: therapeutic drug monitoring involving ATL may allow the optimization of the treatment of IBD patients. The validation results of the phamacokinectic (PK) model for ADA in IBD patients are inadequate. However, additional studies will strengthen the bias and precision of the model

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Validation of a population pharmacokinetic model of adalimumab in a cohort of patients with inflammatory bowel disease.

BACKGROUND: therapeutic monitoring of anti-TNF drugs and anti-drug antibody levels are useful for clinical decision-making, via the rationalization and optimization of the use of anti-TNF treatments. The objective of the present study was to validate the model of Ternant et al., in a cohort of patients with inflammatory bowel diseases (IBD). This model was originally established for patients with rheumatoid arthritis and was used in this study to optimize the adalimumab (ADA) dose and predict ADA trough levels (ATL). METHODS: this study used concentration data points from 30 IBD patients who received ADA treatment between 2014 and 2015. A goodness-of-fit of the model was determined by evaluating the relationship between the observed ATL values and population model-predicted values (PRED) or individual model-predicted values (IPRED). RESULTS: a total of 51 ADA concentration points were analyzed. The bias of the model was 2.39 (95% CI, 1.63-3.15) for PRED and 0.63 (95% CI, 0.23-1.03) for IPRED. The precision was 3.57 (95% CI, 2.90-4.13) and 1.53 (95% CI, 1.22-1.80), respectively. CONCLUSIONS: therapeutic drug monitoring involving ATL may allow the optimization of the treatment of IBD patients. The validation results of the phamacokinectic (PK) model for ADA in IBD patients are inadequate. However, additional studies will strengthen the bias and precision of the model.

Drought and its legacy modulate the post-fire recovery of soil functionality and microbial community structure in a Mediterranean shrubland.

The effects of drought on soil dynamics after fire are poorly known, particularly its long-term (i.e., years) legacy effects once rainfall returns to normal. Understanding this is particularly important for nutrient-poor soils in semi-arid regions affected by fire, in which rainfall is projected to decrease with climate change. Here, we studied the effects of post-fire drought and its legacy on soil microbial community structure and functionality in a Cistus-Erica shrubland (Spain). Rainfall total and patterns were experimentally modified to produce an unburned control (natural rainfall) and four burned treatments: control (natural rainfall), historical control (long-term average rainfall), moderate drought (percentile 8 historical rainfall, 5 months of drought per year), and severe drought (percentile 2, 7 months of drought). Soil nutrients and microbial community composition (ester-linked fatty acid approach) and functionality (enzyme activities and C mineralization rate) were monitored during the first 4 years after fire under rainfall treatments, plus two additional ones without them (six post-fire years). We found that the recovery of burned soils was lower under drought. Post-fire drought increased nitrate in the short term and reduced available phosphorus, exchangeable potassium, soil organic matter, enzyme activities, and carbon mineralization rate. Moreover, drought decreased soil total microbial biomass and fungi, with bacteria becoming relatively more abundant. Two years after discontinuing the drought treatments, the drought legacy was significant for available phosphorus and enzyme activities. Although microbial biomass did not show any drought legacy effect, the proportion of fungi and bacteria (mainly gram-positive) did, being lower and higher, respectively, in former drought-treated plots. We show that drought has an important impact on soil processes, and that some of its effects persist for at least 2 years after the drought ended. Therefore, drought and its legacy effects can be important for modeling biogeochemical processes in burned soils under future climate change.

Water-borne protozoa parasites: The Latin American perspective.

Health systems, sanitation and water access have certain limitations in nations of Latin America (LA): typical matters of developing countries. Water is often contaminated and therefore unhealthy for the consumers and users. Information on prevalence and detection of waterborne parasitic protozoa are limited or not available in LA. Only few reports have documented in this field during the last forty years and Brazil leads the list, including countries in South America and Mexico within Central America region and Caribbean islands. From 1979 to 2015, 16 outbreaks of waterborne-protozoa, were reported in Latin American countries. T. gondii and C. cayetanensis were the protozoa, which caused more outbreaks and Giardia spp. and Cryptosporidium spp. were the most frequently found protozoa in water samples. On the other hand, Latin America countries have not got a coherent methodology for detection of protozoa in water samples despite whole LA is highly vulnerable to extreme weather events related to waterborne-infections; although Brazil and Colombia have some implemented laws in their surveillance systems. It would be important to coordinate all surveillance systems in between all countries for early detection and measures against waterborne-protozoan and to establish effective and suitable diagnosis tools according to the country's economic strength and particular needs.