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1.
Cancer Epidemiol ; 65: 101643, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32058310

RESUMO

BACKGROUND: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence. METHODS: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication. RESULTS: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low. CONCLUSION: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.

2.
High Alt Med Biol ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31976756

RESUMO

Background: Exaggerated pulmonary arterial hypertension (PAH) is a hallmark of high-altitude pulmonary edema (HAPE). The objective of this study was therefore to investigate genetic predisposition to HAPE by analyzing PAH candidate genes in a HAPE-susceptible (HAPE-S) family and in unrelated HAPE-S mountaineers. Materials and Methods: Eight family members and 64 mountaineers were clinically and genetically assessed using a PAH-specific gene panel for 42 genes by next-generation sequencing. Results: Two otherwise healthy family members, who developed re-entry HAPE at 3640 m during childhood, carried a likely pathogenic missense mutation (c.1198T>G p.Cys400Gly) in the Janus Kinase 2 (JAK2) gene. One of them progressed to a mild form of PAH at the age of 23 years. In two of the 64 HAPE-S mountaineers likely pathogenic variants have been detected, one missense mutation in the Cytochrome P1B1 gene, and a deletion in the Histidine-Rich Glycoprotein (HRG) gene. Conclusions: This is the first study identifying an inherited missense mutation of a gene related to PAH in a family with re-entry HAPE showing a progression to borderline PAH in the index patient. Likely pathogenic variants in 3.1% of HAPE-S mountaineers suggest a genetic predisposition in some individuals that might be linked to PAH signaling pathways.

3.
Am J Pathol ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31953036

RESUMO

Papillary thyroid carcinomas (PTCs) account for 90% of human thyroid cancer cases, which represent 1% of all cancer cases. They are likely to develop from papillary thyroid microcarcinomas (PTMCs), found in up to 36% of healthy individuals, due to rare progression events (0.01%). Although the prognosis of PTCs is excellent, 5% to 10% of tumors display an unfavorable outcome. About 45% of PTCs exhibit activating BRAFV600E mutations. Rats of the inbred BD strains postnatally exposed to the carcinogen N-ethyl-N-nitrosourea developed PTMCs, which closely resembled their human counterparts judging from their histology, size, and marginal tendency to progress. DNA sequencing revealed mutations in exon 15 of the Braf gene identical to the human BRAFV600E mutation in 82% of the cases. Predominantly a 50:50 ratio of wild-type to mutant Braf alleles was seen regardless of tumor size or animal age, indicating that the Braf mutation is an early, if not the initial, event in rat PTMC development. Surprisingly, most PTMCs carrying a confirmed BrafV600E mutation did not display BrafV600E protein expression. As the BrafV600Egene is supposed to be the driver in PTC development, down-regulation of expression should contribute to the low risk for progression of PTMC. This model system will enable further insights into the molecular mechanisms of PTMC initiation and progression to PTC, further translating into targeted tumor prevention strategies/therapies.

4.
Int J Cancer ; 146(4): 999-1009, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31081934

RESUMO

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1-56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2-19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8-6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4-12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.

5.
Arthritis Res Ther ; 21(1): 217, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31655622

RESUMO

OBJECTIVE: The objective of this randomized, placebo-controlled, double-blind, parallel group, trial was to assess the effect of ambrisentan on mean pulmonary arterial pressure (mPAP) in patients with systemic sclerosis (SSc) and mildly elevated pulmonary hypertension (PH). METHODS: Thirty-eight SSc patients with mildly elevated mPAP at rest between 21 and 24 mmHg and/or > 30 mmHg during low-dose exercise were randomly assigned to treatment with either ambrisentan 5-10 mg/day or placebo. Right heart catheterization and further clinical parameters were assessed at baseline and after 6 months. The primary endpoint was the difference of mPAP change at rest between groups. RESULTS: After 6 months, the two groups did not differ in the primary endpoint (ambrisentan mPAP - 1 ± 6.4 mmHg vs. placebo - 0.73 ± 3.59 mmHg at rest, p = 0.884). However, three patients from the placebo group but none of the ambrisentan group progressed to SSc-associated pulmonary arterial hypertension. Furthermore, ambrisentan treatment showed significant improvements in the secondary endpoints cardiac index (CI) and pulmonary vascular resistance (PVR) at rest (CI 0.36 ± 0.66 l/min/m2 vs. - 0.31 ± 0.71 l/min/m2, p = 0.010; PVR - 0.70 ± 0.78 WU vs. 0.01 ± 0.71 WU, p = 0.012) and during exercise (CI 0.7 ± 0.81 l/min/m2 vs. - 0.45 ± 1.36 l/min/m2, p = 0.015; PVR - 0.84 ± 0.48 WU vs. - 0.0032 ± 0.34 WU, p < 0.0001). CONCLUSION: This is the first randomized, double-blind, placebo-controlled study testing the effect of ambrisentan in patients with mildly elevated mPAP and/or exercise PH. The primary endpoint change in mPAP did only tendentially improve in the ambrisentan group, but the significant improvement of other hemodynamic parameters points to a possible benefit of ambrisentan and will be helpful to design future trials. TRIAL REGISTRATION: www.ClinicalTrials.gov, unique identifier NCT: NCT02290613 , registered 14th of November 2014.

7.
Arthritis Rheumatol ; 71(5): 805-816, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30615302

RESUMO

OBJECTIVE: This prospective study was undertaken to evaluate right ventricular function and pulmonary arterial compliance (PAC; ratio of stroke volume to pulse pressure) at rest and during exercise in patients with systemic sclerosis (SSc) with normal mean pulmonary artery pressure (PAP), patients with SSc with mildly elevated mean PAP, and patients with SSc with manifest pulmonary hypertension (PH). METHODS: Patients with SSc (n = 112) underwent clinical assessment and right-sided heart catheterization at rest and during exercise and were divided into 3 groups according to their resting mean PAP values: normal mean PAP (≤20 mm Hg), mildly elevated mean PAP (21-24 mm Hg), and PH (mean PAP ≥25 mm Hg). Results were compared between groups by analysis of variance followed by post hoc Student's t-test. RESULTS: Compared to patients with normal mean PAP, patients with mildly elevated mean PAP had a lower 6-minute walking distance (P = 0.008), lower cardiac index (P = 0.027) and higher pulmonary vascular resistance (P = 0.0002) during exercise, and lower PAC at rest (P = 0.016) and different stages of exercise (P = 0.033 for 25W and P = 0.024 for 75W). CONCLUSION: The results of this study suggest that impaired 6-minute walking distance in SSc patients with mildly elevated mean PAP might be caused by reduced PAC during exercise and reduced right ventricular output reserve, presumably due to impaired coupling between the right ventricle and the pulmonary vasculature. These findings provide further evidence of the clinical relevance of mildly elevated mean PAP in patients with SSc.


Assuntos
Débito Cardíaco/fisiologia , Artéria Pulmonar/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Resistência Vascular/fisiologia , Disfunção Ventricular Direita/fisiopatologia , Adulto , Idoso , Pressão Sanguínea/fisiologia , Cateterismo Cardíaco , Estudos de Casos e Controles , Complacência (Medida de Distensibilidade) , Ecocardiografia Doppler , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , Disfunção Ventricular Direita/diagnóstico por imagem , Teste de Caminhada
8.
Front Mol Biosci ; 5: 109, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30560135

RESUMO

Intestinal absorption of dietary amino acids is mediated via two routes. Free amino acids released by hydrolysis of dietary proteins are taken up by a multitude of amino acid transporters while di- and tripeptides released are taken up by the peptide transporter PEPT-1. Loss of PEPT-1 impairs growth, post-embryonic development and reproduction in Caenorhabditis elegans, and supplementation with a mixture of all L-amino acids only partially rescues fertility. In the present study, we demonstrate that dietary L-glutamate is the responsible amino acid that can increase fertility in hermaphrodite pept-1 worms. This effect was associated with a significantly higher uptake of glutamate/aspartate in pept-1 than in wildtype C. elegans. Furthermore, we found that the intestinal transporter proteins SNF-5 of the solute carrier SLC6 family of nutrient amino acid transporters (NAT) and AAT-6 of the SLC7 family as the light subunit of a heteromeric amino acid transporter (HAT) play a key role in glutamate homeostasis in pept-1 C. elegans. Genes encoding these transporters are highly expressed and upon silencing a 95% reduced fertility (snf-5) and sterility (aat-6) was observed. A subsequent L-glutamate supplementation failed to rescue these phenotypes. Dietary glutamate supplementation did neither influence the feeding frequency, nor did it improve mating efficiency of pept-1 males. Most strikingly, pept-1 were more prone to habituation to repeated gentle touch stimuli than wildtype C. elegans, and dietary glutamate supply was sufficient to alter this behavioral output by restoring the mechanosensory response to wildtype levels. Taken together, our data demonstrate a key role of L-glutamate in amino acid homeostasis in C. elegans lacking the peptide transporter in the intestine and demonstrate its distinct role in reproduction and for neural circuits mediating touch sensitivity.

9.
Respir Res ; 19(1): 258, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30567595

RESUMO

BACKGROUND: Riociguat is a soluble guanylate cyclase stimulator approved for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTPEH). The objective of this study was to evaluate right heart size and function assessed by echocardiography during long term treatment with riociguat. METHODS: Patients who started riociguat treatment (1.0-2.5 mg tid) within the trials phase II, PATENT, PATENTplus, EAS, CHEST and continued treatment for 3-12 months were included in this study. Echocardiography was analysed off-line at baseline, after 3, 6 and 12 months by investigators who were blinded to clinical data. Last and baseline observation carried forward method (LOCF, BOCF) were performed as sensitivity analysis. RESULTS: Seventy-one patients (45% PAH, 55% CTEPH; 53.5% female; 60 ± 13 years, mean pulmonary arterial pressure 46 ± 10 mmHg, mean PVR 700 ± 282dynes·sec·cm-5) were included. After 6 months, RA and RV area, RV thickness tricuspid regurgitation velocity showed a significant reduction. After 12 months, patients receiving riociguat therapy showed a significant reduction in right atrial (- 2.6 ± 4.4 cm2, 95% CI -3.84, - 1.33; p < 0.001, n = 49) and right ventricular (RV) area (- 3.5 ± 5.2 cm2, 95% CI -5.1, - 1.9; p < 0.001; n = 44), RV thickness (- 0.76 ± 2.2 mm, 95% CI -1.55, 0.03; n = 32), and a significant increase in TAPSE (2.95 ± 4.78 mm, 95% CI 1.52, 4.39; n = 45) and RV fractional area change (8.12 ± 8.87 mm, 95% CI 4.61, 11.62; n = 27). Both LOCF and BOCF showed similar results but lower effect sizes. CONCLUSION: Patients under long-term treatment with riociguat show significantly reduced right heart size and improved RV function in PAH and CTEPH. Further controlled prospective studies are needed to confirm these results.


Assuntos
Ventrículos do Coração/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Embolia Pulmonar/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Função Ventricular Direita/efeitos dos fármacos , Idoso , Doença Crônica , Método Duplo-Cego , Ativadores de Enzimas/farmacologia , Ativadores de Enzimas/uso terapêutico , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/fisiopatologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Estudos Retrospectivos , Função Ventricular Direita/fisiologia
10.
Respir Res ; 19(1): 216, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30409145

RESUMO

BACKGROUND: The objective of this study was to assess, whether right atrial (RA) and ventricular (RV) size is related to RV pump function at rest and during exercise in patients with pulmonary arterial hypertension (PAH). METHODS: We included 54 patients with invasively diagnosed PAH that had been stable on targeted medication. All patients underwent clinical assessments including right heart catheterization and echocardiography at rest and during exercise. RV output reserve was defined as increase of cardiac index (CI) from rest to peak exercise (∆CIexercise). Patients were classified according to the median of RA and RV-area. RV pump function and further clinical parameters were compared between groups by student's t-test. Uni- and multivariate Pearson correlation analyses were performed. RESULTS: Patients with larger RA and/or RV-areas (above a median of 16 and 20cm2, respectively) showed significantly lower ∆CIexercise, higher mean pulmonary arterial pressure, pulmonary vascular resistance at rest and NT-proBNP levels. Furthermore, patients with higher RV-areas presented with a significantly lower RV stroke volume and pulmonary arterial compliance at peak exercise than patients with smaller RV-size. RV area was identified as the only independent predictor of RV output reserve. CONCLUSION: RV and RA areas represent valuable and easily accessible indicators of RV pump function at rest and during exercise. Cardiac output reserve should be considered as an important clinical parameter. Prospective studies are needed for further evaluation.


Assuntos
Função do Átrio Direito/fisiologia , Átrios do Coração/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Função Ventricular Direita/fisiologia , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/fisiologia , Estudos Retrospectivos
11.
Respiration ; 96(3): 249-258, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30001556

RESUMO

BACKGROUND: Right ventricular (RV) dysfunction is a major prognostic predictor in pulmonary arterial hypertension (PAH). OBJECTIVES: The objective of this study was to assess the prognostic impact of a newly developed index merging haemodynamic parameters into 1 variable. METHODS: We retrospectively assessed 2 cohorts of 248 patients (164 from Hamburg and 84 from Heidelberg) with invasively diagnosed PAH. During a median follow-up time of 3.6 years (3.1 and 4.0 years for Hamburg and Heidelberg, respectively), the composite endpoint of all-cause mortality and lung transplantation occurred in 57 patients (53 and 4 patients for Hamburg and Heidelberg, respectively). The RV index was developed in the Hamburg cohort and validated in the Heidelberg cohort: (right atrial pressure × pulmonary vascular resistance)/mixed venous oxygen saturation. RESULTS: Patients with a high RV index had a higher incidence of the combined endpoint in Kaplan-Meier analyses in the Hamburg and Heidelberg cohort (p = 0.017 and p = 0.034, respectively). The calculated RV index cut-off value was 91 and identified patients with a worse outcome in the Hamburg cohort and showed a trend in the Heidelberg cohort (p < 0.001 and p = 0.089, respectively). The RV index in Cox regression hazard models was an independent predictor of outcomes after adjustment for sex and age in both cohorts (Hamburg: hazard ratio [HR] 1.26 [95% CI 1.08, 1.47], p = 0.0027; Heidelberg: HR 2.27 [95% CI 1.46, 3.51], p < 0.001). A nomogram based on these results allowed risk stratification. CONCLUSION: Merging 3 haemodynamic variables into 1 variable, the RV index increased the prognostic power up to an independent risk factor. The RV index is easy to calculate and allows the construction of a nomogram for an individualized risk assessment.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Índice de Gravidade de Doença , Função Ventricular Direita , Idoso , Feminino , Alemanha/epidemiologia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/mortalidade , Masculino , Pessoa de Meia-Idade , Nomogramas , Prognóstico , Estudos Retrospectivos , Medição de Risco
12.
J Neurodev Disord ; 10(1): 15, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29665782

RESUMO

BACKGROUND: Mutations in the SHANK genes, which encode postsynaptic scaffolding proteins, have been linked to a spectrum of neurodevelopmental disorders. The SHANK genes and the schizophrenia-associated microRNA-137 show convergence on several levels, as they are both expressed at the synapse, influence neuronal development, and have a strong link to neurodevelopmental and neuropsychiatric disorders like intellectual disability, autism, and schizophrenia. This compiled evidence raised the question if the SHANKs might be targets of miR-137. METHODS: In silico analysis revealed a putative binding site for microRNA-137 (miR-137) in the SHANK2 3'UTR, while this was not the case for SHANK1 and SHANK3. Luciferase reporter assays were performed by overexpressing wild type and mutated SHANK2-3'UTR and miR-137 in human neuroblastoma cells and mouse primary hippocampal neurons. miR-137 was also overexpressed or inhibited in hippocampal neurons, and Shank2 expression was analyzed by quantitative real-time PCR and Western blot. Additionally, expression levels of experimentally validated miR-137 target genes were analyzed in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control individuals using the RNA-Seq data from the CommonMind Consortium. RESULTS: miR-137 directly targets the 3'UTR of SHANK2 in a site-specific manner. Overexpression of miR-137 in mouse primary hippocampal neurons significantly lowered endogenous Shank2 protein levels without detectable influence on mRNA levels. Conversely, miR-137 inhibition increased Shank2 protein expression, indicating that miR-137 regulates SHANK2 expression by repressing protein translation rather than inducing mRNA degradation. To find out if the miR-137 signaling network is altered in schizophrenia, we compared miR-137 precursor and miR-137 target gene expression in the DLPFC of schizophrenia and control individuals using the CommonMind Consortium RNA sequencing data. Differential expression of 23% (16/69) of known miR-137 target genes was detected in the DLPFC of schizophrenia individuals compared with controls. We propose that in further targets (e.g., SHANK2, as described in this paper) which are not regulated on RNA level, effects may only be detectable on protein level. CONCLUSION: Our study provides evidence that a direct regulatory link exists between miR-137 and SHANK2 and supports the finding that miR-137 signaling might be altered in schizophrenia.


Assuntos
Hipocampo/metabolismo , MicroRNAs/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/metabolismo , Regiões 3' não Traduzidas , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Humanos , Camundongos , MicroRNAs/química , Proteínas do Tecido Nervoso/química , Cultura Primária de Células , Esquizofrenia/genética
13.
Eur Respir J ; 51(4)2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29563168

RESUMO

The objective of this study was to evaluate the incidence of pulmonary hypertension (PH) and determining factors in patients with systemic sclerosis (SSc) and a diffusing capacity of the lung for carbon monoxide (DLCO) <60% predicted.In this bicentric, prospective cohort study, patients with SSc were clinically assessed at baseline and after 3 years, including right heart catheterisation (RHC). Analysis of determining factors for the development of PH was performed using univariate and multivariate analyses.96 patients with a mean pulmonary arterial pressure (mPAP) <25 mmHg at baseline were followed for 2.95±0.7 years (median 3 years). Of these, 71 had a second RHC; 18 of these 71 patients (25.3%) developed PH, and five (7%) developed SSc-associated pulmonary arterial hypertension. For patients with an mPAP of 21-24 mmHg at baseline, the likelihood of presenting with PH as opposed to normal pressures on follow-up was significantly higher (p=0.026). Pulmonary vascular resistance, tricuspid regurgitation velocity, diffusion capacity and the size of the inferior vena cava at baseline were independent predictors for the development of PH during follow-up.In a selected cohort of SSc patients with a DLCO <60%, pulmonary pressures appeared to rise progressively during follow-up. In this population, it was possible to identify manifest PH in almost 25% of patients using prospective RHC during follow-up. Therefore, regular clinical assessment including RHC might be useful in patients with SSc.


Assuntos
Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Escleroderma Sistêmico/complicações , Adulto , Idoso , Pressão Arterial , Cateterismo Cardíaco , Ecocardiografia , Feminino , Humanos , Hipertensão Pulmonar/mortalidade , Incidência , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Testes de Função Respiratória , Análise de Sobrevida , Resistência Vascular
14.
Mov Disord ; 33(2): 282-288, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29205509

RESUMO

OBJECTIVE: Examine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms. BACKGROUND: CSF alpha-synuclein is decreased in PD versus healthy controls, but whether plasma and saliva alpha-synuclein differentiate these groups is controversial. Correlations of alpha-synuclein among biofluids (CSF, plasma, saliva) or biomarkers (eg, beta-amyloid, tau [total, phosphorylated]) are not fully understood. The relationships of these biomarkers with PD clinical features remain unclear. METHODS: BioFIND, a cross-sectional, observational study, examines clinical and biomarker characteristics in moderate-advanced PD and matched healthy controls. We compared alpha-synuclein concentrations across diagnosis, biofluids, and CSF biomarkers. Correlations of CSF biomarkers and MDS-UPDRS, motor phenotype, MoCA, and rapid eye movement sleep behavior disorder questionnaire scores in PD were examined. RESULTS: CSF alpha-synuclein was lower in PD versus controls (P = .01), controlling for age, gender, and education. Plasma and saliva alpha-synuclein did not differ between PD and controls, and alpha-synuclein did not significantly correlate among biofluids. CSF beta-amyloid1-42 was lower in PD versus controls (P < .01), and correlated weakly with MoCA recall scores (r = 0.23, P = .02). CSF alpha-synuclein was lower in the postural instability/gait difficulty phenotype than other motor phenotypes (P < .01). No CSF biomarkers predicted or correlated with total motor or rapid eye movement sleep behavior disorder scores. CSF alpha-synuclein correlated with beta-amyloid1-42 , total-tau, and phosphorylated-tau (r = 0.41, 0.81, 0.43, respectively; Ps < .001). CONCLUSION: Lower CSF alpha-synuclein is associated with diagnosis and motor phenotype in moderate-advanced PD. Plasma and saliva alpha-synuclein neither correlate with CSF alpha-synuclein, nor distinguish PD from controls. CSF beta-amyloid1-42 remains a potential biomarker for cognitive impairment in PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/metabolismo , Saliva/química , Idoso , Peptídeos beta-Amiloides/metabolismo , Estudos de Coortes , Correlação de Dados , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Fragmentos de Peptídeos/metabolismo , Equilíbrio Postural , Transtornos das Sensações/etiologia , Estados Unidos , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
15.
Sci Rep ; 7(1): 14680, 2017 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-29089619

RESUMO

Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3'UTR binding sites. The novel isoform HTR4b_2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.


Assuntos
Síndrome do Intestino Irritável/genética , Jejuno/metabolismo , MicroRNAs/genética , Receptores 5-HT4 de Serotonina/genética , Diarreia , Regulação para Baixo , Regulação da Expressão Gênica , Estudos de Associação Genética , Humanos , Síndrome do Intestino Irritável/metabolismo , Jejuno/patologia , Mutação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Ligação Proteica/genética , Qualidade de Vida , Receptores 5-HT4 de Serotonina/metabolismo , Transdução de Sinais , Desempenho Profissional
16.
Eur Heart J ; 38(46): 3449-3460, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29029073

RESUMO

Aims: In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. Methods and results: In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays. Conclusion: Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome.


Assuntos
Hipertrofia Ventricular Esquerda/genética , Mutação/genética , Adulto , Arritmias Cardíacas/genética , Cardiomiopatia Dilatada/genética , Conectina/genética , Morte Súbita Cardíaca/etiologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Lamina Tipo A/genética , Masculino , Linhagem , Proteínas de Ligação a RNA/genética
17.
Oecologia ; 185(3): 499-511, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28929254

RESUMO

Plant diversity influences many ecosystem functions including root decomposition. However, due to the presence of multiple pathways via which plant diversity may affect root decomposition, our mechanistic understanding of their relationships is limited. In a grassland biodiversity experiment, we simultaneously assessed the effects of three pathways-root litter quality, soil biota, and soil abiotic conditions-on the relationships between plant diversity (in terms of species richness and the presence/absence of grasses and legumes) and root decomposition using structural equation modeling. Our final structural equation model explained 70% of the variation in root mass loss. However, different measures of plant diversity included in our model operated via different pathways to alter root mass loss. Plant species richness had a negative effect on root mass loss. This was partially due to increased Oribatida abundance, but was weakened by enhanced root potassium (K) concentration in more diverse mixtures. Equally, grass presence negatively affected root mass loss. This effect of grasses was mostly mediated via increased root lignin concentration and supported via increased Oribatida abundance and decreased root K concentration. In contrast, legume presence showed a net positive effect on root mass loss via decreased root lignin concentration and increased root magnesium concentration, both of which led to enhanced root mass loss. Overall, the different measures of plant diversity had contrasting effects on root decomposition. Furthermore, we found that root chemistry and soil biota but not root morphology or soil abiotic conditions mediated these effects of plant diversity on root decomposition.


Assuntos
Biodiversidade , Fabaceae/fisiologia , Raízes de Plantas/química , Poaceae/fisiologia , Solo/química , Ecossistema , Microbiologia do Solo
18.
Mol Genet Metab ; 121(4): 297-307, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28688840

RESUMO

Whole exome sequencing (WES) is well established in research and is now being introduced into clinically indicated diagnostics (so-called clinical exomes). We evaluated the diagnostic yield and clinical implications of WES in 72 patients from 60 families with undiagnosed neurodevelopmental disorders (NDD), neurometabolic disorders, and dystonias. Pathogenic or likely pathogenic variants leading to a molecular diagnosis could be identified in 21 of the 60 families (overall 35%, in 36% of patients with NDD, in 43% of patients with neurometabolic disorders, in 25% of patients with dystonias). In one family two coexisting autosomal recessive diseases caused by homozygous pathogenic variants in two different genes were diagnosed. In another family, a homozygous frameshift variant in STRADA was found to cause a severe NDD with early onset epilepsy, brain anomalies, hypotonia, heart defect, nephrocalcinosis, macrocephaly and distinctive facies so far designated as PMSE (polyhydramnios, megalencephaly, symptomatic epilepsy) syndrome. In 7 of the 21 families with a molecular diagnosis the pathogenic variants were only identified by clinical follow-up, manual reevaluation of the literature, a change of filter setting, and/or reconsideration of inheritance pattern. Most importantly, clinical implications included management changes in 8 cases and impact on family planning in 20 families with a molecular diagnosis. This study shows that reevaluation and follow-up can improve the diagnostic rate and that WES results have important implications on medical management and family planning. Furthermore, we could confirm STRADA as a gene associated with syndromic ID but find it questionable if the current designation as PMSE depicts the most important clinical features.


Assuntos
Exoma , Técnicas de Diagnóstico Molecular/métodos , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Serviços de Planejamento Familiar , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Gravidez , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
19.
Biomark Med ; 11(6): 451-473, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28644039

RESUMO

Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset.


Assuntos
Biomarcadores/metabolismo , National Institute of Neurological Disorders and Stroke (USA) , Doença de Parkinson/metabolismo , Estudos de Coortes , Humanos , Estados Unidos
20.
PLoS One ; 12(5): e0177893, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28542378

RESUMO

PURPOSE: The German Consortium for hereditary breast/ovarian cancer (GC-HBOC) aims for nationwide access to professional, individualized yet structured care for families at high risk. The identification of such families remains key for optimal care. Our study evaluates counselees' characteristics, referral practices, expectations and motivations in respect to their first genetic consultation. The impact of the Angelina Jolie Effect (AJE) was prospectively assessed. METHODS: All counselees could participate through a questionnaire. Groups were built in respect to neoadjuvant chemotherapy (FT) and before/after AJE. RESULTS: The 917 (88.5%) counselees (FT: 8.2%) were on average female (97.3%), with a mean age of 44.6, had children (71.9%), higher education (88%), personal (46.4%) or at least one first-degree relative (74.6%) with BC/OC or known BRCA1/2 mutation (11.8%), were in a relationship (76.1%), and living in a village (40.7%). The AJE is associated with significantly fewer cancelations (p = 0.005), more attendance among men (4.2% vs. 0.8%, p = 0.002), and people with familial BRCA1/2 (14.8% vs. 7.5%, p = 0.003). The majority seek information regarding their cancer risk (83%) or relatives' risk (74.8%), HBOC (69.1%), and surveillance programs for themselves (66.6%) or relatives (60.6%). CONCLUSION: Enhanced media awareness of genetic cancer motivates patients, including other patient groups. A higher number of participants, including more men, are attending GC due to the AJE. In terms of the rising complexity of genetic testing, the analysis of patients' expectations and initiators for GC suggests that there is an urgent need to develop to participate motivation analysis. The factors revealed as impediments to accessing GC-HBOC guide recommendations to optimize access to genetic counseling. Medical educational programs for primary gynecologists and families at risk might be options to reach more participants.


Assuntos
Neoplasias da Mama/genética , Adulto , Feminino , Aconselhamento Genético/métodos , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fatores de Risco , Inquéritos e Questionários
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