Origin, accumulation and fate of dissolved organic matter in an extreme hypersaline shallow lake.

Hypersaline endorheic aquatic systems (H-SEAS) are lakes/shallow playas in arid and semiarid regions that undergo extreme oscillations in salinity and severe drought episodes. Although their geochemical uniqueness and microbiome have been deeply studied, very little is known about the availability and quality of dissolved organic matter (DOM) in the water column.. A H-SEAS from the Monegros Desert (Zaragoza, NE Spain) was studied during a hydrological wetting-drying-rewetting cycle. DOM analysis included: (i) a dissolved organic carbon (DOC) mass balance; (ii) spectroscopy (absorbance and fluorescence) and (iii) a molecular characterization with Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). The studied system stored a large amount of DOC and under the highest salinity conditions, salt-saturated waters (i.e., brines with salinity > 30%) accumulated a disproportionate quantity of DOC, indicating a significant in-situ net DOM production. Simultaneously, during the hydrological transition from wet to dry, the DOM pool showed strong alterations of it molecular composition. Spectroscopic methods indicated that aromatic and degraded DOM was rapidly replaced by fresher, relatively small, microbial-derived moieties with a large C/N ratio. FT-ICR-MS highlighted the accumulation of small, saturated and oxidized molecules (molecular O/C > 0.5), with a remarkable increase in the relative contribution of highly oxygenated (molecular O/C>0.9) compounds and a decrease of aliphatic and carboxyl-rich alicyclic moleculesThese results indicated that H-SEAS are extremely active in accumulating and processing DOM, with the notable release of organic solutes probably originated from decaying microplankton under large osmotic stress at extremely high salinities.

The relationship between second-hand smoke and wheezing in infants from Córdoba, Argentina.

BACKGROUND: Wheezing constitutes a common respiratory symptom in children, and several risk factors have been associated with the prevalence of recurrent wheezing (RW) and its severity, especially viral respiratory infections and second-hand smoke (SHS) exposure. OBJECTIVE: To analyze the relationship between smoking patterns in the home and wheezing, in infants from the city of Córdoba, Argentina, during their first year of life. METHODS: Parents of infants were invited to complete a standardized questionnaire voluntarily and anonymously (WQ-P1-EISL). Wheezing in the first 12 months of life was classified as occasional wheezing (OW) when having one or two episodes during the first 12 months of life; recurrent wheezing (RW) if having three or more, and more frequent wheezing (MFW) ≥6 episodes. RESULTS: 409 infants (39.0%) had one or more episodes of wheezing in the first 12 months. Of these, 214 infants (52.3%) presented occasional wheezing (OW), 135 (33%) had recurrent wheezing (RW), and 60 (14.7%) more frequent wheezing (MFW). SHS was significantly related to MFW, especially if the mother smoked (OR=2.7; IC 95%: 1.4-5.18; p=0.0009) or if she smoked during pregnancy (OR=4; IC 95%: 1.8-8.5; p=0.0001). This group of MFW was also associated with SHS as well as having been to the emergency room for wheezing (40.87%, p=0.0056). CONCLUSION: The results indicate that second-hand tobacco smoke is a significant risk factor for the presence of wheezing in infants, and for its severity. Our findings have significant implications for public health, as smoking is a modifiable behavior.

[Diagnostic approach of pheochromocytomas and paragangliomas]. / Enfoque diagnóstico de feocromocitomas y paragangliomas.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumours associated with high morbidity and mortality. Recognizing the clinical presentation is the first step for diagnosis. Biochemical studies may determine an excess of catecholamines and their metabolites. However, the available tests offer varying diagnosis precision. Computed tomography and magnetic resonance are highly sensitive for locating these tumours. Functional tests are reserved for when metastatic and multifocal disease are suspected. One third of the patients have a germline mutation and many genes are involved in the development of these tumours.

Neoplasias malignas en acromegalia / Malignant neoplasms in acromegaly

RESUMEN La asociación entre acromegalia y cáncer ha sido hipotetizada, aunque no existe evidencia clara que defina los mecanismos causales. Los estudios que evaluaron incidencia de cáncer y mortalidad en población acromegálica, aportan información contradictoria. La mayor controversia de la relación entre acromegalia y cáncer es respecto del cáncer colorrectal. Sin embargo, en la actualidad, el cáncer diferenciado de tiroides es el más frecuente en este grupo. Resulta vital el abordaje integral de la acromegalia con el objetivo de lograr control de la enfermedad y de las comorbilidades, que permitan disminuir el impacto en la calidad de la vida y sostener expectativas de vida e incidencia de neoplasias malignas comparables a la población general.

ABSTRACT The association of acromegaly and cancer has been suggested, but there is a lack of evidence of causal mechanisms. Studies that evaluated cancer incidence and mortality in acromegaly, provided contradictory information. The major controversy is about colorectal cancer but thyroid differentiated carcinoma is currently the most frequent. A comprehensive approach is of utmost importance in order to achieve control of the disease and comorbidities, which can reduce the impact on quality of life and sustain life expectancy and incidence of malignancies comparable to the general population.

Why a registry of Chronic Urticaria (CUR) is needed.

Chronic urticaria (CU) has a major effect on patients' quality of life. While there have been progressive advances regarding its pathogenesis and treatment, much remains to be done. Registries of other chronic non-communicable diseases have shown many benefits, such as additional basic knowledge and management approaches to diabetes mellitus. Standards of care as well as diagnostic approaches can be elaborated and compared from different sites, using validated instruments. Registries in allergic diseases are also becoming well recognized, and the first registry on CU, accessible from SLaai's webpage, includes parameters for identification, evaluation and management. In our vision, informatics strategies have the potential to improve care for chronic illnesses such as CU. The registry represents a valid instrument from which to obtain a sufficient sample size for epidemiological studies and/or clinical research planning, including feasibility and potential enrollment. It can also provide invaluable data for adapting guidelines to local populations, as well as diagnostic approaches and cost-effective interventions in the context of organizational efforts to improve patient care.

Allergy immunotherapy across the life cycle to promote active and healthy ageing: from research to policies: An AIRWAYS Integrated Care Pathways (ICPs) programme item (Action Plan B3 of the European Innovation Partnership on active and healthy ageing) and the Global Alliance against Chronic Respiratory Diseases (GARD), a World Health Organization GARD research demonstration project.

Allergic diseases often occur early in life and persist throughout life. This life-course perspective should be considered in allergen immunotherapy. In particular it is essential to understand whether this al treatment may be used in old age adults. The current paper was developed by a working group of AIRWAYS integrated care pathways for airways diseases, the model of chronic respiratory diseases of the European Innovation Partnership on active and healthy ageing (DG CONNECT and DG Santé). It considered (1) the political background, (2) the rationale for allergen immunotherapy across the life cycle, (3) the unmet needs for the treatment, in particular in preschool children and old age adults, (4) the strategic framework and the practical approach to synergize current initiatives in allergen immunotherapy, its mechanisms and the concept of active and healthy ageing.

The prevalence of BRCA1 and BRCA2 mutations among young Mexican women with triple-negative breast cancer.

Various guidelines recommend that women with triple-negative breast cancer should be tested for BRCA1 mutations, but the prevalence of mutations may vary with ethnic group and with geographic region, and the optimal cutoff age for testing has not been established. We estimated the frequencies of BRCA1 and BRCA2 (BRCA) mutations among 190 women with triple-negative breast cancer, unselected for family history, diagnosed at age 50 or less at a single hospital in Mexico City. Patients were screened for 115 recurrent BRCA mutations, which have been reported previously in women of Hispanic origin, including a common large rearrangement Mexican founder mutation (BRCA1 ex9-12del). A BRCA mutation was detected in 44 of 190 patients with triple-negative breast cancer (23 %). Forty-three mutations were found in BRCA1 and one mutation was found in BRCA2. Seven different mutations accounted for 39 patients (89 % of the total mutations). The Mexican founder mutation (BRCA1 ex9-12del) was found 18 times and accounted for 41 % of all mutations detected. There is a high prevalence of BRCA1 mutations among young triple-negative breast cancer patients in Mexico. Women with triple-negative breast cancer in Mexico should be screened for mutations in BRCA1.

Research efforts to control highly pathogenic arenaviruses: a summary of the progress and gaps.

Significant progress has been made in the past 10 years in unraveling the molecular biology of highly pathogenic arenaviruses that are endemic in several West African countries (Lassa fever virus) and in some regions of South America (Argentine and Bolivian hemorrhagic fever viruses). While this has resulted in proof-of-concept studies of novel vaccine candidates in non-human primates and in the discovery of several novel antiviral small molecule drug candidates, none of them has been tested in the clinic to date. The recent Ebola outbreak in West Africa has demonstrated very clearly that there is an urgent need to develop the prophylactic and therapeutic armamentarium against viral hemorrhagic fever viruses as part of a global preparedness for future epidemics. As it pertains to this goal, the present article summarizes the current knowledge of highly pathogenic arenaviruses and identifies opportunities for translational research.

Platelets interact with Coxsackieviruses B and have a critical role in the pathogenesis of virus-induced myocarditis.

BACKGROUND: To further understand the role of platelets in the pathogenesis of viral infections we explored platelet interaction with Coxsackieviruses B (CVB) 1 and 3. CVB is a group of viruses that cause the majority of human enterovirus-related viral myocarditis; their receptor (CAR) is expressed on the platelet surface and there is a well-characterized CVB3-induced myocarditis murine model. METHODS: Human platelets were infected with CVB1 and 3 and viruses were detected in pellets and in supernatants. C57BL/6J mice with or without platelet depletion were inoculated with CVB3 and peripheral blood and heart samples collected at different times post-infection. RESULTS: CVB1 and 3 RNA and a capsid protein were detected in infected platelets. Despite the fact that titration assays in Vero cells showed increasing infectivity titers over time, supernatants and pellets from infected platelets showed similar levels, suggesting that platelets were not susceptible to a replicative infectivity cycle. CVB binding was CAR-independent and resulted in P-selectin and phosphatidylserine (PS) exposure. CVB3-infected mice showed a rapid thrombocytopenia that correlated with an increase in platelet PS exposure and platelet-leukocyte aggregates without modification of platelet P-selectin expression or von Willebrand factor levels. Mortality, viremia, heart viral titers and myocarditis were significantly higher in platelet-depleted than normal animals. Type I IFN levels were not changed but IgG levels were lower in infected and platelet-depleted mice. CONCLUSIONS: Our data reveal that platelets play a critical role in host survival and immune response against CVB3 infection.

Expression and functionality of type I interferon receptor in the megakaryocytic lineage.

BACKGROUND: Type I interferons (IFN-I) negatively regulate megakaryo/thrombopoiesis. However, expression of the IFN-I receptor (IFNAR) in the megakaryocytic lineage is poorly characterized. OBJECTIVES: To study the expression and functionality of IFNAR in the megakaryocytic lineage. METHODS AND RESULTS: Although IFNAR mRNA was found in every cell type studied, its protein expression showed differences between them. According to flow cytometry and immunofluorescence, IFNAR1 was observed in Meg-01, Dami, CD34+ cells and megakaryocytes, but not in proplatelets or platelets. Immunoblotting assays showed that IFNAR1 and IFNAR2 were highly expressed in all cell types, except in platelets where it was barely detectable. Regarding IFNAR1, 130- and 90-kDa bands were detected in Meg-01 and Dami, whereas 130- and 60-kDa bands were found in CD34+ cells and megakaryocytes. Activation of megakaryocytic IFNAR by IFN-ß induced pSTAT1/2 and upregulated the antiviral genes IRF7 and MXA. The latter response was completely suppressed by IFNAR blockade. In contrast, the low levels of IFNAR in platelets were not functional as pSTAT1/2, aggregation and P-selectin expression were not induced by IFN-I. In addition, megakaryocytes increased IFN-I transcript levels and produced IFN-ß upon stimulation with PolyI:C, a synthetic dsRNA that mimics viral infection. CONCLUSIONS: Early progenitors and mature megakaryocytes, but not platelets, express functional IFNAR and synthetize/release IFN-ß, revealing not only that megakaryo/thrombopoiesis regulation by IFN-I is associated with a specific interaction with its receptor, but also that megakaryocytes may play a role in the antiviral defense by being both IFN producers and responders.

Systematic review on the efficacy of fexofenadine in seasonal allergic rhinitis: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials.

RATIONALE: Evidence-based medicine represents the effort to highlight the best intervention for patients, clinicians, and policy makers, each from their respective viewpoint, to solve a particular health condition. According to a recently diffused grading system of evidence and recommendations for medical interventions, efficacy and safety represent 2 of the most important features to consider, and data from meta-analyses of randomized controlled clinical trials (RCTs) is the strongest supporting demonstration. Fexofenadine has been used for its efficacy and safety in the treatment of allergic rhinitis (AR) for many years although no meta-analyses supporting its use currently exist. The aim of this study is to assess for the first time the efficacy and safety of fexofenadine in the treatment of AR by means of a meta-analytic analysis of existing RCTs. Since specific evidence should be provided to address recommendations in a pediatric population, the quality of the estimates of this subgroup analysis is assessed. METHODS: All double-blind, placebo-controlled randomized trials assessing the efficacy of fexofenadine in AR were searched for in OVID, Medline, and Embase databases up to December 2007. Outcomes were extracted from original articles; when this information was not available, the authors of each trial were contacted. Some graphics were digitalized. The RevMan 5 program was used to perform the analysis. GradePro 3.2.2 was used to assess the quality of the evidence for a pediatric population. RESULTS: Of 2,152 identified articles, 20 were potentially relevant trials. Eight studies satisfied the inclusion criteria and were included in the meta-analysis. The main reasons for exclusion were: unnatural exposure, strong study limitations, an atypical outcome measurement, a design for other outcomes, and not being a placebo-controlled, single-blind study. Seven trials investigated a mixed population of adults and children, 1 trial investigated only children, and 1 trial only adults. In 1,833 patients receiving fexofenadine (1,699 placebo), a significant reduction of the daily reflective total symptom scores (TSS) (SMD ­0.42; 95% CI ­0.49 to ­0.35, p < 0.00001) was found. Positive results were also found for morning instantaneous TSS and individual nasal symptom scores (sneezing, rhinorrhea, itching, and congestion). The safety analysis did not show a significant difference in reported adverse events (AE) between the active and placebo treatment groups (OR = 1.03; 95% CI 0.87­1.22, p = 0.75). A very low heterogeneity between the studies was detected, so a fixed-effects model was used. The mean quality level of the included trials was medium. Specific information for a pediatric population may be assumed with a moderate quality of evidence from only 1 study and with a low quality of evidence, mainly due to indirectness, from the others. CONCLUSIONS: This study has 5 major strengths: it represents the first attempt to evaluate the efficacy and safety of fexofenadine in the treatment of AR by means of a meta-analysis of RCTs; there was consistency between positive results in terms of efficacy in TSS and in individual symptoms; a large population was studied; there was an irrelevant interstudy heterogeneity, and the AE frequency was similar in both groups. All of these values encourage the recommendation of fexofenadine for AR. Further research focused on the benefits and disadvantages for a pediatric population is needed.

Determinación del valor de corte de la relación aldosterona/actividad de renina plasmática para la detección de hiperaldosteronismo primario en hipertensión arterial esencial: estudio multicéntrico / Determination of the Aldosterone/Plasma Renin Activity Ratio for the Screening of Primary Hyperaldosteronism in Essential Hypertension: a Multicentric Study

El hiperaldosteronismo primario (HAP) es una afección caracterizada por la producción inapropiadamente elevada y una relativa autonomía del sistema renina-angiotensina. Estimaciones previas, basadas sólo en la evaluación de hipertensos con hipokalemia, consideraban al HAP como una causa poco frecuente de hipertensión (1%). Sin embargo, estudios actuales fundamentados en el cálculo de la relación aldosterona/ actividad de renina plasmática (RAA) arrojan una incidencia mayor (5-10%), siendo la hipertensión arterial (HTA) normokalémica la presentación más frecuente. Dada la amplitud de los valores de corte de la RAA, el Departamento de Suprarrenal de SAEM diseñó un estudio multicéntrico prospectivo en una población de Argentina con el objetivo de establecer nuestro propio valor y determinar así la prevalencia de HAP. Fueron estudiados 353 individuos de ambos sexos, 104 controles normotensos, sin antecedentes familiares de HTA y 249 pacientes hipertensos. Se indicó dieta normosódica y la suspensión de antihipertensivos que interfieran con el eje mineralocorticoideo. Las determinaciones de la actividad de renina plasmática (ARP), DIA-SorinRIA, y de aldosterona, RIA-DPC, fueron realizadas en un único laboratorio. Se realizó ionograma y se evaluaron parámetros clínicos y bioquímicos de síndrome metabólico. La RAA calculada según el percentilo 95 en los controles, fue establecida en la cifra de 36 como valor de corte para sospechar HAP en los hipertensos, requiriéndose una concentración de aldosterona >15 ng/ml. Con una RAA≥36, se realizaron pruebas confirmatorias de sobrecarga salina o de fludrocortisona. La RAA fue ≥36 en 31/249 pacientes, confirmándose HAP en 8 (7 adenomas y 1 hiperplasia), con una prevalencia del 3.2%. Los restantes no completaron estudios confirmatorios. La presencia de síndrome metabólico fue similar en los hipertensos con y sin HAP. En conclusión, este primer estudio multicéntrico argentino determinó nuestro valor de corte de la RAA en 36. Su aplicación permitió establecer una prevalencia de HAP del 3,2% que, aunque podría estar subestimada, resulta significativamente mayor que la previa histórica y concuerda con la incidencia referida en la bibliografía.

Primary hyperaldosteronism (PHA) or Conn's disease was classically suspected in the presence of hypertension (H) and hypokalemia. It was previously considered as a rare cause of H, being reported in only 1% of hypertensive patients. It can be caused by an adrenal adenoma (the former usual presentation) or by adrenal hyperplasia. But since the use of the aldosterone/plasma renin activity ratio (AAR) as the screening method in the last years, it is currently considered as almost the most frequent cause of secondary H., accounting for 5-10% of essential H. Plasma rennin activity (PRA) determination is a laborious procedure with low reproducibility and it directly affects the AAR; thus each laboratory must assess its own cut-off value. Therefore, in the Adrenal Department of the Argentine Society of Endocrinology and Metabolism (SAEM), we performed this multicentric prospective study of a population of Argentina with the aim of assessing our own AAR cut-off level in normotensive controls in order to apply it for PHA screening in essential hypertensive patients. We studied 353 adult subjects: 104 controls, aged 45,18 ± 13,78 years-old ( X±SD), with no history of arterial hypertension in their first-degree relatives and with two separate day-registry of blood pressure≤ 139/85 mmHg and 249 hypertensive patients, aged 51± 13,6 years-old ( X ± SD), with arterial blood pressure≥ 140/90 mmHg in the sitting position. Subjects with cardiac, renal, hepatic and neurological diseases were excluded as well as those with Cushing´s syndrome, hyperthyroidism, untreated hypothyroidism, diabetes mellitus and patients under glucocorticoids, oral contraceptive pills or estrogen therapy. A normal sodium diet was indicated and potassium was supplemented when needed. Blood was withdrawn between 8 and 10:00 a.m. with the subjects in the upright position. Aldosterone (A) was determined by DPC radioimmunoassay (RIA) and PRA, by DIA-Sorin RIA. The A normal levels are 4-30 ng/dl for ambulatory individuals on a normal sodium diet and the PRA normal values are < 3,3 ng/ml/h. In order to avoid false positive results in the hypertensive group, AAR was calculated when A was above 15 ng/dl. We measured the waist circumference and we determined the body mass index. Blood sodium, potassium, calcium, urea, creatinine, cholesterol, HDL-C, LDL-C, triglyceride and liver function tests were performed. Statistical Analysis and Results Since the AAR variable showed a non-normal distribution, the cut-off value was considered as the 95th percentile in the control group, which was calculated as 36. This is also in accordance to the function of the empirical distribution of Collings and Hamilton. In our 249 hypertensive patients, 31 had an AAR ≥ 36. PHA was confirmed in 8: seven has an adrenal adenoma and one had hyperplasia. The prevalence of PHA in our population was 3,2 %, with a 95th confidence interval ranging from 1,4 to 6,2 %. In the remaining 23 patients, confirmatory tests could not be completed. There was no correlation between the severity of the hypertension and the AAR value, with no statistical significant differences between those with or without PHA. Likewise, we found no correlation between PRA and advancing age. In hypertensive patients, metabolic syndrome was more prevalent than in controls, but it was present to the same extent in those with or without PHA. Conclusions To our knowledge, this is the first multicentric study performed in Argentina to determine the aldosterone/ plasma renin activity ratio in our normotensive control population. Our AAR value of 36 agrees with the levels reported in the international literature: thus an AAR ≥ 36 along with an aldosterone ≥ 15 ng/ml in hypertensive patients lead us to suspect PHA and to perform confirmatory tests. Applying these criteria, we found a prevalence of 3,2% of PHA in essential HTA. It is possible that this value may be underestimated due to the fact that confirmatory tests could not be completed in all the hypertensive subjects with an AAR≥ 36. In spite of this, our prevalence is significantly greater than the historical one and it lies in the range reported in the literature.

Evaluation of the expression and protective potential of leptospiral sphingomyelinases

Leptospirosis is a zoonotic disease of global distribution, which affects both animals and humans. Pathogenic leptospires, the bacteria that cause this disease, require iron for their growth, and these spirochetes probably use their hemolysins, such as the sphingomyelinases, as a way to obtain this important nutrient from host red blood cells during infection. We expressed and purified the leptospiral sphingomyelinases Sph1, Sph2, Sph4, and SphH in a heterologous system. However, the recombinant proteins were not able to lyse sheep erythrocytes, despite having regular secondary structures. Transcripts for all sphingomyelinases tested were detected by RT-PCR analyses, but only Sph2 and SphH native proteins could be detected in Western blot assays using Leptospira whole extracts as well as in renal tubules of infected hamsters. Moreover, antibodies present in the serum of a human patient with laboratory-confirmed leptospirosis recognized Sph2, indicating that this sphingomyelinase is expressed and exposed to the immune system during infection in humans. However, in an animal challenge model, none of the sphingomyelinases tested conferred protection against leptospirosis.

Leptospiral TlyC is an extracellular matrix-binding protein and does not present hemolysin activity

The role of TlyA, TlyB and TlyC proteins in the biology of Leptospira is still uncertain. Although these proteins have been considered as putative hemolysins, we demonstrate that leptospiral recombinant TlyB and TlyC do not possess hemolytic activity. However, further experiments showed that TlyC is a surface-exposed protein that seems to bind to laminin, collagen IV and fibronectin. The expression of both proteins was detected both in vitro and in vivo. Our findings suggest that TlyB and TlyC are not directly involved in hemolysis, and that TlyC may contribute to Leptospira binding to extracellular matrix (ECM) during host infection.