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The clinical validity of drug susceptibility testing (DST) for pyrazinamide, ethambutol, and second-line antituberculosis drugs is uncertain. In an individual patient data meta-analysis of 8955 patients with confirmed multidrug-resistant tuberculosis, DST results for these drugs were associated with treatment outcomes

EDITOR'S NOTE: This paper represents 1 of 4 companion articles resulting from a SETAC Pellston Workshop® on “Improving the Usability of Ecotoxicology in Regulatory Decision-Making,” held August 2015 in Shepherdstown, West Virginia, USA. The main workshop objectives were to improve the reliability and reproducibility of ecotoxicity studies, improve the use of peer-reviewed studies in regulatory risk assessment of chemicals, and improve the methods used in risk assessments when evaluating single or multiple lines of evidence. Copyright © 2017 The Authors. Ecological risk assessments and risk management decisions are only as sound as the underlying information and processes to integrate them. It is important to develop transparent and reproducible procedures a priori to integrate often-heterogeneous evidence. Current weight-of-evidence (WoE) approaches for effects or hazard assessment tend to conflate aspects of the assessment of the quality of the data with the strength of the body of evidence as a whole.We take forward recent developments in the critical appraisal of the reliability and relevance of individual ecotoxicological studies as part of the effect or hazard assessment of prospective risk assessments and propose a streamlined WoE approach. The aim is to avoid overlap and double accounting of criteria used in reliability and relevance with that used in current WoE methods. The protection goals, problem formulation, and evaluation process need to be clarified at the outset. The data are first integrated according to lines of evidence (LoEs), typically mechanistic insights (e.g., cellular, subcellular, genomic), in vivo experiments, and higher-tiered field or observational studies. Data are then plotted on the basis of both relevance and reliability scores or categories. This graphical approach provides a means to visually assess and communicate the credibility (reliability and relevance of available individual studies), quantity, diversity, and consistencyof the evidence. In addition, the external coherenceof the body of evidence needs tobe considered. The final step in the process is to derive an expression of the confidence in the conclusions of integrating the information considering these 5 aspects in the context of remaining uncertainties.We suggest that this streamlined approach to WoE for the effects or hazard characterization should facilitate reproducible and transparent assessments of data across different regulatory requirements.

Integrated care ICT Platform to support patients, care-givers and health/social professionals in the care of dementia and Parkinson''s disease with training, empowerment, sensor-based data analysis and cooperation services based on user-friendly interfaces.

Human proteins are vulnerable towards disease-associated single amino acid replacements affecting protein stability and function. Interestingly, a few studies have shown that consensus amino acids from mammals or vertebrates can enhance protein stability when incorporated into human proteins. Here, we investigate yet unexplored relationships between the high vulnerability of human proteins towards disease-associated inactivation and recent evolutionary site-specific divergence of stabilizing amino acids. Using phylogenetic, structural and experimental analyses, we show that divergence from the consensus amino acids at several sites during mammalian evolution has caused local protein destabilization in two human proteins linked to disease: cancer-associated NQO1 and alanine: glyoxylate aminotransferase, mutated in primary hyperoxaluria type I. We demonstrate that a single consensus mutation (H80R) acts as a disease suppressor on the most common cancer-associated polymorphism in NQO1 (P187S). The H80R mutation reactivates P187S by enhancing FAD binding affinity through local and dynamic stabilization of its binding site. Furthermore, we show how a second suppressor mutation (E247Q) cooperates with H80R in protecting the P187S polymorphism towards inactivation through long-range allosteric communication within the structural ensemble of the protein. Our results support that recent divergence of consensus amino acids may have occurred with neutral effects on many functional and regulatory traits of wild-type human proteins. However, divergence at certain sites may have increased the propensity of some human proteins towards inactivation due to disease-associated mutations and polymorphisms. Consensus mutations also emerge as a potential strategy to identify structural hot-spots in proteins as targets for pharmacological rescue in loss-of-function genetic diseases.

Las bacteriocinas son sustancias de naturaleza peptídica que muestran un elevado potencial como bioconservantes gracias a su actividad antibacteriana frente a microorganismos patógenos y alterantes. En leche y derivados lácteos, se han hecho numerosos estudios que demuestran la eficacia de las bacteriocinas frente a patógenos como Listeria monocytogenes o alterantes como los clostridios productores de gas. El efecto antimicrobiano de las bacteriocinas en productos lácteos puede mejorar considerablemente cuando se emplean en combinación con otras barreras como conservantes químicos o tratamientos físicos no térmicos. Otras posibles aplicaciones de las bacteriocinas incluyen acelerar el tiempo de maduración del queso y un mejor control de la fermentación. Bacteriocins are antibacterial peptides with a strong potential in food biopreservation due to their antibacterial activities against pathogenic and spoilage bacteria. Many studies have demonstrated the efficacy of bacteriocins in milk and dairy products against human pathogens like Listeria monocytogenes or food spoilage bacteria like gas-producing clostridia. The antibacterial effect of bacteriocins in dairy products can be improved in combination with other hurdles such as chemical preservatives or non-thermal physical preservation methods. Other possible applications of bacteriocins include accelaration of cheese ripening and a better control of lactic acid fermentations in dairy products.

Aunque las acciones típicas de los delitos sexuales son conocidas desde los mismos albores de la humanidad, los diversos factores de la globalización y del desarrollo socio económico, demográfico, cultural, político y criminológico de nuestros pueblos modernos, han provocado un incremento de cierto tipo de crímenes, dentro de los cuales resaltamos al Proxenetismo y la Rufianería, así como, su regulación particular en Costa Rica.

SETTING: Randomised Phase IIB clinical trial.\ud \ud OBJECTIVES: To assess whether increasing the dose of rifampicin (RMP) from 10 mg/kg to 15 or 20 mg/kg results in an increase in grade 3 or 4 hepatic adverse events and/or serious adverse events (SAE).\ud \ud METHODS: Three hundred human immunodeficiency virus negative patients with newly diagnosed microscopy-positive pulmonary tuberculosis (TB) were randomly assigned to one of three regimens: 1) the control regimen (R10), comprising daily ethambutol (EMB), isoniazid (INH), RMP and pyrazinamide for 8 weeks, followed by INH and RMP daily for 18 weeks; 2) Study Regimen 1 (R15), as above, with the RMP dose increased to 15 mg/kg body weight daily for the first 16 weeks; and 3) Study Regimen 2 (R20), as above, with RMP increased to 20 mg/kg. Serum alanine transferase (ALT) levels were measured at regular intervals.\ud \ud RESULTS: There were seven grade 3 increases in ALT levels, 1/100 (1%) among R10 arm patients, 2/100 (2%) in the R15 arm and 4/100 (4%) in the R20 arm (trend test P = 0.15). One (R15) patient developed jaundice, requiring treatment modification. There were no grade 4 ALT increases. There was a non-significant increase in culture negativity at 8 weeks with increasing RMP dosage: 75% (69/92) in R10, 82.5% (66/80) in R15 and 83.1% (76/91) R20 patients (P = 0.16).\ud \ud CONCLUSIONS: No significant increase in adverse events occurred when the RMP dose was increased from 10 mg/kg to 15 mg/kg or 20 mg/kg.

This critical review examines the definition and implementation of environmental protection goals\ud for chemicals in current European Union (EU) legislation, guidelines and international agreements\ud to which EU countries are party. The European chemical industry is highly regulated and\ud prospective environmental risk assessments (ERAs) are tailored for different classes of chemical,\ud according to their specific hazards, use patterns and environmental exposure profiles. However,\ud environmental protection goals are often highly generic, requiring the prevention of ‘unacceptable’\ud or ‘adverse’ impacts on ‘biodiversity’ and ‘ecosystems’ or the ‘environment as a whole’. This\ud review aims to highlight working examples, challenges, solutions and best practices for defining\ud specific protection goals (SPGs), which are seen to be essential for refining and improving ERA.\ud SPGs hinge on discerning acceptable versus unacceptable ‘adverse’ effects on the key attributes of\ud relevant, sensitive ecological entities (ranging from organisms to ecosystems). There are some\ud isolated examples of SPGs for terrestrial and aquatic biota in prospective ERA guidance for Plant\ud Protection Products (PPPs). However, SPGs are generally limited to environmental/nature\ud legislation requiring environmental monitoring and retrospective ERA. This is due mainly to the\ud availability of baseline defining acceptable versus unacceptable environmental effects on the key\ud attributes of sentinel species, populations and/or communities, such as reproductive status,\ud abundance or diversity. Nevertheless, there are very few regulatory case examples in which SPGs\ud incorporate effect magnitude, spatial extent and temporal duration. We conclude that more holistic\ud approaches are needed for defining SPGs, particularly with respect to protecting population\ud sustainability, ecosystem function and integrity, which are implicit in generic protection goals, and\ud explicit in the International Programme for Chemical Safety (IPCS) definition of adverse effect. A\ud possible solution, which the chemical industry is currently assessing, is wider application of the\ud ecosystem services approach proposed by the European Food Safety Authority (EFSA) for the risk\ud assessment of PPPs.

The multimedia model SimpleTreat, evaluates the distribution and elimination of chemicals by municipal sewage treatment plants (STP). It is applied in the framework of REACH (Registration, Evaluation, Authorization and Restriction of Chemicals). This article describes an adaptation of this model for application to industrial sewage treatment plants (I-STP). The intended use of this re-parametrized model is focused on risk assessment during manufacture and subsequent uses of chemicals, also in the framework of REACH. The results of an inquiry on the operational characteristics of industrial sewage treatment installations were used to re-parameterize the model. It appeared that one property of industrial sewage, i.e. Biological Oxygen Demand (BOD) in combination with one parameter of the activated sludge process, the hydraulic retention time (HRT) is satisfactory to define treatment of industrial wastewater by means of the activated sludge process. The adapted model was compared to the original municipal version, SimpleTreat 4.0, by means of a sensitivity analysis. The consistency of the model output was assessed by computing the emission to water from an I-STP of a set of fictitious chemicals. This set of chemicals exhibit a range of physico-chemical and biodegradability properties occurring in industrial wastewater. Predicted removal rates of a chemical from raw sewage are higher in industrial than in municipal STPs. The latter have typically shorter hydraulic retention times with diminished opportunity for elimination of the chemical due to volatilization and biodegradation.

Se ha aislado una colección de cepas de diferentes muestras de pescado fresco y marisco, y se ha determinado la resistencia a diferentes biocidas. En la mayoría de los productos de la pesca estudiados, las unidades formadoras de colonias (UFC) por gramo están entre 103 y 107. En el estudio morfológico predominan los bacilos Gram -, salvo en productos donde la manipulación ha sido más importante que encontramos cocos Gram +. Respecto a los ensayos de resistencia a biocidas, hay mayor número de cepas resistentes para triclosán, oxonia, cloruro de benzalconio y hexadecilpiridinio. En general, la resistencia a biocidas es baja. A collection of bacterial strains isolated from raw seafood has been studied regarding its biocide tolerance. Viable bacterial counts obtained for most samples analyzed ranged from 103 to 107 colony forming units (CFU) per gram. Most isolates were Gram-negative bacilli, except for raw processed products where Gram-positive bacilli were more abundant. Highest percentages of biocide tolerance were obtained for triclosan, oxonia, benzalkonium chloride and hexadecylpyridinium chloride. In general, biocide tolerance is low.

The inhibitory effects of novel prodrugs, inclusion complexes of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid (GOFA) and auraptene (AUR) with beta-cyclodextrin (CD), on colon carcinogenesis were investigated using an azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of AOM (10 mg/kg body weight) were promoted by the addition of 1.5% (w/v) DSS to their drinking water for 7 days. They were then given a basal diet containing 2 dose levels (100 and 500 ppm) of GOFA/beta-CD or AUR/beta-CD for 15 weeks. At Week 18, the development of colonic adenocarcinoma was significantly inhibited by feeding with GOFA/beta-CD at dose levels of 100 ppm (63% reduction in multiplicity, p < 0.05) and 500 ppm (83% reduction in the multiplicity, p < 0.001), when compared with the AOM/DSS group (multiplicity: 3.36 +/- 3.34). In addition, feeding with 100 and 500 ppm (p < 0.01) of AUR/beta-CD suppressed the development of colonic adenocarcinomas. The dietary administration with GOFA/beta-CD and AUR/beta-CD inhibited colonic inflammation and also modulated proliferation, apoptosis and the expression of several proinflammatory cytokines, such as nuclear factor-kappaB, tumor necrosis factor-alpha, Stat3, NF-E2-related factor 2, interleukin (IL)-6 and IL-1beta, which were induced in the adenocarcinomas. Our findings indicate that GOFA/beta-CD and AUR/beta-CD, especially GOFA/beta-CD, are therefore able to inhibit colitis-related colon carcinogenesis by modulating inflammation, proliferation and the expression of proinflammatory cytokines in mice.

Los alimentos de origen vegetal están a menudo implicados en la aparición de brotes de intoxicaciones alimentarias. El control biológico de los microorganismos patógenos o alterantes en alimentos vegetales no deja de ser una herramienta interesante, como lo demuestra la intensidad de los estudios realizados en este campo sobre los agentes antimicrobianos producidos por microorganismos, en especial los conocidos como bacteriocinas, así como los antimicrobianos naturales presentes en las plantas y sus aceites esenciales. Los bacteriófagos son una herramienta muy interesante para la inactivación de patógenos en alimentos, como lo demuestra el reciente desarrollo de preparados comerciales. Los antimicrobianos naturales funcionan mejor cuando se emplean como parte de la tecnología de obstáculos o barreras, pudiendo establecer efectos sinérgicos con otros agentes antimicrobianos o con tratamientos físico químicos. Vegetable foods are often involved in outbreaks of foodborne illnesses. Biological control of human pathogenic and food spoiling bacteria in vegetable foods still remains a viable approach, as shown by the numerous studies published in recent years on antimicrobial substances from microorganismos, especially the so-called bacteriocins, as well as on plant-derived natural antimicrobial compounds and essential oils. Bacteriophages are also a relevant tool for inactivation of foodborne pathogens, as shown by recent development of commercial phage preparations. The efficacy of natural antimicrobials can be improved considerably if they are used as part of hurdle technology, since they can act synergistically with other antimicrobials or with physico-chemical treatments.

The Measurement Problem in Quantum Mechanics Revisited

En el presente trabajo se muestra los resultados más relevantes de la actividad reproductora de Donax trunculus en el caladero del Golfo de cÁDIZ.

La calidad metodológica (CM) es un constructo multidimensional complejo que evalúa diferentes variables. Una aproximación al tema fue la generación de escalas para valorar CM de estudios de terapia, diagnóstico y pronóstico por parte de nuestro grupo de trabajo; todas ellas validadas. El objetivo de este artículo es entregar una pauta para estandarizar la aplicación para la escala MINCir, para valorar CM de estudios de terapia. Se realiza una descripción detallada de cada ítem y dominio que conforman la escala MINCir Terapia, junto con una guía de cómo dar respuesta a cada uno de ellos. Se generó una guía de usuario para aplicar la escala MINCir Terapia. Methodological quality (MQ) is a complex multidimensional construct that tests different types of variables. An approach to this issue was the potential to generate a group of valid scales to assess MQ in therapy, diagnosis and prognosis studies. The aim of this article is to provide a guideline to standardize the implementation of a MinCir scale to assess MQ in therapy studies. A detailed description of each item and discipline of the therapy MinCir scale is provided, along with guidelines on how to respond each query. A user guide for applying the therapy MinCir scale was generated.

Los trabajos publicados sobre el ciclo gonadal de D. trunculus en el litoral andaluz coinciden en apuntar que se trata de una especie con un amplio periodo reproductor (Gaspar et al. 1999; Tirado y Salas, 1998; Tirado et al., 2011). En este estudio nos planteamos, en primer lugar, conocer la fracción reproductora de la población estimando la talla de primera madurez. En segundo lugar, decidimos cuantificar la influencia de la talla del individuo en su fecundidad, así como analizar posibles variaciones en su intensidad a lo largo del periodo reproductor. En el periodo de mayor actividad reproductiva (marzo-agosto 2013) se recogieron muestras de D. trunculus en la zona intermareal de la playa de Doñana (Huelva), mediante rastro manual con luz malla de 3 mm, para estimar mediante técnicas histológicas y de análisis de imagen: (1) Talla de primera madurez (L50) (2) Cambios en la fecundidad parcial: (2.a) Asociados al tamaño del individuo (marzo 2013) (2.b) A lo largo del periodo de reproducción (marzo-agosto 2013) (2.c) En un periodo corto de emisión de gametos (mayo-julio 2013). La talla de primera madurez (L50) para el total de la población se situó en 10,9 mm. A partir de los 12 mm más del 80% de la población se encontró madura. A la vista de estos resultados, se decidió estimar la fecundidad parcial de los individuos que conforman la fracción reproductora de la población. El volumen gonadal (Gv) estableció una relación significativa con la talla (Gv = 10,51*L-165,83 r2:0.80), mientras que el porcentaje de masa visceral ocupado por la gónada no varío con dicho parámetro. La fecundidad parcial total (No) osciló entre 159.147 y 3.453.044 por hembra. El número de ovocitos previtelogénicos (Po) varió entre 110.163 y 2.185.276, mientras que el de ovocitos vitelogénicos y maduros (Vo+Mo) entre 48.985 y 1.341.552. En todos los casos se establecieron relaciones estadísticamente significativas con el tamaño del individuo (Po = 3,169*L3,899, r2:0,88; Vo+Mo = 0,813L4,159, r2:0,78). A lo largo de todo el periodo reproductor coinciden simultáneamente dos procesos complementarios: La emisión continuada de gametos (signos de puesta parcial) y una alta capacidad de regeneración ovocitaria en las paredes foliculares (presencia de Po). Esta continua emisión de gametos (en mayor o menor grado), impide determinar la fecundidad total de esta especie, al igual que en muchos otros moluscos bivalvos, de ahí que definamos la fecundidad parcial de la misma. No obstante, la intensidad en la actividad reproductora presentó diferencias significativas en su transcurso. Por un lado, la presencia de Vo+Mo aumentó en la primera fase del periodo reproductor hasta alcanzar su máximo valor en junio, mientras que en la etapa final de dicho periodo (agosto) se observó una claro descenso tanto del número de Vo+Mo (ANOVA, p=0,00) como de Po (ANOVA, p=0.00), características previas al final del periodo reproductor. Por otro lado, y aunque la continua incorporación de ovocitos (regeneración ovocitaria) dificultó la cuantificación de las emisiones parciales, en el seguimiento quincenal realizado se observó una caída de aproximadamente 293.000 Vo+Mo entre la segunda quincena de junio y la primera de julio (ANOVA, p

Introducción: La ruta de señalización de Notch está activada en una gran variedad de patologías renales humanas. Recientemente hemos demostrado que la activación de esta ruta no estaría implicada en la fibrosis renal experimental inducida por angiotensina II o hipertensión. Objetivos: Evaluar si la vía Notch está activada en la fibrosis renal asociada a nefroesclerosis hipertensiva. Para validar la hipótesis se estudiaron varias patologías glomerulares caracterizadas por fibrosis túbulo-intersticial. Métodos: Se utilizaron biopsias renales de pacientes con nefroesclerosis hipertensiva, en comparación con nefropatía diabética y nefropatía membranosa en diferentes etapas de progresión. La expresión génica y proteica se evaluó por hibridación in situ e inmunohistoquímica, respectivamente. Resultados: En nefroesclerosis hipertensiva se observó baja expresión renal de proteínas de la vía Notch, no existiendo asociación entre la fibrosis túbulo-intersticial y los niveles de estas proteínas. Por el contrario, en las patologías glomerulares estudiadas se observó una elevada expresión de los transcritos Jagged-1, HES-1 y TGF-β, y de las proteínas Jagged-1 y Notch-1, localizados principalmente en células túbulo-epiteliales. Los niveles de expresión de los componentes de la vía Notch se relacionaron con el grado de fibrosis túbulo-intersticial, lo que confirma la activación de esta vía en nefropatías progresivas. Conclusiones: Nuestros datos muestran que la vía Notch no está activada en el riñón de pacientes con nefropatía hipertensiva, ampliando los resultados de los modelos experimentales de daño renal asociado a hipertensión a la patología humana. Nuestros estudios aportan nueva información sobre la compleja regulación del sistema Notch en el riñón.

Introducción: La ruta de señalización de Notch está activada en una gran variedad de patologías renales humanas. Recientemente hemos demostrado que la activación de esta ruta no estaría implicada en la fibrosis renal experimental inducida por angiotensina II o hipertensión. Objetivos: Evaluar si la vía Notch está activada en la fibrosis renal asociada a nefroesclerosis hipertensiva. Para validar la hipótesis se estudiaron varias patologías glomerulares caracterizadas por fibrosis túbulo-intersticial. Métodos: Se utilizaron biopsias renales de pacientes con nefroesclerosis hipertensiva, en comparación con nefropatía diabética y nefropatía membranosa en diferentes etapas de progresión. La expresión génica y proteica se evaluó por hibridación in situ e inmunohistoquímica, respectivamente. Resultados: En nefroesclerosis hipertensiva se observó baja expresión renal de proteínas de la vía Notch, no existiendo asociación entre la fibrosis túbulo-intersticial y los niveles de estas proteínas. Por el contrario, en las patologías glomerulares estudiadas se observó una elevada expresión de los transcritos Jagged-1, HES-1 y TGF-β, y de las proteínas Jagged-1 y Notch-1, localizados principalmente en células túbulo-epiteliales. Los niveles de expresión de los componentes de la vía Notch se relacionaron con el grado de fibrosis túbulo-intersticial, lo que confirma la activación de esta vía en nefropatías progresivas. Conclusiones: Nuestros datos muestran que la vía Notch no está activada en el riñón de pacientes con nefropatía hipertensiva, ampliando los resultados de los modelos experimentales de daño renal asociado a hipertensión a la patología humana. Nuestros estudios aportan nueva información sobre la compleja regulación del sistema Notch en el riñón. Introduction: The Notch signalling pathway is activated in a wide variety of human renal diseases. We have recently demonstrated that the activation of this pathway is not involved in experimental renal fibrosis induced by angiotensin II or hypertension. Objectives: To assess whether the Notch pathway is activated in renal fibrosis related to hypertensive nephrosclerosis. To test the hypothesis, various glomerular diseases characterised by tubulointerstitial fibrosis were analysed. Method: Renal biopsies were performed on patients with hypertensive nephrosclerosis, in comparison with diabetic nephropathy and membranous nephropathy at various stages. Gene and protein expression were evaluated by in-situ hybridisation and immunohistochemistry respectively. Results: In hypertensive nephrosclerosis low renal expression of notch-related proteins was observed. There was no link between tubulointerstitial fibrosis and the levels of these proteins. By contrast, in the glomerular diseases studied we observed high expression of the transcripts Jagged-1, HES-1 and TGF-β and the proteins Jagged-1 y Notch-1, localised primarily in tubuloepithelial cells. The levels of expression of the components of the Notch pathway correlate to the degree of tubulointerstitial fibrosis, which confirms the activation of this pathway in progressive nephropathies. Conclusions: Our data demonstrate that the Notch pathway is not activated in the kidneys of patients with hypertensive nephropathy, which extends the results of experimental models of kidney damage related to hypertension to the realm of human pathology. Our studies provide new information on the complex regulation of the Notch pathway in the kidney.