Epidemiology of fungal infection in COVID 19 in Spain during 2020 and 2021: a nationwide study.

We realize a nationwide population-based retrospective study to analyze the characteristics and risk factors of fungal co-infections in COVID-19 hospitalized patients as well as describe their causative agents in the Spanish population in 2020 and 2021. Data were obtained from records in the Minimum Basic Data Set of the National Surveillance System for Hospital Data in Spain, provided by the Ministry of Health, and annually published with two years lag. The assessment of the risk associated with the development of healthcare-associated fungal co-infections was assessed using an adjusted logistic regression model. The incidence of fungal co-infection in COVID-19 hospitalized patients was 1.41%. The main risk factors associated were surgery, sepsis, age, male gender, obesity, and COPD. Co-infection was associated with worse outcomes including higher in-hospital and in ICU mortality, and higher length of stay. Candida spp. and Aspergillus spp. were the microorganisms more frequent. This is the first study analyzing fungal coinfection at a national level in hospitalized patients with COVID-19 in Spanish population and one of the few studies available that demonstrate that surgery was an independent risk factor of Aspergillosis coinfection in COVID-19 patients.

Epidemiology of bacterial co-infections and risk factors in COVID-19-hospitalized patients in Spain: a nationwide study.

BACKGROUND: We performed a nationwide population-based retrospective study to describe the epidemiology of bacterial co-infections in coronavirus disease 2019 (COVID-19)-hospitalized patients in Spain in 2020. We also analyzed the risk factors for co-infection, the etiology and the impact in the outcome. METHODS: Data were obtained from records in the Minimum Basic Data Set (MBDS) of the National Surveillance System for Hospital Data in Spain, provided by the Ministry of Health and annually published with 2 years lag. COVID-19 circulated in two waves in 2020: from its introduction to 31st June and from 1st July to 31st December. The risk of developing a healthcare-associated bacterial co-infection and the risk for in-hospital and intensive care unit (ICU) mortality in co-infected patients was assessed using an adjusted logistic regression model. RESULTS: The incidence of bacterial co-infection in COVID-19 hospitalized patients was 2.3%. The main risk factors associated with bacterial co-infection were organ failure, obesity and male sex. Co-infection was associated with worse outcomes including higher in-hospital, in-ICU mortality and higher length of stay. Gram-negative bacteria caused most infections. Causative agents were similar between waves, although higher co-infections with Pseudomonas spp. were detected in the first wave and with Haemophilus influenzae and Streptococcus pneumoniae in the second. CONCLUSIONS: Co-infections are not as common as those found in other viral respiratory infections; therefore, antibiotics should be used carefully. Screening for actual co-infection to prescribe antibiotic therapy when required should be performed.

Post-fire management effects on hillslope-stream sediment connectivity in a Mediterranean forest ecosystem.

Forest fires intensify sediment transport and aggravate local and off-site consequences of soil erosion. This study evaluates the influence of post-fire measures on structural and functional sediment connectivity (SC) in five fire-affected Mediterranean catchments, which include 929 sub-catchments, by using the "aggregated index of connectivity" (AIC) at two temporal scenarios: I) immediately after the fire and before implementing post-fire practices ('Pre-man'), and II) two years after the fire ('Post-man'). The latter includes all the emergency stabilization practices, that are hillslope barriers, check-dams and afforestation. The stream system was set as the target of the computation (STR), to be representative of intense rainfall-runoff events with effective sediment delivery outside the catchments. Output normalization (AICN) allows comparing the results of the five basins between them. The sedimentological analysis is based on specific sediment yield (SSY) -measured at the check-dams installed after the fire -, and this data is used for output evaluation. Stream density and slope variables were the most influential factors on AICN-STR results at the sub-catchment scale. Post-fire hillslope treatments (barriers when built in high densities and afforestation) significantly reduced AICN-STR in comparison with untreated areas in both structural and functional approaches. Despite the presence of hillslope treatments, the higher erosive rainfall conditions resulted in higher AICN-STR values in the Post-man scenario (functional approach). A positive and good correlation was found between the measured SSY and the AICN-STR changes due to the post-fire practices and vegetation recovery, showing the good correspondence of the computation results and the real sediment dynamics of the studied catchments. Overall, AICN demonstrated to be a useful and versatile tool for post-fire management, which needs further research to optimize its applicability.

Endothelial dysfunction is an early indicator of sepsis and neutrophil degranulation of septic shock in surgical patients.

BACKGROUND: Stratification of the severity of infection is currently based on the Sequential Organ Failure Assessment (SOFA) score, which is difficult to calculate outside the ICU. Biomarkers could help to stratify the severity of infection in surgical patients. METHODS: Levels of ten biomarkers indicating endothelial dysfunction, 22 indicating emergency granulopoiesis, and six denoting neutrophil degranulation were compared in three groups of patients in the first 12 h after diagnosis at three Spanish hospitals. RESULTS: There were 100 patients with infection, 95 with sepsis and 57 with septic shock. Seven biomarkers indicating endothelial dysfunction (mid-regional proadrenomedullin (MR-ProADM), syndecan 1, thrombomodulin, angiopoietin 2, endothelial cell-specific molecule 1, vascular cell adhesion molecule 1 and E-selectin) had stronger associations with sepsis than infection alone. MR-ProADM had the highest odds ratio (OR) in multivariable analysis (OR 11·53, 95 per cent c.i. 4·15 to 32·08; P = 0·006) and the best area under the curve (AUC) for detecting sepsis (0·86, 95 per cent c.i. 0·80 to 0·91; P < 0·001). In a comparison of sepsis with septic shock, two biomarkers of neutrophil degranulation, proteinase 3 (OR 8·09, 1·34 to 48·91; P = 0·028) and lipocalin 2 (OR 6·62, 2·47 to 17·77; P = 0·002), had the strongest association with septic shock, but lipocalin 2 exhibited the highest AUC (0·81, 0·73 to 0·90; P < 0·001). CONCLUSION: MR-ProADM and lipocalin 2 could be alternatives to the SOFA score in the detection of sepsis and septic shock respectively in surgical patients with infection.

ANTECEDENTES: La estratificación de la gravedad de una infección se basa actualmente en la puntuación SOFA (Sequential Organ Failure Assessment), que es difícil de calcular fuera de la unidad de cuidados intensivos. Los biomarcadores podrían ayudar a estratificar la gravedad de la infección en pacientes quirúrgicos. MÉTODOS: Se compararon las concentraciones de 10 biomarcadores que denotan disfunción endotelial, 22 que indican granulopoyesis de emergencia y 6 que expresan la degranulación de neutrófilos en tres grupos de pacientes de tres hospitales españoles (100 con infección, 95 con sepsis y 57 con shock séptico) en las primeras doce horas después del diagnóstico. RESULTADOS: Siete biomarcadores que expresan disfunción endotelial (proadrenomedulina, sindecan-1, trombomodulina, angiopoyetina-2, endocan-1, molécula de adhesión endotelial 1 y E-selectina) mostraron una fuerte asociación con la sepsis en comparación con la infección aislada. La proadrenomedulina presentó el valor más alto de la razón de oportunidades (odds ratio, OR) en el análisis multivariable (OR 11,53, i.c. del 95% 4,15-32,08, P = 0,006) y la mejor área bajo la curva para detectar sepsis (AUC 0,86, i.c. del 95% 0,80-0,91, P < 0,001). En la comparación entre sepsis y shock séptico, los biomarcadores que mostraron la asociación más estrecha con el shock séptico fueron dos biomarcadores de degranulación de neutrófilos (proteinasa-3 y lipocalina-2) (OR 8,09, i.c. del 9% 1,34-48,91, P = 0,028; OR 6.62, i.c. del 95% 2,47-17,77, P = 0,002), pero la lipocalina-2 presentó la mejor AUC (0,81, i.c. del 95% 0,73-0,90, P < 0,001). CONCLUSIÓN: la proadrenomedulina y la lipocalina-2 podrían representar alternativas a la puntuación SOFA para detectar sepsis y shock séptico en pacientes quirúrgicos con infección.

Effects of post-fire hillslope stabilisation techniques on chemical, physico-chemical and microbiological soil properties in mediterranean forest ecosystems.

Postfire restoration practices encompass those which aim to reduce negative wildfire impacts and to improve burned area rehabilitation. Contour-felled log debris (CFD) and log erosion barriers (LEB) are two techniques used worldwide on hillslopes after wildfires in order to avoid soil erosion. In this context, it is essential to evaluate how these restoration techniques can affect soil properties by increasing or decreasing wildfire impacts. The effects on several physico-chemical and biological soil parameters were here investigated by comparing three differently treated post-fire zones. Three randomly 20 × 20 m distributed plots were set up five years after wildfire in the burned and contour-felled log debris areas (CFD plots), three others in the burned and log erosion barriers area (LEB plots) and three others in the burned and unmanaged plots (BNa plots). Three more plots were set up in an unburned area close to the burned area (UB plots). The results revealed that LEB and, to a lesser extent CFD, improved postfire soil quality, which a priori favoured helped the recovery of ecosystem functions. Our results also indicate greater efficacy of LEB and CFD in retaining sediments by limiting loss of nutrients, which is considered essential to recover vegetation after a wildfire. Post-fire restoration plans should consider the use of LEB and CFD when aiming to favour ecosystem recovery processes after wildfires.

Encuesta de Percepción en Capacidad Instalada para la Formación de Médicos Residentes en Ortopedia (Traumatología) y Necesidades de la Atención en Patología Musculoesquelética Aguda y Crónica en México. Primera Parte / Installed Capacity Perception Survey for the Training of Resident's Program in Orthopedics and Care Needs in Acute and Chronic Musculoskeletal Pathology in Mexico

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Abstract: Introduction: It is essential that orthopaedic resident physicians be highly proficient in all aspects, considering the balance between supply, demand, need and context. Fundamental to identify the capacity and quality installed for their training in Mexico. Material and methods: Observational Study, transverse, non-probabilistic sampling-conglomerates, in two phases. The instrument has 8 domains, 57 variables and 4,867 items. 60 graduate professors of 20 states, 50 hospital sites, 22 university programs. Results: 1,038 years of experience (collective intelligence), 17 years of experience/teacher (01 to 50 years). Identified: acute pathology 30 (2 to 90%), chronic pathology 30 (5 to 96%), patients ˂ 15 years, 10 (3 to 30%), patients between 15 and 65 years, 47 (2 to 78%), patients ˃ 65 years, 20 (2 to 60%), number of beds/seat 20 (2 to 510), number of clinics 3 (1 to 48), number of surgical procedures/headquarters per year at the national level, was 960 (50 to 24,650). The national average per resident doctor is 362 surgeries/year with 1,450 surgical times/year. Conclusions: The needs and resources for the training of physicians specializing in orthopedics/traumatology are highly heterogeneous, so it should be adapted to the epidemiological needs of the region of influence, in an area of epidemiological transition. 62.2% expressed not having or have bad academic and scientific infrastructure at its headquarters, more than 50% without rotation overseas and ˃ 90% without regular scientific production.

[Installed Capacity Perception Survey for the Training of Residents Program in Orthopedics and Care Needs in Acute and Chronic Musculoskeletal Pathology in Mexico]. / Encuesta de Percepción en Capacidad Instalada para la Formación de Médicos Residentes en Ortopedia (Traumatología) y Necesidades de la Atención en Patología Musculoesquelética Aguda y Crónica en México. Primera Parte.

INTRODUCTION: It is essential that orthopaedic resident physicians be highly proficient in all aspects, considering the balance between supply, demand, need and context. Fundamental to identify the capacity and quality installed for their training in Mexico. MATERIAL AND METHODS: Observational Study, transverse, non-probabilistic sampling-conglomerates, in two phases. The instrument has 8 domains, 57 variables and 4,867 items. 60 graduate professors of 20 states, 50 hospital sites, 22 university programs. RESULTS: 1,038 years of experience (collective intelligence), 17 years of experience/teacher (01 to 50 years). Identified: acute pathology 30 (2 to 90%), chronic pathology 30 (5 to 96%), patients 15 years, 10 (3 to 30%), patients between 15 and 65 years, 47 (2 to 78%), patients 65 years, 20 (2 to 60%), number of beds/seat 20 (2 to 510), number of clinics 3 (1 to 48), number of surgical procedures/headquarters per year at the national level, was 960 (50 to 24,650). The national average per resident doctor is 362 surgeries/year with 1,450 surgical times/year. CONCLUSIONS: The needs and resources for the training of physicians specializing in orthopedics/traumatology are highly heterogeneous, so it should be adapted to the epidemiological needs of the region of influence, in an area of epidemiological transition. 62.2% expressed not having or have bad academic and scientific infrastructure at its headquarters, more than 50% without rotation overseas and 90% without regular scientific production.

INTRODUCCIÓN: Es fundamental que los médicos residentes de ortopedia (traumatología) sean altamente competentes en todos los aspectos, considerando el equilibrio entre la oferta, demanda, necesidad y contexto. Es primordial identificar la capacidad y calidad instalada para su formación en México. MATERIAL Y MÉTODOS: Estudio observacional, transversal, muestreo no probabilístico-conglomerados, en dos fases. El instrumento tiene ocho dominios, 57 variables y 4,867 ítems. Sesenta profesores de postgrado de 20 estados, 50 sedes hospitalarias, 22 programas universitarios. RESULTADOS: 1,038 años de experiencia (inteligencia colectiva), 17 años de experiencia/profesor (01 a 50 años). Se identificó: patología aguda 30 (2 a 90%), patología crónica 30 (5 a 96%), pacientes 15 años, 10 (3 a 30%), pacientes entre 15 y 65 años, 47 (2 a 78%), pacientes 65 años, 20 (2 a 60%), número de camas/sede 20 (2 a 510), número de consultorios 3 (1 a 48), el número de procedimientos quirúrgicos/sede al año a nivel nacional fue de 960 (50 a 24,650). La media nacional por médico residente es de 362 cirugías/año con 1,450 momentos quirúrgicos/año. CONCLUSIONES: Las necesidades y recursos para la formación de médicos especialistas en ortopedia/traumatología son en alto grado heterogéneos, por lo cual se debería adaptar a las necesidades epidemiológicas de la región de influencia, en un ámbito de transición epidemiológica. Sesenta y dos punto dos por ciento expresó no tener o tener deficiente infraestructura académica y científica en su sede, más de 50% sin rotación al extranjero y 90% sin producción científica regular.

Impact of empirical treatment with antifungal agents on survival of patients with candidemia.

OBJECTIVE: The objective of this study was to evaluate the impact of echinocandins and fluconazole) on mortality 7 and 30 days after candidemia onset and overall in-hospital mortality), in patients with candidemia at a Spanish tertiary hospital. METHODS: A retrospective study was conducted that enrolled all non-neutropenic adult patients diagnosed with candidemia at Hospital Clínico Universitario de Valladolid between 2007 and 2016. A total of 179 patients were evaluated, they were divided into two sub-groups: surviving patients (n = 92) and non-surviving patients (n = 87). RESULTS: The 7-day mortality was 25,1% (45), 30-day mortality was 46,9% (84), and overall in-hospital mortality was 48,6% (87). 40.8% of patients received no antifungal treatment (43.8% of surviving patients and 37.8% of non-surviving patients; p=0.15). A total of 106 (59.2%) patients were treated, of which 90 patients (50.3%) received empiric treatment. 19.6% and 47.8% of surviving patients were treated with echinocandins and fluconazole, respectively. By contrast, of non-surviving patients, 31.0% were treated with echinocandins and 47.1% received fluconazole. Survival for the first 7 days was significantly higher in treated with antifungal agents (log-rank = 0.029), however, there were not significant differences in 30-day survival. Factors linked to a significant increase in overall in-hospital mortality were age (OR 1.040), septic shock (OR 2.694) and need for mechanical ventilation > 48 h (OR 2.812). CONCLUSIONS: Patients who received antifungal treatment, regardless of whether they received fluconazole or echinocandins, had a significantly lower mortality rate after 7 days than untreated patients, although no significant differences in 30-day mortality were seen.

Antifungal treatment with echinocandins: a 10-year clinical experience.

OBJECTIVE: The number of studies evaluating the use of echinocandins, whether or not its indication meets international guidelines, in clinical practice is limited. The objective of the present study was to determine the use of echinocandins in a tertiary Spanish hospital in 10 years of clinical practice, and to evaluate its impact on prognosis. METHODS: This retrospective study involved adult nonneutropenic ill patients with suspicion of fungal invasion who started treatment with echinocandins between 2006 and 2015. RESULTS: The number of patients treated with echinocandins was 153, and candidemia was detected thereafter in 25.5%. Factors associated with in-hospital mortality in patients receiving echinocandins were: sex male, septic shock, Charlson comorbidity index, and total stay at the hospital. In-hospital mortality after 7, 30 and 90 days was 13.7%, 24.8%, and 56.8%, respectively. From patients receiving echinocandins, 98 did no show multifocal colonization, 50 had Candida score <2.5, and 49 did not meet Ostrosky-Zeichner prediction rule. A total of 19 patients did not show any of these 3 potential risk factors for candidemia. CONCLUSIONS: The use of echinocandins in 10 years of clinical practice in our tertiary hospital has been performed according to international guidelines; however, candidemia was only diagnosed thereafter in only 25.5% of cases. Furthermore, according to our results, the adequate use of echinocandins seems not to be associated with reduced mortality rates. Further studies, involving a large cohort of patients and more hospitals, are required to corroborate these results.

Increased expression of the mineralocorticoid receptor in the brain of spontaneously hypertensive rats.

The mineralocorticoid receptor (MR) has been considered as both neuroprotective and damaging to the function of the central nervous system. MR may be also involved in central regulation of blood pressure. In the present study, we compared the expression of MR and the glucocorticoid receptor (GR) in the hippocampus and hypothalamus of 16-week-old spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats. In the hippocampus, MR expression was studied by in situ hybridization (ISH), quantitative polymerase chain reaction (PCR) and immunohistochemistry, whereas GR expression was analysed using the latter two procedures. Hypertensive animals showed an increased expression of MR mRNA in the whole hippocampus according to qPCR data and also in CA3 by ISH. Immunocytochemical staining for MR of the dorsal hippocampus, however, did not reveal differences between SHR and WKY rats. SHR showed elevated hypothalamic MR mRNA by qPCR, as well as an increased number of MR immunopositive cells in the magnocellular paraventricular region, compared to WKY rats. By contrast, expression levels of GR mRNA or protein in the hippocampus and hypothalamus of SHR were similar to those of WKY rats. Furthermore, we investigated the role of MR in the hypertensive rats by i.c.v. injection of the MR antagonist RU-2831. This compound produced a significant drop in blood pressure for SHR. In conclusion, MR expression is increased in the hippocampus and hypothalamus of SHR. We suggest that pathological MR overdrive may take responsibility for up-regulation of blood pressure and the encephalopathy of hypertension.

Respuesta espectacular de una encefalomielitis aguda diseminada tras altas dosis de esteroides / Spectacular response of acute disseminated encephalomyelitis after high-dose steroid therapy

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[Acute disseminated encephalomyelitis. Experience of a tertiary hospital in Spain]. / Encefalomielitis aguda. Experiencia de un hospital terciario español.

INTRODUCTION: To describe the epidemiological, clinical, microbiological, neuroimaging and laboratory features, treatment, and outcome in a cohort of children with acute disseminated encephalomyelitis (ADEM). PATIENTS AND METHODS: Retrospective chart review was performed of children with a diagnosis of ADEM over a 23-year period in a tertiary hospital in Spain. RESULTS: Twelve cases were identified. Ten cases (83%) occurred after 1992. Nine patients (75%) presented between April and September. The mean age was 6 years. Nine patients (75%) were male. Fifty percent of the patients had a history of infectious disease or vaccination. The most frequent nonspecific symptom was fever in 75%. The most frequent neurological manifestations were motor deficits and altered consciousness in 75%. Cerebrospinal fluid abnormalities were found in 83%. All patients had at least one brain scan and one brain magnetic resonance imaging (MRI) scan. Three patients underwent spinal MRI. The sensitivity of MRI was greater than that of the scanner in the diagnosis of ADEM. An etiologic diagnosis was made in four patients: Mycoplasma pneumoniae, beta hemolytic streptococcus group A, Epstein-Barr virus and measles-mumps-rubella vaccination. Eleven patients were treated with corticosteroids and one was treated with intravenous immunoglobulin therapy. One patient died while 75 % of the patients had a good outcome. CONCLUSIONS: ADEM is in an infrequent disease in children. The clinical features are similar to those of infectious encephalitis. Etiologic diagnosis is difficult to establish but this entity is usually preceded by an infection. The neuroimaging test of choice to establish the diagnosis is MRI. In most patients, the prognosis is good.

Encefalomielitis aguda. Experiencia de un hospital terciario / Acute disseminated encephalomyelitis. Experience of a tertiary hospital in Spain

Introducción. El objetivo de este estudio es describir las características epidemiológicas, clínicas, microbiológicas, parámetros de laboratorio, estudios de neuroimagen, tratamiento y resultado de una cohorte de niños con diagnóstico de encefalomielitis aguda diseminada (EMAD). Pacientes y métodos. Estudio retrospectivo de las historias clínicas de los niños con diagnóstico de EMAD atendidos durante 23 años en un hospital terciario español. Resultados. Se identificaron 12 casos. Diez (83 %) a partir del año 1992. Nueve (75 %) se presentaron entre abril y septiembre. La edad media fue de 6 años. El 75 % eran varones. En el 50 % hubo infección o vacunación previa. El síntoma general más frecuente fue la fiebre, en el 75 %. La afectación motora y alteración de conciencia fueron las principales manifestaciones neurológicas, presentes en el 75 %. El estudio del líquido cefalorraquídeo (LCR) fue anormal en el 83 %. En todos los pacientes se realizó al menos un escáner y una resonancia magnética (RM) craneal y en 3 casos RM espinal. La RM se mostró más sensible que el escáner para el diagnóstico. Se estableció el diagnóstico etiológico en 4 casos: Mycoplasma, estreptococo betahemolítico del grupo A (EBHGA), virus de Epstein-Barr (VEB) y vacunación triple vírica. Once pacientes recibieron tratamiento con corticoides y en 1 caso se asociaron inmunoglobulinas intravenosas. Un paciente falleció y el 75 % tuvo una evolución favorable. Conclusiones. Se trata de una enfermedad poco frecuente en la infancia. La sintomatología es superponible a la de las encefalitis agudas infecciosas. La etiología es difícil de establecer, pero suele estar precedida por un antecedente infeccioso. La RM fue la prueba de imagen de elección para establecer el diagnóstico. El pronóstico suele ser favorable

Introduction. To describe the epidemiological, clinical, microbiological, neuroimaging and laboratory features, treatment, and outcome in a cohort of children with acute disseminated encephalomyelitis (ADEM). Patients and methods. Retrospective chart review was performed of children with a diagnosis of ADEM over a 23-year period in a tertiary hospital in Spain. Results. Twelve cases were identified. Ten cases (83 %) occurred after 1992. Nine patients (75 %) presented between April and September. The mean age was 6 years. Nine patients (75 %) were male. Fifty percent of the patients had a history of infectious disease or vaccination. The most frequent nonspecific symptom was fever in 75 %. The most frequent neurological manifestations were motor deficits and altered consciousness in 75 %. Cerebrospinal fluid abnormalities were found in 83 %. All patients had at least one brain scan and one brain magnetic resonance imaging (MRI) scan. Three patients underwent spinal MRI. The sensitivity of MRI was greater than that of the scanner in the diagnosis of ADEM. An etiologic diagnosis was made in four patients: Mycoplasma pneumoniae, beta hemolytic streptococcus group A, Epstein-Barr virus and measles-mumps-rubella vaccination. Eleven patients were treated with corticosteroids and one was treated with intravenous immunoglobulin therapy. One patient died while 75 % of the patients had a good outcome. Conclusions. ADEM is in an infrequent disease in children. The clinical features are similar to those of infectious encephalitis. Etiologic diagnosis is difficult to establish but this entity is usually preceded by an infection. The neuroimaging test of choice to establish the diagnosis is MRI. In most patients, the prognosis is good

muARTMAP: use of mutual information for category reduction in Fuzzy ARTMAP.

A new architecture called muARTMAP is proposed to impact a category proliferation problem present in Fuzzy ARTMAP. Under a probabilistic setting, it seeks a partition of the input space that optimizes the mutual information with the output space, but allowing some training error, thus avoiding overfitting. It implements an inter-ART reset mechanism that permits handling exceptions correctly, thus using few categories, especially in high dimensionality problems. It compares favorably to Fuzzy ARTMAP and Boosted ARTMAP in several synthetic benchmarks, being more robust to noise than Fuzzy ARTMAP and degrading less as dimensionality increases. Evaluated on a real-world task, the recognition of handwritten characters, it performs comparably to Fuzzy ARTMAP, while generating a much more compact rule set.

The 11beta hydroxysteroid dehydrogenase 2 exists as an inactive dimer.

The 11beta-hydroxysteroid dehydrogenase types 1 and 2 enzymes (11beta-HSD1 and 11beta-HSD2), modulate glucocorticoid occupation of the mineralocorticoid and glucocorticoid receptors by interconverting corticosterone and cortisol to the inactive metabolites 11-dehydrocorticosterone and cortisone within the target cells. The NAD(+)-dependent 11-HSD 2 in the kidney inactivates corticosterone and cortisol, allowing aldosterone, which is not metabolized, access to the receptor. Studies of the kinetics of 11-HSD 2 activity in the rat kidney have produced inconsistent results. Western blots done in the absence of the reducing agent beta-mercaptoethanol showed two bands with approximate MW of 40 and 80 kDa. When beta-mercaptoethanol was used, only the 40 kDa was detected, indicating that under non-denaturing conditions a significant proportion of the 11beta-HSD 2 exists as a dimer. NAD(+)-dependent conversion of 3H-corticosterone by 20 microg of microsomal protein increased approximately 10 fold with the addition of 5 mM DTT concentration. NADP(+)-dependent activity with 20 microg of microsomal protein was very low and did not change significantly when using DTT. In the presence of DTT, the predominant 11-HSD activity in the rat kidney is NAD(+)-dependent with a K(m) of 15.1 nM, similar to that of the cloned and expressed enzyme. These data suggest that dimerization and subsequent enzyme inactivation occur when protocols promoting oxidation of this protein are used.

Learning from noisy information in FasArt and FasBack neuro-fuzzy systems.

Neuro-fuzzy systems have been in the focus of recent research as a solution to jointly exploit the main features of fuzzy logic systems and neural networks. Within the application literature, neuro-fuzzy systems can be found as methods for function identification. This approach is supported by theorems that guarantee the possibility of representing arbitrary functions by fuzzy systems. However, due to the fact that real data are often noisy, generation of accurate identifiers is presented as an important problem. Within the Adaptive Resonance Theory (ART), PROBART architecture has been proposed as a solution to this problem. After a detailed comparison of these architectures based on their design principles, the FasArt and FasBack models are proposed. They are neuro-fuzzy identifiers that offer a dual interpretation, as fuzzy logic systems or neural networks. FasArt and FasBack can be trained on noisy data without need of change in their structure or data preprocessing. In the simulation work, a comparative study is carried out on the performances of Fuzzy ARTMAP, PROBART, FasArt and FasBack, focusing on prediction error and network complexity. Results show that FasArt and FasBack clearly enhance the performance of other models in this important problem.

Aldosterone esters and the heart.

There are clinical and experimental situations in which symptoms of mineralocorticoid excess are remediable with mineralocorticoid receptor antagonist treatment, in spite of paradoxically low levels of plasma renin and aldosterone. Several decades ago, a factor isolated from the heart was described that had mineralocorticoid properties like those of aldosterone, but much more potent. It was thought to be similar to aldosterone-18-monoacetate or -21-monoacetate, acetyl derivatives of aldosterone that are very rapidly hydrolyzed in the circulation. In our efforts to confirm and extend these observations, we extracted rat hearts and plasma harvested in a manner that would minimize hydrolysis. The product was subjected to several forms of TLC and HPLC and compared to several acetylated derivatives of aldosterone standards. We found that 68% of the aldosterone extracted from fresh myocardium corresponded to an aldosterone derivative that migrates at the same rate as aldosterone-20-monoacetate. The identity of this compound awaits definitive analysis. Tritiated aldosterone-21-monoacetate hydrolyzed to form aldosterone very rapidly; negligible monoacetate remained in blood left at 37 degrees C for 5 min or in hearts left at room temperature for 30 min. Regulation of aldosterone production serves the requirements of fluid and electrolyte homeostasis provided by transport epithelia, primarily that of the kidney. Nonepithelial actions of aldosterone would be freed of these regulatory constraints if the formation of a more potent derivative of the parent compound to which it is almost immediately hydrolyzed in the circulation were regulated within the nonepithelial target tissues.

Role of central mineralocorticoid receptors in cardiovascular disease.

Mineralocorticoids act directly through their receptors in specific centers in the central nervous system, kidneys, heart, and vascular smooth muscle to mediate hemodynamic homeostasis. These steroids also modulate renal and cardiovascular function indirectly through the autonomic nervous system. Complex homeostatic mechanisms under normal hormonal control become pathogenic when there is an excess of regulatory hormone. Experiments in which mineralocorticoid receptor antagonists or antisense oligodeoxynucleotides were administered centrally have clearly shown that centrally mediated effects on salt appetite, baroreceptor function, and autonomic drive to the renal and cardiovascular systems are crucial to the pathogenesis of hypertension and cardiovascular disease of hyperaldosteronism, and certain forms of genetic hypertension.