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1.
Ann Hematol ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31691002

RESUMO

Knowledge of social inequalities in monoclonal gammopathy of undetermined significance (MGUS) will contribute to understanding multiple myeloma (MM) etiology, as MGUS consistently precedes MM. The aim of the present study was to examine whether socioeconomic position (SEP) is associated with MGUS in a population-based cohort including information on potential MGUS risk factors. Overall, 4787 study participants aged 45-75 years with information on MGUS were included. SEP indicators (education, income) and potential risk factors (i.e., body mass index, diabetes, smoking, dietary factors) were assessed at baseline. Overall, 260 MGUS cases were detected at baseline and prospectively over a 10-year follow-up. In age-adjusted logistic regression models, a lower chance of having MGUS at baseline or developing MGUS during 10 years of follow-up was indicated for groups of low SEP with odds ratios (OR) of 0.39 (95% confidence interval [95%-CI] 0.19-0.76) for women and 0.48 (95% CI 0.10-1.16) for men in the lowest compared to the highest educational group. After additionally including potential mediating risk factors in the regression models, the estimated ORs changed only slightly in magnitude. Similar results were obtained for income. Current smoking and low fruit consumption were associated with MGUS independently of SEP in women, but not in men. The present study indicates a lower MGUS risk in lower SEP groups. Supporting evidence is given that smoking and diet play a role in the development of MGUS independently of SEP, while it has to be assumed that risk factors unknown to date are responsible for the observed social inequalities in MGUS.

2.
Eur J Haematol ; 2018 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-30471148

RESUMO

OBJECTIVES: The GMALL-B-ALL/NHL2002 protocol is effective in Burkitt-lymphoma/leukaemia (BL). Its role in other aggressive lymphomas and in patients with simultaneous central nervous system (CNS) and peripheral involvement is unclear. METHODS: This is a retrospective outcome analysis in 76 patients with BL (n=26), B-lymphoblastic lymphoma (B-LBL; n=3), diffuse large B-cell lymphoma (DLBCL; n=31), mantle-cell lymphoma (MCL; n=6), transformed B-cell non-Hodgkin lymphomas (tB-NHL; n=7) and T-cell NHL (T-NHL; n=3) treated with the GMALL-B-ALL/NHL2002 protocol. RESULTS: 73.1% of scheduled chemotherapy cycles were administered. Treatment was discontinued in 38 patients (50.0%) due to progression (n=14), toxicities (n=11), scheduled treatment change (n=6) and unknown reasons (n=7). All BL/B-LBL patients were treated first-line and at a median follow-up of 124.7 months median progression free survival was not reached. In DLBCL, median PFS was 68.4 months in first-line treated patients and 3.7 months in relapsed/refractory patients. CNS involvement was present in 10 non-BL/B-LBL cases and did not have a negative impact on survival in first-line treated patients but was fatal in all relapsed/refractory patients. CONCLUSION: This study confirmed the activity of the GMALL-B-ALL/NHL2002 protocol in BL/B-LBL. It was also effective in first-line treated non-BL/B-LBL lymphomas with and without simultaneous CNS-/peripheral involvement, but ineffective in relapsed/refractory disease. This article is protected by copyright. All rights reserved.

3.
Ann Hematol ; 97(8): 1463-1469, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29629484

RESUMO

We determined the 10-year progression rate of light chain monoclonal gammopathy of undetermined significance (LCMGUS) and investigated potential associations with cancer utilizing the German population-based Heinz Nixdorf Recall Study. The Heinz Nixdorf Recall Study comprises 4814 men and women aged 45-75 years. Serum samples from baseline (2000-2003) and five-year (2006-2008) and 10-year (2011-2015) follow-up examinations were screened for monoclonal free light chains (FLC). LCMGUS was defined as abnormal FLC ratio, increase of involved FLC with complete loss of immunoglobulin heavy chain, and absence of a history of lymphoproliferative disease (LPD). Seventy-five individuals with LCMGUS were identified across all three evaluation time points (median age 64 years; 43 (57%) male; FLCR > 1.65 65 (87%); FLCR ≤ 0.65 10 (13%)). After a median observation time of 11.5 years, none of the LCMGUS cases had progressed to overt LPD; in particular, we did not observe incident light chain multiple myeloma. On serial analysis 17/31 (55%), LCMGUS could not be confirmed and disappearance of the monoclonal protein was associated with low concentrations of the involved FLC. Individuals with LCMGUS had a 1.5-fold increased risk of cancer but did not show differences in overall survival or renal function as compared to individuals with normal FLC. In conclusion, LCMGUS represents a relatively benign condition with a high disappearance rate of the monoclonal protein on longitudinal analysis and normal overall survival at least in the population-based setting.


Assuntos
Biomarcadores Tumorais/sangue , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/epidemiologia , Progressão da Doença , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Gamopatia Monoclonal de Significância Indeterminada/mortalidade , Vigilância da População , Prevalência
4.
Ann Work Expo Health ; 61(9): 1118-1131, 2017 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-29136419

RESUMO

Objectives: Exposure to manganese (Mn) may cause movement disorders, but less is known whether the effects persist after the termination of exposure. This study investigated the association between former exposure to Mn and fine motor deficits in elderly men from an industrial area with steel production. Methods: Data on the occupational history and fine motor tests were obtained from the second follow-up of the prospective Heinz Nixdorf Recall Study (2011-2014). The study population included 1232 men (median age 68 years). Mn in blood (MnB) was determined in archived samples (2000-2003). The association between Mn exposure (working as welder or in other at-risk occupations, cumulative exposure to inhalable Mn, MnB) with various motor functions (errors in line tracing, steadiness, or aiming and tapping hits) was investigated with Poisson and logistic regression, adjusted for iron status and other covariates. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated for substantially impaired dexterity (errors >90th percentile, tapping hits <10th percentile). Results: The median of cumulative exposure to inhalable Mn was 58 µg m-3 years in 322 men who ever worked in at-risk occupations. Although we observed a partly better motor performance of exposed workers at group level, we found fewer tapping hits in men with cumulative Mn exposure >184.8 µg m-3 years (OR 2.15, 95% CI 1.17-3.94). MnB ≥ 15 µg l-1, serum ferritin ≥ 400 µg l-1, and gamma-glutamyl transferase ≥74 U l-1 were associated with a greater number of errors in line tracing. Conclusions: We found evidence that exposure to inhalable Mn may carry a risk for dexterity deficits. Whether these deficits can be exclusively attributed to Mn remains to be elucidated, as airborne Mn is strongly correlated with iron in metal fumes, and high ferritin was also associated with errors in line tracing. Furthermore, hand training effects must be taken into account when testing for fine motor skills.


Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Manganês/efeitos adversos , Destreza Motora/fisiologia , Transtornos dos Movimentos/etiologia , Neurotoxinas/efeitos adversos , Exposição Ocupacional/efeitos adversos , Idoso , Humanos , Íons , Masculino , Manganês/sangue , Pessoa de Meia-Idade , Fenômenos Fisiológicos Musculoesqueléticos , Neurotoxinas/sangue , Ocupações/estatística & dados numéricos , Razão de Chances , Estudos Prospectivos , Análise de Regressão
5.
Scand J Work Environ Health ; 43(6): 560-568, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28879368

RESUMO

Objectives We investigated the association of shift and night work with the incidence of prostate cancer using data of the population-based prospective Heinz Nixdorf Recall Study from the highly industrialized Ruhr area in Germany. Methods Participants of the baseline survey were recruited between 2000-2003. A follow-up survey including, a detailed interview on shift and night work, was conducted from 2011-2014. We included 1757 men who did not report a history of prostate cancer at baseline. We assessed shift- and night-work exposure up to time of the baseline interview. Incident prostate cancers were recorded from baseline through September 2014. We calculated hazard ratios (HR) of shift- and night-work exposure using Cox proportional hazards regression with age at event as timescale, adjusting for smoking status, family history of prostate cancer, education (≤13, 14-17, ≥18 years), and equivalent income (low, medium, high). Results We observed a twofold increased HR for prostate cancer among shift and night workers. Ever employment in shift work was associated with HR 2.29, 95% confidence interval (CI) 1.43-3.67 and night work with HR 2.27, 95% CI 1.42-3.64. HR increased steadily with duration of employment in shift or night work. Stratifying analyses by preferred midpoint of sleep, yielded strongly elevated HR among subjects with early sleep preference, although these analyses were limited by small number of cases. Conclusions We identified increased risks for prostate cancer among men with employment in shift or night work. HR were strongly elevated among long-term employed shift workers and men with early preferred midpoint of sleep.


Assuntos
Neoplasias da Próstata/epidemiologia , Jornada de Trabalho em Turnos/efeitos adversos , Tolerância ao Trabalho Programado/fisiologia , Idoso , Seguimentos , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários
6.
Environ Int ; 108: 237-245, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28886417

RESUMO

BACKGROUND: Exposure to air pollution activates the innate immune system and influences the adaptive immune system in experimental settings. We investigated the association of residential long-term exposure to particulate matter (PM) and NO2 air pollution with monoclonal gammopathy of undetermined significance (MGUS) as a marker of adaptive immune system activation. METHODS: We used data from the baseline (2000-2003), 5-year (2006-2008) and 10-year (2011-2015) follow-up examinations of the German Heinz Nixdorf Recall cohort study of 4814 participants (45-75years). Residential exposure to PM size fractions and NO2 was estimated by land-use regression (ESCAPE-LUR, annual mean 2008/2009) and dispersion chemistry transport models (EURAD-CTM, 3-year mean at baseline). We used logistic regression to estimate the effects of air pollutants on incident MGUS, adjusting for age, sex, education, smoking status, physical activity, and BMI. As a non-linear approach, we looked at quartiles (2-4) of the air pollutants in comparison to quartile 1. RESULTS: Of the 3949 participants with complete data, 100 developed MGUS during the 10-year follow-up. In the main model, only PMcoarse was associated with incident MGUS (OR per IQR (1.9µg/m3): 1.32, 95% CI 1.04-1.67). We further found positive associations between PM size fractions estimated by ESCAPE-LUR and incident MGUS by quartiles of exposure (OR Q4 vs Q1: PM2.5 2.03 (1.08-3.80); PM10 1.97 (1.05-3.67); PMcoarse 1.98 (1.09-3.60)). CONCLUSIONS: Our results indicate that an association between long-term exposure to PM and MGUS may exist. Further epidemiologic studies are needed to corroborate this possible link.


Assuntos
Poluentes Atmosféricos/toxicidade , Gamopatia Monoclonal de Significância Indeterminada/etiologia , Dióxido de Nitrogênio/toxicidade , Material Particulado/toxicidade , Idoso , Poluentes Atmosféricos/análise , Biomarcadores , Estudos de Coortes , Exposição Ambiental/análise , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/epidemiologia , Material Particulado/análise , Estudos Prospectivos , Fatores de Tempo
7.
Infection ; 45(5): 659-667, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28776165

RESUMO

OBJECTIVES: Prolonged QT interval is associated with arrhythmias and sudden death. An increased prevalence of QT interval prolongation in human immunodeficiency virus-infected (HIV) subjects was previously described. The impact of different medications and HIV infection itself on the QT interval is rarely investigated in large HIV+ cohorts. METHODS: We compared QT interval measurement in 496 HIV(+) patients of the HIV-HEART study (HIVH) and 992 sex- and age-matched controls of the population-based German Heinz Nixdorf Recall study (HNR). QT corrected for heart rate (QTc) >440 ms in male and >460 ms in female was considered pathological. We analysed the impact of HIV status and HIV medication on QTc prolongation in the HIVH subjects. RESULTS: We observed longer QTc in HIVH subjects compared with HNR controls: 424.1 ms ± 23.3 vs. 411.3 ± 15.3 ms for male and 435.5 ms ± 19.6 vs. 416.4 ms ± 17.3 for female subjects (p < 0.0001 for both sexes). Adjusting for QT prolonging medication the mean differences in QTc between the two studies remained significant with 12.6 ms (95% CI 10.5-14.8; p value <0.0001) for male and 19.3 ms (95% CI 14.5-24.2; p value <0.0001) for female subjects. Prolongation of QTc was pathologic in 22.8 vs. 3.9% of HIV(+) and non-infected males and in 12.1 vs. 1.8% of the females [OR of 7.9 (5.0-12.6) and OR of 6.7 (1.8-24.2), respectively]. Smoking behaviour was an independent factor to lengthen QTc in HIV(+) patients. Diabetes mellitus was not a risk factor itself, but might be associated with medication which was associated with LQT. We could not observe any influence of the HIV status, ART, or any co-medication on the QTc. CONCLUSIONS: Our study showed that HIV(+) patients had significantly longer QTc intervals compared to the general population. The number of patients with pathologic QTc prolongation was significantly increased in HIV(+) population.


Assuntos
Infecções por HIV/complicações , Frequência Cardíaca/efeitos dos fármacos , Síndrome do QT Longo/epidemiologia , Idoso , Estudos de Casos e Controles , Eletrocardiografia , Feminino , Alemanha/epidemiologia , Infecções por HIV/tratamento farmacológico , Humanos , Síndrome do QT Longo/etiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco
8.
Int J Hyg Environ Health ; 220(6): 998-1005, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28606700

RESUMO

OBJECTIVE: This study investigated the metal distribution in blood samples from the general population and the risk of having high metal concentration for metal workers. METHODS: Metal concentrations were determined in archived blood samples from 1411 men and 1410 women (median age 59 and 57 years, respectively) collected at baseline (2000-2003) of the prospective Heinz Nixdorf Recall Study. Retrospective information on working in metal industry was obtained from previous follow-up survey (2011-2014). Odds ratios (ORs) with 95% confidence intervals (CI) of having a metal concentration >90th percentile (P90) for working in metal industry were calculated using logistic regression with adjustment for covariates. RESULTS: More men than women worked in metal industry (57 vs. 3 at baseline). Male metal workers had increased blood lead (Pb) (OR: 2.86; 95% CI: 1.38-5.91) and manganese (Mn) (OR: 2.92; 95% CI: 1.46-5.81). Smoking (≥30 cigarettes/day) strongly influenced cadmium (Cd) in blood (OR: 168; 95% CI: 55-510). Women had higher Mn (8.92µg/L) and Cd (0.36µg/L) concentrations than men (Mn: 8.11µg/L; Cd: 0.29µg/L). Blood Pb in women (29.2µg/L) was lower than in men (33.2µg/L). None of the studied risk factors was significantly associated with chromium and nickel concentrations above their 90th percentiles. CONCLUSIONS: In this population-based cohort we found evidence that working in metal industry was predictive for having elevated blood Pb and Mn concentrations. However, the 95th percentiles of all investigated metals were not significantly influenced by metal-related occupations. The present study is supportive for gender-specific reference values to limit occupational exposure to Mn and Pb. The strong influence of smoking on blood Cd hinders establishing reference values.


Assuntos
Poluentes Ambientais/sangue , Metais Pesados/sangue , Idoso , Monitoramento Ambiental , Feminino , Alemanha , Humanos , Masculino , Metalurgia , Pessoa de Meia-Idade , Exposição Ocupacional , Fatores de Risco
9.
Int J Mol Sci ; 18(6)2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-28613249

RESUMO

Hypoxia-inducible-factor-2α (HIF-2α) and HIF-2 degrading prolyl-hydroxylases (PHD) are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS). Specifically, functionally active genetic variants of HIF-2α (single nucleotide polymorphism (SNP) [ch2:46441523(hg18)]) and PHD2 (C/T; SNP rs516651 and T/C; SNP rs480902) are associated with improved adaptation to hypoxia i.e., in high-altitude residents. However, little is known about these SNPs' prevalence in Caucasians and impact on ARDS-outcome. Thus, we tested the hypotheses that in Caucasian ARDS patients SNPs in HIF-2α or PHD2 genes are (1) common, and (2) independent risk factors for 30-day mortality. After ethics-committee approval, 272 ARDS patients were prospectively included, genotyped for PHD2 (Taqman SNP Genotyping Assay) and HIF-2α-polymorphism (restriction digest + agarose-gel visualization), and genotype dependent 30-day mortality was analyzed using Kaplan-Meier-plots and multivariate Cox-regression analyses. Frequencies were 99.62% for homozygous HIF-2α CC-carriers (CG: 0.38%; GG: 0%), 2.3% for homozygous PHD2 SNP rs516651 TT-carriers (CT: 18.9%; CC: 78.8%), and 3.7% for homozygous PHD2 SNP rs480902 TT-carriers (CT: 43.9%; CC: 52.4%). PHD2 rs516651 TT-genotype in ARDS was independently associated with a 3.34 times greater mortality risk (OR 3.34, CI 1.09-10.22; p = 0.034) within 30-days, whereas the other SNPs had no significant impact (p = ns). The homozygous HIF-2α GG-genotype was not present in our Caucasian ARDS cohort; however PHD2 SNPs exist in Caucasians, and PHD2 rs516651 TT-genotype was associated with an increased 30-day mortality suggesting a relevance for adaptive responses in ARDS.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Polimorfismo de Nucleotídeo Único , Síndrome do Desconforto Respiratório do Adulto/genética , Adulto , Idoso , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Síndrome do Desconforto Respiratório do Adulto/epidemiologia
10.
Diabetes ; 66(11): 2888-2902, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28566273

RESUMO

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.


Assuntos
Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu , Regulação da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Variação Genética , Humanos
11.
Circ Cardiovasc Genet ; 10(2)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28411192

RESUMO

BACKGROUND: Genetic variants of a locus within the chromosome 9p21.3 region are consistently associated with coronary artery disease and coronary artery calcification (CAC). The aim of this study was to examine whether a 9p21.3 common variant interacts with socioeconomic status (SES) to influence CAC and incident coronary events in a population-based cohort. METHODS AND RESULTS: 9p21.3 single nucleotide polymorphism rs2891168 was genotyped in 4116 participants of the Heinz Nixdorf Recall study. SES indicators (education and income) and CAC were assessed at baseline. Incident coronary events were ascertained over a median follow-up of 9.3 years. Multiple regression models were fitted to estimate genetic effects on loge(CAC+1) and incident coronary events. Genetic effects were highest in the lower income tertile with a 53.1% (95% confidence interval, 30.6%-79.6%; P=1.8×10 -7) increase in CAC and a hazard ratio of 1.44 (95% confidence interval, 1.01-2.07; P=0.049) for incident coronary events per additional risk allele. After including genotype×SES interaction terms in the regression models, genotype×income interactions were observed for CAC (exp[ßg×income]=0.85 [95% confidence interval, 0.74-0.98; Pg×income=0.02] per 1000€/mo increase and additional risk allele) and for incident coronary events (hazard ratiog×income=0.69 [95% confidence interval, 0.48-0.98; Pg×income=0.04] per 1000€/mo increase and additional risk allele). No interaction was observed using education as SES indicator. CONCLUSIONS: A 9p21.3 common variant seems to interact with SES to influence CAC and incident coronary events in a population-based cohort. This supports the hypothesis that better material, psychosocial, and lifestyle conditions enable higher SES groups to reduce the expression of their genetic susceptibility to coronary artery disease.


Assuntos
Cálcio/análise , Cromossomos Humanos Par 9 , Doença da Artéria Coronariana/genética , Estilo de Vida , Classe Social , Idoso , Alelos , Doença da Artéria Coronariana/etiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Renda , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Fatores de Risco
12.
Sci Rep ; 7: 41071, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112199

RESUMO

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10-12) was associated with increased CLL and HL risk (P = 4.68 × 10-12), and reduced MM risk (P = 1.12 × 10-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10-10) showed opposing effects between CLL (P = 3.52 × 10-3) and HL (P = 3.41 × 10-9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.


Assuntos
Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla , Doença de Hodgkin/genética , Leucemia Linfocítica Crônica de Células B/genética , Mieloma Múltiplo/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Doença de Hodgkin/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Proteínas Oncogênicas/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
13.
Pediatr Blood Cancer ; 64(1): 71-80, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27567086

RESUMO

BACKGROUND: Survivors of heritable retinoblastoma carry a high risk to develop second cancers. Eye-preserving radiotherapy raises this risk, while the impact of chemotherapy remains less defined. PROCEDURE: This population-based study characterizes the impact of all treatment modalities on second cancers incidence and type after retinoblastoma treatment in Germany. Data on second cancer incidence in 648 patients with heritable retinoblastoma treated between 1940 and 2008 at the German national reference center for retinoblastoma were analyzed to identify associations with treatment. RESULTS: The cumulative incidence ratio (per 1,000 person years) of second cancers was 8.6 (95% confidence interval 7.0-10.4). Second cancer incidence was influenced by type of retinoblastoma treatment but not by the year of diagnosis or by sex. Radiotherapy and systemic chemotherapy increased the incidence of second cancers (by 3.0- and 1.8-fold, respectively). While radiotherapy was specifically associated with second cancers arising within the periorbital region in the previously irradiated field, chemotherapy was the strongest risk factor for second cancers in other localizations. Soft tissue sarcomas and osteosarcomas were the most prevalent second cancers (standardized incidence ratio 179.35 compared to the German population). CONCLUSIONS: Second cancers remain a major concern in heritable retinoblastoma survivors. Consistent with previous reports, radiotherapy increased second cancer incidence and influenced type and localization. However, chemotherapy was the strongest risk factor for second malignancies outside the periorbital region. Our results provide screening priorities during life-long oncological follow-up based on the curative therapy the patient has received and emphasize the need for less-detrimental therapies for children with heritable retinoblastoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/mortalidade , Segunda Neoplasia Primária/epidemiologia , Neoplasias da Retina/terapia , Retinoblastoma/terapia , Sobreviventes , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
14.
Neurotoxicology ; 58: 58-65, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27865828

RESUMO

Occupational exposure to manganese (Mn) has been associated with impairments in olfaction and motor functions, but it has yet to be determined if such effects persist upon cessation of exposure. The objective of this study was to evaluate the influence of former occupational Mn exposure on olfaction within the framework of a prospective cohort study among an elderly German population. Information on job tasks with recognized Mn exposure and data on odor identification assessed with Sniffin' sticks was collected during the second follow-up of the Heinz Nixdorf Recall Study. The study population consisted of 1385 men aged 55-86 years, 354 of whom ever worked in jobs with potential Mn exposure (median 58.3µg/m3 years, interquartile range 19.0-185µg/m3 years). Multiple exposure measures, including job tasks, cumulative Mn exposure, and Mn determined in blood samples (MnB) archived at baseline, were used to estimate effects of Mn on olfaction. Having ever worked as welder was associated with better olfaction compared to other blue-collar workers without Mn exposure. Blue-collar workers identified less odors in comparison to white-collar workers. Concentrations of previous Mn exposure >185µg/m3 years or MnB ≥15µg/L were not associated with impaired olfaction. In addition to a strong age effect, participants with lower occupational qualification identified less odors. We found no relevant association of former Mn exposure at relatively low levels with impaired olfaction. Possible neurotoxic Mn effects may not be persistent after cessation.


Assuntos
Envelhecimento , Manganês/toxicidade , Exposição Ocupacional/efeitos adversos , Odorantes , Transtornos do Olfato/induzido quimicamente , Transtornos do Olfato/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Planejamento em Saúde Comunitária , Humanos , Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Manganês/sangue , Pessoa de Meia-Idade , Estatísticas não Paramétricas
15.
BMC Anesthesiol ; 16(1): 61, 2016 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-27515179

RESUMO

BACKGROUND: Hypoxia-inducible-factor-1α (HIF-1α) and HIF-1 degrading prolyl-hydroxylases (PHD) are key regulators of the hypoxic-inflammatory response. Functionally active genetic variants in the HIF-1α (C/T; Single Nucleotide Polymorphism (SNP) rs11549465) and the PHD2 gene (EGLN1; C/T; SNP rs516651 and T/C; SNP rs480902) are associated with altered HIF-1α mRNA nuclear translocation and an altered adaptation to hypoxia. Furthermore, the HIF system is important in surviving inflammatory disorders and sepsis. Thus, we tested the hypotheses, that SNPs in the HIF-1α or PHD2 genes are (1) common in Caucasians, with 2) the HIF-1α genetic variant being associated with an altered HIF-1α mRNA expression; and 3) independent risk factors for 30-day mortality in severe sepsis. METHODS: After ethics approval, 128 septic patients (Caucasian descent) were included prospectively within 24 h after first diagnosing sepsis. Patients characteristics and severity of illness (simplified acute physiology score II), genotypes (Taqman assay), and their influence on leukocyte HIF-1α-mRNA-expression (Real-Time PCR) and 30-day mortality were determined. RESULTS: Frequencies were 0.8 % for homozygous HIF-1α TT-carriers (CT 17.6 %; CC 81.6 %), 2.5 % for homozygous PHD2 SNP rs516651 TT-allele carriers (CT 17.5 % and CC 80 %), and 9.4 % for homozygous PHD2 SNP rs480902 TT-allele carriers (CT 34.4 % and CC 56.3 %). While HIF-1α T-allele carriers had a borderline decrease in HIF-1α-mRNA-expression (p = 0.06) neither HIF-1α nor PHD2 SNPs were (independent) risk factors for 30-day mortality. CONCLUSIONS: Genetic variants in HIF-1α and PHD2 genes exist in Caucasians but do not appear to alter 30-day mortality in sepsis.


Assuntos
Variação Genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Sepse/fisiopatologia , Idoso , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Sepse/genética , Sepse/mortalidade , Índice de Gravidade de Doença
16.
J Clin Oncol ; 34(26): 3183-8, 2016 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-27382102

RESUMO

PURPOSE: Intraocular retinoblastoma is curable, but survivors with a heritable predisposition are at high risk for second malignancies. Because second malignancies are associated with high mortality, prognostic factors for second malignancy influence long-term overall survival. This study investigates the impact of all types of eye-preserving therapies on long-term survival in the complete German cohort of patients with heritable retinoblastoma. PATIENTS AND METHODS: Overall survival, disease staging using international scales, time period of diagnosis, and treatment type were analyzed in the 633 German children treated at the national reference center for heritable retinoblastoma. RESULTS: The 5-year overall survival of children diagnosed in Germany with heritable retinoblastoma between 1940 and 2008 was 93.2% (95% CI, 91.2% to 95.1%), but long-term mortality was increased compared with patients with nonheritable disease. Overall survival correlated with tumor staging, and 92% of patients were diagnosed with a favorable tumor stage (International Retinoblastoma Staging System stage 0 or I). Despite a 5-year overall survival of 97.4% (95% CI, 96.0% to 98.8%) in patients with stage 0 or I, only 79.5% (95% CI, 74.2% to 84.8%) of these patients survived 40 years after diagnosis. Long-term overall survival was reduced in children treated with eye-preserving radiotherapy compared with enucleation alone, and adding chemotherapy aggravated this effect. CONCLUSION: The benefits of preserving vision must be balanced with the impact of eye-preserving treatments on long-term survival in heritable retinoblastoma, and the genetic background of the patient influences choice of eye-preserving treatment. Germline RB1 genetic analysis is important to identify heritable retinoblastoma among unilateral retinoblastoma cases. Eye-preserving radiotherapy should be carefully considered in patients with germline RB1 mutations. Life-long oncologic follow-up is crucial for all retinoblastoma survivors, and less detrimental eye-preserving therapies must be developed.


Assuntos
Quimiorradioterapia/efeitos adversos , Enucleação Ocular/efeitos adversos , Tratamentos com Preservação do Órgão/efeitos adversos , Neoplasias da Retina/terapia , Retinoblastoma/terapia , Sobreviventes , Biomarcadores Tumorais/genética , Quimiorradioterapia/mortalidade , Criança , Pré-Escolar , Análise Mutacional de DNA , Enucleação Ocular/mortalidade , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Alemanha , Hereditariedade , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias , Tratamentos com Preservação do Órgão/métodos , Tratamentos com Preservação do Órgão/mortalidade , Fenótipo , Modelos de Riscos Proporcionais , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/genética , Neoplasias da Retina/mortalidade , Retinoblastoma/diagnóstico , Retinoblastoma/genética , Retinoblastoma/mortalidade , Proteínas de Ligação a Retinoblastoma/genética , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ubiquitina-Proteína Ligases/genética , Visão Ocular/efeitos dos fármacos , Visão Ocular/efeitos da radiação
17.
Acta Haematol ; 136(2): 101-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27189086

RESUMO

Oral prednisone is considered the standard first-line therapy of adult immune thrombocytopenia, but its long-term efficacy is limited. We performed a prospective, randomized, multicenter trial comparing daily prednisone (1-2 mg/kg/day for 2-4 weeks with subsequent dose reduction) with six 3-week cycles of pulsed dexamethasone (0.6 mg/kg/day, days 1-4). The primary endpoint was remission duration. Of 26 patients enrolled, 22 were evaluable for response. Nine were treated with prednisone and 13 with dexamethasone. The median follow-up was 46 months. The initial response rate (PLT ≥50 × 109/l) was 100% in both groups. Long-term remissions were significantly more frequent with pulsed dexamethasone than with daily prednisone (12 months posttreatment: 77 vs. 22%; p = 0.027). The side effects were similar, but patients on dexamethasone suffered significantly more often from insomnia, while patients on prednisone tended to have more infectious complications. Although the cumulative cortisol equivalent dose was comparable during the first 4 weeks of therapy, it was significantly higher in the dexamethasone arm than in the prednisone arm during the ensuing treatment period. We conclude that repeated cycles of pulsed dexamethasone are a good alternative to daily prednisone as a first-line treatment of immune thrombocytopenia. The duration and intensity of glucocorticoid therapy are important determinants of treatment outcome.


Assuntos
Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Prednisona/administração & dosagem , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Adulto , Idoso , Dexametasona/efeitos adversos , Esquema de Medicação , Seguimentos , Glucocorticoides/efeitos adversos , Humanos , Pessoa de Meia-Idade , Infecções Oportunistas/induzido quimicamente , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/fisiopatologia , Prednisona/efeitos adversos , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/fisiopatologia , Indução de Remissão , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Resultado do Tratamento
18.
PLoS One ; 11(4): e0154259, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27123581

RESUMO

Genome-wide association studies (GWASs) have identified several, mainly co-dominantly acting, single-nucleotide polymorphisms (SNPs) associated with Hodgkin lymphoma (HL). We searched for recessively acting disease loci by performing an analysis of runs of homozygosity (ROH) based on windows of homozygous SNP-blocks and by calculating genomic inbreeding coefficients on a SNP-wise basis. We used data from a previous GWAS with 906 cases and 1217 controls from a population with a long history of no matings between relatives. Ten recurrent ROHs were identified among 25 055 ROHs across all individuals but their association with HL was not genome-wide significant. All recurrent ROHs showed significant evidence for natural selection. As a novel finding genomic inbreeding among cases was significantly higher than among controls (P = 2.11*10-14) even after correcting for covariates. Higher inbreeding among the cases was mainly based on a group of individuals with a higher average length of ROHs per person. This result suggests a correlation of higher levels of inbreeding with higher cancer incidence and might reflect the existence of recessive alleles causing HL. Genomic inbreeding may result in a higher expression of deleterious recessive genes within a population.


Assuntos
Consanguinidade , Predisposição Genética para Doença , Doença de Hodgkin/genética , Homozigoto , Reprodução/genética , Seleção Genética , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genes Recessivos , Loci Gênicos , Genoma Humano , Estudo de Associação Genômica Ampla , Alemanha , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/patologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
19.
Atherosclerosis ; 249: 83-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27085157

RESUMO

Carotid intima media thickness (cIMT) is a marker for subclinical atherosclerosis. The most recent genome-wide association meta-analysis (GWAMA) from the CHARGE consortium identified four genomic regions showing either significant (ZHX2, APOC1, PINX1) or suggestive evidence (SLC17A4) for an association. Here we assess these four cIMT loci in a pooled analysis of four independent studies including 5446 individuals by providing updated unbiased effect estimates of the cIMT association signals. The pooled estimates of our four independent samples pointed in the same direction and were similar to those of the GWAMA. When updating the independent second stage replication results from the earlier CHARGE GWAMA by our estimates, effect size estimates were closer to those of the original CHARGE discovery. A fine-mapping approach within a ±50 kb region around each lead SNP from CHARGE revealed 27 variants with larger estimated effect sizes than the lead SNPs but only three of them showed a r(2) > 0.40 with these respective lead SNPs from CHARGE. Some variants are located within potential functional loci.


Assuntos
Doenças Cardiovasculares/genética , Espessura Intima-Media Carotídea , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/genética , Mapeamento Cromossômico , Interpretação Estatística de Dados , Saúde da Família , Feminino , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Estudos Prospectivos , Projetos de Pesquisa
20.
J Alzheimers Dis ; 49(4): 1031-42, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26599053

RESUMO

There is increasing evidence that anemia is associated with cognitive impairment. Therefore, the aim of the study was to examine the cross-sectional association of anemia as well as the persistence of anemia over the last five years with mild cognitive impairment (MCI) and MCI subtypes (amnestic/non-amnestic MCI (aMCI/naMCI)). Out of 4,157 participants (50% men, 50-80 years) of the second examination (t1) of a cohort study (baseline (t0) 2000-2003), we included 4,033 participants with available hemoglobin information and complete cognitive assessment. Anemia was defined as hemoglobin <13 g/dl in men (n = 84) and <12 g/dl in women (n = 79). Group comparisons were used to compare the cognitive subtests. To determine the association of MCI with anemia at t1, with anemia five years prior to the cognitive assessment (t0) and anemia at both time points, we used logistic regression models and included 579 participants with MCI and 1,438 cognitively normal participants out of the total cohort. Anemic participants showed lower performances in verbal memory and executive functions. The fully adjusted odds ratios (OR) for MCI, aMCI, and naMCI in anemic versus non-anemic participants were 1.92 (95% -CI, 1.09-3.39), 1.96 (1.00-3.87), and 1.88 (0.91-3.87). Anemia at both times points showed a non-significant association with naMCI (OR 3.74, 0.94-14.81, fully adjusted). Our results suggest that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. The association of anemia and MCI has important clinical relevance, because many causes of anemia can be treated effectively.


Assuntos
Anemia/epidemiologia , Disfunção Cognitiva/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Anemia/psicologia , Estudos de Coortes , Função Executiva , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Memória , Pessoa de Meia-Idade , Testes Neuropsicológicos , Prevalência , Percepção da Fala
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