RESUMO
OBJECTIVES: During times of emergency response, the CDC Foundation leverages partnerships and relationships to better understand the situation and respond rapidly to save lives. As the COVID-19 pandemic began to unfold, an opportunity became clear to improve our work in emergency response through documentation of lessons learned and incorporating them into best practices. STUDY DESIGN: This was a mixed methods study. METHODS: The CDC Foundation Response, Crisis and Preparedness Unit conducted an internal evaluation via an intra-action review to evaluate and rapidly improve emergency response activities to provide effective and efficient response-related program management. RESULTS: The processes developed during the COVID-19 response to conduct timely and actionable reviews of the CDC Foundation's operations led to the identification of gaps in the work and management processes and to creation of subsequent actions to address these issues. Such solutions include surge hiring, establishing standard operating procedures for processes not yet documented, and creating tools and templates to streamline emergency response operations. CONCLUSIONS: The creation of manuals and handbooks, intra-action reviews, and impact sharing for emergency response projects led to actionable items meant to improve processes and procedures and the ability of the Response, Crisis and Preparedness Unit to quickly mobilize resources directed toward saving lives. These products are now open-source resources that can be used by other organizations to improve their own emergency response management systems.
Assuntos
COVID-19 , Humanos , Estados Unidos , Saúde Pública/métodos , Pandemias , Centers for Disease Control and Prevention, U.S.RESUMO
The term Castleman's disease encompasses a group of rare lymphoproliferative diseases that show histopathological similarities in lymph node biopsy. Diagnostic criteria and a specific ICD-10 code have been available for a few years. Case studies listed at the beginning illustrate that close cooperation between clinicians and pathologists is required to enable a reliable diagnosis. For an optimal histopathological assessment, the pathologist is also dependent on the removal of a complete lymph node. Before distinguishing a potentially fatal multicentric idiopathic Castleman's disease from the resectable unicentric form, which is important in terms of prognosis and treatment, early diagnosis presupposes that Castleman's disease is considered in the differential diagnosis. Various immune phenomena and overlaps with autoimmune diseases can increase the probability of misdiagnosis or undetected cases in the clinical routine of rheumatologists. The intention of the present overview is therefore to point out the similarities with autoimmune diseases that are relevant for differential diagnoses and to point out situations that justify a review of the previous diagnosis.
RESUMO
Immunohistochemical staining of tissue sections is a vital technique in pathological diagnostics and theranostics. Several kinds of detection systems are available-each of them with their advantages and disadvantages. Here we present the results of a study assessing a prototype immunohistochemical detection technology (PIDT) for visualization of antigens in tissue sections. Different tumor tissues (n = 11) were stained with selected antibodies (n = 30) and a subset of these under different fixation conditions. The staining properties were assessed according to six staining quality parameters (signal distribution, intensity, tissue and slide background, acutance, clarity of details, and subcellular morphological details), and the results were compared with those of a well-established detection system (EnVision FLEX). Overall, both detection methods revealed good to optimal results regarding the evaluated parameters even under unfavorable fixation conditions. However, with the prototype detection technology a quicker turnaround time was reached primarily due to shorter primary antibody incubation times. Moreover, PIDT-stained tissues showed higher signal intensity and a uniform signal distribution over the tissue slide, still, with well-preserved tissue morphology and without impairing the gradation of staining intensity of different cell types. In particular, the prototype detection technology performed better in poorly or delayed fixed tissue. In situations where rapid and profound results are in demand, and particularly in the context of a small laboratory setting, this prototype detection technology could be a useful addition to the established detection systems.
Assuntos
Anticorpos/química , Antígenos/análise , Imuno-Histoquímica , Coloração e Rotulagem , Humanos , Fixação de TecidosRESUMO
AIMS: In atrial fibrillation, increased function of the Na+/Ca2+-exchanger (NCX) is one among several electrical remodeling mechanisms. METHODS/RESULTS: Using the patch-clamp- and Ca2+ imaging-methods, we investigated atrial myocytes from NCX-homozygous-overexpressor (OE)- and heterozygous-knockout (KO)-mice and their corresponding wildtypes (WTOE; WTKO). NCX mediated Ca2+ extrusion capacity was reduced in KO and increased in OE. There was no evidence for structural or molecular remodeling. During a proarrhythmic pacing-protocol, the number of low amplitude delayed afterdepolarizations (DADs) was unaltered in OE vs. WTOE and KO vs. WTKO. However, DADs triggered full spontaneous action potentials (sAP) significantly more often in OE vs. WTOE (ratio sAP/DAD: OE:0.18±0.05; WTOE:0.02±0.02; p<0.001). Using the same protocol, a DAD triggered an sAP by tendency less often in KO vs. WTKO (p=0.06) and significantly less often under a more aggressive proarrhythmic protocol (ratio sAP/DAD: KO:0.01±0.003; WT KO: 0.12±0.05; p=0.007). The DAD amplitude was increased in OE vs. WTOE and decreased in KO vs. WTKO. There were no differences in SR-Ca2+-load, the number of spontaneous Ca2+-release-events or IKACh/IK1. CONCLUSIONS: Atrial myocytes with increased NCX expression exhibited increased vulnerability towards sAPs while atriomyocytes with reduced NCX expression were protected. The underlying mechanism consists of a modification of the DAD-amplitude by the level of NCX-activity. Thus, although the number of spontaneous Ca2+-releases and therefore DADs is unaltered, the higher DAD-amplitude in OE made a transgression of the voltage-threshold of an sAP more likely. These findings indicate that the level of NCX activity could influence triggered activity in atrial myocytes independent of possible remodeling processes.
Assuntos
Átrios do Coração/metabolismo , Miócitos Cardíacos/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Potenciais de Ação/genética , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Feminino , Expressão Gênica , Masculino , Potenciais da Membrana/genética , Camundongos , Camundongos Transgênicos , Contração Miocárdica/genética , Miocárdio/metabolismo , Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/genéticaRESUMO
Chronic ß-adrenergic stimulation is regarded as a pivotal step in the progression of heart failure which is associated with a high risk for arrhythmia. The cAMP-dependent transcription factors cAMP-responsive element binding protein (CREB) and cAMP-responsive element modulator (CREM) mediate transcriptional regulation in response to ß-adrenergic stimulation and CREM repressor isoforms are induced after stimulation of the ß-adrenoceptor. Here, we investigate whether CREM repressors contribute to the arrhythmogenic remodeling in the heart by analyzing arrhythmogenic alterations in ventricular cardiomyocytes (VCMs) from mice with transgenic expression of the CREM repressor isoform CREM-IbΔC-X (TG). Patch clamp analyses, calcium imaging, immunoblotting and real-time quantitative RT-PCR were conducted to study proarrhythmic alterations in TG VCMs vs. wild-type controls. The percentage of VCMs displaying spontaneous supra-threshold transient-like Ca(2+) releases was increased in TG accompanied by an enhanced transduction rate of sub-threshold Ca(2+) waves into these supra-threshold events. As a likely cause we discovered enhanced NCX-mediated Ca(2+) transport and NCX1 protein level in TG. An increase in I NCX and decrease in I to and its accessory channel subunit KChIP2 was associated with action potential prolongation and an increased proportion of TG VCMs showing early afterdepolarizations. Finally, ventricular extrasystoles were augmented in TG mice underlining the in vivo relevance of our findings. Transgenic expression of CREM-IbΔC-X in mouse VCMs leads to distinct arrhythmogenic alterations. Since CREM repressors are inducible by chronic ß-adrenergic stimulation our results suggest that the inhibition of CRE-dependent transcription contributes to the formation of an arrhythmogenic substrate in chronic heart disease.
Assuntos
Arritmias Cardíacas/metabolismo , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Potenciais de Ação , Animais , Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Células Cultivadas , Modulador de Elemento de Resposta do AMP Cíclico/antagonistas & inibidores , Modulador de Elemento de Resposta do AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ventrículos do Coração/fisiopatologia , Isoproterenol , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Potássio/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismoRESUMO
Transcription factors of the cAMP response element-binding protein (Creb)/cAMP response element modulator (Crem) family were linked to the switch from a contractile to a proliferating phenotype in vascular smooth muscle cells (VSMCs). Here, we analyzed the vascular function of Crem in mice with a global inactivation of Crem (Crem(-/-)). CRE-mediated transcriptional activity was enhanced in primary Crem(-/-) VSMCs under nonstimulated conditions and under stimulation with Forskolin and platelet-derived growth factor (Pdgf) whereas stimulation with nitric oxide or cGMP showed no effect. This elevated CRE-mediated transcriptional activity as a result of Crem inactivation did not alter aortic contractility or fractions of proliferating or apoptotic aortic VSMCs in situ, and no impact of Crem inactivation on the development of atherosclerotic plaques was observed. Crem(-/-) mice exhibited an increased neointima formation after carotid ligation associated with an increased proliferation of VSMCs in the carotid media. Pdgf-stimulated proliferation of primary aortic Crem(-/-) VSMCs was increased along with an upregulation of messenger RNA (mRNA) levels of Pdgf receptor, alpha polypeptide (Pdgfra), cyclophilin A (Ppia), the regulator of G-protein signaling 5 (Rgs5), and Rho GTPase-activating protein 12 (Arhgap12). Taken together, our data reveal the inhibition of Pdgf-stimulated proliferation of VSMCs by repressing the Pdgf-stimulated CRE-mediated transcriptional activation as the predominant function of Crem in mouse vasculature suggesting an important role of Crem in vasculoproliferative diseases.
Assuntos
Proliferação de Células , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Modulador de Elemento de Resposta do AMP Cíclico/genética , Ciclofilina A/genética , Ciclofilina A/metabolismo , Masculino , Camundongos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia , Proteínas RGS/genética , Proteínas RGS/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Regulação para CimaRESUMO
The cosmopolitan fungal genus Alternaria consists of multiple saprophytic and pathogenic species. Based on phylogenetic and morphological studies, the genus is currently divided into 26 sections. Alternaria sect. Alternaria contains most of the small-spored Alternaria species with concatenated conidia, including important plant, human and postharvest pathogens. Species within sect. Alternaria have been mostly described based on morphology and / or host-specificity, yet molecular variation between them is minimal. To investigate whether the described morphospecies within sect. Alternaria are supported by molecular data, whole-genome sequencing of nine Alternaria morphospecies supplemented with transcriptome sequencing of 12 Alternaria morphospecies as well as multi-gene sequencing of 168 Alternaria isolates was performed. The assembled genomes ranged in size from 33.3-35.2 Mb within sect. Alternaria and from 32.0-39.1 Mb for all Alternaria genomes. The number of repetitive sequences differed significantly between the different Alternaria genomes; ranging from 1.4-16.5 %. The repeat content within sect. Alternaria was relatively low with only 1.4-2.7 % of repeats. Whole-genome alignments revealed 96.7-98.2 % genome identity between sect. Alternaria isolates, compared to 85.1-89.3 % genome identity for isolates from other sections to the A. alternata reference genome. Similarly, 1.4-2.8 % and 0.8-1.8 % single nucleotide polymorphisms (SNPs) were observed in genomic and transcriptomic sequences, respectively, between isolates from sect. Alternaria, while the percentage of SNPs found in isolates from different sections compared to the A. alternata reference genome was considerably higher; 8.0-10.3 % and 6.1-8.5 %. The topology of a phylogenetic tree based on the whole-genome and transcriptome reads was congruent with multi-gene phylogenies based on commonly used gene regions. Based on the genome and transcriptome data, a set of core proteins was extracted, and primers were designed on two gene regions with a relatively low degree of conservation within sect. Alternaria (96.8 and 97.3 % conservation). Their potential discriminatory power within sect. Alternaria was tested next to nine commonly used gene regions in sect. Alternaria, namely the SSU, LSU, ITS, gapdh, rpb2, tef1, Alt a 1, endoPG and OPA10-2 gene regions. The phylogenies from the two gene regions with a relatively low conservation, KOG1058 and KOG1077, could not distinguish the described morphospecies within sect. Alternaria more effectively than the phylogenies based on the commonly used gene regions for Alternaria. Based on genome and transcriptome comparisons and molecular phylogenies, Alternaria sect. Alternaria consists of only 11 phylogenetic species and one species complex. Thirty-five morphospecies, which cannot be distinguished based on the multi-gene phylogeny, are synonymised under A. alternata. By providing guidelines for the naming and identification of phylogenetic species in Alternaria sect. Alternaria, this manuscript provides a clear and stable species classification in this section.
RESUMO
Within a few months a 31-year-old female patient was diagnosed with a psammomatous melanotic schwannoma, an atrial myxoma and microfollicular adenomas in both thyroid lobes. Therefore, sufficient diagnostic criteria of a Carney complex were fulfilled. The Carney complex is an inherited autosomal dominant disorder with highly variable phenotypes, which was initially described by Carney in 1985 as a complex of myxomas, spotty skin pigmentation and endocrine overactivity. Pathologists should consider this differential diagnosis in reports when confronted with a psammomatous melanotic schwannoma.
Assuntos
Adenoma/patologia , Complexo de Carney/patologia , Neoplasias Cardíacas/patologia , Mixoma/patologia , Neoplasias Primárias Múltiplas/patologia , Neurilemoma/patologia , Neoplasias da Glândula Tireoide/patologia , Adenoma/genética , Adulto , Complexo de Carney/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Átrios do Coração/patologia , Neoplasias Cardíacas/genética , Humanos , Mixoma/genética , Neoplasias Primárias Múltiplas/genética , Neurilemoma/genética , Fenótipo , Transdução de Sinais/genética , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genéticaRESUMO
The cAMP response element binding protein (CREB) belongs to the CREB/cAMP response element binding modulator/activating transcription factor 1 family of cAMP-dependent transcription factors mediating a regulation of gene transcription in response to cAMP. Chronic stimulation of ß-adrenergic receptors and the cAMP-dependent signal transduction pathway by elevated plasma catecholamines play a central role in the pathogenesis of heart failure. Ion channel remodeling, particularly a decreased transient outward current (I(to)), and subsequent action potential (AP) prolongation are hallmarks of the failing heart. Here, we studied the role of CREB for ion channel regulation in mice with a cardiomyocyte-specific knockout of CREB (CREB KO). APs of CREB KO cardiomyocytes were prolonged with increased AP duration at 50 and 70% repolarization and accompanied by a by 51% reduction of I(to) peak amplitude as detected in voltage-clamp measurements. We observed a 29% reduction of Kcnd2/Kv4.2 mRNA in CREB KO cardiomyocytes mice while the other I(to)-related channel subunits Kv4.3 and KChIP2 were not different between groups. Accordingly, Kv4.2 protein was reduced by 37% in CREB KO. However, we were not able to detect a direct regulation of Kv4.2 by CREB. The I(to)-dependent AP prolongation went along with an increase of I(Na) and a decrease of I(Ca,L) associated with an upregulation of Scn8a/Nav1.6 and downregulation of Cacna1c/Cav1.2 mRNA in CREB KO cardiomyocytes. Our results from mice with cardiomyocyte-specific inactivation of CREB definitively indicate that CREB critically regulates the AP shape and duration in the mouse ventricle, which might have an impact on ion channel remodeling in situations of altered cAMP-dependent signaling like heart failure.
Assuntos
Potenciais de Ação/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Ventrículos do Coração/citologia , Canais Iônicos/fisiologia , Miócitos Cardíacos/fisiologia , Função Ventricular/fisiologia , Animais , Canais de Cálcio Tipo L/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/deficiência , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação para Baixo/fisiologia , Camundongos , Camundongos Knockout , Modelos Animais , Miócitos Cardíacos/citologia , Canal de Sódio Disparado por Voltagem NAV1.6 , Proteínas do Tecido Nervoso/fisiologia , Técnicas de Patch-Clamp , Transdução de Sinais/fisiologia , Canais de Sódio/fisiologia , Regulação para Cima/fisiologiaRESUMO
BACKGROUND: In normal mucosa, intestinal lamina propria macrophages (IMACs) maintain tolerance against food antigens and the commensal bacterial flora. Several mechanisms have been identified that mediate tolerance. The ubiquitin-proteasome system (UPS) is a large multiprotein complex that degrades cellular proteins. As the UPS may modulate immune functions of IMACs, we performed a detailed investigation of UPS expression and function under normal conditions and in cells derived from patients suffering from inflammatory bowel disease (IBD). METHODS: IMACs were isolated from intestinal mucosa. mRNA expression of macrophages differentiated in vitro (i.v. MACs) and IMACs was compared by Affymetrix® oligonucleotide arrays. Quantitative Taqman-PCR was performed on five exemplary proteasomal and five ubiquitinylation genes each. Proteins were analyzed by immunohistochemistry and Western blotting. Proteasome function was assessed by a fluorimetric test. RESULTS: Affymetrix analysis showed downregulation of mRNA expression of almost all represented proteasomal and of 22 ubiquitination-associated genes in IMACs as compared to i.v. MACs and monocytes. By quantitative PCR, up to tenfold higher mRNA expression of 10 exemplary genes of the UPS (UBE2A, UBE2D2, UBE2L6, USP14, UBB and ATPase2, ß2, ß5, ß2i/MECL-1, ß5i/LMP7) was demonstrated in i.v. MACs as compared to IMACs. Immunohistochemistry and Western blots confirmed these findings in intestinal mucosa of controls and patients suffering from diverticulitis. In contrast, a significant increase in protein amounts was found in mucosa of patients with IBD. CONCLUSION: Reduced expression of subunits of the UPS in IMACs of normal mucosa supports the concept of the presence of a nonreactive, anergic macrophage phenotype in the gut under normal conditions. Reinduction in IMACs of IBD mucosa reflects activated IMACs which can present antigenic peptides and thus support inflammation.
Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Regulação para Baixo , Mucosa Intestinal/enzimologia , Macrófagos/enzimologia , Complexos Ubiquitina-Proteína Ligase/genética , Complexos Ubiquitina-Proteína Ligase/metabolismo , Adenosina Trifosfatases/genética , Diferenciação Celular , Células Cultivadas , Colite Ulcerativa/enzimologia , Colo/enzimologia , Doença de Crohn/enzimologia , Diverticulite/enzimologia , Diverticulite/genética , Humanos , Análise em Microsséries , ATPases Mitocondriais Próton-Translocadoras/genética , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Ubiquitina/genética , Ubiquitina/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Complexos Ubiquitina-Proteína Ligase/sangueRESUMO
Neutron diffraction experiments on a solution of LiCl in water (R = 40) at ambient conditions and in the supercooled and hyperquenched states are reported and analyzed within the empirical potential structure refinement framework. Evidence for the modifications of the microscopic structure of the solvent in the presence of such a small amount of salt is found at all investigated thermodynamic states. On the other hand, it is evident that the structure of the hyperquenched salty sample is similar to that of pure low density amorphous water, although all the peaks of the radial distribution functions are broader in the present case. Changes upon supercooling or hyperquenching of the ion's hydration shells and contacts are of limited size and evidence for segregation phenomena at these states does not clearly show up, although the presence of water separated contacts between ion of the same sign is intriguing.
Assuntos
Cloreto de Lítio/química , Vidro/química , Estrutura Molecular , Difração de Nêutrons , Soluções , Propriedades de Superfície , Termodinâmica , Água/químicaRESUMO
INTRODUCTION: The bidirectional connection between the brain and the gut within psychiatric entities has gained increasing scientific attention over the last years. As a regulator of intestinal permeability, zonulin acts as a key player on the interface of this interplay. Like several psychiatric disorders, intestinal permeability was associated with inflammation in previous findings. METHODS: In this study we explored differences in zonulin serum levels in currently depressed (n = 55) versus currently euthymic (n = 37) individuals with an affective disorder. Further, we explored sex differences and possible influences on zonulin and affective symptoms like medication, age, body mass index, and smoking status. RESULTS: Serum zonulin was significantly higher in females than in men independent from affective status (z = -2.412, p = .016). More specifically, females in the euthymic subgroup had higher zonulin levels than euthymic men (z = -2.114, p = .035). There was no difference in zonulin serum levels in individuals taking or not taking a specific psychopharmacotherapy. We found no correlation between zonulin serum levels and depression severity. DISCUSSION: Increased serum zonulin levels as a proxy for increased intestinal permeability in women may indicate a state of elevated susceptibility for depression-inducing stimuli.
Assuntos
Precursores de Proteínas , Caracteres Sexuais , Feminino , Haptoglobinas , Humanos , Masculino , Transtornos do Humor , PermeabilidadeRESUMO
Based on several force fields (COMPASS, modified TIP3P and SPC/E) high-density amorphous ice is simulated by use of isothermal-isobaric molecular dynamics at a pressure of p approximately 0.3 GPa in the temperature range from 70 to 300 K. Starting at low temperature a large number of heating/cooling cycles are performed and several characteristic properties (density, total energy, and mobility) are traced as functions of temperature. While the first cycles are showing irreversible structural relaxation effects data points from further cycles are reproducible and give clear evidence for the existence of a glass-to-liquid transition. Although, the observed transition temperatures T(g) are dependent on the actual force field used and slightly dependent on the method adopted the results indicate that high-density amorphous ices may indeed be low-temperature structural proxies of ultraviscous high-density liquids.
RESUMO
MOTIVATION: Quantitative experimental data is the critical bottleneck in the modeling of dynamic cellular processes in systems biology. Here, we present statistical approaches improving reproducibility of protein quantification by immunoprecipitation and immunoblotting. RESULTS: Based on a large data set with more than 3600 data points, we unravel that the main sources of biological variability and experimental noise are multiplicative and log-normally distributed. Therefore, we suggest a log-transformation of the data to obtain additive normally distributed noise. After this transformation, common statistical procedures can be applied to analyze the data. An error model is introduced to account for technical as well as biological variability. Elimination of these systematic errors decrease variability of measurements and allow for a more precise estimation of underlying dynamics of protein concentrations in cellular signaling. The proposed error model is relevant for simulation studies, parameter estimation and model selection, basic tools of systems biology. AVAILABILITY: Matlab and R code is available from the authors on request. The data can be downloaded from our website www.fdm.uni-freiburg.de/~ckreutz/data.
Assuntos
Interpretação Estatística de Dados , Perfilação da Expressão Gênica/métodos , Immunoblotting/métodos , Imunoprecipitação/métodos , Modelos Estatísticos , Proteínas/análise , Proteínas/metabolismo , Algoritmos , Simulação por Computador , Modelos Biológicos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
This corrects the article DOI: 10.1038/ncomms8349.
RESUMO
BACKGROUND: The molecular pathomechanisms underlying atrial thrombogenesis are multifactorial and still require detailed investigations. Transgenic mice with cardiomyocyte-directed expression of the transcriptional repressor CREM-IbΔC-X (CREM-TG) represent an experimental model of atrial fibrillation (AF) that shows a gradual, age-dependent progression from atrial ectopy to persistent AF. Importantly, this model develops biatrial thrombi. The molecular characteristics related to the thrombogenesis in CREM-TG mice have not been studied, yet. METHODS: The inflammatory and prothrombotic state was evaluated at the transcriptional (qRT-PCR) and protein level in the left (LA) and right atria (RA) from CREM-TG mice at the age of 20weeks and compared to wild-type controls. Moreover, histological analyses of atrial thrombi were performed. RESULTS: The endocardial dysfunction was mirrored by diminished levels of eNOS-mRNA in both atria (RA: 0.79±0.04, LA: 0.72±0.06; each P<0.05). Moreover, the PAI-1/t-PA mRNA ratio was significantly increased in both atria (RA: 3.6±0.6; P<0.01, LA: 4.0±1.0; P<0.05) indicating a high risk of thrombus formation. However, the inflammatory phenotype was more pronounced in the RA and was reflected by a significant increase in the mRNA levels encoding adhesion molecules ICAM-1 (2.1±0.2; P<0.01), VCAM-1 (2.3±0.5; P<0.05), and selectin P (3.6±0.5: P<0.05). CONCLUSIONS: CREM-TG mice represent a valuable model for studying atrial thrombogenesis and assessing therapeutic approaches preventing embolic events in the systemic and pulmonary circulation.
Assuntos
Fibrilação Atrial/genética , Trombose/genética , Animais , Fibrilação Atrial/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Trombose/metabolismoRESUMO
Climate change and increasing demography press local authorities to look after affordable water resources and replacement of drinking water for city necessities like street and pavement cleaning by more available raw water. Though, the substitution of drinking by non-drinking resources demands the evaluation of sanitary hazards. This article aims therefore to evaluate the contribution of cleaning water to the overall exposure of city dwellers in case of wet pavement cleaning using crossed physical, chemical and biological approaches. The result of tracer experiments with fluorescein show that liquid water content of the cleaning aerosol produced is about 0.24 g m(-3), rending possible a fast estimation of exposure levels. In situ analysis of the aerosol particles indicates a significant increase in particle number concentration and particle diameter, though without change in particle composition. The conventional bacterial analysis using total coliforms as tracer suggests that an important part of the contamination is issued from the pavement. The qPCR results show a more than 20-fold increase of background genome concentration for Escherichia coli and 10-fold increase for Enterococcus but a negligible contribution of the cleaning water. The fluorescence analysis of the cleaning aerosol confirms the above findings identifying pavement surface as the major contributor to aerosol organic load. The physical, chemical and microbiological approaches used make it possible to describe accurately the cleaning bioaerosol and to identify the existence of significantly higher levels of all parameters studied during the wet pavement cleaning. Though, the low level of contamination and the very short time of passage of pedestrian in the zone do not suggest a significant risk for the city dwellers. As the cleaning workers remain much longer in the impacted area, more attention should be paid to their chronic exposure.
Assuntos
Aerossóis , Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Exposição Ambiental/estatística & dados numéricos , Pedestres , Poluição da Água/análise , Poluição da Água/estatística & dados numéricosRESUMO
The pressure-temperature phase diagram of ice displays a perplexing variety of structurally distinct phases. In the century-long history of scientific research on ice, the proton-ordered ice phases numbered XIII through XV were discovered only recently. Despite considerable effort, none of the transitions leading from the low-temperature ordered ices VIII, IX, XI, XIII, XIV and XV to their high-temperature disordered counterparts were experimentally found to display the full Pauling entropy. Here we report calorimetric measurements on suitably high-pressure-treated, hydrogen chloride-doped ice XIV that demonstrate just this at the transition to ice XII. Dielectric spectroscopy on undoped and on variously doped ice XII crystals reveals that addition of hydrogen chloride, the agent triggering complete proton order in ice XIV, enhances the precursor dynamics strongest. These discoveries provide new insights into the puzzling observation that different dopants trigger the formation of different proton-ordered ice phases.
RESUMO
Flaxseed and its mammalian lignan precursor secoisolariciresinol diglycoside (SDG) have been shown to be mammary cancer-protective in rats. Thus, the antiestrogenic effects of flaxseed and SDG were compared with tamoxifen, an antiestrogen, by monitoring rat estrous cycling. Four-week supplementation of a high-fat diet with flaxseed (2.5, 5, or 10%) or SDG (0.75, 1.5 or 3.0 mg/day) produced a dose-related cessation or lengthening (by 18-39%) of estrous cycles in up to 66% of rats. With tamoxifen (1 mg/kg body weight/day), 83% of the animals had irregular cycles or were in persistent diestrus. Flaxseed and SDG were antiestrogenic without gross tissue toxicity.