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1.
Cardiovasc Diabetol ; 17(1): 88, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895299

RESUMO

OBJECTIVES: Local, abdominal fat depots may be related to alterations in cardiac function and morphology due to a metabolic linkage. Thus, we aimed to determine their association with subtle cardiac changes and the potential interaction with hyperglycemic metabolic states. METHODS: Subjects from the general population and without history of cardiovascular disease were drawn from the Cooperative Health Research in the Region of Augsburg FF4 cohort and underwent 3 T cardiac and body MRI. Measures of abdominal adiposity such as hepatic proton-density fat fraction [PDFFhepatic], subcutaneous (SAT) and visceral abdominal fat (VAT) as well as established cardiac left-ventricular (LV) measures including LV remodeling index (LVCI) were derived. Associations were determined using linear regression analysis based on standard deviation normalized predictors. RESULTS: Among a total of 374 subjects (56.2 ± 9.1 years, 58% males), 49 subjects had diabetes, 99 subjects had prediabetes and 226 represented normal controls. Only subtle cardiac alterations were observed (e.g. LVCI: 1.13 ± 0.30). While SAT was not associated, increasing VAT and increasing PDFFhepatic were independently associated with increasing LVCI (ß = 0.11 and 0.06, respectively), decreasing LV end-diastolic volume (ß = - 6.70 and 3.23, respectively), and decreasing LV stroke volume (ß = - 3.91 and - 2.20, respectively). Hyperglycemic state did not modify the associations between VAT or PDFF and LV measures (interaction term: all p ≥ 0.29). CONCLUSION: In a healthy population, VAT but also PDFFhepatic were associated with subclinical measures of LV remodeling without evidence for a modifying effect of hyperglycemic state.


Assuntos
Adiposidade , Glicemia/metabolismo , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Gordura Intra-Abdominal/diagnóstico por imagem , Imageamento por Ressonância Magnética , Obesidade Abdominal/diagnóstico por imagem , Estado Pré-Diabético/sangue , Função Ventricular Esquerda , Remodelação Ventricular , Idoso , Doenças Assintomáticas , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/etiologia , Fígado Gorduroso/fisiopatologia , Feminino , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Gordura Intra-Abdominal/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/complicações , Obesidade Abdominal/fisiopatologia , Estado Pré-Diabético/complicações , Estado Pré-Diabético/diagnóstico , Valor Preditivo dos Testes , Fatores de Risco
2.
Eur Radiol ; 28(7): 3105-3113, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29423576

RESUMO

OBJECTIVES: The aim of this study was to assess subclinical changes in right ventricular volumes and function in subjects with prediabetes and diabetes and controls without a history of cardiovascular disease. METHODS: Data from 400 participants in the KORA FF4 study without self-reported cardiovascular disease who underwent 3-T whole-body MRI were obtained. The right ventricle was evaluated using the short axis and a four-chamber view. Diabetes was defined according to WHO criteria. Associations between glucose tolerance and right ventricular parameters were assessed using multivariable adjusted linear regression models. RESULTS: Data from 337 participants were available for analysis. Of these, 43 (13%) had diabetes, 87 (26%) had prediabetes, and 207 (61%) were normoglycaemic controls. There was a stepwise decrease in right ventricular volumes in men with prediabetes and diabetes in comparison with controls, including right ventricular end-diastolic volume (ß = -20.4 and ß = -25.6, respectively; p ≤ 0.005), right ventricular end-systolic volume (ß = -12.3 and ß = -12.7, respectively; p ≤ 0.037) and right ventricular stroke volume (ß = -8.1 and ß = -13.1, respectively, p ≤ 0.016). We did not observe any association between prediabetes or diabetes and right ventricular volumes in women or between prediabetes or diabetes and right ventricular ejection fraction in men and women. CONCLUSIONS: This study points towards early subclinical changes in right ventricular volumes in men with diabetes and prediabetes. KEY POINTS: • MRI was used to detect subclinical changes in right ventricular parameters. • Diabetes mellitus is associated with right ventricular dysfunction. • Impairment of right ventricular volumes seems to occur predominantly in men.


Assuntos
Diabetes Mellitus/diagnóstico por imagem , Disfunção Ventricular Direita/diagnóstico por imagem , Adulto , Idoso , Estudos de Casos e Controles , Diabetes Mellitus/fisiopatologia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Modelos Lineares , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/diagnóstico por imagem , Estado Pré-Diabético/fisiopatologia , Volume Sistólico/fisiologia , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita/fisiologia
3.
BMC Cardiovasc Disord ; 18(1): 162, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30092757

RESUMO

BACKGROUND: Left ventricular (LV) hypertrophy and changes in LV geometry are associated with increased cardiovascular mortality. Subjects with type 2 diabetes have an increased risk of such alterations in cardiac morphology. We sought to assess the association of glycemic status and LV wall thickness measured by cardiac magnetic resonance (CMR), and potential interactions of hypertension and diabetes. METHODS: CMR was performed on 359 participants from a cross-sectional study nested in a population-based cohort (KORA FF4) free of overt cardiovascular disease. Participants were classified according to their glycemic status as either control (normal glucose metabolism), prediabetes or type 2 diabetes. Segmentation of the left ventricle was defined according to the American Heart Association (AHA) 16-segment model. Measurements of wall thickness were obtained at end-diastole and analyzed by linear regression models adjusted for traditional cardiovascular risk factors. RESULTS: LV wall thickness gradually increased from normoglycemic controls to subjects with prediabetes and subjects with diabetes (8.8 ± 1.4 vs 9.9 ± 1.4 vs 10.5 ± 1.6 mm, respectively). The association was independent of hypertension and traditional cardiovascular risk factors (ß-coefficient: 0.44 mm for prediabetes and 0.70 mm for diabetes, p-values compared to controls: p = 0.007 and p = 0.004, respectively). Whereas the association of glycemic status was strongest for the mid-cavity segments, the association of hypertension was strongest for the basal segments. CONCLUSION: Abnormal glucose metabolism, including pre-diabetes, is associated with increased LV wall thickness independent of hypertension.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Cardiomiopatias Diabéticas/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Estado Pré-Diabético/sangue , Função Ventricular Esquerda , Remodelação Ventricular , Idoso , Biomarcadores/sangue , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/etiologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/complicações , Estado Pré-Diabético/diagnóstico , Fatores de Risco
4.
Eur Radiol ; 26(6): 1895-904, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26340812

RESUMO

OBJECTIVES: To determine the feasibility of a multi-step magnetic resonance imaging (MRI) approach for comprehensive assessment of hepatic steatosis defined as liver fat content of ≥5 % in an asymptomatic population. METHODS: The study was approved by the institutional review board and written informed consent of all participants was obtained. Participants of a population-based study cohort underwent a three-step 3-T MRI-based assessment of liver fat. A dual-echo Dixon sequence was performed to identify subjects with hepatic steatosis, followed by a multi-echo Dixon sequence with proton density fat fraction estimation. Finally, single-voxel T2-corrected multi-echo spectroscopy was performed. RESULTS: A total of 215 participants completed the MRI protocol (56.3 % male, average age 57.2 ± 9.4 years). The prevalence of hepatic steatosis was 55 %. Mean liver proton density fat fraction was 9.2 ± 8.5 % by multi-echo Dixon and 9.3 ± 8.6 % by multi-echo spectroscopy (p = 0.51). Dual-echo Dixon overestimated liver fat fraction by 1.4 ± 2.0 % (p < 0.0001). All measurements showed excellent correlations (r ≥ 0.9, p < 0.001). Dual-echo Dixon was highly sensitive for the detection of hepatic steatosis (sensitivity 0.97, NPV 0.96) with good specificity and PPV (0.75 and 0.81, respectively). CONCLUSIONS: A multi-step MRI approach may enable rapid and accurate identification of subjects with hepatic steatosis in an asymptomatic population. KEY POINTS: • Dual-echo Dixon can rapidly and reliably exclude hepatic steatosis without complex post-processing. • Multi-echo Dixon and multi-echo spectroscopy yield similar results regarding hepatic fat quantification. • Each sequence can be performed in one breath-hold. • These sequences can be implemented in routine abdominal MRI protocols. • Thus hepatic fat can be evaluated without relevant increase in scan time.


Assuntos
Fígado Gorduroso/diagnóstico , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Doenças Assintomáticas , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes
5.
Eur Radiol ; 26(9): 3223-33, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26679184

RESUMO

OBJECTIVES: To evaluate the potential of grating-based phase-contrast computed-tomography (gb-PCCT) to classify human carotid and coronary atherosclerotic plaques according to modified American Heart Association (AHA) criteria. METHODS: Experiments were carried out at a laboratory-based set-up consisting of X-ray tube (40 kVp), grating-interferometer and detector. Eighteen human carotid and coronary artery specimens were examined. Histopathology served as the standard of reference. Vessel cross-sections were classified as AHA lesion type I/II, III, IV/V, VI, VII or VIII plaques by two independent reviewers blinded to histopathology. Conservative measurements of diagnostic accuracies for the detection and differentiation of plaque types were evaluated. RESULTS: A total of 127 corresponding gb-PCCT/histopathology sections were analyzed. Based on histopathology, lesion type I/II was present in 12 (9.5 %), III in 18 (14.2 %), IV/V in 38 (29.9 %), VI in 16 (12.6 %), VII in 34 (26.8 %) and VIII in 9 (7.0 %) cross-sections. Sensitivity, specificity and positive and negative predictive value were ≥0.88 for most analyzed plaque types with a good level of agreement (Cohen's kappa = 0.90). Overall, results were better in carotid (kappa = 0.97) than in coronary arteries (kappa = 0.85). Inter-observer agreement was high with kappa = 0.85, p < 0.0001. CONCLUSIONS: These results indicate that gb-PCCT can reliably classify atherosclerotic plaques according to modified AHA criteria with excellent agreement to histopathology. KEY POINTS: • Different atherosclerotic plaque types display distinct morphological features in phase-contrast CT. • Phase-contrast CT can detect and differentiate AHA plaque types. • Calcifications caused streak artefacts and reduced sensitivity in type VI lesions. • Overall agreement was higher in carotid than in coronary arteries.


Assuntos
Artérias Carótidas/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Placa Aterosclerótica/classificação , Placa Aterosclerótica/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , American Heart Association , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Placa Aterosclerótica/patologia , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estados Unidos
6.
Eur Radiol ; 25(12): 3659-68, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25956934

RESUMO

OBJECTIVES: Conventional X-ray attenuation-based contrast is inherently low for the soft-tissue components of the female breast. To overcome this limitation, we investigate the diagnostic merits arising from dark-field mammography by means of certain tumour structures enclosed within freshly dissected mastectomy samples. METHODS: We performed grating-based absorption, absolute phase and dark-field mammography of three freshly dissected mastectomy samples containing bi- and multifocal carcinoma using a compact, laboratory Talbot-Lau interferometer. Preoperative in vivo imaging (digital mammography, ultrasound, MRI), postoperative histopathological analysis and ex vivo digital mammograms of all samples were acquired for the diagnostic verification of our results. RESULTS: In the diagnosis of multifocal tumour growth, dark-field mammography seems superior to standard breast imaging modalities, providing a better resolution of small, calcified tumour nodules, demarcation of tumour boundaries with desmoplastic stromal response and spiculated soft-tissue strands extending from an invasive ductal breast cancer. CONCLUSIONS: On the basis of selected cases, we demonstrate that dark-field mammography is capable of outperforming conventional mammographic imaging of tumour features in both calcified and non-calcified tumours. Presuming dose optimization, our results encourage further studies on larger patient cohorts to identify those patients that will benefit the most from this promising additional imaging modality. KEY POINTS: • X-ray dark-field mammography provides significantly improved visualization of tumour features • X-ray dark-field mammography is capable of outperforming conventional mammographic imaging • X-ray dark-field mammography provides imaging sensitivity towards highly dispersed calcium grains.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Mamografia/métodos , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mastectomia
7.
Radiology ; 269(2): 427-33, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23696682

RESUMO

PURPOSE: To test the hypothesis that the joint distribution of x-ray transmission and dark-field signals obtained with a compact cone-beam preclinical scanner with a polychromatic source can be used to diagnose pulmonary emphysema in ex vivo murine lungs. MATERIALS AND METHODS: The animal care committee approved this study. Three excised murine lungs with pulmonary emphysema and three excised murine control lungs were imaged ex vivo by using a grating-based micro-computed tomographic (CT) scanner. To evaluate the diagnostic value, the natural logarithm of relative transmission and the natural logarithm of dark-field scatter signal were plotted on a per-pixel basis on a scatterplot. Probability density function was fit to the joint distribution by using principle component analysis. An emphysema map was calculated based on the fitted probability density function. RESULTS: The two-dimensional scatterplot showed a characteristic difference between control and emphysematous lungs. Control lungs had lower average median logarithmic transmission (-0.29 vs -0.18, P = .1) and lower average dark-field signal (-0.54 vs -0.37, P = .1) than emphysematous lungs. The angle to the vertical axis of the fitted regions also varied significantly (7.8° for control lungs vs 15.9° for emphysematous lungs). The calculated emphysema distribution map showed good agreement with histologic findings. CONCLUSION: X-ray dark-field scatter images of murine lungs obtained with a preclinical scanner can be used in the diagnosis of pulmonary emphysema. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122413/-/DC1.


Assuntos
Enfisema Pulmonar/diagnóstico por imagem , Microtomografia por Raio-X/métodos , Animais , Desenho de Equipamento , Feminino , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Interpretação de Imagem Radiográfica Assistida por Computador , Microtomografia por Raio-X/instrumentação
8.
Eur Radiol ; 23(2): 381-7, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22932738

RESUMO

OBJECTIVE: Limited contrast between healthy and tumour tissue is a limiting factor in mammography and CT of the breast. Phase-contrast computed tomography (PC-CT) provides improved soft-tissue contrast compared with absorption-based techniques. In this study, we assessed the technical feasibility of grating-based PC-CT imaging of the breast for characterisation of ductal carcinoma in situ (DCIS). METHODS: Grating-based PC-CT was performed on one breast specimen containing an invasive ductal carcinoma and DCIS using monochromatic radiation of 23 keV. Phase-contrast and absorption-based images were compared qualitatively and quantitatively with histopathology in a blinded fashion. RESULTS: Grating-based PC-CT showed improved differentiation of soft-tissue components. Circular structures of high phase-shift contrast corresponding to the walls of the dilated ductuli of the DCIS were visualised with a contrast-to-noise ratio (CNR) of 9.6 using PC-CT but were not detectable on absorption-based images (CNR = 0.27). The high phase-shift structures of the dilated ductuli were identifiable in the PC-CT volume data set allowing for 3D characterisation of DCIS. CONCLUSIONS: Our results indicate that unlike conventional CT, grating-based PC-CT may allow the differentiation between invasive carcinoma and intraductal carcinoma and healthy breast tissue and provide 3D visualisation of DCIS.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador , Tomografia Computadorizada por Raios X/métodos , Idoso , Biópsia por Agulha , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/cirurgia , Meios de Contraste , Diagnóstico Diferencial , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Imuno-Histoquímica , Mamografia/métodos , Mastectomia/métodos , Intensificação de Imagem Radiográfica/métodos , Manejo de Espécimes
9.
Proc Natl Acad Sci U S A ; 107(9): 4105-10, 2010 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-20160105

RESUMO

Alternative splicing plays an important role in generating proteome diversity. The polypyrimidine tract-binding protein (PTB) is a key alternative splicing factor involved in exon repression. It has been proposed that PTB acts by looping out exons flanked by pyrimidine tracts. We present fluorescence, NMR, and in vivo splicing data in support of a role of PTB in inducing RNA loops. We show that the RNA recognition motifs (RRMs) 3 and 4 of PTB can bind two distant pyrimidine tracts and bring their 5' and 3' ends in close proximity, thus looping the RNA. Efficient looping requires an intervening sequence of 15 nucleotides or longer between the pyrimidine tracts. RRM3 and RRM4 bind the 5' and the 3' pyrimidine tracts, respectively, in a specific directionality and work synergistically for efficient splicing repression in vivo.


Assuntos
Processamento Alternativo , Transferência Ressonante de Energia de Fluorescência/métodos , Ressonância Magnética Nuclear Biomolecular/métodos , Proteína de Ligação a Regiões Ricas em Polipirimidinas/química , RNA/química , Western Blotting , Células HeLa , Humanos , Conformação Proteica , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
PLoS One ; 18(4): e0279323, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37058505

RESUMO

BACKGROUND: The differentiation of minimal-fat-or low-fat-angiomyolipomas from other renal lesions is clinically challenging in conventional computed tomography. In this work, we have assessed the potential of grating-based x-ray phase-contrast computed tomography (GBPC-CT) for visualization and quantitative differentiation of minimal-fat angiomyolipomas (mfAMLs) and oncocytomas from renal cell carcinomas (RCCs) on ex vivo renal samples. MATERIALS AND METHODS: Laboratory GBPC-CT was performed at 40 kVp on 28 ex vivo kidney specimens including five angiomyolipomas with three minimal-fat (mfAMLs) and two high-fat (hfAMLs) subtypes as well as three oncocytomas and 20 RCCs with eight clear cell (ccRCCs), seven papillary (pRCCs) and five chromophobe RCC (chrRCC) subtypes. Quantitative values of conventional Hounsfield units (HU) and phase-contrast Hounsfield units (HUp) were determined and histogram analysis was performed on GBPC-CT and grating-based attenuation-contrast computed tomography (GBAC-CT) slices for each specimen. For comparison, the same specimens were imaged at a 3T magnetic resonance imaging (MRI) scanner. RESULTS: We have successfully matched GBPC-CT images with clinical MRI and histology, as GBPC-CT presented with increased soft tissue contrast compared to absorption-based images. GBPC-CT images revealed a qualitative and quantitative difference between mfAML samples (58±4 HUp) and oncocytomas (44±10 HUp, p = 0.057) and RCCs (ccRCCs: 40±12 HUp, p = 0.012; pRCCs: 43±9 HUp, p = 0.017; chrRCCs: 40±7 HUp, p = 0.057) in contrast to corresponding laboratory attenuation-contrast CT and clinical MRI, although not all differences were statistically significant. Due to the heterogeneity and lower signal of oncocytomas, quantitative differentiation of the samples based on HUp or in combination with HUs was not possible. CONCLUSIONS: GBPC-CT allows quantitative differentiation of minimal-fat angiomyolipomas from pRCCs and ccRCCs in contrast to absorption-based imaging and clinical MRI.


Assuntos
Adenoma Oxífilo , Angiomiolipoma , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/patologia , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/patologia , Angiomiolipoma/diagnóstico por imagem , Angiomiolipoma/patologia , Raios X , Tomografia Computadorizada por Raios X/métodos , Adenoma Oxífilo/diagnóstico por imagem , Diagnóstico Diferencial , Estudos Retrospectivos
11.
J Biol Chem ; 286(27): 24023-35, 2011 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-21566117

RESUMO

Gram-negative bacterial pathogens have developed specialized secretion systems to transfer bacterial proteins directly into host cells. These bacterial effectors are central to virulence and reprogram host cell processes to favor bacterial survival, colonization, and proliferation. Knowing the complete set of effectors encoded by a particular pathogen is the key to understanding bacterial disease. In addition, the identification of the molecular assemblies that these effectors engage once inside the host cell is critical to determining the mechanism of action of each effector. In this work we used stable isotope labeling of amino acids in cell culture (SILAC), a powerful quantitative proteomics technique, to identify the proteins secreted by the Salmonella pathogenicity island-2 type three secretion system (SPI-2 T3SS) and to characterize the host interaction partners of SPI-2 effectors. We confirmed many of the known SPI-2 effectors and were able to identify several novel substrate candidates of this secretion system. We verified previously published host protein-effector binding pairs and obtained 11 novel interactions, three of which were investigated further and confirmed by reciprocal co-immunoprecipitation. The host cell interaction partners identified here suggest that Salmonella SPI-2 effectors target, in a concerted fashion, cellular processes such as cell attachment and cell cycle control that are underappreciated in the context of infection. The technology outlined in this study is specific and sensitive and serves as a robust tool for the identification of effectors and their host targets that is readily amenable to the study of other bacterial pathogens.


Assuntos
Proteínas de Bactérias/metabolismo , Sistemas de Secreção Bacterianos/fisiologia , Ilhas Genômicas/fisiologia , Interações Hospedeiro-Patógeno/fisiologia , Proteínas de Membrana/metabolismo , Salmonella typhimurium/fisiologia , Salmonella typhimurium/patogenicidade , Proteínas de Bactérias/genética , Humanos , Proteínas de Membrana/genética
12.
Infect Immun ; 79(11): 4392-400, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21875964

RESUMO

To cause disease, Salmonella enterica serovar Typhimurium requires two type III secretion systems that are encoded by Salmonella pathogenicity islands 1 and 2 (SPI-1 and -2). These secretion systems serve to deliver specialized proteins (effectors) into the host cell cytosol. While the importance of these effectors to promote colonization and replication within the host has been established, the specific roles of individual secreted effectors in the disease process are not well understood. In this study, we used an in vivo gallbladder epithelial cell infection model to study the function of the SPI-2-encoded type III effector, SseL. The deletion of the sseL gene resulted in bacterial filamentation and elongation and the unusual localization of Salmonella within infected epithelial cells. Infection with the ΔsseL strain also caused dramatic changes in host cell lipid metabolism and led to the massive accumulation of lipid droplets in infected cells. This phenotype was directly attributable to the deubiquitinase activity of SseL, as a Salmonella strain carrying a single point mutation in the catalytic cysteine also resulted in extensive lipid droplet accumulation. The excessive buildup of lipids due to the absence of a functional sseL gene also was observed in murine livers during S. Typhimurium infection. These results suggest that SseL alters host lipid metabolism in infected epithelial cells by modifying the ubiquitination patterns of cellular targets.


Assuntos
Proteínas de Bactérias/metabolismo , Endopeptidases/metabolismo , Ilhas Genômicas/fisiologia , Metabolismo dos Lipídeos/fisiologia , Salmonelose Animal/microbiologia , Salmonella typhimurium/metabolismo , Animais , Proteínas de Bactérias/genética , Endopeptidases/genética , Vesícula Biliar/metabolismo , Vesícula Biliar/microbiologia , Regulação Bacteriana da Expressão Gênica , Ilhas Genômicas/genética , Fígado/metabolismo , Fígado/microbiologia , Camundongos , Salmonella typhimurium/enzimologia , Salmonella typhimurium/genética
13.
Eur J Radiol ; 134: 109451, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33279799

RESUMO

OBJECTIVES: Management of incidental findings (IF) remains controversial but highly relevant. Our aim was to assess the frequency, management and psychosocial consequences of IF reporting in a population-based cohort study undergoing whole-body MR imaging. METHODS: The study was nested in a prospective cohort from a longitudinal, population-based cohort (KORA-FF4) in southern Germany. All MR obtained on 3 T MR scanner were reviewed by board-certified radiologists regarding clinically relevant IF. A baseline and follow-up questionnaires including PHQ-9 were completed prior to and 6-month after to the scan. RESULTS: Of 400 participants (56.3 ±â€¯9.2years, 58 % male) undergoing whole-body MR, IF were found in 22 % of participants (n = 89); most frequently located in the abdominal sequences. In the pre-scan survey, most participants stated as the motivation that they wanted to "contribute to a scientific purpose" (91 %), while "knowing whether I'm healthy" was the most frequent motivation reported 6 months post-scan (88 %). The desire for IF reporting increased over time (pre- vs. 6-months-post-scan), also for clinically less important IF (72 % vs. 84 %, p = 0.001). Regarding psychosocial impact, a small portion (3.4 %) reported that awaiting the IF report added "definitely" or "very probably" additional stress burden. Of participants with reported IF, 56.8 % classified the results as "very helpful". In the post-scan survey moderate depression was observed in 3.3 % and severe depression in 1.2 %. This did not differ between participants with and without reported IF. CONCLUSION: In a cohort with whole-body MR imaging, the prevalence of IF was high. Participants considered reporting of IF highly important and added only minor psychological burden.


Assuntos
Achados Incidentais , Imageamento por Ressonância Magnética , Estudos de Coortes , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Estudos Prospectivos
14.
Sci Rep ; 11(1): 2325, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504924

RESUMO

To identify the most important parameters associated with cerebral white matter hyperintensities (WMH), in consideration of potential collinearity, we used a data-driven machine-learning approach. We analysed two independent cohorts (KORA and SHIP). WMH volumes were derived from cMRI-images (FLAIR). 90 (KORA) and 34 (SHIP) potential determinants of WMH including measures of diabetes, blood-pressure, medication-intake, sociodemographics, life-style factors, somatic/depressive-symptoms and sleep were collected. Elastic net regression was used to identify relevant predictor covariates associated with WMH volume. The ten most frequently selected variables in KORA were subsequently examined for robustness in SHIP. The final KORA sample consisted of 370 participants (58% male; age 55.7 ± 9.1 years), the SHIP sample comprised 854 participants (38% male; age 53.9 ± 9.3 years). The most often selected and highly replicable parameters associated with WMH volume were in descending order age, hypertension, components of the social environment (i.e. widowed, living alone) and prediabetes. A systematic machine-learning based analysis of two independent, population-based cohorts showed, that besides age and hypertension, prediabetes and components of the social environment might play important roles in the development of WMH. Our results enable personal risk assessment for the development of WMH and inform prevention strategies tailored to the individual patient.


Assuntos
Hipertensão/fisiopatologia , Aprendizado de Máquina , Substância Branca/fisiologia , Envelhecimento/fisiologia , Pressão Sanguínea/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
15.
Artigo em Inglês | MEDLINE | ID: mdl-34183320

RESUMO

INTRODUCTION: As white matter hyperintensities (WMHs) of the brain are associated with an increased risk of stroke, cognitive decline, and depression, elucidating the associated risk factors is important. In addition to age and hypertension, pre-diabetes and diabetes may play important roles in the development of WMHs. Previous studies have, however, shown conflicting results. We aimed to investigate the effect of diabetes status and quantitative markers of glucose metabolism on WMH volume in a population-based cohort without prior cardiovascular disease. RESEARCH DESIGN AND METHODS: 400 participants underwent 3 T MRI. WMHs were manually segmented on 3D fluid-attenuated inversion recovery images. An oral glucose tolerance test (OGTT) was administered to all participants not previously diagnosed with diabetes to assess 2-hour serum glucose concentrations. Fasting glucose concentrations and glycated hemoglobin (HbA1c) levels were measured. Zero-inflated negative binomial regression analyses of WMH volume and measures of glycemic status were performed while controlling for cardiovascular risk factors and multiple testing. RESULTS: The final study population comprised 388 participants (57% male; age 56.3±9.2 years; n=98 with pre-diabetes, n=51 with diabetes). Higher WMH volume was associated with pre-diabetes (p=0.001) and diabetes (p=0.026) compared with normoglycemic control participants after adjustment for cardiovascular risk factors. 2-hour serum glucose (p<0.001), but not fasting glucose (p=0.389) or HbA1c (p=0.050), showed a significant positive association with WMH volume after adjustment for cardiovascular risk factors. CONCLUSION: Our results indicate that high 2-hour serum glucose concentration in OGTT, but not fasting glucose levels, may be an independent risk factor for the development of WMHs, with the potential to inform intensified prevention strategies in individuals at risk of WMH-associated morbidity.


Assuntos
Disfunção Cognitiva , Diabetes Mellitus , Estado Pré-Diabético , Substância Branca , Idoso , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/epidemiologia , Substância Branca/diagnóstico por imagem
16.
Appl Environ Microbiol ; 76(15): 5300-4, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20562287

RESUMO

We show that dimethyl sulfoxide (DMSO) inhibits Salmonella hilA expression and that this inhibition is stronger under anaerobiosis. Because DMSO can be reduced to dimethyl sulfide (DMS) during anaerobic growth, we hypothesized that DMS was responsible for hilA inhibition. Indeed, DMS strongly inhibited the expression of hilA and multiple Salmonella pathogenicity island 1 (SPI-1)-associated genes as well as the invasion of cultured epithelial cells. Because DMSO and DMS are widespread in nature, we hypothesize that this phenomenon may contribute to environmental sensing by Salmonella.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Células Epiteliais/microbiologia , Salmonella/efeitos dos fármacos , Sulfetos/farmacologia , Transativadores/antagonistas & inibidores , Anaerobiose , Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Salmonella/fisiologia
17.
Sci Rep ; 10(1): 9405, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523085

RESUMO

This study investigates the x-ray scattering characteristics of microsphere particles in x-ray-grating-based interferometric imaging at different concentrations, bubble sizes and tube voltages (kV). Attenuation (ATI), dark-field (DFI) and phase-contrast (PCI) images were acquired. Signal-to-noise (SNR) and contrast-to-noise ratios with water (CNRw) and air as reference (CNRa) were determined. In all modalities, a linear relationship between SNR and microbubbles concentration, respectively, microsphere size was found. A significant gain of SNR was found when varying kV. SNR was significantly higher in DFI and PCI than ATI. The highest gain of SNR was shown at 60 kV for all media in ATI and DFI, at 80 kV for PCI. SNR for all media was significantly higher compared to air and was slightly lower compared to water. A linear relationship was found between CNRa, CNRw, concentration and size. With increasing concentration and decreasing size, CNRa and CNRw increased in DFI, but decreased in PCI. Best CNRa and CNRw was found at specific combination of kV and concentration/size. Highest average CNRa and CNRw was found for microspheres in ATI and PCI, for microbubbles in DFI. Microspheres are a promising contrast-media for grating-based-interferometry, if kV, microsphere size and concentration are appropriately combined.


Assuntos
Meios de Contraste/química , Radiografia/métodos , Tomografia Computadorizada por Raios X/métodos , Microbolhas , Doses de Radiação , Raios X
18.
J Thorac Imaging ; 35(1): 49-55, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30570523

RESUMO

PURPOSE: Myocardial strain analysis is a promising tool for the detection of subtle but relevant alterations of left ventricular function, also in asymptomatic subjects. Thus, we determined the feasibility of cardiac magnetic resonance-based 2D global strain analysis using feature tracking and its association with cardiovascular risk factors in a sample from the general population. MATERIALS AND METHODS: Subjects without a history of cardiocerebrovascular disease were enrolled in a substudy of the population-based KORA (Cooperative Health Research in the Region of Augsburg) cohort. In all participants with the absence of late gadolinium enhancement, longitudinal and circumferential global strains were measured on Cine SSFP imaging (TR: 29.97 ms, TE: 1.46 ms, ST: 8 mm), using a semiautomatic segmentation algorithm (CVI42, Circle, Canada). Differences in strain values according to age, sex, body mass index, hypertension, diabetes mellitus, and hyperlipidemia were derived using linear regression analysis. RESULTS: Among 360 subjects (mean age, 56.2±9.2 y, 57% male), the average global systolic radial strain was 40.1±8.2%, circumferential 19.9±2.7%, and longitudinal 19.8±3.2%. Male sex was associated with decreased global strain values, independent of the strain direction (all P<0.001). Although many cardiovascular risk factors were correlated with strain in univariate analysis, mainly waist-to-hip ratio and HbA1c remained associated with decreased radial and circumferential strains in fully adjusted models. Similarly, higher radial and circumferential strains were observed in older subjects (ß=0.14, P=0.01 and ß=0.11, P=0.04, respectively). CONCLUSIONS: Strain analysis using magnetic resonance feature tracking is feasible in population-based cohort studies and shows differences with respect to age and sex as well as an independent association with markers of metabolic syndrome.


Assuntos
Imagem Cinética por Ressonância Magnética/métodos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Fatores Etários , Algoritmos , Índice de Massa Corporal , Meios de Contraste , Complicações do Diabetes , Feminino , Humanos , Hiperlipidemias/complicações , Hipertensão/complicações , Interpretação de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais
19.
Sci Rep ; 10(1): 8363, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32433583

RESUMO

To identify the most important factors that impact brain volume, while accounting for potential collinearity, we used a data-driven machine-learning approach. Gray Matter Volume (GMV) was derived from magnetic resonance imaging (3T, FLAIR) and adjusted for intracranial volume (ICV). 93 potential determinants of GMV from the categories sociodemographics, anthropometric measurements, cardio-metabolic variables, lifestyle factors, medication, sleep, and nutrition were obtained from 293 participants from a population-based cohort from Southern Germany. Elastic net regression was used to identify the most important determinants of ICV-adjusted GMV. The four variables age (selected in each of the 1000 splits), glomerular filtration rate (794 splits), diabetes (323 splits) and diabetes duration (122 splits) were identified to be most relevant predictors of GMV adjusted for intracranial volume. The elastic net model showed better performance compared to a constant linear regression (mean squared error = 1.10 vs. 1.59, p < 0.001). These findings are relevant for preventive and therapeutic considerations and for neuroimaging studies, as they suggest to take information on metabolic status and renal function into account as potential confounders.


Assuntos
Substância Cinzenta/fisiologia , Aprendizado de Máquina , Modelos Neurológicos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Estudos de Casos e Controles , Fatores de Confusão Epidemiológicos , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Seguimentos , Alemanha/epidemiologia , Taxa de Filtração Glomerular/fisiologia , Substância Cinzenta/diagnóstico por imagem , Humanos , Estilo de Vida , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/fisiologia , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/fisiopatologia , Estudos Prospectivos
20.
Int J Biochem Cell Biol ; 41(2): 380-9, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18775503

RESUMO

Bacterial pathogens have evolved by combinations of gene acquisition, deletion, and modification, which increases their fitness. Additionally, bacteria are able to evolve in "quantum leaps" via the ability to promiscuously acquire new genes. Many bacterial pathogens - especially Gram-negative enteric pathogens - have evolved mechanisms by which to subvert signal transduction pathways of eukaryotic cells by expressing genes that mimic or regulate host protein factors involved in a variety of signaling cascades. This results in the ability to cause diseases ranging from tumor formation in plants to gastroenteritis and bubonic plague. Here, we present recent advances on mechanisms of bacterial pathogen evolution, including specific signaling cascades targeted by their virulence genes with an emphasis on the ubiquitin modification system, Rho GTPase regulators, cytoskeletal modulators, and host innate immunity. We also comment briefly on evolution of host defense mechanisms in place that limit disease caused by bacterial pathogens.


Assuntos
Bactérias/genética , Bactérias/patogenicidade , Evolução Molecular , Interações Hospedeiro-Patógeno/genética , Transdução de Sinais/genética , Animais , Filogenia
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