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Aims: Patients with non-obstructive hypertrophic cardiomyopathy (HCM) exhibit myocardial changes which may cause flow inefficiencies not detectable on echocardiogram. We investigated whether left ventricular (LV) kinetic energy (KE) and hemodynamic forces (HDF) on 4D-flow cardiovascular magnetic resonance (CMR) can provide more sensitive measures of flow in non-obstructive HCM. Methods and results: Ninety participants (70 with non-obstructive HCM and 20 healthy controls) underwent 4D-flow CMR. Patients were categorized as phenotype positive (P+) based on maximum wall thickness (MWT) ≥ 15 mm or ≥13 mm for familial HCM, or pre-hypertrophic sarcomeric variant carriers (P-). LV KE and HDF were computed from 4D-flow CMR. Stroke work was computed using a previously validated non-invasive method. P+ and P- patients and controls had comparable diastolic velocities and LV outflow gradients on echocardiography, LV ejection fraction, and stroke volume on CMR. P+ patients had greater stroke work than P- patients, higher systolic KE compared with controls (5.8 vs. 4.1 mJ, P = 0.0009), and higher late diastolic KE relative to P- patients and controls (2.6 vs. 1.4 vs. 1.9 mJ, P < 0.0001, respectively). MWT was associated with systolic KE (r = 0.5, P < 0.0001) and diastolic KE (r = 0.4, P = 0.005), which also correlated with stroke work. Systolic HDF ratio was increased in P+ patients compared with controls (1.0 vs. 0.8, P = 0.03) and correlated with MWT (r = 0.3, P = 0.004). Diastolic HDF was similar between groups. Sarcomeric variant status was not associated with KE or HDF. Conclusion: Despite normal flow velocities on echocardiography, patients with non-obstructive HCM exhibited greater stroke work, systolic KE and HDF ratio, and late diastolic KE relative to controls. 4D-flow CMR provides more sensitive measures of haemodynamic inefficiencies in HCM, holding promise for clinical trials of novel therapies and clinical surveillance of non-obstructive HCM.
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INTRODUCTION: Bariatric surgery is effective in reversing adverse cardiac remodelling in obesity. However, it is unclear whether the three commonly performed operations; Roux-en-Y Gastric Bypass (RYGB), Laparoscopic Sleeve Gastrectomy (LSG) and Laparoscopic Adjustable Gastric Band (LAGB) are equal in their ability to reverse remodelling. METHODS: Fifty-eight patients underwent CMR to assess left ventricular mass (LVM), LV mass:volume ratio (LVMVR) and LV eccentricity index (LVei) before and after bariatric surgery (26 RYGB, 22 LSG and 10 LAGB), including 46 with short-term (median 251-273 days) and 43 with longer-term (median 983-1027 days) follow-up. Abdominal visceral adipose tissue (VAT) and epicardial adipose tissue (EAT) were also assessed. RESULTS: All three procedures resulted in significant decreases in excess body weight (48-70%). Percentage change in VAT and EAT was significantly greater following RYGB and LSG compared to LAGB at both timepoints (VAT:RYGB -47% and -57%, LSG -47% and -54%, LAGB -31% and -25%; EAT:RYGB -13% and -14%, LSG -16% and -19%, LAGB -5% and -5%). Patients undergoing LAGB, whilst having reduced LVM (-1% and -4%), had a smaller decrease at both short (RYGB: -8%, p < 0.005; LSG: -11%, p < 0.0001) and long (RYGB: -12%, p = 0.009; LSG: -13%, p < 0.0001) term timepoints. There was a significant decrease in LVMVR at the long-term timepoint following both RYGB (-7%, p = 0.006) and LSG (-7%, p = 0.021), but not LAGB (-2%, p = 0.912). LVei appeared to decrease at the long-term timepoint in those undergoing RYGB (-3%, p = 0.063) and LSG (-4%, p = 0.015), but not in those undergoing LAGB (1%, p = 0.857). In all patients, the change in LVM correlated with change in VAT (r = 0.338, p = 0.0134), while the change in LVei correlated with change in EAT (r = 0.437, p = 0.001). CONCLUSIONS: RYGB and LSG appear to result in greater decreases in visceral adiposity, and greater reverse LV remodelling with larger reductions in LVM, concentric remodelling and pericardial restraint than LAGB.
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Cirurgia Bariátrica , Obesidade Mórbida , Remodelação Ventricular , Humanos , Feminino , Masculino , Remodelação Ventricular/fisiologia , Adulto , Pessoa de Meia-Idade , Cirurgia Bariátrica/métodos , Cirurgia Bariátrica/estatística & dados numéricos , Obesidade Mórbida/cirurgia , Obesidade Mórbida/fisiopatologia , Resultado do Tratamento , Derivação Gástrica/métodos , Derivação Gástrica/estatística & dados numéricos , Redução de Peso/fisiologia , Gordura Intra-Abdominal , Gastrectomia/métodos , Laparoscopia/métodosRESUMO
AIMS: Hypertrophic cardiomyopathy (HCM) is characterized by hypercontractility and diastolic dysfunction, which alter blood flow haemodynamics and are linked with increased risk of adverse clinical events. Four-dimensional flow cardiac magnetic resonance (4D-flow CMR) enables comprehensive characterization of ventricular blood flow patterns. We characterized flow component changes in non-obstructive HCM and assessed their relationship with phenotypic severity and sudden cardiac death (SCD) risk. METHODS AND RESULTS: Fifty-one participants (37 non-obstructive HCM and 14 matched controls) underwent 4D-flow CMR. Left-ventricular (LV) end-diastolic volume was separated into four components: direct flow (blood transiting the ventricle within one cycle), retained inflow (blood entering the ventricle and retained for one cycle), delayed ejection flow (retained ventricular blood ejected during systole), and residual volume (ventricular blood retained for >two cycles). Flow component distribution and component end-diastolic kinetic energy/mL were estimated. HCM patients demonstrated greater direct flow proportions compared with controls (47.9 ± 9% vs. 39.4 ± 6%, P = 0.002), with reduction in other components. Direct flow proportions correlated with LV mass index (r = 0.40, P = 0.004), end-diastolic volume index (r = -0.40, P = 0.017), and SCD risk (r = 0.34, P = 0.039). In contrast to controls, in HCM, stroke volume decreased with increasing direct flow proportions, indicating diminished volumetric reserve. There was no difference in component end-diastolic kinetic energy/mL. CONCLUSION: Non-obstructive HCM possesses a distinctive flow component distribution pattern characterised by greater direct flow proportions, and direct flow-stroke volume uncoupling indicative of diminished cardiac reserve. The correlation of direct flow proportion with phenotypic severity and SCD risk highlight its potential as a novel and sensitive haemodynamic measure of cardiovascular risk in HCM.
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Cardiomiopatia Hipertrófica , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Volume Sistólico/fisiologia , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Hemodinâmica , Morte Súbita Cardíaca , Espectroscopia de Ressonância Magnética , Imagem Cinética por Ressonância Magnética/métodosRESUMO
Introduction: Obesity affects cardiac geometry, causing both eccentric (due to increased cardiac output) and concentric (due to insulin resistance) remodelling. Following bariatric surgery, reversal of both processes should occur. Furthermore, epicardial adipose tissue loss following bariatric surgery may reduce pericardial restraint, allowing further chamber expansion. We investigated these changes in a serial imaging study of adipose depots and cardiac geometry following bariatric surgery. Methods: 62 patients underwent cardiac magnetic resonance (CMR) before and after bariatric surgery, including 36 with short-term (median 212 days), 37 medium-term (median 428 days) and 32 long-term (median 1030 days) follow-up. CMR was used to assess cardiac geometry (left atrial volume (LAV) and left ventricular end-diastolic volume (LVEDV)), LV mass (LVM) and LV eccentricity index (LVei - a marker of pericardial restraint). Abdominal visceral (VAT) and epicardial (EAT) adipose tissue were also measured. Results: Patients on average had lost 21kg (38.9% excess weight loss, EWL) at 212 days and 36kg (64.7% EWL) at 1030 days following bariatric surgery. Most VAT and EAT loss (43% and 14%, p<0.0001) occurred within the first 212 days, with non-significant reductions thereafter. In the short-term LVM (7.4%), LVEDV (8.6%) and LAV (13%) all decreased (all p<0.0001), with change in cardiac output correlated with LVEDV (r=0.35,p=0.03) and LAV change (r=0.37,p=0.03). Whereas LVM continued to decrease with time (12% decrease relative to baseline at 1030 days, p<0.0001), both LAV and LVEDV had returned to baseline by 1030 days. LV mass:volume ratio (a marker of concentric hypertrophy) reached its nadir at the longest timepoint (p<0.001). At baseline, LVei correlated with baseline EAT (r=0.37,p=0.0040), and decreased significantly from 1.09 at baseline to a low of 1.04 at 428 days (p<0.0001). Furthermore, change in EAT following bariatric surgery correlated with change in LVei (r=0.43,p=0.0007). Conclusions: Cardiac volumes show a biphasic response to weight loss, initially becoming smaller and then returning to pre-operative sizes by 1030 days. We propose this is due to an initial reversal of eccentric remodelling followed by reversal of concentric remodelling. Furthermore, we provide evidence for a role of EAT contributing to pericardial restraint, with EAT loss improving markers of pericardial restraint.
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Cirurgia Bariátrica , Gordura Intra-Abdominal , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/patologia , Pericárdio/diagnóstico por imagem , Pericárdio/patologia , Obesidade/cirurgia , Obesidade/patologia , Redução de PesoRESUMO
Floating-Harbor syndrome (FLHS) is a rare genetic disease caused by mutations in the SRCAP gene. Here, we generated an induced pluripotent stem cell line from gingival fibroblasts of a male patient with a heterozygous mutation in exon 34 of the SRCAP gene (c.7330C > T, p.Arg2444*). The iPSC colonies have an atypical morphology with diffuse borders and disintegrate quickly upon touch. Still, the cell line expresses pluripotency markers and differentiates into three germ layers. The cell line can be used as patient-specific disease model and help elucidate the molecular mechanisms involving SRCAP in the context of FLHS.
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Anormalidades Múltiplas , Anormalidades Craniofaciais , Células-Tronco Pluripotentes Induzidas , Adenosina Trifosfatases/genética , Transtornos do Crescimento , Comunicação Interventricular , Humanos , Masculino , MutaçãoRESUMO
This Article was originally published under a CC BY NC-ND 4.0 license, but has now been made available under a CC BY 4.0 license.
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In this communication we report that anchoring αvß3 or α5ß1 integrin-selective RGD peptidomimetics to titanium efficiently tunes mesenchymal stem cell response in vitro and bone growth in rat calvarial defects. Our results demonstrate that this molecular chemistry-derived approach could be successful to engineer instructive coatings for orthopedic applications.
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Materiais Biocompatíveis/farmacologia , Osso e Ossos/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Oligopeptídeos/farmacologia , Peptidomiméticos/farmacologia , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Regeneração Óssea/efeitos dos fármacos , Integrina alfa5beta1/química , Integrina alfaVbeta3/química , Ligantes , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Peptidomiméticos/química , Ratos , Titânio/química , Titânio/farmacologia , Cicatrização/efeitos dos fármacosRESUMO
PURPOSE: Corrected T1 (cT1) value is a novel MRI-based quantitative metric for assessing a composite of liver inflammation and fibrosis. It has been shown to distinguish between non-alcoholic fatty liver disease (NAFL) and non-alcoholic steatohepatitis. However, these studies were conducted in patients at high risk for liver disease. This study establishes the normal reference range of cT1 values for a large UK population, and assesses interactions of age and gender. METHODS: MR data were acquired on a 1.5 T system as part of the UK Biobank Imaging Enhancement study. Measures for Proton Density Fat Fraction and cT1 were calculated from the MRI data using a multiparametric MRI software application. Data that did not meet quality criteria were excluded from further analysis. Inter and intra-reader variability was estimated in a set of data. A cohort at low risk for NAFL was identified by excluding individuals with BMI ≥ 25 kg/m2 and PDFF ≥ 5%. Of the 2816 participants with data of suitable quality, 1037 (37%) were classified as at low risk. RESULTS: The cT1 values in the low-risk population ranged from 573 to 852 ms with a median of 666 ms and interquartile range from 643 to 694 ms. Iron correction of T1 was necessary in 36.5% of this reference population. Age and gender had minimal effect on cT1 values. CONCLUSION: The majority of cT1 values are tightly clustered in a population at low risk for NAFL, suggesting it has the potential to serve as a new quantitative imaging biomarker for studies of liver health and disease.
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Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Adulto , Idoso , Bancos de Espécimes Biológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estudos Retrospectivos , Fatores de Risco , Reino UnidoRESUMO
BACKGROUND: Obesity causes diastolic dysfunction, and is one of the leading causes of heart failure with preserved ejection fraction. Myocardial relaxation is determined by both active metabolic processes such as impaired energetic status and steatosis, as well as intrinsic myocardial remodelling. However, the relative contribution of each to diastolic dysfunction in obesity is currently unknown. METHODS: Eighty adult subjects (48 male) with no cardiovascular risk factors across a wide range of body mass indices (18.4-53.0 kg m-2) underwent magnetic resonance imaging for abdominal visceral fat, left ventricular geometry (LV mass:volume ratio) and diastolic function (peak diastolic strain rate), and magnetic resonance spectroscopy for PCr/ATP and myocardial triglyceride content. RESULTS: Increasing visceral obesity was related to diastolic dysfunction (peak diastolic strain rate, r=-0.46, P=0.001). Myocardial triglyceride content (ß=-0.2, P=0.008), PCr/ATP (ß=-0.22, P=0.04) and LV mass:volume ratio (ß=-0.61, P=0.04) all independently predicted peak diastolic strain rate (model R2 0.36, P<0.001). Moderated multiple regression confirmed the full mediating roles of PCr/ATP, myocardial triglyceride content and LV mass:volume ratio in the relationship between visceral fat and peak diastolic strain rate. Of the negative effect of visceral fat on diastolic function, 40% was explained by increased myocardial triglycerides, 39% by reduced PCr/ATP and 21% by LV concentric remodelling. CONCLUSIONS: Myocardial energetics and steatosis are more important in determining LV diastolic function than concentric hypertrophy, accounting for more of the negative effect of obesity on diastolic function than LV geometric remodelling. Targeting these metabolic processes is an attractive strategy to treat diastolic dysfunction in obesity.
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Diástole/fisiologia , Obesidade , Adulto , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Obesidade/diagnóstico por imagem , Obesidade/epidemiologia , Obesidade/fisiopatologia , Triglicerídeos/sangue , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Objectives: The present study aims to investigate the interest of young adults in predictive oncological genetic testing and their willingness to pay for such a test. Furthermore, major determinants of the 2 variables of interest were identified. Methods: 348 students of economics from the Leibniz University of Hanover were queried in July 2013 using an extensive questionnaire. Among other things, the participants were asked if they are interested in information about the probability to develop cancer in the future and their willingness to pay for such information. Data were analysed using descriptive statistics and ordinal probit regressions. Additionally marginal effects were calculated. Results: About 50% of the students were interested in predictive oncological genetic testing and were willing to pay for the test. Moreover, the participants who were willing to pay for the test partly attach high monetary values to the information that could so be obtained. The study shows that the interest of the students and their willingness to pay were primarily influenced by individual attitudes and perceptions. Conclusions: The study proves that young adults were interested in predictive genetic testing and appreciate information about their probability of develop cancer someday.
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Detecção Precoce de Câncer/economia , Detecção Precoce de Câncer/estatística & dados numéricos , Testes Genéticos/economia , Testes Genéticos/estatística & dados numéricos , Neoplasias/diagnóstico , Neoplasias/economia , Estudantes/estatística & dados numéricos , Adulto , Atitude Frente a Saúde , Tomada de Decisão Clínica , Economia/estatística & dados numéricos , Alemanha/epidemiologia , Humanos , Neoplasias/genética , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Inquéritos e Questionários , Adulto JovemRESUMO
AIM: The objective of this pilot study was to determine the accuracy of point-of-care B-line lung ultrasound in comparison to NT Pro-BNP for screening acute heart failure. MATERIALS AND METHODS: An 8-zone lung ultrasound was performed by experienced sonographers in patients presenting with acute dyspnea in the ED. AHF was determined as the final diagnosis by 2 independent reviewers. RESULTS: Contrary to prior studies, B-line ultrasound in our study was highly specific, but moderately sensitive for identifying patients with AHF. There was a strong association between elevated NT-proBNP levels and an increased number of B-lines. CONCLUSION: In conclusion, point-of-care lung ultrasound is a helpful tool for ruling in or ruling out important differential diagnoses in ED patients with acute dyspnea.
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Background: Guidelines have special importance in medicine, however, it is questionable to what extent these recommendations are applied in daily care, and under which conditions claims data can be used for verification of guideline adherence. Method: Advantages and limitations of claims data for verification of guidelines compliance in the therapeutic area as well as the guidelines themselves were analysed and critically assessed. To substantiate these results, claims data of a major German health insurance fund (Techniker Krankenkasse) were analysed. Results: 104 236 patients were identified. With certain limitations, claims data are useful for verifying guideline adherence; it could be shown that in pharmacotherapy the beta-adrenergic receptor blocker was used to the highest extent (70.5%). In contrast, only 56.4% of patients were treated with pure ACE inhibitors and ACE combined preparation. Conclusion: In order to validate guideline adherence by means of claims data analyses, a number of conditions relating to the database, the therapeutic area and the guidelines themselves have to be considered. Guideline recommendations, which, for example, are based on clinical data, cannot be reviewed by using claims data. Despite these limitations, claims data provide a suitable tool for reviewing selected guideline recommendations. They show that the current use of pharmacotherapy as well as clinical and diagnostic interventions might be increased in accordance with the guideline recommendations.
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BACKGROUND: The German national guidelines on chronic heart failure provide treatment recommendations to physicians and reflect the current level of evidence; however, it is questionable to what extent these recommendations are applied in the routine practice and what the effect of guideline adherence on mortality is. METHODS: In this study the claims data of a major German health insurance fund collected over a period of 4 years were analyzed. Using binary logistic regression and Cox regression analyses the influence of drug prescriptions, diagnostic measures, influenza vaccination, the New York Heart Association (NYHA) status, the age and gender on mortality were examined. RESULTS: The study population consisted of 85,465 heart failure patients. Approximately 60 % of the drugs were prescribed according to the guidelines. There was a positive correlation between a higher NYHA status and mortality with an odds ratio (OR) of 3.264. Especially pharmacotherapy with angiotensin-converting enzyme (ACE) inhibitors and beta blockers according to the guidelines was associated with a lower mortality rate (OR 0.448 resp. 0.444). Also patients diagnosed using echocardiography at regular intervals showed a lower risk of dying (OR 0.314). CONCLUSION: The results of this large sample could confirm the results of clinical trials that a therapy according to the guidelines has a significant impact on mortality. By analyzing the claims data evidence was found that in the treatment of heart failure patients the medical results could be improved by adherence to guideline recommendations.
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Cardiotônicos/uso terapêutico , Ecocardiografia/normas , Fidelidade a Diretrizes/estatística & dados numéricos , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Guias de Prática Clínica como Assunto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Cardiologia/normas , Cardiotônicos/normas , Ecocardiografia/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Fidelidade a Diretrizes/normas , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Distribuição por Sexo , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Since metallic biomaterials used for bone replacement possess low bioactivity, the use of cell adhesive moieties is a common strategy to improve cellular response onto these surfaces. In recent years, the use of recombinant proteins has emerged as an alternative to native proteins and short peptides owing to the fact that they retain the biological potency of native proteins, while improving their stability. In the present study, we investigated the biological effect of two different recombinant fragments of fibronectin, spanning the 8-10th and 12-14th type III repeats, covalently attached to a new TiNbHf alloy using APTES silanization. The fragments were studied separately and mixed at different concentrations and compared to a linear RGD, a cyclic RGD and the full-length fibronectin protein. Cell culture studies using rat mesenchymal stem cells demonstrated that low to medium concentrations (30% and 50%) of type III 8-10th fragment mixed with type III 12-14th fragment stimulated cell spreading and proliferation compared to RGD peptides and the fragments separately. On the other hand, type III 12-14th fragment alone or mixed at low volume percentages ≤50% with type III 8-10th fragment increased alkaline phosphatase levels compared to the other molecules. These results are significant for the understanding of the role of fibronectin recombinant fragments in cell responses and thus to design bioactive coatings for biomedical applications.
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Ligas/farmacologia , Fibronectinas/farmacologia , Células-Tronco Mesenquimais/citologia , Proteínas Recombinantes/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Háfnio/farmacologia , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Nióbio/farmacologia , Espectroscopia Fotoeletrônica , Técnicas de Microbalança de Cristal de Quartzo , Ratos Endogâmicos Lew , Titânio/farmacologiaRESUMO
Integrin α5ß1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5ß1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5ß1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5ß1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5ß1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5ß1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5ß1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5ß1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.
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Glioma/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Integrina alfa5beta1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Apoptose/genética , Proteínas Reguladoras de Apoptose , Astrócitos/metabolismo , Astrócitos/patologia , Linhagem Celular Tumoral , Glioma/genética , Glioma/patologia , Humanos , Proteínas Inibidoras de Apoptose/genética , Integrina alfa5beta1/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfoproteínas/genética , Survivina , Proteína Supressora de Tumor p53/genéticaRESUMO
Implant materials require optimal biointegration, including strong and stable cell-material interactions from the early stages of implantation. Ti-based alloys with low elastic modulus are attracting a lot of interest for avoiding stress shielding, but their osseointegration potential is still very low. In this study, we report on how cell adhesion is influenced by linear RGD, cyclic RGD, and recombinant fibronectin fragment III8-10 coated on titanium versus a novel low-modulus TiNbHf alloy. The bioactive molecules were either physisorbed or covalently coupled to the substrates and their conformation on the surfaces was investigated with atomic force microscopy (AFM). The influence of the different bioactive coatings on the adhesion of rat mesenchymal stem cells was evaluated using cell culture assays and quantitatively analyzed at the single cell level by AFM-based single-cell force spectroscopy. Our results show that bioactive moieties, particularly fibronectin fragment III8-10, improve cell adhesion on titanium and TiNbHf and that the covalent tethering of such molecules provides the most promising strategy to biofunctionalize these materials. Therefore, the use of recombinant protein fragments is of high importance for improving the osseointegration potential of implant materials.
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Ligas , Adesão Celular , Titânio/química , Microscopia de Força AtômicaRESUMO
Obesity is an independent risk factor for developing heart failure and the combination of the two disease states will prove to be a significant health burden over the coming years. Obesity is likely to contribute to the development of heart failure through a variety of mechanisms, including structural and functional changes, lipotoxicity and steatosis and altered substrate selection. However, once heart failure has developed, it seems that obesity confers a beneficial influence on prognosis in what has been termed the 'obesity paradox'. This may be a statistical phenomenon, but it should be considered that there is truly a protective state in the physiology of obesity. There is little evidence regarding the impact of weight loss in obese heart failure and whether or not this is beneficial. There have been small studies regarding the cardiovascular effects of both dietary weight loss and bariatric surgery, but few in heart failure. This is an important and increasingly relevant clinical question which must be addressed.
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Cardiomiopatias/complicações , Cardiomiopatias/prevenção & controle , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Obesidade/complicações , Redução de Peso , Índice de Massa Corporal , Cardiomiopatias/etiologia , Cardiomiopatias/mortalidade , Insuficiência Cardíaca/mortalidade , Humanos , Obesidade/terapia , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Programas de Redução de PesoRESUMO
A reduced myocardial phosphocreatine/adenosine triphosphate (PCr/ATP) ratio is linked to both diastolic dysfunction and heart failure. Although obesity is well known to cause diastolic dysfunction a link to impaired cardiac energetics has only recently been established. We assessed whether or not long-term weight loss in obesity, which is known to reduce mortality, is accompanied by both improved cardiac energetics and diastolic function. Normal weight (BMI 22 ± 2; n = 18) and obese subjects (BMI 34 ± 4; n = 13) underwent cine-MRI (1.5 Tesla) to determine left ventricular diastolic function using volume-time curve analysis, and (31)P-MR spectroscopy (3 Tesla) to assess cardiac energetics (PCr/ATP ratio). Obese subjects (n = 13) underwent repeat assessment after 1 year of supervised weight loss. Obesity, in the absence of identifiable cardiovascular risk factors, was associated with significantly impaired myocardial high energy phosphate metabolism (PCr/ATP ratio, normal; 2.03 ± 0.27 vs. obese; 1.58 ± 0.47, p = 0.002) and significantly lower peak diastolic filling rate (normal; 4.8 ± 0.8 vs. obese; 3.8 ± 0.7 EDV/s, p = 0.01). Weight loss (on average 9 kg, 55% excess weight) over 1 year resulted in a 24% increase in PCr/ATP ratio (p = 0.01) and an 18% improvement in peak diastolic filling rate (p = 0.01). Myocardial PCr/ATP ratio remained positively correlated with peak diastolic filling rate after weight loss (r = 0.63, p = 0.02). In obesity, weight loss improves impaired cardiac energetics and myocardial relaxation. Improved myocardial energetics appear to play a key role in diastolic functional recovery accompanying weight loss.