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2.
J Thromb Haemost ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33171004

RESUMO

BACKGROUND: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by anti-ADAMTS13 autoantibodies inducing a severe deficiency of ADAMTS13. Epitope mapping studies on samples obtained during acute iTTP episodes have shown that the iTTP immune response is polyclonal, with almost all patients having autoantibodies targeting the spacer domain of ADAMTS13. OBJECTIVES: To identify the immunogenic hotspots in the spacer domain of ADAMTS13. PATIENTS/METHODS: A library of 11 full-length ADAMTS13 spacer hybrids was created in which amino acids regions of the spacer domain of ADAMTS13 were exchanged by the corresponding region of the spacer domain of ADAMTS1. Next, the full-length ADAMTS13 spacer hybrids were used in ELISA to epitope map anti-spacer autoantibodies in 138 samples from acute and remission iTTP patients. RESULTS: Sixteen different anti-spacer autoantibody profiles were identified with a similar distribution in acute and remission patients. There was no association between the anti-spacer autoantibody profiles and disease severity. Almost all iTTP samples contained anti-spacer autoantibodies against the following three regions: amino acid residues 588-592, 602-610 and 657-666 (hybrids E, G and M). Between 31 and 57% of the samples had anti-spacer autoantibodies against amino acid regions 572-579, 629-638, 667-676 (hybrids C, J and N). In contrast, none of the samples had anti-spacer autoantibodies against amino acid regions 556-563, 564-571, 649-656 and 677-685 (hybrids A, B, L and O). CONCLUSION: We identified 3 hotspot regions (amino acid regions 588-592, 602-610, and 657-666) in the spacer domain of ADAMTS13 that are targeted by anti-spacer autoantibodies found in a large cohort of iTTP patients.

3.
J Thromb Haemost ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33073460

RESUMO

BACKGROUND: Severe prekallikrein deficiency (PK deficiency) is an autosomal-recessive condition thought to be very rare. Recently we reported that the previously unnoticed variant c.451dupT, p.Ser151Phefs*34 in KLKB1, which is listed in databases aggregating genome data, causes PK deficiency and is common in Africans according to gnomAD (allele frequency 1.43%). PATIENTS/METHODS: The most common African (c.451dupT) and European (c.1643G>A, p.Cys548Tyr) PK deficiency causing KLKB1 variants were analyzed in two population-based collectives of 300 Nigerian and 300 German subjects. Genome databases were evaluated for variant frequencies and ethnicity of the subjects. The geographic origin of PK-deficient cases due to 451dupT was assessed. RESULTS: Two of five patients with PK deficiency caused by homozygous 451dupT were African, one African American, one from Oman, and one of unknown origin. The frequency of 451dupT was 1.17% in the Nigerian collective (7/600 alleles); none had Cys548Tyr. Subjects with 451dupT were found among different Nigerian ethnicities. Both variants were absent in the European collective. Database research was compatible with these findings, even though mainly data of African Americans (451dupT: 1.12%-1.78%) was accessible. A relevant number of non-American Africans are included only in the 1000Genomes collective: 451dupT frequency was 1.29% in native Africans and 1.56% in African Caribbeans. CONCLUSIONS: This study underlines the higher prevalence of PK deficiency among people with African descent compared to Europeans. In order to avoid delay of necessary surgical procedures in patients of African origin, diagnostic algorithms for isolated, unexplained, activated partial thromboplastin time prolongation in these subjects should include PK deficiency screening.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33118542

RESUMO

BACKGROUND AND AIMS: Nutritional support (NS) in patients with malignancies and malnutrition improves outcome and treatment tolerance. The underlying mechanisms are not completely understood. We aimed to investigate for the first time the influence of an early individualized NS in newly diagnosed patients with gastrointestinal/hepato-pancreatic malignancies and malnutrition on DNA damage, oxidative stress and subclinical inflammation. METHODS: This prospective case-control study included 43 patients with newly diagnosed malignancies and malnutrition. At baseline (F0), we documented patients' data, oncological diagnosis, comorbidities, alcohol/ nicotine consume. Nutritional parameters, DNA damage [histone-variant H2AX phosphorylated on the 139-serine residue (γ-H2AX) foci/cell], oxidative status, subclinical inflammation were measured. During diagnostic workup, patients received an individualized NS, and got a follow-up before the start of treatment (F1), (n=21). Healthy controls (n=21) were included for comparison of DNA damage at baseline. RESULTS: γ-H2AX-values at baseline were higher than in controls (p<0.001) and higher than after the NS at F1 (p=0.011). Patients with severe gastrointestinal symptoms (SGS) had higher baseline foci compared to patients with mild gastrointestinal symptoms (MGS) at F0 (p<0.001) and showed a stronger decrease of DNA damage under NS (p=0.002). Laboratory data were stable, with tendential reduction in oxidative stress, without progression of subclinical inflammation. The number of γ-H2AX foci did not differ among patients divided by sex, age, nicotine or alcohol intake or the presence of distant metastases. CONCLUSION: Increased baseline DNA damage in patients with newly diagnosed tumors and malnutrition decreased under pretherapeutic NS, independent of other known genotoxic factors. This contributes towards understanding the positive effects of early NS in cancer management.

6.
Blood ; 136(3): 353-361, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32356859

RESUMO

Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was <50%. The open ADAMTS13 conformation was found during acute iTTP, as well as in patients in remission with ADAMTS13 activity <50% and in half of the patients with ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.

7.
J Thromb Haemost ; 18(7): 1598-1617, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32202057

RESUMO

BACKGROUND: Severe plasma prekallikrein (PK) deficiency is an autosomal-recessive defect characterized by isolated activated partial thromboplastin time prolongation. To date, no comprehensive methodologically firm analysis has investigated the diagnostic, clinical, and genetic characteristics of PK deficiency, and its prevalence remains unknown. PATIENTS/METHODS: We described new families with PK deficiency, retrieved clinical and laboratory information of cases systematically searched in the (gray) literature, and collected blood of these cases for complementary analyses. The Genome Aggregation Database (gnomAD) and the population-based Gutenberg Health Study served to study the prevalence of mutations and relevant genetic variants. RESULTS: We assembled a cohort of 111 cases from 89 families and performed new genetic analyses in eight families (three unpublished). We identified new KLKB1 mutations, excluded the pathogenicity of some of the previously described ones, and estimated a prevalence of severe PK deficiency of 1/155 668 overall and 1/4725 among Africans. One individual reported with PK deficiency had, in fact, congenital kininogen deficiency associated with decreased PK activity. One quarter of individuals had factor XII clotting activity below the reference range. Four major bleeding events were described in 96 individuals, of which 3 were provoked, for a prevalence of 4% and an annualized rate of 0.1%. The prevalence of cardiovascular events was 15% (6% <40 years; 21% 40-65 years; 33% >65 years) for an annualized rate of 0.4%. CONCLUSIONS: We characterized the genetic background of severe PK deficiency, critically appraised mutations, and provided prevalence estimates. Our data on laboratory characteristics and clinical course of severe PK deficiency may have clinical implications.

8.
Mol Genet Metab ; 130(1): 27-35, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32222271

RESUMO

BACKGROUND: Interpretation of genetic variants detected by sequencing of genomic DNA, which may cause splicing defects, regularly requires mRNA analysis. Usually, only bioinformatic testing is provided, because simple and non-invasive assay protocols are lacking. Furthermore, the detection of mis-splicing is often hampered by nonsense mediated mRNA decay (NMD). METHODS: Starting from a case of Pompe disease with two potential splicing variants an assay for the analysis of splice defects in general was developed. We analyzed the transcripts from the gene of interest by standard methods after short-term culture of the patient's lymphocytes in the presence and absence of a NMD inhibitor. Variant and wild type transcript expression were quantified by allele specific PCR in the patient and both parents and the expression ratio with/without NMD inhibition was calculated for each transcript. RESULTS: NMD detection in lymphocytes was optimized and evaluated by analyzing a naturally occurring NMD transcript. Several compounds inhibited NMD successfully, including potential therapeutic agents. Sample storage for up to 4 days at room temperature prior to lymphocyte isolation did not affect results. In a proof of concept we identified two candidate variants as severe splicing variants in a patient with Pompe disease, but the strategy can also be used to screen for any mis-spliced transcripts prone to NMD. CONCLUSIONS: We developed a simple, non-invasive assay for the detection and characterization of potential splicing variants. This is essential, because early and near-term diagnosis and disease classification is required to facilitate therapy in many genetic diseases.

9.
Front Pediatr ; 7: 260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31294007

RESUMO

Background: Central venous access devices (CVAD) provide important benefits in the management of oncological pediatric patients. However, these catheters are responsible for severe complications. Methods: In this context, we aimed to analyze all patients receiving a CVAD in the Department of Pediatric Hematology and Oncology of the University hospital of Mainz over a period of 9 years, focused on CVAD related complications. Data on demographics, as well as intraoperative and postoperative complications were extracted. Results: A total of 296 patients with a mean age 93.2 ± 62.4 months were analyzed. The majority suffered from leukemia (n = 91, 30.7%), lymphomas (n = 50, 16.9%), and brain tumors (n = 48, 16.2%). In 63 (21.3) patients, complications were observed. No death caused by complications of CVADs was found in our series. Catheter-related blood stream infections (BSI) (7.4%) were most prevalent, followed by dislodgements (5.4%), occlusions (2.7%), thrombosis (2.4%), and catheter leakage (2.4%). Insertion site infections were observed in three patients (1.0%). Fifty-nine percent of all patients with catheter-related BSI suffered from Leukemia. In patients with Catheter-related BSIs we detected the condition leukemia as the underlying disease as a risk factor compared to solid tumors as the underlying disease. Overall, totally implanted devices (ports) have a lower complication rate than tunneled catheter. Conclusion: Implantation of CVADs seems to be safe and reliable in this large pediatric patient cohort. Even if complications occur in the long-term management of CVADs, they can be treated successfully and long-term catheter survival rates are excellent.

11.
J Hypertens ; 37(7): 1372-1383, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31145709

RESUMO

OBJECTIVE: Although several risk factors for retinal vein occlusion (RVO) are known, what triggers RVO is unclear in many cases. We aimed to evaluate the relevance of multiple risk factors in patients with RVO. METHODS: The Gutenberg RVO Study is an observational case-control study that assessed thrombophilic, cardiovascular, ophthalmic, and drug-related risk factors in participants with RVO and the same number of matched controls. Conditional logistic regression analysis was chosen to estimate the risk of RVO due to several risk factors. RESULTS: Of 92 patients with RVO, 46 (50%) had central RVO, 31 (33.7%) had branch RVO, and 15 (16.3) had hemi-RVO. Systemic hypertension was associated with RVO [any RVO: odds ratio (OR): 1.81; 95% confidence interval (CI): 1.14-2.88; branch RVO: OR: 2.56; 95% CI: 1.08-6.10]. The most frequent combinations of risk factors were hypertension with dyslipidemia (33 of 92, 35.9%) and hyperhomocysteinemia and high levels of factor VIII (10 of 92, 10.9%). An increase in the risk sum score by one additional risk factor corresponded to ORs of 1.74 (95% CI: 1.31-2.32) for cardiovascular risk factors, 1.38 (95% CI: 1.04-1.82) for thrombophilic risk factors, and 1.43 (95% CI: 1.20-1.70) for the total number of risk factors for RVO. CONCLUSION: Cardiovascular risk factors are more important than other risk factors for the presence of RVO. The risk of RVO increased by approximately 40% with any additional risk factor and by 70% with any additional cardiovascular risk factor.


Assuntos
Doenças Cardiovasculares/complicações , Hipertensão/complicações , Oclusão da Veia Retiniana/etiologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
12.
Ther Clin Risk Manag ; 14: 2069-2080, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30498352

RESUMO

Purpose: Osteopathy/osteoporosis in Gaucher disease type 1 (GD1) shows variable responses to enzyme replacement therapy (ERT); the pathogenesis is incompletely understood. We aimed to investigate the effects of several gene variants on bone mineral density (BMD) and serum markers of bone metabolism in GD1. Patients and methods: Fifty adult Caucasian patients with GD1/117 controls were genotyped for gene variants in the osteoprotegerin (TNFRSF11B; OPG), estrogen receptor alpha, calcitonin receptor (CALCR), and vitamin D receptor (VDR) genes. In patients and 50 matched healthy controls, we assessed clinical data, serum markers of bone metabolism, and subclinical inflammation. BMD was measured for the first time before/during ERT (median 6.7 years). Results: Forty-two percent of patients were splenectomized. ERT led to variable improvements in BMD. Distribution of gene variants was comparable between patients/controls. The AA genotype (c.1024+283G>A gene variant; VDR gene) was associated with lower Z scores before ERT vs GA (P=0.033), was encountered in 82.3% of patients with osteoporosis and was more frequent in patients with pathological fractures. Z score increases during ERT were higher in patients with the CC genotype (c.9C>G variant, TNFRSF11B; OPG gene; P=0.003) compared with GC (P=0.003). The CC genotype (c.1340T>C variant, CALCR gene) was associated with higher Z scores before ERT than the TT genotype (P=0.041) and was absent in osteoporosis. Osteocalcin and OPG were lower in patients vs controls; beta crosslaps, interleukin-6, and ferritin were higher. Conclusions: We suggest for the first time a protective role against osteoporosis in GD1 patients for the CC genotype of the c.9C>G gene variant in the TNFRSFB11 (OPG) gene and for the CC genotype of the c.1340T>C gene variant (CALCR gene), while the AA genotype of the c.1024+283G>A gene variant in the VDR gene appears as a risk factor for lower BMDs. Serum markers suggest decreased osteosynthesis, reduced inhibition of osteoclast activation, increased bone resorption, and subclinical inflammation during ERT.

13.
Thromb Haemost ; 116(1): 115-23, 2016 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-27098658

RESUMO

The antiphospholipid syndrome (APS) is characterised by venous and/or arterial thrombosis and pregnancy morbidity in women combined with the persistent presence of antiphospholipid antibodies (aPL). We aimed to identify genetic factors associated with the presence of aPL in a population based cohort. Furthermore, we wanted to clarify if the presence of aPL affects gene expression in circulating monocytes. Titres of IgG and IgM against cardiolipin, ß2glycoprotein 1 (anti-ß2GPI), and IgG against domain 1 of ß2GPI (anti-domain 1) were determined in approx. 5,000 individuals from the Gutenberg Health Study (GHS) a population based cohort of German descent. Genotyping was conducted on Affymetrix Genome-Wide Human SNP 6.0 arrays. Monocyte gene expression was determined in a subgroup of 1,279 individuals by using the Illumina HT-12 v3 BeadChip. Gene expression data were confirmed in vitro and ex vivo by qRT-PCR. Genome wide analysis revealed significant associations of anti-ß2GPI IgG and APOH on chromosome 17, which had been previously identified by candidate gene approaches, and of anti-domain1 and MACROD2 on chromosome 20 which has been listed in a previous GWAS as a suggestive locus associated with the occurrence of anti-ß2GPI antibodies. Expression analysis confirmed increased expression of TNFα in monocytes and identified and confirmed neuron navigator 3 (NAV3) as a novel gene induced by aPL. In conclusion, MACROD2 represents a novel genetic locus associated with aPL. Furthermore, we show that aPL induce the expression of NAV3 in monocytes and endothelial cells. This will stimulate further research into the role of these genes in the APS.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/genética , Síndrome Antifosfolipídica/imunologia , Monócitos/metabolismo , Adulto , Idoso , Síndrome Antifosfolipídica/sangue , Estudos de Coortes , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Monócitos/imunologia , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Gravidez , Estudos Prospectivos , RNA/sangue , RNA/genética
14.
Clin Chem Lab Med ; 54(10): 1663-70, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27028736

RESUMO

BACKGROUND: Antiphospholipid syndrome (APS) is the most common acquired thrombophilia. Diagnosis is based on clinical criteria and the presence of antiphospholipid antibodies (aPLs) above the 99th percentile of a reference group. Data on the distribution of aPL in the population are limited. The distribution of aPL including diagnostic cutoffs should be determined in a population-based cohort. METHODS: The Gutenberg Health Study (GHS) is a population-based cohort aged 35-74 years. We determined the presence of antibodies against cardiolipin (aCL, IgG, and IgM), ß2-glycoprotein I (anti-ß2GPI, IgG, and IgM), and domain 1 of ß2-glycoprotein I (anti-domain 1, IgG) in a sample of 4979 participants. RESULTS: aPL titers were similar in the whole sample and in an apparently healthy subgroup of 1049 individuals. There was a strong age-dependent increase of both aCL and anti-ß2GPI IgM, while aPL IgG titers were stable or tended to decrease with age. A relevant decrease was observed for aCL IgG in women and anti-domain 1 IgG in both sexes. There was no association of aPL titers with a history of venous thromboembolism (VTE). CONCLUSIONS: Our data show that for IgM aPL, age-dependent reference ranges should be used. In fact, the controversy regarding the clinical utility of IgM aPL might be related to the use of inappropriate reference ranges among other causes. In our population, aPLs were not associated with a history of VTE.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/diagnóstico , Imunoglobulina G/sangue , Adulto , Idoso , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/epidemiologia , Síndrome Antifosfolipídica/imunologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Alemanha/epidemiologia , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Valores de Referência
15.
Case Rep Genet ; 2016: 8154910, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26885414

RESUMO

Background. Glycogen storage disease type III (GSDIII) is a rare metabolic disorder with autosomal recessive inheritance, caused by deficiency of the glycogen debranching enzyme. There is a high phenotypic variability due to different mutations in the AGL gene. Methods and Results. We describe a 2.3-year-old boy from a nonconsanguineous Romanian family, who presented with severe hepatomegaly with fibrosis, mild muscle weakness, cardiomyopathy, ketotic fasting hypoglycemia, increased transaminases, creatine phosphokinase, and combined hyperlipoproteinemia. GSD type IIIa was suspected. Accordingly, genomic DNA of the index patient was analyzed by next generation sequencing of the AGL gene. For confirmation of the two mutations found, genetic analysis of the parents and grandparents was also performed. The patient was compound heterozygous for the novel mutation c.3235C>T, p.Gln1079(⁎) (exon 24) and the known mutation c.1589C>G, p.Ser530(⁎) (exon 12). c.3235 >T, p.Gln1079(⁎) was inherited from the father, who inherited it from his mother. c.1589C>G, p.Ser530(⁎) was inherited from the mother, who inherited it from her father. Conclusion. We report the first genetically confirmed case of a Romanian patient with GSDIIIa. We detected a compound heterozygous genotype with a novel mutation, in the context of a severe hepatopathy and an early onset of cardiomyopathy.

17.
Trans Am Ophthalmol Soc ; 114: T7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-28050052

RESUMO

PURPOSE: To determine if paraproteinemic keratopathy (PPK) in the setting of monoclonal gammopathy of undetermined significance (MGUS) causes distinct patterns of corneal opacification that can be distinguished from hereditary, immunologic, or inflammatory causes. METHODS: A retrospective, interventional study of patients showed distinct bilateral opacity patterns of the cornea at the eye clinics of Hanau, Mainz, Helsinki, Marburg, and Berlin between 1993 and 2015. Data on patient characteristics and clinical features on ophthalmic examination were collected, and serum protein profiles were evaluated. A literature review and analysis of all published studies of MGUS with PPK is also presented. RESULTS: The largest group of patients diagnosed with MGUS-induced PPK is analyzed in this study. We studied 22 eyes of 11 patients (6 male, aged 43 to 65, mean age 54; 5 female, aged 49 to 76, mean age 61) with distinct corneal opacities and visual impairment who were first suspected of having hereditary, inflammatory, or immunologic corneal entities. Subsequently, serum protein electrophoresis revealed MGUS to be the cause of the PPK. Literature review revealed 72 patients with bilateral PPK (34 male, mean age 57; 38 female, mean age 58) in 51 studies of MGUS published from 1934 to 2015 and disclosed six additional corneal opacity patterns. CONCLUSIONS: This thesis shows that MGUS is not always an asymptomatic disorder, in contrast to the hematologic definition, which has no hint of PPK. The MGUS-induced PPK can mimic many other diseases of the anterior layer of the eye. A new clinical classification for PPK in MGUS is proposed.


Assuntos
Córnea/diagnóstico por imagem , Doenças da Córnea/etiologia , Gamopatia Monoclonal de Significância Indeterminada/complicações , Paraproteinemias/etiologia , Adulto , Idoso , Doenças da Córnea/sangue , Doenças da Córnea/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Oftalmologia , Paraproteinemias/sangue , Paraproteinemias/diagnóstico , Estudos Retrospectivos , Sociedades Médicas , Estados Unidos
18.
Eur Respir J ; 46(6): 1701-10, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26493800

RESUMO

The prognostic value of copeptin, the C-terminal fragment of the precursor protein of vasopressin which is released upon stress, and hypotension in pulmonary embolism is unknown, especially if combined with biomarkers reflecting different pathophysiological axes such as myocardial injury (high-sensitivity troponin T (hsTnT)) and stretch (N-terminal pro-brain natriuretic peptide (NT-proBNP)).We prospectively studied 268 normotensive pulmonary embolism patients included in a single-centre cohort study.Patients with an adverse 30-day outcome (5.6%) had higher copeptin levels than patients with a favourable course (median (interquartile range) 51.8 (21.6-90.8) versus 13.2 (5.9-39.3) pmol·L(-1); p=0.020). Patients with copeptin levels above the calculated optimal cut-off value of 24 pmol·L(-1) had a 5.4-fold increased risk for an adverse outcome (95% CI 1.68-17.58; p=0.005). We developed a strategy for risk stratification based on biomarkers. None of 141 patients (52.6%) with hsTnT <14 pg·mL(-1) or NT-proBNP <600 pg·mL(-1) had an adverse outcome (low risk). Copeptin ≥24 pmol·L(-1) stratified patients with elevated hsTnT and NT-proBNP as intermediate-low and intermediate-high risk (5.6% and 20.0% adverse outcome, respectively). Compared to the algorithm proposed by the 2014 European Society of Cardiology guideline, more patients were classified as low risk (52.8% versus 17.5%, p<0.001) and more patients in the intermediate-high risk group had an adverse outcome (20.0% versus 11.6%).Copeptin might be helpful for risk stratification of normotensive patients with pulmonary embolism, especially if integrated into a biomarker-based algorithm.


Assuntos
Glicopeptídeos/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Embolia Pulmonar/sangue , Troponina T/sangue , Disfunção Ventricular Direita/sangue , Idoso , Biomarcadores/sangue , Reanimação Cardiopulmonar/estatística & dados numéricos , Catecolaminas/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Embolia Pulmonar/mortalidade , Embolia Pulmonar/terapia , Respiração Artificial/estatística & dados numéricos , Medição de Risco
19.
Eur Heart J ; 36(48): 3437-46, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26516175

RESUMO

AIMS: Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 determines the extent of vascular dysfunction in mice and humans. METHODS AND RESULTS: Decreased HO-1 activity and expression was paralleled by increased aortic expression and activity of the nicotinamide dinucleotide phosphate oxidase Nox2 in HO-1 deficient Hmox1⁻/⁻ and Hmox1(⁺/⁻) compared with Hmox1⁺/⁺ mice. When subjected to angiotensin II-infusion, streptozotocin-induced diabetes mellitus and aging, HO-1 deficient mice showed increased vascular dysfunction inversely correlated with HO activity. In a primary prevention population-based cohort, we assessed length polymorphisms of the HMOX1 promoter region and established a bipolar frequency pattern of allele length (long vs. short repeats) in 4937 individuals. Monocytic HMOX1 mRNA expression was positively correlated with flow-mediated dilation and inversely with CD14 mRNA expression indicating pro-inflammatory monocytes in 733 hypertensive individuals of this cohort. Hmox1⁻/⁻ mice showed drastically increased expression of the chemokine receptor CCR2 in monocytes and the aorta. Angiotensin II-infused Hmox1⁻/⁻ mice had amplified endothelial inflammation in vivo, significantly increased aortic infiltration of pro-inflammatory CD11b⁺ Ly6C(hi) monocytes and Ly6G⁺ neutrophils and were marked by Ly6C(hi) monocytosis in the circulation and an increased blood pressure response. Finally, individuals with unfavourable HMOX1 gene promoter length had increased prevalence of arterial hypertension and reduced cumulative survival after a median follow-up of 7.23 years. CONCLUSIONS: Heme oxygenase-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes with possible implications for all-cause mortality.


Assuntos
Endotélio Vascular/fisiopatologia , Heme Oxigenase-1/fisiologia , Hipertensão/fisiopatologia , Animais , Estudos Transversais , Feminino , Heme Oxigenase-1/deficiência , Heme Oxigenase-1/genética , Humanos , Hipertensão/mortalidade , Masculino , Camundongos , Monócitos/fisiologia , Neutrófilos/fisiologia , Estresse Oxidativo/fisiologia , Fenótipo , Polimorfismo Genético , RNA Mensageiro/metabolismo
20.
J Clin Endocrinol Metab ; 99(3): E489-96, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24423348

RESUMO

CONTEXT: Mutations in the four subunits of succinate dehydrogenase (SDH) are the cause for the hereditary paraganglioma (PGL) syndrome types 1-4 and are associated with multiple and recurrent pheochromocytomas and PGLs. SDHC mutations most frequently result in benign, nonfunctional head-and neck PGLs (HNPGLs). The malignant potential of SDHC mutations remains unclear to date. OBJECTIVES: We report a patient with malignant PGL carrying a SDHC mutation and compare her case with two others of the same genotype but presenting with classic benign HNPGLs. Loss of heterozygosity (LOH) was demonstrated in the malignant PGL tissue. DESIGN: In three unrelated patients referred for routine genetic testing, SDHB, SDHC, and SDHD genes were sequenced, and gross deletions were excluded by multiplex ligation-dependent probe amplification (MLPA). LOH was determined by pyrosequencing-based allele quantification and SDHB immunohistochemistry. RESULTS: In a patient with a nonfunctioning thoracic PGL metastatic to the bone, the lungs, and mediastinal lymph nodes, we detected the SDHC mutation c.397C>T predicting a truncated protein due to a premature stop codon (p.Arg133*). We demonstrated LOH and loss of SDHB protein expression in the malignant tumor tissue. The two other patients also carried c.397C>T, p.Arg133*; they differed from each other with respect to their tumor characteristics, but both showed benign HNPGLs. CONCLUSIONS: We describe the first case of a malignant PGL with distant metastases caused by a SDHC germline mutation. The present case shows that SDHC germline mutations can have highly variable phenotypes and may cause malignant PGL, although malignancy is probably rare.


Assuntos
Mutação em Linhagem Germinativa , Proteínas de Membrana/genética , Paraganglioma/genética , Neoplasias da Coluna Vertebral/genética , Arginina/genética , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Tumor do Glomo Jugular/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/secundário , Humanos , Perda de Heterozigosidade , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Paraganglioma/patologia , Fenótipo , Fatores de Risco , Neoplasias da Coluna Vertebral/patologia
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