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BACKGROUND: Physical sequelae of anorexia nervosa (AN) include a marked reduction in whole brain volume and subcortical structures such as the hippocampus. Previous research has indicated aberrant levels of inflammatory markers and growth factors in AN, which in other populations have been shown to influence hippocampal integrity. METHODS: Here we investigated the influence of concentrations of two pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and brain-derived neurotrophic factor (BDNF) on the whole hippocampal volume, as well as the volumes of three regions (the hippocampal body, head, and tail) and 18 subfields bilaterally. Investigations occurred both cross-sectionally between acutely underweight adolescent/young adult females with AN (acAN; n = 82) and people recovered from AN (recAN; n = 20), each independently pairwise age-matched with healthy controls (HC), and longitudinally in acAN after partial renourishment (n = 58). Hippocampal subfield volumes were quantified using FreeSurfer. Concentrations of molecular factors were analyzed in linear models with hippocampal (subfield) volumes as the dependent variable. RESULTS: Cross-sectionally, there was no evidence for an association between IL-6, TNF-α, or BDNF and between-group differences in hippocampal subfield volumes. Longitudinally, increasing concentrations of BDNF were positively associated with longitudinal increases in bilateral global hippocampal volumes after controlling for age, age2, estimated total intracranial volume, and increases in body mass index (BMI). CONCLUSIONS: These findings suggest that increases in BDNF may contribute to global hippocampal recovery over and above increases in BMI during renourishment. Investigations into treatments targeted toward increasing BDNF in AN may be warranted.
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Previous studies of brain structure in anorexia nervosa (AN) have reported reduced gray matter in underweight patients, which largely normalizes upon weight gain. One underlying biological mechanism may be glial cell alterations related to low-grade inflammation. Here, we investigated relationships between brain structure as measured by magnetic resonance imaging and serum concentrations of two pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor alpha) cross-sectionally in 82 underweight adolescent and young adult female patients (mean age 16.8 years; 59 of whom were observed longitudinally after short-term weight restoration; mean duration 2.8 months), 20 individuals long-term weight-recovered from AN (mean age 22.7 years) and 105 healthy control (HC) participants (mean age 17.2 years). We measured cortical thickness, subcortical volumes and local gyrification index, a measure of cortical folding. In contrast to most previous studies of cytokine concentrations in AN, we found no cross-sectional group differences (interleukin-6: p = 0.193, tumor necrosis factor alpha: p = 0.057) or longitudinal changes following weight restoration (interleukin-6: p = 0.201, tumor necrosis factor alpha: p = 0.772). As expected, widespread gray matter reductions (cortical thickness, subcortical volumes, cortical folding) were observed in underweight patients with AN compared to HC. However, we found no evidence of associations between cytokine concentrations and structural brain measures in any participant group. Furthermore, longitudinal changes in cytokine concentrations were unrelated to changes in gray matter. In conclusion, we did not identify any association between (sub-)inflammatory processes and structural brain changes in AN. Future studies are needed to elucidate which other factors besides nutritional status may contribute to brain morphological alterations.
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Anorexia Nervosa , Encéfalo , Interleucina-6 , Fator de Necrose Tumoral alfa , Adolescente , Adulto , Feminino , Humanos , Adulto Jovem , Anorexia Nervosa/sangue , Anorexia Nervosa/patologia , Anorexia Nervosa/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Estudos Transversais , Interleucina-6/sangue , Estudos Longitudinais , Imageamento por Ressonância Magnética , Fator de Necrose Tumoral alfa/sangueRESUMO
Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (PodΔF3) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in PodΔF3 mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation.
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Transdução de Sinais , Tromboplastina , Animais , Camundongos , Inflamação , Interferon-alfa , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Tromboplastina/genéticaRESUMO
Background Indication for prophylactic surgical abdominal aortic aneurysm (AAA) repair depends on the maximal aortic diameter. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for uptake of oxidized low-density lipoprotein cholesterol and is implicated in atherosclerosis. A soluble form of LOX-1 (sLOX-1) has been discussed as a novel biomarker in coronary artery disease and stroke. Herein, we assessed the regulation of aortic LOX-1 as well as the diagnostic and risk stratification potential of sLOX-1 in patients with AAA. Methods and Results Serum sLOX-1 was assessed in a case-control study in AAA (n=104) and peripheral artery disease (n=104). sLOX-1 was not statistically different between AAA and peripheral artery disease but was higher in AAA (ß=1.28, P=0.04) after adjusting for age, atherosclerosis, type 2 diabetes, prescription of statins, ß-blockers, ACE inhibitors, and therapeutic anticoagulation. sLOX-1 was not associated with the aortic diameter, AAA volume, or the thickness of the intraluminal thrombus. Aortic LOX-1 mRNA expression tended to be higher in AAA when compared with disease, and expression was positively associated with cleaved caspase-3, smooth muscle actin, collagen, and macrophage content. Conclusions In AAA, sLOX-1 was differently affected by age, cardiometabolic diseases, and corresponding medical therapies. Comparison with nonatherosclerotic disease would be beneficial to further elucidate the diagnostic potential of sLOX-1, although it was not useful for risk stratification. Aneurysmal LOX-1 mRNA expression was increased and positively associated with smooth muscle cells and collagen content, suggesting that LOX-1 is eventually not deleterious in human AAA and could counteract AAA rupture.
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Aneurisma da Aorta Abdominal , Aterosclerose , Diabetes Mellitus Tipo 2 , Doença Arterial Periférica , Humanos , Aneurisma da Aorta Abdominal/genética , Biomarcadores , Estudos de Casos e Controles , RNA Mensageiro , Receptores Depuradores Classe ERESUMO
Red blood cells are found within the abdominal aortic aneurysm (AAA), in the intraluminal thrombus (ILT), and in neovessels. Hemolysis promotes aortic degeneration, e.g., by heme-induced reactive oxygen species formation. To reduce its toxicity, hemoglobin is endocytosed by the CD163 receptor and heme is degraded by heme oxygenase-1 (HO-1). A soluble form (sCD163) is discussed as an inflammatory biomarker representing the activation of monocytes and macrophages. HO-1 and NAD(P)H quinone dehydrogenase 1 (NQO1) are antioxidant genes that are induced by the Nrf2 transcription factor, but their regulation in AAA is only poorly understood. The aim of the present study was to analyze linkages between CD163, Nrf2, HO-1, and NQO1 and to clarify if plasma sCD163 has diagnostic and risk stratification potential. Soluble CD163 was 1.3-fold (p = 0.015) higher in AAA compared to patients without arterial disease. The difference remained significant after adjusting for age and sex. sCD163 correlated with the thickness of the ILT (rs = 0.26; p = 0.02) but not with the AAA diameter or volume. A high aneurysmal CD163 mRNA was connected to increases in NQO1, HMOX1, and Nrf2 mRNA. Further studies are needed to analyze the modulation of the CD163/HO-1/NQO1 pathway with the overall goal of minimizing the detrimental effects of hemolysis.
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Carotid artery stenosis (CAS) develops from atherosclerotic lesions and plaques. Plaque rupture or stenosis may result in occlusion of the carotid artery. Accordingly, the asymptomatic disease becomes symptomatic, characterized by ischemic stroke or transient ischemic attacks, indicating an urgent need for better understanding of the underlying molecular mechanisms and eventually prevent symptomatic CAS. NOX4, a member of the NADPH oxidase family, has anti-atherosclerotic and anti-inflammatory properties in animal models of early atherosclerosis. We hypothesized that NOX4 mRNA expression is linked to protective mechanisms in CAS patients with advanced atherosclerotic lesions as well. Indeed, NOX4 mRNA expression is lower in patients with symptomatic CAS. A low NOX4 mRNA expression is associated with an increased risk of the development of clinical symptoms. In fact, NOX4 appears to be linked to plaque stability, apoptosis and plaque hemorrhage. This is supported by cleaved caspase-3 and glycophorin C and correlates inversely with plaque NOX4 mRNA expression. Even healing of a ruptured plaque appears to be connected to NOX4, as NOX4 mRNA expression correlates to fibrous cap collagen and is reciprocally related to MMP9 activity. In conclusion, low intra-plaque NOX4 mRNA expression is associated with an increased risk for symptomatic outcome and with reduced plaque stabilizing mechanisms suggesting protective effects of NOX4 in human advanced atherosclerosis.
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Although extramedullary manifestations (EMs) are frequent in patients with acute myeloid leukemia (AML), they are often not detected during clinical workup and neither imaging- nor molecularly based diagnostic strategies are established to reveal their existence. Still, the detection of EM is essential for therapeutic decision-making, as EM present with aggressive and resistant disease and since mutational profiling might render patients within a different risk category, requiring personalized therapeutic strategies. Here, we report the case of an AML patient presenting with AML bone marrow (BM) infiltration and molecularly distinct EM at time of diagnosis followed by multiple EM relapses while undergoing several intensive chemotherapies including allogeneic hematopoietic cell transplantations (alloHCTs). 18Fluorodesoxy-glucose positron emission tomography (18FDG-PET)-imaging revealed EM sites in the mediastinum, duodenum, skin, and in retroperitoneal tissue, whereas recurrent BM biopsies showed continuous cytomorphologic and cytogenetic remission after alloHCT. To investigate the molecular background of the aggressive character of extramedullary disease and its differential treatment response, we performed amplicon-based next generation sequencing. An exon 4 (c.497_498insGA) frameshift RUNX1 mutation was exclusively found in all of the patient's EM sites, but not in the BM or in peripheral blood samples at time of EM reoccurrence. In addition, we detected an exon 13 (c.3306G>T) ASXL1 point mutation only in the retroperitoneal tumor tissue at the time of the fourth relapse. In contrast to the patient's intermediate-risk BM AML at diagnosis according to ELN2017, EM sites showed molecular adverse-risk features implicating intensified strategies like cellular therapies. Notably, disease relapse could only be detected by imaging throughout the course of disease. This case demonstrates both the necessity of continuous molecular profiling of EM to reveal differential molecular composition of EM and BM-derived AML, supposedly leading to divergent susceptibility to established therapies, as well as recurrent 18FDG-PET-imaging for detecting residual disease and assessment of treatment response in case of EM AML.
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BACKGROUND: Treatment of cardiovascular risk factors slows the progression of small abdominal aortic aneurysms (AAA). Heme oxygenase-1 (HO-1) is a stress- and hemin-induced enzyme providing cytoprotection against oxidative stress when overexpressed. However, nothing is known about the effects of cardiometabolic standard therapies on HO-1 expression in aortic walls in patients with end-stage AAA. METHODS: The effects of statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), beta-blockers, diuretics, acetylsalicylic acid (ASA), and therapeutic anticoagulation on HO-1 mRNA and protein expressions were analyzed in AAA patients using multivariate logistic regression analysis and comparison of monotherapy. RESULTS: Analysis of monotherapy revealed that HO-1 mRNA and protein expressions were higher in patients on diuretics and lower in patients on statin therapy. Tests on combinations of antihypertensive medications demonstrated that ACE inhibitors and diuretics, ARBs and diuretics, and beta-blockers and diuretics were associated with increase in HO-1 mRNA expression. ASA and therapeutic anticoagulation were not linked to HO-1 expression. CONCLUSION: Diuretics showed the strongest association with HO-1 expression, persisting even in combination with other antihypertensive medications. Hence, changes in aortic HO-1 expression in response to different medical therapies and their effects on vessel wall degeneration should be analyzed in future studies.
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The key players of the hypoxic response are the hypoxia-inducible factors (Hif), whose α-subunits are tightly regulated by Prolyl-4-hydroxylases (PHD), predominantly by PHD2. Monocytes/Macrophages are involved in atherosclerosis but also restenosis and were found at hypoxic and sites of the lesion. Little is known about the role of the myeloid PHD2 in atherosclerosis and neointima formation. The study aimed to investigate the consequences of a myeloid deficiency of PHD2 in the process of neointima formation using an arterial denudation model. LysM-cre mice were crossed with PHD2fl/fl, PHD2fl/fl/Hif1αfl/fl and PHD2fl/fl/Hif2αfl/fl to get myeloid specific knockout of PHD2 and the Hif-α subunits. Denudation of the femoral artery was performed and animals were fed a western type diet afterwards with analysis of neointima formation 5 and 35 days after denudation. Increased neointima formation in myeloid PHD2 knockouts was observed, which was blunted by double-knockout of PHD2 and Hif1α whereas double knockout of PHD2 and Hif-2α showed comparable lesions to the PHD2 knockouts. Macrophage infiltration was comparable to the neointima formation, suggesting a more inflammatory reaction, and was accompanied by increased intimal VEGF-A expression. Collagen-content inversely correlated to the extent of neointima formation suggesting a destabilization of the plaque. This effect might be triggered by macrophage polarization. Therefore, in vitro results showed a distinct expression pattern in differentially polarized macrophages with high expression of Hif-1α, VEGF and MMP-1 in proinflammatory M1 macrophages. In conclusion, the results show that myeloid Hif-1α is involved in neointima hyperplasia. Our in vivo and in vitro data reveal a central role for this transcription factor in driving plaque-vascularization accompanied by matrix-degradation leading to plaque destabilization.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Artéria Femoral , Prolina Dioxigenases do Fator Induzível por Hipóxia , Macrófagos , Neointima , Placa Aterosclerótica , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia , Prolina Dioxigenases do Fator Induzível por Hipóxia/deficiência , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Macrófagos/metabolismo , Camundongos , Neointima/genética , Neointima/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Pró-Colágeno-Prolina Dioxigenase/genéticaRESUMO
Hepatic involvement in anorexia nervosa (AN) has been previously reported, but a link to elevated vitamin B12 concentrations, which can be a sign for liver damage, has not been thoroughly examined. We measured liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase) and vitamin B12 parameters (total B12, holotranscobalamin, methylmalonic acid) in the plasma of young female patients with acute AN (n=77) and after short-term weight restoration (n=58, median body mass increase=25%), in comparison to healthy control participants (n=63). For a comprehensive assessment of vitamin B12 status, the combined marker cB12 was calculated. In acute AN, activities of alanine aminotransferase and gamma-glutamyltransferase as well as holotranscobalamin concentrations were elevated, and alanine aminotransferase activities positively correlated with total B12, holotranscobalamin and cB12 in patients with elevated liver enzyme activities. After weight restoration, alanine aminotransferase activities and holotranscobalamin concentrations were elevated, and cB12 increased above the level of the healthy control group. The present study provides further evidence for a hepatic involvement in acute AN in concert with vitamin B12 parameters and points to refeeding-associated alterations of liver and vitamin B12 parameters. Future studies should include non-invasive methods to characterize hepatic involvement and evaluate vitamin B12 status as a potential marker of liver damage/irritation.
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Anorexia Nervosa , Vitamina B 12 , Alanina Transaminase , Anorexia Nervosa/complicações , Biomarcadores , Feminino , Humanos , Fígado , Transcobalaminas , Vitaminas , gama-GlutamiltransferaseRESUMO
BACKGROUND: There is sound evidence that the hypothalamic-pituitary-thyroid axis plays a role in mood regulation. Alterations in this axis, particularly low triiodothyronine syndrome, are a common neuroendocrine adaptation to semi-starvation in patients with anorexia nervosa (AN), who also frequently suffer from co-existing depressive symptoms. We therefore aimed to investigate the associations between pituitary-thyroid function and psychopathology, in particular depressive symptoms, at different stages of AN using a combined cross-sectional and longitudinal study design. METHODS: Pituitary-thyroid status (FT3, free triiodothyronine; FT4, free thyroxine; conversion ratio FT3/FT4; TSH, thyroid-stimulating hormone) was assessed in 77 young acutely underweight females with AN (acAN) and in 55 long-term weight-recovered individuals with former AN (recAN) in a cross-sectional comparison to 122 healthy controls (HC). Further, pituitary-thyroid status of 48 acAN was reassessed after short-term weight-restoration. We performed correlation analyses of pituitary-thyroid parameters with self-reported measures of psychopathology. RESULTS: AcAN showed significantly lower FT3, FT4, FT3/FT4 ratio, and TSH levels compared to HC. Pituitary-thyroid alterations were partly reversed after short-term weight-restoration. RecAN still had lower FT3 concentrations than HC. Lower FT3 concentrations and FT3/FT4 ratios were associated with more severe depressive symptoms in acAN, occurring prominently in cases of manifest low triiodothyronine syndrome. Longitudinally increasing FT3/FT4 ratios (change scores) were inversely correlated with depressive and general psychiatric symptoms after short-term weight-restoration. CONCLUSIONS: Our results suggest a potential modulation of the severity of depressive symptoms by temporarily decreased FT3 concentrations and inhibited thyroid hormone conversion (FT3/FT4 ratios) in acutely underweight AN. Associations between conversion ratios FT3/FT4 and psychopathology seem to persist across short-term weight-restoration. The findings of our study might have relevant clinical implications, ranging from thyroid monitoring to experimental low-dose thyroid hormone supplementation in certain patients with AN showing severe psychiatric impairment and overt thyroid hormone alterations.
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Anorexia Nervosa , Depressão , Hormônios Tireóideos , Anorexia Nervosa/complicações , Anorexia Nervosa/psicologia , Estudos Transversais , Depressão/complicações , Feminino , Humanos , Estudos Longitudinais , Magreza , Testes de Função Tireóidea , Glândula Tireoide , Tireotropina , Tiroxina , Tri-IodotironinaRESUMO
BACKGROUND: Doppler microembolic signals (MES) occur during atrial fibrillation ablation despite of permanent flushed transseptal sheaths, frequent controls of periprocedural coagulation status and the use of irrigated ablation catheters PURPOSE: To investigate the number and type of MES depending on the procedure time, prespecified procedure steps, the activated clotting time (ACT) during the ablation procedure and the catheter contact force. METHODS: In a prospective trial, 53 consecutive atrial fibrillation patients underwent pulmonary vein isolation by super-irrigated "point-by-point" ablation. All patients underwent a periinterventional, continuous transcranial Doppler examination (TCD) of the bilateral middle cerebral arteries during the complete ablation procedure. RESULTS: An average of 686±226 microembolic signals were detected by permanent transcranial Doppler. Thereby, 569±208 signals were differentiated as gaseous and 117±31 as solid MES. The number of MES with regard to defined procedure steps were as follows: gaseous: [transseptal puncture, 26 ± 28; sheath flushing, 24±12; catheter change, 21±11; angiography, 101±28; mapping, 9±9; ablation, 439±192; protamine administration, 0±0]; solid: [transseptal puncture, 8±8; sheath flushing, 9±5; catheter replacement, 6±6; angiography, not measurable; mapping, 2±5; ablation, 41±22; protamine administration, 0±0]. Significantly less MES occurred with shorter procedure time, higher ACT and the use of tissue contact force monitoring. CONCLUSION: The current study demonstrates that during atrial fibrillation ablation using irrigated, "point-by-point" RF ablation, masses of microembolic signals are detected in transcranial ultrasound especially in the period of RF current application. The number of MES depends on the total procedure time and the reached ACT during ablation. The use of contact force monitoring might reduce MES during RF ablation.
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Fibrilação Atrial , Ablação por Cateter , Embolia Intracraniana , Veias Pulmonares , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Humanos , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/prevenção & controle , Estudos Prospectivos , Protaminas , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Calpains are calcium activated cysteine proteases that play a pivotal role in the pathophysiology of cardiac remodeling. METHODS: Here, we performed left anterior descending coronary artery ligation in rats as a model for ischemic systolic heart failure and examined the time- and region-specific regulation of calpain-1 and calpain-2 in the left ventricular myocardium. RESULTS: Following anterior wall myocardial infarction, calpain activity was significantly increased restricted to the ischemic anterior area at days 1, 5 and 14. No changes in calpain activity at neither time point were detected in the borderzone and remote posterior area of the left ventricle. Of note, calpain activity in the infarcted anterior myocardium was regulated differentially in the acute vs. subacute and chronic phase. In the acute phase, calpain translocation to the plasma membrane and attenuation of the expression of its endogenous inhibitor, calpastatin, were identified as the driving forces. In the subacute and chronic phase, calpain activity was regulated at the level of protein expression that was shown to be essentially independent of transcriptional activity. CONCLUSIONS: We conclude that myocardial infarction leads to a distinct calpain regulation pattern in the left ventricular myocardium that is region specific and time dependent. Considering the results from our previous studies, a spatio-temporal interaction between calpains and calcium dependent natriuretic peptide production in the infarcted myocardium is possible. GENERAL SIGNIFICANCE: Our results shed more light in the differential regulation of calpain activity in the myocardium and might aid in the development of targeted post-infarct and/or heart failure therapeutics.
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Background Rupture of abdominal aortic aneurysm (rAAA) is associated with high case fatality rates, and risk of rupture increases with the AAA diameter. Heme oxygenase-1 (gene HMOX1, protein HO-1) is a stress-induced protein and induction has protective effects in the vessel wall. HMOX1-/- mice are more susceptible to angiotensin II-induced AAA formation, but the regulation in human nonruptured and ruptured AAA is only poorly understood. Our hypothesis proposed that HO-1 is reduced in AAA and lowering is inversely associated with the AAA diameter. Methods and Results AAA walls from patients undergoing elective open repair (eAAA) or surgery because of rupture (rAAA) were analyzed for aortic HMOX1/HO-1 expression by quantitative real-time polymerase chain reaction and Western blot. Aortas from patients with aortic occlusive disease served as controls. HMOX1/HO-1 expression was 1.1- to 7.6-fold upregulated in eAAA and rAAA. HO-1 expression was 3-fold higher in eAAA specimen with a diameter >84.4 mm, whereas HO-1 was not different in rAAA. Other variables that are known for associations with AAA and HO-1 induction were tested. In eAAA, HO-1 expression was negatively correlated with aortic collagen content and oxidative stress parameters H2O2 release, oxidized proteins, and thiobarbituric acid reactive substances. Serum HO-1 concentrations were analyzed in patients with eAAA, and maximum values were found in an aortic diameter of 55 to 70 mm with no further increase >70 mm, compared with <55 mm. Conclusions Aortic HO-1 expression was increased in eAAA and rAAA. HO-1 increased with the severity of disease but was additionally connected to less oxidative stress and vasoprotective mechanisms.
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Aneurisma da Aorta Abdominal , Heme Oxigenase-1 , Animais , Aneurisma da Aorta Abdominal/genética , Heme Oxigenase-1/genética , Humanos , Camundongos , Índice de Gravidade de DoençaRESUMO
Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.
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AIM OF THE STUDY: Frail patients with high grade aortic valve stenosis (AS) undergoing Transcatheter Aortic Valve Implantation (TAVI) have an increased mortality. A connection between frailty and inflammation has been suggested. Monocyte subpopulations are associated with both cardiovascular diseases and chronic inflammatory diseases. This study investigates the association of frailty with monocyte subpopulations and systemic inflammatory parameters in elderly patients undergoing TAVI. METHODS: A total of 120 patients with symptomatic AS was examined. Before TAVI implantation, frailty was assessed by a bedside evaluation (eyeball test). In all patients a flow cytometry analysis has been performed. Monocyte subpopulations were defined as follows: classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++). Expression of CD11b was measured as a marker for monocyte activation. Pro-inflammatory cytokines such as interleukin IL-8, as well as CRP were measured with Cytometric Bead Array or standard laboratory methods. RESULTS: 28 out of 120 patients were frail. These patients showed both, signs of elevated chronic systemic inflammation reflected by elevated CRP (3.7 (1.4-5.4) vs. 5.9 (3.7-29.1), p = 0.001) and an elevated level of intermediate monocytes (37 (24-54) vs. 53 (47-63), p = 0.001). At 6 months after TAVI, 19 of 120 patients died, primarily without relevant dysfunction of the implanted aortic valve. Mortality was significantly higher in the frail as compared with non-frail patients (9 of 28 frail patients vs. 10 of 92 non frail patients, p < 0.001). A binary logistic regression analysis validated frailty and intermediate monocytes as independent predictors for early mortality after TAVI. CONCLUSION: Chronic systemic inflammation and increased levels of intermediate monocytes are associated with frailty in old patients with severe aortic valve stenosis. Both the syndrome of frailty and elevated intermediate monocytes showed an association with early mortality after TAVI.
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Estenose da Valva Aórtica , Fragilidade , Substituição da Valva Aórtica Transcateter , Idoso , Estenose da Valva Aórtica/cirurgia , Idoso Fragilizado , Humanos , Inflamação , Monócitos , Fatores de Risco , Resultado do TratamentoRESUMO
ABSTRACT: The calcium sensitizer levosimendan is indicated for the hemodynamic stabilization of patients with acutely decompensated heart failure and has been shown to be protective against reperfusion injury after myocardial infarction. However, affected forms of cell death and underlying signaling pathways remain controversial. Therefore, the aim of this study was to examine the influence of levosimendan preconditioning and postconditioning on anoxia/reoxygenation-induced apoptosis, necrosis, and autophagy in H9c2 myoblasts. To mimic conditions of myocardial ischemia/reperfusion, rat cardiac H9c2 myoblasts were exposed to anoxia/starvation, followed by reoxygenation/refeeding. Apoptosis, necrosis, autophagy, cell viability, survival signaling, and mitochondrial permeability transition pore (mPTP) opening were measured. Both, pharmacological preconditioning and postconditioning with levosimendan were capable to reduce apoptosis as well as necrosis in stressed H9c2 cells. However, preconditioning showed to have the stronger impact compared with postconditioning. Moreover, levosimendan preconditioning increased autophagy, suggesting enhanced repair processes initiated by the early presence of the drug. Underlying mechanisms differ between both interventions: Although both are associated with PI3/Akt activation and reduced mPTP opening, only postconditioning but not preconditioning depended on mKATP activation. This variation might indicate that a pharmacological treatment after the onset of reoxygenation at least in part directly addresses mitochondrial structures for protection. In conclusion, we demonstrate that both pharmacological preconditioning and postconditioning with levosimendan protect anoxia/reoxygenation-stressed cells but differ in the underlying mechanisms. These results are decisive to obtain more insights into the beneficial effects of levosimendan in the treatment of reperfusion-mediated damage.
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Fármacos Cardiovasculares/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Simendana/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Hipóxia Celular , Linhagem Celular , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Necrose , Canais de Potássio/metabolismo , Ratos , Transdução de SinaisRESUMO
We investigated why a clinical meticillin-resistant Staphylococcus aureus (MRSA) isolate yielded false-negative results with some commercial PCR tests for MRSA detection. We found that an epidemic European CC1-MRSA-IV clone generally exhibits this behaviour. The failure of the assays was attributable to a large insertion in the orfX/SCCmec integration site. To ensure the reliability of molecular MRSA tests, it is vital to monitor emergence of new SCCmec types and junction sites.
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Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Infecções Estafilocócicas/diagnóstico , Áustria/epidemiologia , Reações Falso-Negativas , Feminino , Alemanha/epidemiologia , Humanos , Irlanda/epidemiologia , Staphylococcus aureus Resistente à Meticilina/genética , Pessoa de Meia-Idade , Infecções Estafilocócicas/epidemiologiaRESUMO
BACKGROUND: Diagnosis of primary aldosteronism (PA) involves a multistep process reliant on the accuracy of aldosterone measurements at each step. We report on immunoassay interference leading to a wrongful diagnosis and indication for surgical intervention. CASE: A 38-year old hypertensive male with a 1.4 cm left adrenal mass was diagnosed with PA based on an elevated aldosterone:renin ratio and a positive saline infusion test. Adrenal venous sampling (AVS) indicated left-sided aldosterone hypersecretion, supporting a decision to remove the left adrenal. The patient was also enrolled in a study to evaluate mass spectrometry-based steroid profiling, which indicated plasma aldosterone concentrations measured in five different peripheral samples averaging only 11% those of the immunoassay. Mass spectrometric measurements did not support left-sided adrenal aldosterone hypersecretion. Two independent laboratories confirmed differences in measurements by immunoassay and mass spectrometry. Lowered concentrations measured by the immunoassay that matched those by mass spectrometry were achieved after sample purification to remove macromolecules, confirming immunoassay interference. CONCLUSIONS: Although our patient may represent an isolated case of immunoassay interference leading to misdiagnosis of PA, unnecessary AVS and potentially wrongful removal of an adrenal, it is also possible that such inaccuracies may impact the diagnostic process and treatment for other patients.